Clinical Review

The VHA is the largest healthcare delivery system in the U.S. It includes 146 medical centers (VAMCs), 1,063 community-based outpatient centers (CBOCs) and various other sites of care. General Omar Bradley, the first VA Secretary, established education as one of VA’s 4 statutory missions in Policy Memorandum No.2.¹ In addition to training physicians to care for active-duty service members and veterans, 38 USC §7302 directs the VA to assist in providing an adequate supply of health personnel. The 4 statutory missions of the VA are inclusive of not only developing, operating, and maintaining a health care system for veterans, but also including contingency support services as part of emergency preparedness, conducting research, and offering a program of education for health professions.

Background

Today, with few exceptions, the VHA does not act as a graduate medical education (GME) sponsoring institution. Through its Office of Academic Affiliations (OAA), the VHA develops partnerships with Liaison Committee for Medical Education (LCME)/American Osteopathic Association (AOA)-approved medical colleges/universities and with institutions that sponsor Accreditation Council for Graduate Medical Education (ACGME)/AOA-accredited residency program-sponsoring institutions. These collaborations include 144 out of 149 allopathic medical schools and all 34 osteopathic medical schools. The VHA provided training to 43,565 medical residents and 24,683 medical students through these partnerships in 2017.² Since funding of the GME positions is not provided through the Centers for Medicare & Medicaid Services (CMS), program sponsors may use these partnerships to expand GME positions beyond their funding (but not ACGME) cap.

The gap between supply and demand of physicians continues to grow nationally.^3,4 This gap is particularly significant in rural and other underserved areas. U.S. Census Bureau data show that about 5 million veterans (24%) live in rural areas.⁵ Compared with the urban veteran population, the rural veteran experiences higher disease prevalence and lower physical and mental quality-of-life scores.⁶ Addressing the problem of physician shortages is a mission-critical priority for the VHA.⁷

With an eye toward enhancing 2 of the 4 statutory missions of the VA and to mitigate the shortage of physicians and improve the access of veterans to VHA medical services, on August 7, 2014, the Veterans Access, Choice, and Accountability Act of 2014 (Public Law [PL] 113-146), known as the Choice Act was enacted.⁸ Title III, §301(b) of the Choice Act requires VHA to increase GME residency positions by:

Establishing new medical residency programs, or ensuring that already established medical residency programs have a sufficient number of residency positions, at any VHA medical facility that is: (a) experiencing a shortage of physicians and (b) located in a community that is designated as a health professional shortage area.

The legislation specifies that priority must be placed on medical occupations that experience the largest staffing shortages throughout the VHA and “programs in primary care, mental health, and any other specialty that the Secretary of the VA determines appropriate.” The Choice Act authorized the VHA to increase the number of GME residency positions by up to 1,500 over a 5-year period. In December 2016, as amended by PL 114–315, Title VI, §617(a), this authorization was extended by another 5 years for a total of 10 years and will run through 2024.⁹

GME Development/Distribution

To distribute these newly created GME positions as mandated by Congress, the OAA is using a system with 3 types of request for proposal (RFP) applications. These include planning, infrastructure, and position grants. This phased approach was taken with the understanding that the development of new training sites requires a properly staffed education office and dedicated faculty time. Planning and infrastructure grants provide start-up funds for smaller VAMCs, allowing them to keep facility resources focused on their clinical mission.

Planning grants (of up to $250,000 over 2 years) primarily were designed for VA facilities with no or low numbers of physician residents at the desired teaching location. Priority was given to facilities in rural and/or underserved areas as well as those developing new affiliations. Applications were reviewed by OAA staff along with peer-selected Designated Education Officers (DEOs) from VA facilities across the nation that were not applying for the grants. Awards were based on the priorities mentioned earlier, with additional credit for programs focused on 2 VHA fundamental services areas—primary care and/or mental health training. Facilities receiving planning grants were mentored by an OAA physician staff member, anticipating a 2- to 3-year time line to request positions and begin GME training.

Infrastructure grants (of up to $520,000 used over 2-3 years) were designed as bridge funds after approval of Veterans Access, Choice, and Accountability Act (VACAA) GME positions. Infrastructure grants are appropriate to sustain a local education office, develop VA faculty, purchase equipment, and make minor modifications to the clinical space in the VAMCs or CBOCs to enhance the learning environment during the period before VA supportive funds from the Veterans Equitable Resource Allocation (VERA) (similar to indirect GME funds from CMS) become available. Applications were managed the same as planning grant submissions.

Position RFPs, unlike planning and infrastructure RFPs, are available to all VAMCs. The primary purpose of the VACAA Position RFP is to fund new positions in primary care and psychiatry. Graduate medical education positions in subspecialty programs also are considered when there is documentation of critical need to improve access to these services. Applications were reviewed by OAA staff along with selected DEOs from VA facilities around the U.S. Award criteria prioritized primary care (family medicine, internal medicine, geriatrics), and mental health (psychiatry and psychiatry subspecialties). Priority also was given to positions in areas with a documented shortage of physicians and areas with high concentrations of veterans.

Current Progress

To date the OAA has offered 3 RFP cycles consisting of planning/infrastructure grants, and 4 RFP cycles for salary/benefit support for additional resident full-time equivalent (FTE) positions. Resident positions were defined as residency or fellowship FTEs that were part of an ACGME or AOA-accredited training program. Figure 1 illustrates the geographic distribution of awarded GME positions. 

In primary care specialties (family medicine, internal medicine, and geriatrics, a total of 349.4 FTE positions have been approved (Table 1). Due to a low number of applications, only 6.3 of these positions were awarded in geriatrics. In mental health, 167.6 FTE positions have been approved, whereas in critical needs specialties (needed to support rural/underserved healthcare and improve specialty access) 256.5 FTE positions have been added. 

Discussion

There are several important desired short-term outcomes from VACAA. The first is improved access to high-quality care for both rural and urban veterans. There is an emphasis on primary care and mental health because shortages in these areas across the U.S. are well established.^3,4,10 Likewise, rural areas have been prioritized because often there is a disparity of care. 

One area of concern is the small number of applicants in geriatrics. Even with VACAA specifically targeting geriatrics as a primary care specialty, we have only received enough applications to approve 6.3 positions over the first 3 years of the program. As the veteran and overall population in the U.S. ages, it is important to develop a medical workforce that is willing and able to address their needs.

The VACAA statute is not intended to alter medical students’ career choice but rather to provide funded positions for those choosing primary care, geriatrics, psychiatry (including psychiatric subspecialties), and experience in the VA clinical settings. The hope is that this experience will encourage practitioners to competently care for veterans after training in the VA and/or other civilian settings.

By enabling smaller VA facilities to become training sites through planning and infrastructure grants, residents have the opportunity to gain experience in more rural settings. Physicians who choose to train in rural areas are likely to spend time practicing in those areas after they complete training.¹⁵ The process of developing facilities with no GME into training sitestakes time and resources. Establishing an education office and choosing site directors and core faculty are all important steps that must be done before resident rotations begin. Resources provided through VACAA have enabled the VHA to reduce the number of VAMCs with no GME activity to just 3.

Another benefit of VACAA GME expansion is the opportunity to engage new LCME/AOA-accredited medical schools and ACGME/AOA-accredited residency-sponsoring institutions.^16,17 Representatives of these institutions may have perceived a reluctance of their local VAs to develop GME affiliations in the past. This statute has enabled many VAMCs to use nontraditional training sites and modalities to overcome barriers and create new academic affiliations.

However, VACAA only provides funds for training that occurs in established VA sites of care. This can hinder the development of partnerships where other funding sources are required for non-VA rotations. Another VACAA limitation is that it does not fund undergraduate medical education as does the Armed Forces Health Professional Scholarship Program (HPSP). In addition, the primary financial relationship is between the VA and the sponsoring institution, thus VHA cannot send residents to underserved locations.

Conclusion

The VHA has a rich tradition of educating physician and other health care providers in the U.S. More than 60% of U.S. trained physicians received a portion of their training through VHA.² Through VACAA GME expansion initiative, the 113th Congress has asked VHA to continue its important training mission “to bind up the Nations wounds” and “to care for him who shall have borne the battle.”¹⁸

Acknowledgments
In memoriam – Robert Louis Jesse MD, PhD. Dr. Jesse, the Chief of the Office of Academic Affiliations passed away on September 2, 2017, at age 64. He had an illustrious medical career as a cardiologist and served in many leadership roles including Principal Deputy Under Secretary for Health in the U.S. Department of Veterans Affairs. His expertise, visionary leadership, and friendship will be missed by all involved in the VA’s academic training mission but particularly by those of us who worked for and with him at OAA.

The VHA is the largest healthcare delivery system in the U.S. It includes 146 medical centers (VAMCs), 1,063 community-based outpatient centers (CBOCs) and various other sites of care. General Omar Bradley, the first VA Secretary, established education as one of VA’s 4 statutory missions in Policy Memorandum No.2.¹ In addition to training physicians to care for active-duty service members and veterans, 38 USC §7302 directs the VA to assist in providing an adequate supply of health personnel. The 4 statutory missions of the VA are inclusive of not only developing, operating, and maintaining a health care system for veterans, but also including contingency support services as part of emergency preparedness, conducting research, and offering a program of education for health professions.

Background

Today, with few exceptions, the VHA does not act as a graduate medical education (GME) sponsoring institution. Through its Office of Academic Affiliations (OAA), the VHA develops partnerships with Liaison Committee for Medical Education (LCME)/American Osteopathic Association (AOA)-approved medical colleges/universities and with institutions that sponsor Accreditation Council for Graduate Medical Education (ACGME)/AOA-accredited residency program-sponsoring institutions. These collaborations include 144 out of 149 allopathic medical schools and all 34 osteopathic medical schools. The VHA provided training to 43,565 medical residents and 24,683 medical students through these partnerships in 2017.² Since funding of the GME positions is not provided through the Centers for Medicare & Medicaid Services (CMS), program sponsors may use these partnerships to expand GME positions beyond their funding (but not ACGME) cap.

The gap between supply and demand of physicians continues to grow nationally.^3,4 This gap is particularly significant in rural and other underserved areas. U.S. Census Bureau data show that about 5 million veterans (24%) live in rural areas.⁵ Compared with the urban veteran population, the rural veteran experiences higher disease prevalence and lower physical and mental quality-of-life scores.⁶ Addressing the problem of physician shortages is a mission-critical priority for the VHA.⁷

With an eye toward enhancing 2 of the 4 statutory missions of the VA and to mitigate the shortage of physicians and improve the access of veterans to VHA medical services, on August 7, 2014, the Veterans Access, Choice, and Accountability Act of 2014 (Public Law [PL] 113-146), known as the Choice Act was enacted.⁸ Title III, §301(b) of the Choice Act requires VHA to increase GME residency positions by:

Establishing new medical residency programs, or ensuring that already established medical residency programs have a sufficient number of residency positions, at any VHA medical facility that is: (a) experiencing a shortage of physicians and (b) located in a community that is designated as a health professional shortage area.

The legislation specifies that priority must be placed on medical occupations that experience the largest staffing shortages throughout the VHA and “programs in primary care, mental health, and any other specialty that the Secretary of the VA determines appropriate.” The Choice Act authorized the VHA to increase the number of GME residency positions by up to 1,500 over a 5-year period. In December 2016, as amended by PL 114–315, Title VI, §617(a), this authorization was extended by another 5 years for a total of 10 years and will run through 2024.⁹

GME Development/Distribution

To distribute these newly created GME positions as mandated by Congress, the OAA is using a system with 3 types of request for proposal (RFP) applications. These include planning, infrastructure, and position grants. This phased approach was taken with the understanding that the development of new training sites requires a properly staffed education office and dedicated faculty time. Planning and infrastructure grants provide start-up funds for smaller VAMCs, allowing them to keep facility resources focused on their clinical mission.

Planning grants (of up to $250,000 over 2 years) primarily were designed for VA facilities with no or low numbers of physician residents at the desired teaching location. Priority was given to facilities in rural and/or underserved areas as well as those developing new affiliations. Applications were reviewed by OAA staff along with peer-selected Designated Education Officers (DEOs) from VA facilities across the nation that were not applying for the grants. Awards were based on the priorities mentioned earlier, with additional credit for programs focused on 2 VHA fundamental services areas—primary care and/or mental health training. Facilities receiving planning grants were mentored by an OAA physician staff member, anticipating a 2- to 3-year time line to request positions and begin GME training.

Infrastructure grants (of up to $520,000 used over 2-3 years) were designed as bridge funds after approval of Veterans Access, Choice, and Accountability Act (VACAA) GME positions. Infrastructure grants are appropriate to sustain a local education office, develop VA faculty, purchase equipment, and make minor modifications to the clinical space in the VAMCs or CBOCs to enhance the learning environment during the period before VA supportive funds from the Veterans Equitable Resource Allocation (VERA) (similar to indirect GME funds from CMS) become available. Applications were managed the same as planning grant submissions.

Position RFPs, unlike planning and infrastructure RFPs, are available to all VAMCs. The primary purpose of the VACAA Position RFP is to fund new positions in primary care and psychiatry. Graduate medical education positions in subspecialty programs also are considered when there is documentation of critical need to improve access to these services. Applications were reviewed by OAA staff along with selected DEOs from VA facilities around the U.S. Award criteria prioritized primary care (family medicine, internal medicine, geriatrics), and mental health (psychiatry and psychiatry subspecialties). Priority also was given to positions in areas with a documented shortage of physicians and areas with high concentrations of veterans.

Current Progress

To date the OAA has offered 3 RFP cycles consisting of planning/infrastructure grants, and 4 RFP cycles for salary/benefit support for additional resident full-time equivalent (FTE) positions. Resident positions were defined as residency or fellowship FTEs that were part of an ACGME or AOA-accredited training program. Figure 1 illustrates the geographic distribution of awarded GME positions. 

In primary care specialties (family medicine, internal medicine, and geriatrics, a total of 349.4 FTE positions have been approved (Table 1). Due to a low number of applications, only 6.3 of these positions were awarded in geriatrics. In mental health, 167.6 FTE positions have been approved, whereas in critical needs specialties (needed to support rural/underserved healthcare and improve specialty access) 256.5 FTE positions have been added. 

Discussion

There are several important desired short-term outcomes from VACAA. The first is improved access to high-quality care for both rural and urban veterans. There is an emphasis on primary care and mental health because shortages in these areas across the U.S. are well established.^3,4,10 Likewise, rural areas have been prioritized because often there is a disparity of care. 

One area of concern is the small number of applicants in geriatrics. Even with VACAA specifically targeting geriatrics as a primary care specialty, we have only received enough applications to approve 6.3 positions over the first 3 years of the program. As the veteran and overall population in the U.S. ages, it is important to develop a medical workforce that is willing and able to address their needs.

The VACAA statute is not intended to alter medical students’ career choice but rather to provide funded positions for those choosing primary care, geriatrics, psychiatry (including psychiatric subspecialties), and experience in the VA clinical settings. The hope is that this experience will encourage practitioners to competently care for veterans after training in the VA and/or other civilian settings.

By enabling smaller VA facilities to become training sites through planning and infrastructure grants, residents have the opportunity to gain experience in more rural settings. Physicians who choose to train in rural areas are likely to spend time practicing in those areas after they complete training.¹⁵ The process of developing facilities with no GME into training sitestakes time and resources. Establishing an education office and choosing site directors and core faculty are all important steps that must be done before resident rotations begin. Resources provided through VACAA have enabled the VHA to reduce the number of VAMCs with no GME activity to just 3.

Another benefit of VACAA GME expansion is the opportunity to engage new LCME/AOA-accredited medical schools and ACGME/AOA-accredited residency-sponsoring institutions.^16,17 Representatives of these institutions may have perceived a reluctance of their local VAs to develop GME affiliations in the past. This statute has enabled many VAMCs to use nontraditional training sites and modalities to overcome barriers and create new academic affiliations.

However, VACAA only provides funds for training that occurs in established VA sites of care. This can hinder the development of partnerships where other funding sources are required for non-VA rotations. Another VACAA limitation is that it does not fund undergraduate medical education as does the Armed Forces Health Professional Scholarship Program (HPSP). In addition, the primary financial relationship is between the VA and the sponsoring institution, thus VHA cannot send residents to underserved locations.

Conclusion

The VHA has a rich tradition of educating physician and other health care providers in the U.S. More than 60% of U.S. trained physicians received a portion of their training through VHA.² Through VACAA GME expansion initiative, the 113th Congress has asked VHA to continue its important training mission “to bind up the Nations wounds” and “to care for him who shall have borne the battle.”¹⁸

Acknowledgments
In memoriam – Robert Louis Jesse MD, PhD. Dr. Jesse, the Chief of the Office of Academic Affiliations passed away on September 2, 2017, at age 64. He had an illustrious medical career as a cardiologist and served in many leadership roles including Principal Deputy Under Secretary for Health in the U.S. Department of Veterans Affairs. His expertise, visionary leadership, and friendship will be missed by all involved in the VA’s academic training mission but particularly by those of us who worked for and with him at OAA.

The VHA is the largest healthcare delivery system in the U.S. It includes 146 medical centers (VAMCs), 1,063 community-based outpatient centers (CBOCs) and various other sites of care. General Omar Bradley, the first VA Secretary, established education as one of VA’s 4 statutory missions in Policy Memorandum No.2.¹ In addition to training physicians to care for active-duty service members and veterans, 38 USC §7302 directs the VA to assist in providing an adequate supply of health personnel. The 4 statutory missions of the VA are inclusive of not only developing, operating, and maintaining a health care system for veterans, but also including contingency support services as part of emergency preparedness, conducting research, and offering a program of education for health professions.

Background

Today, with few exceptions, the VHA does not act as a graduate medical education (GME) sponsoring institution. Through its Office of Academic Affiliations (OAA), the VHA develops partnerships with Liaison Committee for Medical Education (LCME)/American Osteopathic Association (AOA)-approved medical colleges/universities and with institutions that sponsor Accreditation Council for Graduate Medical Education (ACGME)/AOA-accredited residency program-sponsoring institutions. These collaborations include 144 out of 149 allopathic medical schools and all 34 osteopathic medical schools. The VHA provided training to 43,565 medical residents and 24,683 medical students through these partnerships in 2017.² Since funding of the GME positions is not provided through the Centers for Medicare & Medicaid Services (CMS), program sponsors may use these partnerships to expand GME positions beyond their funding (but not ACGME) cap.

The gap between supply and demand of physicians continues to grow nationally.^3,4 This gap is particularly significant in rural and other underserved areas. U.S. Census Bureau data show that about 5 million veterans (24%) live in rural areas.⁵ Compared with the urban veteran population, the rural veteran experiences higher disease prevalence and lower physical and mental quality-of-life scores.⁶ Addressing the problem of physician shortages is a mission-critical priority for the VHA.⁷

With an eye toward enhancing 2 of the 4 statutory missions of the VA and to mitigate the shortage of physicians and improve the access of veterans to VHA medical services, on August 7, 2014, the Veterans Access, Choice, and Accountability Act of 2014 (Public Law [PL] 113-146), known as the Choice Act was enacted.⁸ Title III, §301(b) of the Choice Act requires VHA to increase GME residency positions by:

Establishing new medical residency programs, or ensuring that already established medical residency programs have a sufficient number of residency positions, at any VHA medical facility that is: (a) experiencing a shortage of physicians and (b) located in a community that is designated as a health professional shortage area.

The legislation specifies that priority must be placed on medical occupations that experience the largest staffing shortages throughout the VHA and “programs in primary care, mental health, and any other specialty that the Secretary of the VA determines appropriate.” The Choice Act authorized the VHA to increase the number of GME residency positions by up to 1,500 over a 5-year period. In December 2016, as amended by PL 114–315, Title VI, §617(a), this authorization was extended by another 5 years for a total of 10 years and will run through 2024.⁹

GME Development/Distribution

To distribute these newly created GME positions as mandated by Congress, the OAA is using a system with 3 types of request for proposal (RFP) applications. These include planning, infrastructure, and position grants. This phased approach was taken with the understanding that the development of new training sites requires a properly staffed education office and dedicated faculty time. Planning and infrastructure grants provide start-up funds for smaller VAMCs, allowing them to keep facility resources focused on their clinical mission.

Planning grants (of up to $250,000 over 2 years) primarily were designed for VA facilities with no or low numbers of physician residents at the desired teaching location. Priority was given to facilities in rural and/or underserved areas as well as those developing new affiliations. Applications were reviewed by OAA staff along with peer-selected Designated Education Officers (DEOs) from VA facilities across the nation that were not applying for the grants. Awards were based on the priorities mentioned earlier, with additional credit for programs focused on 2 VHA fundamental services areas—primary care and/or mental health training. Facilities receiving planning grants were mentored by an OAA physician staff member, anticipating a 2- to 3-year time line to request positions and begin GME training.

Infrastructure grants (of up to $520,000 used over 2-3 years) were designed as bridge funds after approval of Veterans Access, Choice, and Accountability Act (VACAA) GME positions. Infrastructure grants are appropriate to sustain a local education office, develop VA faculty, purchase equipment, and make minor modifications to the clinical space in the VAMCs or CBOCs to enhance the learning environment during the period before VA supportive funds from the Veterans Equitable Resource Allocation (VERA) (similar to indirect GME funds from CMS) become available. Applications were managed the same as planning grant submissions.

Position RFPs, unlike planning and infrastructure RFPs, are available to all VAMCs. The primary purpose of the VACAA Position RFP is to fund new positions in primary care and psychiatry. Graduate medical education positions in subspecialty programs also are considered when there is documentation of critical need to improve access to these services. Applications were reviewed by OAA staff along with selected DEOs from VA facilities around the U.S. Award criteria prioritized primary care (family medicine, internal medicine, geriatrics), and mental health (psychiatry and psychiatry subspecialties). Priority also was given to positions in areas with a documented shortage of physicians and areas with high concentrations of veterans.

Current Progress

To date the OAA has offered 3 RFP cycles consisting of planning/infrastructure grants, and 4 RFP cycles for salary/benefit support for additional resident full-time equivalent (FTE) positions. Resident positions were defined as residency or fellowship FTEs that were part of an ACGME or AOA-accredited training program. Figure 1 illustrates the geographic distribution of awarded GME positions. 

In primary care specialties (family medicine, internal medicine, and geriatrics, a total of 349.4 FTE positions have been approved (Table 1). Due to a low number of applications, only 6.3 of these positions were awarded in geriatrics. In mental health, 167.6 FTE positions have been approved, whereas in critical needs specialties (needed to support rural/underserved healthcare and improve specialty access) 256.5 FTE positions have been added. 

Discussion

There are several important desired short-term outcomes from VACAA. The first is improved access to high-quality care for both rural and urban veterans. There is an emphasis on primary care and mental health because shortages in these areas across the U.S. are well established.^3,4,10 Likewise, rural areas have been prioritized because often there is a disparity of care. 

One area of concern is the small number of applicants in geriatrics. Even with VACAA specifically targeting geriatrics as a primary care specialty, we have only received enough applications to approve 6.3 positions over the first 3 years of the program. As the veteran and overall population in the U.S. ages, it is important to develop a medical workforce that is willing and able to address their needs.

The VACAA statute is not intended to alter medical students’ career choice but rather to provide funded positions for those choosing primary care, geriatrics, psychiatry (including psychiatric subspecialties), and experience in the VA clinical settings. The hope is that this experience will encourage practitioners to competently care for veterans after training in the VA and/or other civilian settings.

By enabling smaller VA facilities to become training sites through planning and infrastructure grants, residents have the opportunity to gain experience in more rural settings. Physicians who choose to train in rural areas are likely to spend time practicing in those areas after they complete training.¹⁵ The process of developing facilities with no GME into training sitestakes time and resources. Establishing an education office and choosing site directors and core faculty are all important steps that must be done before resident rotations begin. Resources provided through VACAA have enabled the VHA to reduce the number of VAMCs with no GME activity to just 3.

Another benefit of VACAA GME expansion is the opportunity to engage new LCME/AOA-accredited medical schools and ACGME/AOA-accredited residency-sponsoring institutions.^16,17 Representatives of these institutions may have perceived a reluctance of their local VAs to develop GME affiliations in the past. This statute has enabled many VAMCs to use nontraditional training sites and modalities to overcome barriers and create new academic affiliations.

However, VACAA only provides funds for training that occurs in established VA sites of care. This can hinder the development of partnerships where other funding sources are required for non-VA rotations. Another VACAA limitation is that it does not fund undergraduate medical education as does the Armed Forces Health Professional Scholarship Program (HPSP). In addition, the primary financial relationship is between the VA and the sponsoring institution, thus VHA cannot send residents to underserved locations.

Conclusion

The VHA has a rich tradition of educating physician and other health care providers in the U.S. More than 60% of U.S. trained physicians received a portion of their training through VHA.² Through VACAA GME expansion initiative, the 113th Congress has asked VHA to continue its important training mission “to bind up the Nations wounds” and “to care for him who shall have borne the battle.”¹⁸

Acknowledgments
In memoriam – Robert Louis Jesse MD, PhD. Dr. Jesse, the Chief of the Office of Academic Affiliations passed away on September 2, 2017, at age 64. He had an illustrious medical career as a cardiologist and served in many leadership roles including Principal Deputy Under Secretary for Health in the U.S. Department of Veterans Affairs. His expertise, visionary leadership, and friendship will be missed by all involved in the VA’s academic training mission but particularly by those of us who worked for and with him at OAA.

CASE Managing pain associated with prolapse and SUI surgery

A 46-year-old woman (G4P4) described 3 years of worsening symptoms related to recurrent stage-3 palpable uterine prolapse. She had associated symptomatic stress urinary incontinence. She had been treated for uterine prolapse 5 years ago with vaginal hysterectomy, bilateral salpingectomy, and high uterosacral-ligament suspension.

After consultation, the patient elected to undergo laparoscopic sacral colpopexy, a mid-urethral sling, and possible anterior and posterior colporrhaphy. Appropriate discussion about the risks and benefits of mesh was provided preoperatively. The surgical team judged her to be highly motivated; she wanted same-day outpatient surgery so that she could go home and then return to work. She had excellent support at home.

How would you counsel this patient about expected postoperative pain? Which medications would you administer to her preoperatively and perioperatively? Which ones would you prescribe for her to manage pain postoperatively?

Adverse impact of prescription opioids in the United States

Although fewer than 5% of the world’s population live in the United States, nearly 80% of the world’s opioids are written for them.¹ In 2012, 259 million prescriptions were written for opioids in the United States—more than enough to give every American adult their own bottle of pills.² Sadly, drug overdose is now a leading cause of accidental death in the United States, with 52,404 lethal drug overdoses in 2015. A startling statistic is that prescription opioid abuse is driving this epidemic, with 20,101 overdose deaths related to prescription pain relievers and 12,990 overdose deaths related to heroin in 2015.³

It is likely that there are multiple reasons prescribing of opioids is epidemic. Surgical pain is a common indication for opioid prescriptions; fewer than half of patients who undergo surgery report adequate postoperative pain relief.⁴ Recognition of these deficits in pain management has inspired national campaigns to improve patients’ experience with pain and aggressively address pain with drugs such as opioids.⁵

At the same time, marketing efforts by the pharmaceutical industry sought to reassure the medical community that patients would not become addicted to prescription opioid pain relievers if physical pain was the indication for such prescriptions. In response, health care providers began to prescribe opioids at a greater rate. As providers were encouraged to increase prescriptions, opioid medications began to be misused—and only then did it become clear that these medications are, in fact, highly addictive.⁶ Opioid abuse and overdose rates began to increase; in 2015, more than 33,000 Americans died because of an opioid overdose, including prescription opioids and heroin⁷ (FIGURE). In fact, although most people recognize the threat posed by illegal heroin, most of the 2 million who abused opioids in 2015 in the United States suffered from prescription abuse; only about a quarter, or about 600,000, abused heroin.⁸ In addition, more than 80% of people who abuse heroin initially abused prescription opioids.⁹

Read about medications and strategies for multimodal pain management.

Multimodal approach to pain management

The goals of postsurgical pain treatment are to relieve suffering, optimize bodily functioning after surgery, limit length of the stay, and optimize patient satisfaction. Pain-control regimens should consider the specific surgical procedure and the patient’s medical, psychological, and physical conditions; age; level of fear or anxiety; personal preference; and response to previous treatments.¹⁰

Optimally, postsurgical pain management starts well before the day of surgery. Employing such strategies as Enhanced Recovery after Surgery (ERAS) protocols does not necessarily mean providing the same care for every patient, every time. Rather, ERAS serves as a checklist to ensure that all applicable categories of pain medication and pain-control strategies are considered, selected, and dosed according to individual needs.¹¹ (See “Preoperative management of pain expectations.”)

Opioids

Opioids have been employed to treat pain for 700 years.¹² They are powerful pain relievers because they target central mechanisms involved in the perception of pain. Regrettably, because of their central action, opioids have many adverse effects in addition to being highly addictive.

Nonopioid alternatives

Expert consensus, including recommendations of the World Health Organization,¹¹ favors using nonopioids as first-line medications to address surgical pain. Nonopioid analgesic options are acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), and adjuvant medications. In addition, nonanalgesic medications such as sedatives, sleep aids, and muscle relaxants can relieve postsurgical pain. Optimal use of these nonopioid medications can significantly reduce or eliminate the need for opioid medications to treat pain. Goals are to 1) reserve opioids for the most severe pain and 2) minimize the number of doses/pills of opioids required to control postsurgical pain.

Acetaminophen. At dosages of 325 to 1,000 mg orally every 4 to 6 hours, to a maximum dosage of 4,000 mg/d, acetaminophen can be used to treat mild pain and, in combination with other medications, moderate-to-severe pain. The drug also can be administered intravenously (IV), although use of the IV route is limited in many hospitals because of its significantly higher expense compared to the oral form.

The mechanism of action of acetaminophen is unique among pain relievers; it can therefore be used in combination with other pain relievers to more effectively treat pain with fewer concerns about medication-induced adverse effects or opioid overdose. However, keep in mind when considering combining analgesics, that acetaminophen is an active ingredient in hundreds of over-the-counter (OTC) and prescription formulations, and that a combination of more than one acetaminophen-containing product can create the risk of overdose.

Acetaminophen should be used with caution in patients with liver disease. That being said, multiple trials have documented safe use in normal body weight adults who do not have hepatic disease, at dosages as high as 4,000 mg over a 24-hour period.¹³

NSAIDs. A combination of an NSAID and acetaminophen has been documented to reduce the amount of opioid medications required to treat postsurgical pain. In most circumstances, especially for minor surgery, acetaminophen and NSAIDS can be administered just before surgery starts. This preoperative treatment, called “preventive analgesia” or “preemptive analgesia,” has been demonstrated in multiple clinical trials to reduce postoperative pain.¹⁴

Adjuvant pain medications. Antidepressants, antiepileptic agents, and muscle relaxants—agents that have a primary indication for a condition (or conditions) other than pain and do not directly provide analgesia—have been used as adjuvant pain medications. When employed with traditional analgesics, they have been demonstrated to reduce postsurgical pain scores and the amount of opioids required. These medications need to be used cautiously because some are associated with serious sedation and vertigo (TABLE). Take caution when using adjuvant pain medications in patients older than 65 years; guidance on their use in older patients has been outlined by the American Geriatrics Society and other professional organizations.¹⁵

Case Continued

The patient was given the expectation that the 11-mm left lower-quadrant port site would likely be the most bothersome site of pain—a rating of 4 or 5 on a visual analogue scale of 1 to 10, on postoperative day 1, while standing. The other 3 (5-mm) laparoscopic ports, she was told, would, typically, be less bothersome. The patient was educated regarding the role of analgesics and adjuvant medications and cautioned not to exceed 4,000 mg of acetaminophen in any 24-hour period. She was told that gabapentin may make her feel sedated or dizzy, or both; she was encouraged to hold this medication if she found these adverse effects bothersome or limiting.

The following multimodal pain management was established.

Preoperatively, the patient was given:

• Acetaminophen 1.5 g orally (as a liquid, 45 mL of a suspension of 500 mg/15 mL liquid), 2 to 3 hours preoperatively; the surgical suite did not stock IV acetaminophen.
• Gabapentin 600 mg orally, with a sip of water, the morning of surgery.
• Celecoxib 100 mg orally, with a sip of water, the morning of surgery.

Prescriptions for home postoperative pain management were provided preoperatively:

• OTC acetaminophen 1,000 mg (as 2 500-mgtablets) taken as a scheduled dose every 8 hours for the first 48 hours postoperatively.
• Meloxicam 15 mg daily as the NSAID, taken as a scheduled dose once per day for the first 48 hours postoperatively, then as needed.
• Gabapentin 300 mg (in addition to the preoperative dose, above), taken as a scheduled dose every 8 hours for the first 48 hours postoperatively, then as needed.
• Oxycodone 5 mg (without acetaminophen) for breakthrough pain.

Intraoperatively:

• Meticulous attention was paid to patient positioning, to reduce the possibility of back and upper- and lower-extremity injury postoperatively.
• A corticosteroid (dexamethasone 8 mg IV) was administered to minimize postoperative nausea and vomiting and as an adjuvant medication for postoperative pain control.
• Careful attention was paid to limit residual CO₂ gas and intraoperative intra-abdominal pressures.
• All laparoscopic port sites were injected with 30 mL of 0.25% bupivacaine with epinephrine, extending to subcutaneous, fascial, and peritoneal layers.

Read about why a multimodal approach is best for postsurgical pain.

Why a multimodal plan to treat pain?

Pain following laparoscopy has been associated with many variables, including patient positioning, port size and placement, amount of port manipulation, and gas retention. After a laparoscopic surgical procedure, patients report pain in the abdomen, back, and shoulders.

Postsurgical pain has 3 components:

• Shoulder pain, thought to result from phrenic nerve irritation caused by lingering CO₂ in the abdominal cavity.
• Visceral pain, occurring secondary to stretching of the abdominal cavity.
• Somatic pain, caused by the surgical incision; of the 3 components to pain, somatic pain can have the least impact because laparoscopic incisions are small.

For our patient, prior to the incisions being made, she received local anesthesia intraoperatively to the laparoscopic port sites to include the subcutaneous, fascial, and peritoneal layers. Involving these layers allows for more of a block. An ultrasonography-guided transversus abdominis plane (TAP) block, if available, is highly effective at decreasing postoperative pain, but its efficacy is dependent on the anatomy and the skill of the physician (whether anesthesiologist, gynecologist, or surgeon) who is placing it.¹⁶

We used dexamethasone 8 mg IV, intraoperatively because this single dose has been shown to decrease the perception of pain postoperatively. Dexamethasone also has been shown to decrease consumption of oxycodone during the 24 hours after laparoscopic gynecologic surgery.¹⁷

CO₂ used to insufflate the patient’s abdomen can take as long as 2 days to fully resorb, resulting in increased pain. This discomfort has been described as delayed; the patient might not notice it until she goes home. In a study, 70% of patients had shoulder discomfort following laparoscopy 24 hours after their procedure.¹⁸ For this reason, we employed several techniques to reduce this effect:

• We reduced the intra-abdominal pressure limit to 10 mm Hg (from 15 mm Hg) once dissection was complete.
• At the end of the procedure, careful attention was paid to removing as much intra-abdominal gas as possible, including placing the patient in the Trendelenburg position and having the anesthesiologist induce a Valsalva maneuver. This action has been shown to significantly improve pain control compared to placebo intervention.¹⁹
• We used humidified CO₂, which has been demonstrated to reduce pain in laparoscopic surgery.²⁰

Preemptively, we provided this patient with acetaminophen, celecoxib, and gabapentin, which have been demonstrated to be effective in gynecologic patients to decrease the need for postoperative opioids.²¹ Also, our patient received counseling, with specific expectations for what to expect following the surgical procedure.

CASE Resolved

Our patient did exceptionally well following surgery. She used only one of the oxycodone pills and did not require unplanned interventions. She took gabapentin, acetaminophen, and meloxicam at their scheduled doses for 2 days. She continued to use meloxicam for 4 more days for mild abdominal pain, then discontinued all medications.She flushed her 9 unused oxycodone pills down the toilet. (See “A word about disposal of ‘excess’ opioids”²²) The patient returned to her administrative duties at work 2 weeks after the procedure and reported that she was “very satisfied” with her surgical experience.

In conclusion

Postoperative pain is a complex entity that must be considered to require individualized strategies and, possibly, multiple interventions. Optimally, thorough education, including pain management options, is provided to the patient prior to surgery. Given the current state of opioid abuse in the United States, all gynecologic surgeons should be familiar with multimodal pain therapy and how to employ nonmedical techniques to reduce postsurgical pain without relying solely on opioids. (See “Online resources for pain management”.)

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

CASE Managing pain associated with prolapse and SUI surgery

A 46-year-old woman (G4P4) described 3 years of worsening symptoms related to recurrent stage-3 palpable uterine prolapse. She had associated symptomatic stress urinary incontinence. She had been treated for uterine prolapse 5 years ago with vaginal hysterectomy, bilateral salpingectomy, and high uterosacral-ligament suspension.

After consultation, the patient elected to undergo laparoscopic sacral colpopexy, a mid-urethral sling, and possible anterior and posterior colporrhaphy. Appropriate discussion about the risks and benefits of mesh was provided preoperatively. The surgical team judged her to be highly motivated; she wanted same-day outpatient surgery so that she could go home and then return to work. She had excellent support at home.

How would you counsel this patient about expected postoperative pain? Which medications would you administer to her preoperatively and perioperatively? Which ones would you prescribe for her to manage pain postoperatively?

Adverse impact of prescription opioids in the United States

Although fewer than 5% of the world’s population live in the United States, nearly 80% of the world’s opioids are written for them.¹ In 2012, 259 million prescriptions were written for opioids in the United States—more than enough to give every American adult their own bottle of pills.² Sadly, drug overdose is now a leading cause of accidental death in the United States, with 52,404 lethal drug overdoses in 2015. A startling statistic is that prescription opioid abuse is driving this epidemic, with 20,101 overdose deaths related to prescription pain relievers and 12,990 overdose deaths related to heroin in 2015.³

It is likely that there are multiple reasons prescribing of opioids is epidemic. Surgical pain is a common indication for opioid prescriptions; fewer than half of patients who undergo surgery report adequate postoperative pain relief.⁴ Recognition of these deficits in pain management has inspired national campaigns to improve patients’ experience with pain and aggressively address pain with drugs such as opioids.⁵

At the same time, marketing efforts by the pharmaceutical industry sought to reassure the medical community that patients would not become addicted to prescription opioid pain relievers if physical pain was the indication for such prescriptions. In response, health care providers began to prescribe opioids at a greater rate. As providers were encouraged to increase prescriptions, opioid medications began to be misused—and only then did it become clear that these medications are, in fact, highly addictive.⁶ Opioid abuse and overdose rates began to increase; in 2015, more than 33,000 Americans died because of an opioid overdose, including prescription opioids and heroin⁷ (FIGURE). In fact, although most people recognize the threat posed by illegal heroin, most of the 2 million who abused opioids in 2015 in the United States suffered from prescription abuse; only about a quarter, or about 600,000, abused heroin.⁸ In addition, more than 80% of people who abuse heroin initially abused prescription opioids.⁹

Read about medications and strategies for multimodal pain management.

Multimodal approach to pain management

The goals of postsurgical pain treatment are to relieve suffering, optimize bodily functioning after surgery, limit length of the stay, and optimize patient satisfaction. Pain-control regimens should consider the specific surgical procedure and the patient’s medical, psychological, and physical conditions; age; level of fear or anxiety; personal preference; and response to previous treatments.¹⁰

Optimally, postsurgical pain management starts well before the day of surgery. Employing such strategies as Enhanced Recovery after Surgery (ERAS) protocols does not necessarily mean providing the same care for every patient, every time. Rather, ERAS serves as a checklist to ensure that all applicable categories of pain medication and pain-control strategies are considered, selected, and dosed according to individual needs.¹¹ (See “Preoperative management of pain expectations.”)

Opioids

Opioids have been employed to treat pain for 700 years.¹² They are powerful pain relievers because they target central mechanisms involved in the perception of pain. Regrettably, because of their central action, opioids have many adverse effects in addition to being highly addictive.

Nonopioid alternatives

Expert consensus, including recommendations of the World Health Organization,¹¹ favors using nonopioids as first-line medications to address surgical pain. Nonopioid analgesic options are acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), and adjuvant medications. In addition, nonanalgesic medications such as sedatives, sleep aids, and muscle relaxants can relieve postsurgical pain. Optimal use of these nonopioid medications can significantly reduce or eliminate the need for opioid medications to treat pain. Goals are to 1) reserve opioids for the most severe pain and 2) minimize the number of doses/pills of opioids required to control postsurgical pain.

Acetaminophen. At dosages of 325 to 1,000 mg orally every 4 to 6 hours, to a maximum dosage of 4,000 mg/d, acetaminophen can be used to treat mild pain and, in combination with other medications, moderate-to-severe pain. The drug also can be administered intravenously (IV), although use of the IV route is limited in many hospitals because of its significantly higher expense compared to the oral form.

The mechanism of action of acetaminophen is unique among pain relievers; it can therefore be used in combination with other pain relievers to more effectively treat pain with fewer concerns about medication-induced adverse effects or opioid overdose. However, keep in mind when considering combining analgesics, that acetaminophen is an active ingredient in hundreds of over-the-counter (OTC) and prescription formulations, and that a combination of more than one acetaminophen-containing product can create the risk of overdose.

Acetaminophen should be used with caution in patients with liver disease. That being said, multiple trials have documented safe use in normal body weight adults who do not have hepatic disease, at dosages as high as 4,000 mg over a 24-hour period.¹³

NSAIDs. A combination of an NSAID and acetaminophen has been documented to reduce the amount of opioid medications required to treat postsurgical pain. In most circumstances, especially for minor surgery, acetaminophen and NSAIDS can be administered just before surgery starts. This preoperative treatment, called “preventive analgesia” or “preemptive analgesia,” has been demonstrated in multiple clinical trials to reduce postoperative pain.¹⁴

Adjuvant pain medications. Antidepressants, antiepileptic agents, and muscle relaxants—agents that have a primary indication for a condition (or conditions) other than pain and do not directly provide analgesia—have been used as adjuvant pain medications. When employed with traditional analgesics, they have been demonstrated to reduce postsurgical pain scores and the amount of opioids required. These medications need to be used cautiously because some are associated with serious sedation and vertigo (TABLE). Take caution when using adjuvant pain medications in patients older than 65 years; guidance on their use in older patients has been outlined by the American Geriatrics Society and other professional organizations.¹⁵

Case Continued

The patient was given the expectation that the 11-mm left lower-quadrant port site would likely be the most bothersome site of pain—a rating of 4 or 5 on a visual analogue scale of 1 to 10, on postoperative day 1, while standing. The other 3 (5-mm) laparoscopic ports, she was told, would, typically, be less bothersome. The patient was educated regarding the role of analgesics and adjuvant medications and cautioned not to exceed 4,000 mg of acetaminophen in any 24-hour period. She was told that gabapentin may make her feel sedated or dizzy, or both; she was encouraged to hold this medication if she found these adverse effects bothersome or limiting.

The following multimodal pain management was established.

Preoperatively, the patient was given:

• Acetaminophen 1.5 g orally (as a liquid, 45 mL of a suspension of 500 mg/15 mL liquid), 2 to 3 hours preoperatively; the surgical suite did not stock IV acetaminophen.
• Gabapentin 600 mg orally, with a sip of water, the morning of surgery.
• Celecoxib 100 mg orally, with a sip of water, the morning of surgery.

Prescriptions for home postoperative pain management were provided preoperatively:

• OTC acetaminophen 1,000 mg (as 2 500-mgtablets) taken as a scheduled dose every 8 hours for the first 48 hours postoperatively.
• Meloxicam 15 mg daily as the NSAID, taken as a scheduled dose once per day for the first 48 hours postoperatively, then as needed.
• Gabapentin 300 mg (in addition to the preoperative dose, above), taken as a scheduled dose every 8 hours for the first 48 hours postoperatively, then as needed.
• Oxycodone 5 mg (without acetaminophen) for breakthrough pain.

Intraoperatively:

• Meticulous attention was paid to patient positioning, to reduce the possibility of back and upper- and lower-extremity injury postoperatively.
• A corticosteroid (dexamethasone 8 mg IV) was administered to minimize postoperative nausea and vomiting and as an adjuvant medication for postoperative pain control.
• Careful attention was paid to limit residual CO₂ gas and intraoperative intra-abdominal pressures.
• All laparoscopic port sites were injected with 30 mL of 0.25% bupivacaine with epinephrine, extending to subcutaneous, fascial, and peritoneal layers.

Read about why a multimodal approach is best for postsurgical pain.

Why a multimodal plan to treat pain?

Pain following laparoscopy has been associated with many variables, including patient positioning, port size and placement, amount of port manipulation, and gas retention. After a laparoscopic surgical procedure, patients report pain in the abdomen, back, and shoulders.

Postsurgical pain has 3 components:

• Shoulder pain, thought to result from phrenic nerve irritation caused by lingering CO₂ in the abdominal cavity.
• Visceral pain, occurring secondary to stretching of the abdominal cavity.
• Somatic pain, caused by the surgical incision; of the 3 components to pain, somatic pain can have the least impact because laparoscopic incisions are small.

For our patient, prior to the incisions being made, she received local anesthesia intraoperatively to the laparoscopic port sites to include the subcutaneous, fascial, and peritoneal layers. Involving these layers allows for more of a block. An ultrasonography-guided transversus abdominis plane (TAP) block, if available, is highly effective at decreasing postoperative pain, but its efficacy is dependent on the anatomy and the skill of the physician (whether anesthesiologist, gynecologist, or surgeon) who is placing it.¹⁶

We used dexamethasone 8 mg IV, intraoperatively because this single dose has been shown to decrease the perception of pain postoperatively. Dexamethasone also has been shown to decrease consumption of oxycodone during the 24 hours after laparoscopic gynecologic surgery.¹⁷

CO₂ used to insufflate the patient’s abdomen can take as long as 2 days to fully resorb, resulting in increased pain. This discomfort has been described as delayed; the patient might not notice it until she goes home. In a study, 70% of patients had shoulder discomfort following laparoscopy 24 hours after their procedure.¹⁸ For this reason, we employed several techniques to reduce this effect:

• We reduced the intra-abdominal pressure limit to 10 mm Hg (from 15 mm Hg) once dissection was complete.
• At the end of the procedure, careful attention was paid to removing as much intra-abdominal gas as possible, including placing the patient in the Trendelenburg position and having the anesthesiologist induce a Valsalva maneuver. This action has been shown to significantly improve pain control compared to placebo intervention.¹⁹
• We used humidified CO₂, which has been demonstrated to reduce pain in laparoscopic surgery.²⁰

Preemptively, we provided this patient with acetaminophen, celecoxib, and gabapentin, which have been demonstrated to be effective in gynecologic patients to decrease the need for postoperative opioids.²¹ Also, our patient received counseling, with specific expectations for what to expect following the surgical procedure.

CASE Resolved

Our patient did exceptionally well following surgery. She used only one of the oxycodone pills and did not require unplanned interventions. She took gabapentin, acetaminophen, and meloxicam at their scheduled doses for 2 days. She continued to use meloxicam for 4 more days for mild abdominal pain, then discontinued all medications.She flushed her 9 unused oxycodone pills down the toilet. (See “A word about disposal of ‘excess’ opioids”²²) The patient returned to her administrative duties at work 2 weeks after the procedure and reported that she was “very satisfied” with her surgical experience.

In conclusion

Postoperative pain is a complex entity that must be considered to require individualized strategies and, possibly, multiple interventions. Optimally, thorough education, including pain management options, is provided to the patient prior to surgery. Given the current state of opioid abuse in the United States, all gynecologic surgeons should be familiar with multimodal pain therapy and how to employ nonmedical techniques to reduce postsurgical pain without relying solely on opioids. (See “Online resources for pain management”.)

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

CASE Managing pain associated with prolapse and SUI surgery

A 46-year-old woman (G4P4) described 3 years of worsening symptoms related to recurrent stage-3 palpable uterine prolapse. She had associated symptomatic stress urinary incontinence. She had been treated for uterine prolapse 5 years ago with vaginal hysterectomy, bilateral salpingectomy, and high uterosacral-ligament suspension.

After consultation, the patient elected to undergo laparoscopic sacral colpopexy, a mid-urethral sling, and possible anterior and posterior colporrhaphy. Appropriate discussion about the risks and benefits of mesh was provided preoperatively. The surgical team judged her to be highly motivated; she wanted same-day outpatient surgery so that she could go home and then return to work. She had excellent support at home.

How would you counsel this patient about expected postoperative pain? Which medications would you administer to her preoperatively and perioperatively? Which ones would you prescribe for her to manage pain postoperatively?

Adverse impact of prescription opioids in the United States

Although fewer than 5% of the world’s population live in the United States, nearly 80% of the world’s opioids are written for them.¹ In 2012, 259 million prescriptions were written for opioids in the United States—more than enough to give every American adult their own bottle of pills.² Sadly, drug overdose is now a leading cause of accidental death in the United States, with 52,404 lethal drug overdoses in 2015. A startling statistic is that prescription opioid abuse is driving this epidemic, with 20,101 overdose deaths related to prescription pain relievers and 12,990 overdose deaths related to heroin in 2015.³

It is likely that there are multiple reasons prescribing of opioids is epidemic. Surgical pain is a common indication for opioid prescriptions; fewer than half of patients who undergo surgery report adequate postoperative pain relief.⁴ Recognition of these deficits in pain management has inspired national campaigns to improve patients’ experience with pain and aggressively address pain with drugs such as opioids.⁵

At the same time, marketing efforts by the pharmaceutical industry sought to reassure the medical community that patients would not become addicted to prescription opioid pain relievers if physical pain was the indication for such prescriptions. In response, health care providers began to prescribe opioids at a greater rate. As providers were encouraged to increase prescriptions, opioid medications began to be misused—and only then did it become clear that these medications are, in fact, highly addictive.⁶ Opioid abuse and overdose rates began to increase; in 2015, more than 33,000 Americans died because of an opioid overdose, including prescription opioids and heroin⁷ (FIGURE). In fact, although most people recognize the threat posed by illegal heroin, most of the 2 million who abused opioids in 2015 in the United States suffered from prescription abuse; only about a quarter, or about 600,000, abused heroin.⁸ In addition, more than 80% of people who abuse heroin initially abused prescription opioids.⁹

Read about medications and strategies for multimodal pain management.

Multimodal approach to pain management

The goals of postsurgical pain treatment are to relieve suffering, optimize bodily functioning after surgery, limit length of the stay, and optimize patient satisfaction. Pain-control regimens should consider the specific surgical procedure and the patient’s medical, psychological, and physical conditions; age; level of fear or anxiety; personal preference; and response to previous treatments.¹⁰

Optimally, postsurgical pain management starts well before the day of surgery. Employing such strategies as Enhanced Recovery after Surgery (ERAS) protocols does not necessarily mean providing the same care for every patient, every time. Rather, ERAS serves as a checklist to ensure that all applicable categories of pain medication and pain-control strategies are considered, selected, and dosed according to individual needs.¹¹ (See “Preoperative management of pain expectations.”)

Opioids

Opioids have been employed to treat pain for 700 years.¹² They are powerful pain relievers because they target central mechanisms involved in the perception of pain. Regrettably, because of their central action, opioids have many adverse effects in addition to being highly addictive.

Nonopioid alternatives

Expert consensus, including recommendations of the World Health Organization,¹¹ favors using nonopioids as first-line medications to address surgical pain. Nonopioid analgesic options are acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), and adjuvant medications. In addition, nonanalgesic medications such as sedatives, sleep aids, and muscle relaxants can relieve postsurgical pain. Optimal use of these nonopioid medications can significantly reduce or eliminate the need for opioid medications to treat pain. Goals are to 1) reserve opioids for the most severe pain and 2) minimize the number of doses/pills of opioids required to control postsurgical pain.

Acetaminophen. At dosages of 325 to 1,000 mg orally every 4 to 6 hours, to a maximum dosage of 4,000 mg/d, acetaminophen can be used to treat mild pain and, in combination with other medications, moderate-to-severe pain. The drug also can be administered intravenously (IV), although use of the IV route is limited in many hospitals because of its significantly higher expense compared to the oral form.

The mechanism of action of acetaminophen is unique among pain relievers; it can therefore be used in combination with other pain relievers to more effectively treat pain with fewer concerns about medication-induced adverse effects or opioid overdose. However, keep in mind when considering combining analgesics, that acetaminophen is an active ingredient in hundreds of over-the-counter (OTC) and prescription formulations, and that a combination of more than one acetaminophen-containing product can create the risk of overdose.

Acetaminophen should be used with caution in patients with liver disease. That being said, multiple trials have documented safe use in normal body weight adults who do not have hepatic disease, at dosages as high as 4,000 mg over a 24-hour period.¹³

NSAIDs. A combination of an NSAID and acetaminophen has been documented to reduce the amount of opioid medications required to treat postsurgical pain. In most circumstances, especially for minor surgery, acetaminophen and NSAIDS can be administered just before surgery starts. This preoperative treatment, called “preventive analgesia” or “preemptive analgesia,” has been demonstrated in multiple clinical trials to reduce postoperative pain.¹⁴

Adjuvant pain medications. Antidepressants, antiepileptic agents, and muscle relaxants—agents that have a primary indication for a condition (or conditions) other than pain and do not directly provide analgesia—have been used as adjuvant pain medications. When employed with traditional analgesics, they have been demonstrated to reduce postsurgical pain scores and the amount of opioids required. These medications need to be used cautiously because some are associated with serious sedation and vertigo (TABLE). Take caution when using adjuvant pain medications in patients older than 65 years; guidance on their use in older patients has been outlined by the American Geriatrics Society and other professional organizations.¹⁵

Case Continued

The patient was given the expectation that the 11-mm left lower-quadrant port site would likely be the most bothersome site of pain—a rating of 4 or 5 on a visual analogue scale of 1 to 10, on postoperative day 1, while standing. The other 3 (5-mm) laparoscopic ports, she was told, would, typically, be less bothersome. The patient was educated regarding the role of analgesics and adjuvant medications and cautioned not to exceed 4,000 mg of acetaminophen in any 24-hour period. She was told that gabapentin may make her feel sedated or dizzy, or both; she was encouraged to hold this medication if she found these adverse effects bothersome or limiting.

The following multimodal pain management was established.

Preoperatively, the patient was given:

• Acetaminophen 1.5 g orally (as a liquid, 45 mL of a suspension of 500 mg/15 mL liquid), 2 to 3 hours preoperatively; the surgical suite did not stock IV acetaminophen.
• Gabapentin 600 mg orally, with a sip of water, the morning of surgery.
• Celecoxib 100 mg orally, with a sip of water, the morning of surgery.

Prescriptions for home postoperative pain management were provided preoperatively:

• OTC acetaminophen 1,000 mg (as 2 500-mgtablets) taken as a scheduled dose every 8 hours for the first 48 hours postoperatively.
• Meloxicam 15 mg daily as the NSAID, taken as a scheduled dose once per day for the first 48 hours postoperatively, then as needed.
• Gabapentin 300 mg (in addition to the preoperative dose, above), taken as a scheduled dose every 8 hours for the first 48 hours postoperatively, then as needed.
• Oxycodone 5 mg (without acetaminophen) for breakthrough pain.

Intraoperatively:

• Meticulous attention was paid to patient positioning, to reduce the possibility of back and upper- and lower-extremity injury postoperatively.
• A corticosteroid (dexamethasone 8 mg IV) was administered to minimize postoperative nausea and vomiting and as an adjuvant medication for postoperative pain control.
• Careful attention was paid to limit residual CO₂ gas and intraoperative intra-abdominal pressures.
• All laparoscopic port sites were injected with 30 mL of 0.25% bupivacaine with epinephrine, extending to subcutaneous, fascial, and peritoneal layers.

Read about why a multimodal approach is best for postsurgical pain.

Why a multimodal plan to treat pain?

Pain following laparoscopy has been associated with many variables, including patient positioning, port size and placement, amount of port manipulation, and gas retention. After a laparoscopic surgical procedure, patients report pain in the abdomen, back, and shoulders.

Postsurgical pain has 3 components:

• Shoulder pain, thought to result from phrenic nerve irritation caused by lingering CO₂ in the abdominal cavity.
• Visceral pain, occurring secondary to stretching of the abdominal cavity.
• Somatic pain, caused by the surgical incision; of the 3 components to pain, somatic pain can have the least impact because laparoscopic incisions are small.

For our patient, prior to the incisions being made, she received local anesthesia intraoperatively to the laparoscopic port sites to include the subcutaneous, fascial, and peritoneal layers. Involving these layers allows for more of a block. An ultrasonography-guided transversus abdominis plane (TAP) block, if available, is highly effective at decreasing postoperative pain, but its efficacy is dependent on the anatomy and the skill of the physician (whether anesthesiologist, gynecologist, or surgeon) who is placing it.¹⁶

We used dexamethasone 8 mg IV, intraoperatively because this single dose has been shown to decrease the perception of pain postoperatively. Dexamethasone also has been shown to decrease consumption of oxycodone during the 24 hours after laparoscopic gynecologic surgery.¹⁷

CO₂ used to insufflate the patient’s abdomen can take as long as 2 days to fully resorb, resulting in increased pain. This discomfort has been described as delayed; the patient might not notice it until she goes home. In a study, 70% of patients had shoulder discomfort following laparoscopy 24 hours after their procedure.¹⁸ For this reason, we employed several techniques to reduce this effect:

• We reduced the intra-abdominal pressure limit to 10 mm Hg (from 15 mm Hg) once dissection was complete.
• At the end of the procedure, careful attention was paid to removing as much intra-abdominal gas as possible, including placing the patient in the Trendelenburg position and having the anesthesiologist induce a Valsalva maneuver. This action has been shown to significantly improve pain control compared to placebo intervention.¹⁹
• We used humidified CO₂, which has been demonstrated to reduce pain in laparoscopic surgery.²⁰

Preemptively, we provided this patient with acetaminophen, celecoxib, and gabapentin, which have been demonstrated to be effective in gynecologic patients to decrease the need for postoperative opioids.²¹ Also, our patient received counseling, with specific expectations for what to expect following the surgical procedure.

CASE Resolved

Our patient did exceptionally well following surgery. She used only one of the oxycodone pills and did not require unplanned interventions. She took gabapentin, acetaminophen, and meloxicam at their scheduled doses for 2 days. She continued to use meloxicam for 4 more days for mild abdominal pain, then discontinued all medications.She flushed her 9 unused oxycodone pills down the toilet. (See “A word about disposal of ‘excess’ opioids”²²) The patient returned to her administrative duties at work 2 weeks after the procedure and reported that she was “very satisfied” with her surgical experience.

In conclusion

Postoperative pain is a complex entity that must be considered to require individualized strategies and, possibly, multiple interventions. Optimally, thorough education, including pain management options, is provided to the patient prior to surgery. Given the current state of opioid abuse in the United States, all gynecologic surgeons should be familiar with multimodal pain therapy and how to employ nonmedical techniques to reduce postsurgical pain without relying solely on opioids. (See “Online resources for pain management”.)

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Clinicians always should consider endometriosis in the diagnostic work-up of an infertility patient. But the diagnosis of endometriosis is often difficult, and management is complex. In this Update, we summarize international consensus documents on endometriosis with the aim of enhancing clinicians’ ability to make evidence-based decisions. In addition, we explore the interesting results of a large hysterosalpingography trial in which 2 different contrast mediums were used. Finally, we urge all clinicians to adapt the new standardized lexicon of infertility and fertility care terms that comprise the recently revised international glossary.

Endometriosis and infertility: The knowns and unknowns

Johnson NP, Hummelshoj L, Adamson GD, et al; World Endometriosis Society Sao Paulo Consortium. World Endometriosis Society consensus on the classification of endometriosis. Hum Reprod. 2017;32(2):315-324.

Johnson NP, Hummelshoj L; World Endometriosis Society Montpellier Consortium. Consensus on current management of endometriosis. Hum Reprod. 2013;28(6):1552-1568.

Rogers PA, Adamson GD, Al-Jefout M, et al; WES/WERF Consortium for Research Priorities in Endometriosis. Research priorities for endometriosis. Reprod Sci. 2017;24(2):202-226.

Endometriosis is defined as "a disease characterized by the presence of endometrium-like epithelium and stroma outside the endometrium and myometrium. Intrapelvic endometriosis can be located superficially on the peritoneum (peritoneal endometriosis), can extend 5 mm or more beneath the peritoneum (deep endometriosis) or can be present as an ovarian endometriotic cyst (endometrioma)."¹ Always consider endometriosis in the infertile patient.

Although many professional societies and numerous Cochrane Database Systematic Reviews have provided guidelines on endometriosis, controversy and uncertainty remain. The World Endometriosis Society (WES) and the World Endometriosis Research Foundation (WERF), however, have now published several consensus documents that assess the global literature and professional organization guidelines in a structured, consensus-driven process.^2-4 These WES and WERF documents consolidate known information and can be used to inform the clinician in making evidence-linked diagnostic and treatment decisions. Recommendations offered in this discussion are based on those documents.

Establishing the diagnosis can be difficult

Diagnosis of endometriosis is often difficult and is delayed an average of 7 years from onset of symptoms. These include severe dysmenorrhea, deep dyspareunia, chronic pelvic pain, ovulation pain, cyclical or perimenstrual symptoms (bowel or bladder associated) with or without abnormal bleeding, chronic fatigue, and infertility. A major difficulty is that the predictive value of any one symptom or set of symptoms remains uncertain, as each of these symptoms can have other causes, and a significant proportion of affected women are asymptomatic.

For a definitive diagnosis of endometriosis, visual inspection of the pelvis at laparoscopy is the gold standard investigation, unless disease is visible in the vagina or elsewhere. Positive histology confirms the diagnosis of endometriosis; negative histology does not exclude it. Whether histology should be obtained if peritoneal disease alone is present is controversial: visual inspection usually is adequate, but histologic confirmation of at least one lesion is ideal. In cases of ovarian endometrioma (>4 cm in diameter) and in deeply infiltrating disease, histology should be obtained to identify endometriosis and to exclude rare instances of malignancy.

Compared with laparoscopy, transvaginal ultrasonography (TVUS) has no value in diagnosing peritoneal endometriosis, but it is a useful tool for both making and excluding the diagnosis of an ovarian endometrioma. TVUS may have a role in the diagnosis of disease involving the bladder or rectum.

At present, evidence is insufficient to indicate that magnetic resonance imaging (MRI) is useful for diagnosing or excluding endometriosis compared with laparoscopy. MRI should be reserved for when ultrasound results are equivocal in cases of rectovaginal or bladder endometriosis.

Serum cancer antigen 125 (CA 125) levels may be elevated in endometriosis. However, measuring serum CA 125 levels has no value as a diagnostic tool.

No fertility benefit with ovarian suppression

More than 2 dozen randomized controlled trials (RCTs) provide strong evidence that there is no fertility benefit from ovarian suppression. The drug costs and delayed time to pregnancy mean that ovarian suppression with oral contraceptives, other progestational agents, or gonadotropin-releasing hormone (GnRH) agonists before fertility treatment is not indicated, with the possible exception of using it prior to in vitro fertilization (IVF).

Ovarian suppression also has been suggested as beneficial in conjunction with surgery. However, at least 16 RCTs have failed to show fertility improvement when ovarian suppression is given either preoperatively or postoperatively. Again, the delay in attempting pregnancy, drug costs, and adverse effects render ovarian suppression not appropriate.

While ovarian suppression has not been shown to increase pregnancy rates, ovarian stimulation (OS) likely does, especially when combined with intrauterine insemination (IUI).⁵

Laparoscopy: Appropriate for selected patients

A major decision for clinicians and patients dealing with infertility is whether to perform a laparoscopy, both for diagnostic and for treatment reasons. Currently, data are insufficient to recommend laparoscopic surgery prior to OS/IUI unless there is a history of evidence of anatomic disease and/or the patient has sufficient pain to justify the physical, emotional, financial, and time costs of laparoscopy. Laparoscopy therefore can be considered as possibly appropriate in younger women (<37 years of age) with short duration of infertility (<4 years), normal male factor, normal or treatable uterus, normal or treatable ovulation disorder, and limited prior treatment.

It is important to consider what disease might be found and how much of an increase in fertility can be obtained by treatment, so that the number needed to treat (NNT) can be used as an estimate of the potential value of laparoscopy in a given patient. A patient also should have no contraindications to laparoscopy and accept 9 to 15 months of attempting pregnancy before undergoing IVF treatment.

When laparoscopy is performed for minimal to mild disease, the odds ratio for pregnancy is 1.66 with treatment. It is important to remove all visible disease without injuring healthy tissue. When disease is moderate to severe, there is often severe anatomic distortion and a very low background pregnancy rate. Numerous uncontrolled trials show benefit of operative laparoscopy, especially for invasive, adhesive, and cystic endometriosis. However, repeat surgery is rarely indicated. After surgery, the Endometriosis Fertility Index (EFI) can be used to determine prognosis and plan management (FIGURE  1).⁶ An easy-to-use electronic EFI calculator is available online at www.endometriosisefi.com.

Management of endometriomas

Endometriomas are often operated on because of pain. Initial pain relief occurs in 60% to 100% of patients, but cysts recur following stripping about 10% of the time, and drainage without stripping, about 20%. With recurrence, pain is present about 75% of the time.

Pregnancy rates following endometrioma treatment depend on patient age and the status of the pelvis following operative intervention. This can be determined from the EFI. Often, the dilemma with endometriomas is how aggressive to be in removing them. The principles involved are to remove all the cyst wall if possible, but absolutely to minimize ovarian tissue damage, because reduced ovarian reserve is a possible major negative consequence of ovarian surgery. 

Recommendations

While endometriosis is often a cause of infertility, often infertile patients do not have endometriosis. A careful history, physical examination, and ultrasonography, and possibly other imaging studies, are prerequisites to careful clinical judgment in diagnosing and treating infertile patients who might or do have endometriosis.

When pelvic pain is present, initially nonsteroidal anti-inflammatory drugs (NSAIDs), oral contraceptives (OCs), progestational agents, or an intrauterine device can be helpful. These ovarian suppression medications do not increase fertility, however, and should be stopped in any patient who desires to get pregnant.

When pelvic and male fertility factors appear reasonably normal (even if minimal or mild endometriosis is suspected), treatment with clomiphene 100 mg on cycle days 3 through 7 and IUI for 3 to 6 cycles is an effective first step. However, if the patient has persistent pain and/or infertility without other significant infertility factors, then diagnostic laparoscopy with intraoperative treatment of disease is indicated.

Surgery well performed is effective treatment for all stages of endometriosis and endometriomas, both for infertility and for pain. Repeat surgery, however, is rarely indicated because of limited results, so it is important to obtain the best possible result on the first surgery. Surgery is indicated for large endometriomas (>4 cm). Endometriosis has almost no effect on the IVF live birth rate unless ovarian reserve has been reduced by endometriomas or surgery, so endometriosis surgery should be performed by skilled and experienced surgeons.

Read about why oil-based contrast may be better than water-based contrast with HSG.

Oil-based contrast medium use in hysterosalpingography is associated with higher pregnancy rates compared with water-based contrast

Dreyer K, van Rijswijk J, Mijatovic V, et al. Oil-based or water-based contrast for hysterosalpingography in infertile women. N Engl J Med. 2017;376(21):2043-2052.

Hysterosalpingography (HSG) to assess tubal patency has been a mainstay of infertility diagnosis for decades. Some, but not all, studies also have suggested that pregnancy rates are higher after this tubal flushing procedure, especially if performed with oil contrast.^7,8 A recent multicenter, randomized, controlled trial by Dreyer and colleagues that compared ongoing pregnancy rates and other outcomes among women who had HSG with oil contrast versus with water contrast provides additional valuable information.⁹

Trial details

In this study, 1,294 infertile women in 27 academic, teaching and nonteaching hospitals were screened for trial eligibility; 1,119 women provided written informed consent. Of these, 557 women were randomly assigned to HSG with oil contrast and 562 to water contrast. The women had spontaneous menstrual cycles, had been attempting pregnancy for at least 1 year, and had indications for HSG.

Exclusion criteria were known endocrine disorders, fewer than 8 menstrual cycles per year, a high risk of tubal disease, iodine allergy, and a total motile sperm count after sperm wash of less than 3 million/mL in the male partner (or a total motile sperm count of less than 1 million/mL when an analysis after sperm wash was not performed).

Just prior to undergoing HSG, the women were randomly assigned to receive either oil contrast or water contrast medium. (The trial was not blinded to participants or caregivers.) HSG was performed according to local protocols using cervical vacuum cup, metal cannula (hysterophore), or balloon catheter and approximately 5 to 10 mL of contrast medium.

After HSG, couples received expectant management when the predicted likelihood of pregnancy within 12 months, based on the prognostic model of Hunault, was 30% or greater.¹⁰ IUI was offered for pregnancy likelihood less than 30%, mild male infertility, or failure after a period of expectant management. IUI with or without mild ovarian stimulation (2-3 follicles) with clomiphene or gonadotropins was initiated after a minimum of 2 months of expectant management after HSG.

The primary outcome measure was ongoing pregnancy, defined as a positive fetal heartbeat on ultrasonographic examination after 12 weeks of gestation, with the first day of the last menstrual cycle for the pregnancy within 6 months after randomization. Secondary outcome measures were clinical pregnancy, live birth, miscarriage, ectopic pregnancy, time to pregnancy, and pain scores after HSG. All data were analyzed according to intention-to-treat.

Pregnancy rates increased with oil-contrast HSG

The baseline characteristics of the 2 groups were similar. HSG showed bilateral tubal patency in 477 of 554 women (86.1%) in the oil contrast group and in 491 of 554 women (88.6%) who received the water contrast (rate ratio, 0.97; 95% confidence interval [CI], 0.93-1.02). Bilateral tubal occlusion occurred in 9 women in the oil group (1.6%) and in 13 in the water group (2.3%) (relative risk, 0.69; 95% CI, 0.30-1.61).

A total of 58.3% of the women assigned to oil contrast and 57.2% of those assigned to water contrast received expectant management. Similar percentages of women in the oil group and in the water group underwent IUI (39.7% and 41.0%, respectively), IVF or intracytoplasmic sperm injection (ICSI) (2.3% and 2.2%), laparoscopy (6.2% in each group), and hysteroscopy (4.4% and 4.2%).

Ongoing pregnancy occurred in 220 of 554 women (39.7%) in the oil contrast group and in 161 of 554 women (29.1%) in the water contrast group (rate ratio, 1.37; 95% CI, 1.16-1.61; P<.001). The median time to the onset of pregnancy in the oil group was 2.7 months (interquartile range, 1.5-4.7) (FIGURE 2), while in the water group it was 3.1 months (interquartile range, 1.6-4.8) (P = .44).

While the proportion of women getting pregnant with or without the different interventions was similar in both groups, the live birth rate was 38.8% in the oil group versus 28.1% in the water group (rate ratio, 1.38; 95% CI, 1.17-1.64; P<.001). Three of 554 women (0.5%) assigned to oil contrast and 4 of  554 women (0.7%) in the water contrast group had an adverse event during the trial period. Three women (1.4%), all in the oil group, delivered a child with a congenital anomaly.

Why this study is important

This is the largest and best methodologic study on this clinical issue. It showed higher pregnancy and live birth rates within 6 months of HSG performed with oil compared with water. Although the study was not blinded, the group similarities and objective outcomes support minimal bias. Importantly, these results can be generalized only to women with similar inclusion characteristics. 

It is unclear why oil HSG might enhance fertility. Suggested mechanisms include flushing of debris and/or mucous plugs or an effect on peritoneal macrophages or endometrial receptivity. Since HSG is minimally invasive and inexpensive, and the 10% increase in pregnancy rates corresponds to an NNT of 10, it is reasonable to consider, although formal cost-effectiveness data are lacking.

Concerns include the rare theoretical risk of intravasation with subsequent allergic  reaction or fat embolism. Three infants in the oil group and none in the water group had congenital anomalies. This is likely due to chance, since this rate is not higher than that in the general population and no other data suggest an increased risk. Comparison of these results with other new techniques, such as sonohysterography (saline infusion sonogram), awaits further studies.

Recommendation

HSG with oil contrast should be considered a potential therapeutic as well as diagnostic intervention in selected patients.

Read about new definitions of infertility terminology you should know.

Infertility glossary is newly updated

Zegers-Hochchild F, Adamson GD, Dyer S, et al. The International Glossary on Infertility and Fertility Care, 2017. Fertil Steril. 2017;108(3):393-406.

Terms and definitions used in infertility and fertility care frequently have had different meanings for different stakeholders, especially on a global basis. This can result in misunderstandings and inappropriate interpretation and comparison of published information and research. To help address these issues, international fertility organizations recently developed an updated glossary on infertilityterminology.

The consensus process for updating the glossary

The International Glossary on Infertility and Fertility Care, 2017, was recently published simultaneously in Fertility and Sterility and Human Reproduction. This is the second revision; the first glossary was published in 2006 and revised in 2009. This revision's 25 lead experts began work in 2014. Their teams of professionals interacted by electronic mail, at international and regional society meetings, and at 2 consultations held in Geneva, Switzerland. This glossary represents consensus agreement reached on 283 evidence-driven terms and definitions.

The work was led by the International Committee for Monitoring Assisted Reproductive Technologies in partnership with the American Society for Reproductive Medicine, European Society of Human Reproduction and Embryology, International Federation of Fertility Societies, March of Dimes, African Fertility Society, Groupe Inter-africain d'Etude de Recherche et d'Application sur la Fertilité, Asian Pacific Initiative on Reproduction, Middle East Fertility Society, Red Latinoamericana de Reproducción Asistida, and the International Federation of Gynecology and Obstetrics.

All together, 108 international professional experts (clinicians, basic scientists, epidemiologists, and social scientists), along with national and regional representatives of infertile persons, participated in the development of this evidence-base driven glossary. As such, these definitions now set the standard for international communication among clinicians, scientists, and policymakers.

Definition of infertility is broadened

The definitions take account of ethics, human rights, cultural sensitivities, ethnic minorities, and gender equality. For example, the first modification included broadening the concept of infertility to be an "impairment of individuals" in their capacity to reproduce, irrespective of whether the individual has a partner. (See “Broadened definition of infertility” below). Reproductive rights are individual human rights and do not depend on a relationship with another individual. The revised definition also reinforces the concept of infertility as a disease that can generate an impairment of function. 

New--and changed--definitions

Certain terms need to be consistent with those used currently internationally, for example, at which gestational age a miscarriage/abortion becomes a stillbirth.

Some terms are confusing, such as subfertility, which does not define a different or less severe fertility status than infertility, does not exist before infertility is diagnosed, and should not be confused with sterility, which is a permanent state of infertility. The term subfertility therefore is redundant and has been removed and replaced by infertility (See “Some terms with an important new definition” below).

In a different context, the term conception, and its derivatives such as conceiving or conceived, was removed because it cannot be described biologically during the process of reproduction. Instead, terms such as fertilization, implantation, pregnancy, and live birth should be used.

Important male terms also changed: oligospermia is a term for low semen volume that is now replaced by hypospermia to avoid confusion with oligozoospermia, which is low concentration of spermatozoa in the ejaculate below the lower reference limit. When reporting results, the reference criteria should be specified.

Lastly, owing to the lack of standardization in determining the burden of infertility, and to better ensure comparability of prevalence data published globally, this glossary includes definitions for terms frequently used in epidemiology and public health. Examples include voluntary and involuntary childlessness, primary and secondary infertility, fertility care, fecundity, and fecundability, among others. 

Getting the word out

The glossary has been approved by all of the participating organizations who are assisting in its distribution. It is being presented at national and international meetings and is used in The FIGO Fertility Toolbox (www.fertilitytool.com). It is hoped that all professionals and other stakeholders will begin to use its terminology globally to provide quality care and ensure consistency in registering specific fertility care interventions and more accurate reporting of their outcomes.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Clinicians always should consider endometriosis in the diagnostic work-up of an infertility patient. But the diagnosis of endometriosis is often difficult, and management is complex. In this Update, we summarize international consensus documents on endometriosis with the aim of enhancing clinicians’ ability to make evidence-based decisions. In addition, we explore the interesting results of a large hysterosalpingography trial in which 2 different contrast mediums were used. Finally, we urge all clinicians to adapt the new standardized lexicon of infertility and fertility care terms that comprise the recently revised international glossary.

Endometriosis and infertility: The knowns and unknowns

Johnson NP, Hummelshoj L, Adamson GD, et al; World Endometriosis Society Sao Paulo Consortium. World Endometriosis Society consensus on the classification of endometriosis. Hum Reprod. 2017;32(2):315-324.

Johnson NP, Hummelshoj L; World Endometriosis Society Montpellier Consortium. Consensus on current management of endometriosis. Hum Reprod. 2013;28(6):1552-1568.

Rogers PA, Adamson GD, Al-Jefout M, et al; WES/WERF Consortium for Research Priorities in Endometriosis. Research priorities for endometriosis. Reprod Sci. 2017;24(2):202-226.

Endometriosis is defined as "a disease characterized by the presence of endometrium-like epithelium and stroma outside the endometrium and myometrium. Intrapelvic endometriosis can be located superficially on the peritoneum (peritoneal endometriosis), can extend 5 mm or more beneath the peritoneum (deep endometriosis) or can be present as an ovarian endometriotic cyst (endometrioma)."¹ Always consider endometriosis in the infertile patient.

Although many professional societies and numerous Cochrane Database Systematic Reviews have provided guidelines on endometriosis, controversy and uncertainty remain. The World Endometriosis Society (WES) and the World Endometriosis Research Foundation (WERF), however, have now published several consensus documents that assess the global literature and professional organization guidelines in a structured, consensus-driven process.^2-4 These WES and WERF documents consolidate known information and can be used to inform the clinician in making evidence-linked diagnostic and treatment decisions. Recommendations offered in this discussion are based on those documents.

Establishing the diagnosis can be difficult

Diagnosis of endometriosis is often difficult and is delayed an average of 7 years from onset of symptoms. These include severe dysmenorrhea, deep dyspareunia, chronic pelvic pain, ovulation pain, cyclical or perimenstrual symptoms (bowel or bladder associated) with or without abnormal bleeding, chronic fatigue, and infertility. A major difficulty is that the predictive value of any one symptom or set of symptoms remains uncertain, as each of these symptoms can have other causes, and a significant proportion of affected women are asymptomatic.

For a definitive diagnosis of endometriosis, visual inspection of the pelvis at laparoscopy is the gold standard investigation, unless disease is visible in the vagina or elsewhere. Positive histology confirms the diagnosis of endometriosis; negative histology does not exclude it. Whether histology should be obtained if peritoneal disease alone is present is controversial: visual inspection usually is adequate, but histologic confirmation of at least one lesion is ideal. In cases of ovarian endometrioma (>4 cm in diameter) and in deeply infiltrating disease, histology should be obtained to identify endometriosis and to exclude rare instances of malignancy.

Compared with laparoscopy, transvaginal ultrasonography (TVUS) has no value in diagnosing peritoneal endometriosis, but it is a useful tool for both making and excluding the diagnosis of an ovarian endometrioma. TVUS may have a role in the diagnosis of disease involving the bladder or rectum.

At present, evidence is insufficient to indicate that magnetic resonance imaging (MRI) is useful for diagnosing or excluding endometriosis compared with laparoscopy. MRI should be reserved for when ultrasound results are equivocal in cases of rectovaginal or bladder endometriosis.

Serum cancer antigen 125 (CA 125) levels may be elevated in endometriosis. However, measuring serum CA 125 levels has no value as a diagnostic tool.

No fertility benefit with ovarian suppression

More than 2 dozen randomized controlled trials (RCTs) provide strong evidence that there is no fertility benefit from ovarian suppression. The drug costs and delayed time to pregnancy mean that ovarian suppression with oral contraceptives, other progestational agents, or gonadotropin-releasing hormone (GnRH) agonists before fertility treatment is not indicated, with the possible exception of using it prior to in vitro fertilization (IVF).

Ovarian suppression also has been suggested as beneficial in conjunction with surgery. However, at least 16 RCTs have failed to show fertility improvement when ovarian suppression is given either preoperatively or postoperatively. Again, the delay in attempting pregnancy, drug costs, and adverse effects render ovarian suppression not appropriate.

While ovarian suppression has not been shown to increase pregnancy rates, ovarian stimulation (OS) likely does, especially when combined with intrauterine insemination (IUI).⁵

Laparoscopy: Appropriate for selected patients

A major decision for clinicians and patients dealing with infertility is whether to perform a laparoscopy, both for diagnostic and for treatment reasons. Currently, data are insufficient to recommend laparoscopic surgery prior to OS/IUI unless there is a history of evidence of anatomic disease and/or the patient has sufficient pain to justify the physical, emotional, financial, and time costs of laparoscopy. Laparoscopy therefore can be considered as possibly appropriate in younger women (<37 years of age) with short duration of infertility (<4 years), normal male factor, normal or treatable uterus, normal or treatable ovulation disorder, and limited prior treatment.

It is important to consider what disease might be found and how much of an increase in fertility can be obtained by treatment, so that the number needed to treat (NNT) can be used as an estimate of the potential value of laparoscopy in a given patient. A patient also should have no contraindications to laparoscopy and accept 9 to 15 months of attempting pregnancy before undergoing IVF treatment.

When laparoscopy is performed for minimal to mild disease, the odds ratio for pregnancy is 1.66 with treatment. It is important to remove all visible disease without injuring healthy tissue. When disease is moderate to severe, there is often severe anatomic distortion and a very low background pregnancy rate. Numerous uncontrolled trials show benefit of operative laparoscopy, especially for invasive, adhesive, and cystic endometriosis. However, repeat surgery is rarely indicated. After surgery, the Endometriosis Fertility Index (EFI) can be used to determine prognosis and plan management (FIGURE  1).⁶ An easy-to-use electronic EFI calculator is available online at www.endometriosisefi.com.

Management of endometriomas

Endometriomas are often operated on because of pain. Initial pain relief occurs in 60% to 100% of patients, but cysts recur following stripping about 10% of the time, and drainage without stripping, about 20%. With recurrence, pain is present about 75% of the time.

Pregnancy rates following endometrioma treatment depend on patient age and the status of the pelvis following operative intervention. This can be determined from the EFI. Often, the dilemma with endometriomas is how aggressive to be in removing them. The principles involved are to remove all the cyst wall if possible, but absolutely to minimize ovarian tissue damage, because reduced ovarian reserve is a possible major negative consequence of ovarian surgery. 

Recommendations

While endometriosis is often a cause of infertility, often infertile patients do not have endometriosis. A careful history, physical examination, and ultrasonography, and possibly other imaging studies, are prerequisites to careful clinical judgment in diagnosing and treating infertile patients who might or do have endometriosis.

When pelvic pain is present, initially nonsteroidal anti-inflammatory drugs (NSAIDs), oral contraceptives (OCs), progestational agents, or an intrauterine device can be helpful. These ovarian suppression medications do not increase fertility, however, and should be stopped in any patient who desires to get pregnant.

When pelvic and male fertility factors appear reasonably normal (even if minimal or mild endometriosis is suspected), treatment with clomiphene 100 mg on cycle days 3 through 7 and IUI for 3 to 6 cycles is an effective first step. However, if the patient has persistent pain and/or infertility without other significant infertility factors, then diagnostic laparoscopy with intraoperative treatment of disease is indicated.

Surgery well performed is effective treatment for all stages of endometriosis and endometriomas, both for infertility and for pain. Repeat surgery, however, is rarely indicated because of limited results, so it is important to obtain the best possible result on the first surgery. Surgery is indicated for large endometriomas (>4 cm). Endometriosis has almost no effect on the IVF live birth rate unless ovarian reserve has been reduced by endometriomas or surgery, so endometriosis surgery should be performed by skilled and experienced surgeons.

Read about why oil-based contrast may be better than water-based contrast with HSG.

Oil-based contrast medium use in hysterosalpingography is associated with higher pregnancy rates compared with water-based contrast

Dreyer K, van Rijswijk J, Mijatovic V, et al. Oil-based or water-based contrast for hysterosalpingography in infertile women. N Engl J Med. 2017;376(21):2043-2052.

Hysterosalpingography (HSG) to assess tubal patency has been a mainstay of infertility diagnosis for decades. Some, but not all, studies also have suggested that pregnancy rates are higher after this tubal flushing procedure, especially if performed with oil contrast.^7,8 A recent multicenter, randomized, controlled trial by Dreyer and colleagues that compared ongoing pregnancy rates and other outcomes among women who had HSG with oil contrast versus with water contrast provides additional valuable information.⁹

Trial details

In this study, 1,294 infertile women in 27 academic, teaching and nonteaching hospitals were screened for trial eligibility; 1,119 women provided written informed consent. Of these, 557 women were randomly assigned to HSG with oil contrast and 562 to water contrast. The women had spontaneous menstrual cycles, had been attempting pregnancy for at least 1 year, and had indications for HSG.

Exclusion criteria were known endocrine disorders, fewer than 8 menstrual cycles per year, a high risk of tubal disease, iodine allergy, and a total motile sperm count after sperm wash of less than 3 million/mL in the male partner (or a total motile sperm count of less than 1 million/mL when an analysis after sperm wash was not performed).

Just prior to undergoing HSG, the women were randomly assigned to receive either oil contrast or water contrast medium. (The trial was not blinded to participants or caregivers.) HSG was performed according to local protocols using cervical vacuum cup, metal cannula (hysterophore), or balloon catheter and approximately 5 to 10 mL of contrast medium.

After HSG, couples received expectant management when the predicted likelihood of pregnancy within 12 months, based on the prognostic model of Hunault, was 30% or greater.¹⁰ IUI was offered for pregnancy likelihood less than 30%, mild male infertility, or failure after a period of expectant management. IUI with or without mild ovarian stimulation (2-3 follicles) with clomiphene or gonadotropins was initiated after a minimum of 2 months of expectant management after HSG.

The primary outcome measure was ongoing pregnancy, defined as a positive fetal heartbeat on ultrasonographic examination after 12 weeks of gestation, with the first day of the last menstrual cycle for the pregnancy within 6 months after randomization. Secondary outcome measures were clinical pregnancy, live birth, miscarriage, ectopic pregnancy, time to pregnancy, and pain scores after HSG. All data were analyzed according to intention-to-treat.

Pregnancy rates increased with oil-contrast HSG

The baseline characteristics of the 2 groups were similar. HSG showed bilateral tubal patency in 477 of 554 women (86.1%) in the oil contrast group and in 491 of 554 women (88.6%) who received the water contrast (rate ratio, 0.97; 95% confidence interval [CI], 0.93-1.02). Bilateral tubal occlusion occurred in 9 women in the oil group (1.6%) and in 13 in the water group (2.3%) (relative risk, 0.69; 95% CI, 0.30-1.61).

A total of 58.3% of the women assigned to oil contrast and 57.2% of those assigned to water contrast received expectant management. Similar percentages of women in the oil group and in the water group underwent IUI (39.7% and 41.0%, respectively), IVF or intracytoplasmic sperm injection (ICSI) (2.3% and 2.2%), laparoscopy (6.2% in each group), and hysteroscopy (4.4% and 4.2%).

Ongoing pregnancy occurred in 220 of 554 women (39.7%) in the oil contrast group and in 161 of 554 women (29.1%) in the water contrast group (rate ratio, 1.37; 95% CI, 1.16-1.61; P<.001). The median time to the onset of pregnancy in the oil group was 2.7 months (interquartile range, 1.5-4.7) (FIGURE 2), while in the water group it was 3.1 months (interquartile range, 1.6-4.8) (P = .44).

While the proportion of women getting pregnant with or without the different interventions was similar in both groups, the live birth rate was 38.8% in the oil group versus 28.1% in the water group (rate ratio, 1.38; 95% CI, 1.17-1.64; P<.001). Three of 554 women (0.5%) assigned to oil contrast and 4 of  554 women (0.7%) in the water contrast group had an adverse event during the trial period. Three women (1.4%), all in the oil group, delivered a child with a congenital anomaly.

Why this study is important

This is the largest and best methodologic study on this clinical issue. It showed higher pregnancy and live birth rates within 6 months of HSG performed with oil compared with water. Although the study was not blinded, the group similarities and objective outcomes support minimal bias. Importantly, these results can be generalized only to women with similar inclusion characteristics. 

It is unclear why oil HSG might enhance fertility. Suggested mechanisms include flushing of debris and/or mucous plugs or an effect on peritoneal macrophages or endometrial receptivity. Since HSG is minimally invasive and inexpensive, and the 10% increase in pregnancy rates corresponds to an NNT of 10, it is reasonable to consider, although formal cost-effectiveness data are lacking.

Concerns include the rare theoretical risk of intravasation with subsequent allergic  reaction or fat embolism. Three infants in the oil group and none in the water group had congenital anomalies. This is likely due to chance, since this rate is not higher than that in the general population and no other data suggest an increased risk. Comparison of these results with other new techniques, such as sonohysterography (saline infusion sonogram), awaits further studies.

Recommendation

HSG with oil contrast should be considered a potential therapeutic as well as diagnostic intervention in selected patients.

Read about new definitions of infertility terminology you should know.

Infertility glossary is newly updated

Zegers-Hochchild F, Adamson GD, Dyer S, et al. The International Glossary on Infertility and Fertility Care, 2017. Fertil Steril. 2017;108(3):393-406.

Terms and definitions used in infertility and fertility care frequently have had different meanings for different stakeholders, especially on a global basis. This can result in misunderstandings and inappropriate interpretation and comparison of published information and research. To help address these issues, international fertility organizations recently developed an updated glossary on infertilityterminology.

The consensus process for updating the glossary

The International Glossary on Infertility and Fertility Care, 2017, was recently published simultaneously in Fertility and Sterility and Human Reproduction. This is the second revision; the first glossary was published in 2006 and revised in 2009. This revision's 25 lead experts began work in 2014. Their teams of professionals interacted by electronic mail, at international and regional society meetings, and at 2 consultations held in Geneva, Switzerland. This glossary represents consensus agreement reached on 283 evidence-driven terms and definitions.

The work was led by the International Committee for Monitoring Assisted Reproductive Technologies in partnership with the American Society for Reproductive Medicine, European Society of Human Reproduction and Embryology, International Federation of Fertility Societies, March of Dimes, African Fertility Society, Groupe Inter-africain d'Etude de Recherche et d'Application sur la Fertilité, Asian Pacific Initiative on Reproduction, Middle East Fertility Society, Red Latinoamericana de Reproducción Asistida, and the International Federation of Gynecology and Obstetrics.

All together, 108 international professional experts (clinicians, basic scientists, epidemiologists, and social scientists), along with national and regional representatives of infertile persons, participated in the development of this evidence-base driven glossary. As such, these definitions now set the standard for international communication among clinicians, scientists, and policymakers.

Definition of infertility is broadened

The definitions take account of ethics, human rights, cultural sensitivities, ethnic minorities, and gender equality. For example, the first modification included broadening the concept of infertility to be an "impairment of individuals" in their capacity to reproduce, irrespective of whether the individual has a partner. (See “Broadened definition of infertility” below). Reproductive rights are individual human rights and do not depend on a relationship with another individual. The revised definition also reinforces the concept of infertility as a disease that can generate an impairment of function. 

New--and changed--definitions

Certain terms need to be consistent with those used currently internationally, for example, at which gestational age a miscarriage/abortion becomes a stillbirth.

Some terms are confusing, such as subfertility, which does not define a different or less severe fertility status than infertility, does not exist before infertility is diagnosed, and should not be confused with sterility, which is a permanent state of infertility. The term subfertility therefore is redundant and has been removed and replaced by infertility (See “Some terms with an important new definition” below).

In a different context, the term conception, and its derivatives such as conceiving or conceived, was removed because it cannot be described biologically during the process of reproduction. Instead, terms such as fertilization, implantation, pregnancy, and live birth should be used.

Important male terms also changed: oligospermia is a term for low semen volume that is now replaced by hypospermia to avoid confusion with oligozoospermia, which is low concentration of spermatozoa in the ejaculate below the lower reference limit. When reporting results, the reference criteria should be specified.

Lastly, owing to the lack of standardization in determining the burden of infertility, and to better ensure comparability of prevalence data published globally, this glossary includes definitions for terms frequently used in epidemiology and public health. Examples include voluntary and involuntary childlessness, primary and secondary infertility, fertility care, fecundity, and fecundability, among others. 

Getting the word out

The glossary has been approved by all of the participating organizations who are assisting in its distribution. It is being presented at national and international meetings and is used in The FIGO Fertility Toolbox (www.fertilitytool.com). It is hoped that all professionals and other stakeholders will begin to use its terminology globally to provide quality care and ensure consistency in registering specific fertility care interventions and more accurate reporting of their outcomes.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Clinicians always should consider endometriosis in the diagnostic work-up of an infertility patient. But the diagnosis of endometriosis is often difficult, and management is complex. In this Update, we summarize international consensus documents on endometriosis with the aim of enhancing clinicians’ ability to make evidence-based decisions. In addition, we explore the interesting results of a large hysterosalpingography trial in which 2 different contrast mediums were used. Finally, we urge all clinicians to adapt the new standardized lexicon of infertility and fertility care terms that comprise the recently revised international glossary.

Endometriosis and infertility: The knowns and unknowns

Johnson NP, Hummelshoj L, Adamson GD, et al; World Endometriosis Society Sao Paulo Consortium. World Endometriosis Society consensus on the classification of endometriosis. Hum Reprod. 2017;32(2):315-324.

Johnson NP, Hummelshoj L; World Endometriosis Society Montpellier Consortium. Consensus on current management of endometriosis. Hum Reprod. 2013;28(6):1552-1568.

Rogers PA, Adamson GD, Al-Jefout M, et al; WES/WERF Consortium for Research Priorities in Endometriosis. Research priorities for endometriosis. Reprod Sci. 2017;24(2):202-226.

Endometriosis is defined as "a disease characterized by the presence of endometrium-like epithelium and stroma outside the endometrium and myometrium. Intrapelvic endometriosis can be located superficially on the peritoneum (peritoneal endometriosis), can extend 5 mm or more beneath the peritoneum (deep endometriosis) or can be present as an ovarian endometriotic cyst (endometrioma)."¹ Always consider endometriosis in the infertile patient.

Although many professional societies and numerous Cochrane Database Systematic Reviews have provided guidelines on endometriosis, controversy and uncertainty remain. The World Endometriosis Society (WES) and the World Endometriosis Research Foundation (WERF), however, have now published several consensus documents that assess the global literature and professional organization guidelines in a structured, consensus-driven process.^2-4 These WES and WERF documents consolidate known information and can be used to inform the clinician in making evidence-linked diagnostic and treatment decisions. Recommendations offered in this discussion are based on those documents.

Establishing the diagnosis can be difficult

Diagnosis of endometriosis is often difficult and is delayed an average of 7 years from onset of symptoms. These include severe dysmenorrhea, deep dyspareunia, chronic pelvic pain, ovulation pain, cyclical or perimenstrual symptoms (bowel or bladder associated) with or without abnormal bleeding, chronic fatigue, and infertility. A major difficulty is that the predictive value of any one symptom or set of symptoms remains uncertain, as each of these symptoms can have other causes, and a significant proportion of affected women are asymptomatic.

For a definitive diagnosis of endometriosis, visual inspection of the pelvis at laparoscopy is the gold standard investigation, unless disease is visible in the vagina or elsewhere. Positive histology confirms the diagnosis of endometriosis; negative histology does not exclude it. Whether histology should be obtained if peritoneal disease alone is present is controversial: visual inspection usually is adequate, but histologic confirmation of at least one lesion is ideal. In cases of ovarian endometrioma (>4 cm in diameter) and in deeply infiltrating disease, histology should be obtained to identify endometriosis and to exclude rare instances of malignancy.

Compared with laparoscopy, transvaginal ultrasonography (TVUS) has no value in diagnosing peritoneal endometriosis, but it is a useful tool for both making and excluding the diagnosis of an ovarian endometrioma. TVUS may have a role in the diagnosis of disease involving the bladder or rectum.

At present, evidence is insufficient to indicate that magnetic resonance imaging (MRI) is useful for diagnosing or excluding endometriosis compared with laparoscopy. MRI should be reserved for when ultrasound results are equivocal in cases of rectovaginal or bladder endometriosis.

Serum cancer antigen 125 (CA 125) levels may be elevated in endometriosis. However, measuring serum CA 125 levels has no value as a diagnostic tool.

No fertility benefit with ovarian suppression

More than 2 dozen randomized controlled trials (RCTs) provide strong evidence that there is no fertility benefit from ovarian suppression. The drug costs and delayed time to pregnancy mean that ovarian suppression with oral contraceptives, other progestational agents, or gonadotropin-releasing hormone (GnRH) agonists before fertility treatment is not indicated, with the possible exception of using it prior to in vitro fertilization (IVF).

Ovarian suppression also has been suggested as beneficial in conjunction with surgery. However, at least 16 RCTs have failed to show fertility improvement when ovarian suppression is given either preoperatively or postoperatively. Again, the delay in attempting pregnancy, drug costs, and adverse effects render ovarian suppression not appropriate.

While ovarian suppression has not been shown to increase pregnancy rates, ovarian stimulation (OS) likely does, especially when combined with intrauterine insemination (IUI).⁵

Laparoscopy: Appropriate for selected patients

A major decision for clinicians and patients dealing with infertility is whether to perform a laparoscopy, both for diagnostic and for treatment reasons. Currently, data are insufficient to recommend laparoscopic surgery prior to OS/IUI unless there is a history of evidence of anatomic disease and/or the patient has sufficient pain to justify the physical, emotional, financial, and time costs of laparoscopy. Laparoscopy therefore can be considered as possibly appropriate in younger women (<37 years of age) with short duration of infertility (<4 years), normal male factor, normal or treatable uterus, normal or treatable ovulation disorder, and limited prior treatment.

It is important to consider what disease might be found and how much of an increase in fertility can be obtained by treatment, so that the number needed to treat (NNT) can be used as an estimate of the potential value of laparoscopy in a given patient. A patient also should have no contraindications to laparoscopy and accept 9 to 15 months of attempting pregnancy before undergoing IVF treatment.

When laparoscopy is performed for minimal to mild disease, the odds ratio for pregnancy is 1.66 with treatment. It is important to remove all visible disease without injuring healthy tissue. When disease is moderate to severe, there is often severe anatomic distortion and a very low background pregnancy rate. Numerous uncontrolled trials show benefit of operative laparoscopy, especially for invasive, adhesive, and cystic endometriosis. However, repeat surgery is rarely indicated. After surgery, the Endometriosis Fertility Index (EFI) can be used to determine prognosis and plan management (FIGURE  1).⁶ An easy-to-use electronic EFI calculator is available online at www.endometriosisefi.com.

Management of endometriomas

Endometriomas are often operated on because of pain. Initial pain relief occurs in 60% to 100% of patients, but cysts recur following stripping about 10% of the time, and drainage without stripping, about 20%. With recurrence, pain is present about 75% of the time.

Pregnancy rates following endometrioma treatment depend on patient age and the status of the pelvis following operative intervention. This can be determined from the EFI. Often, the dilemma with endometriomas is how aggressive to be in removing them. The principles involved are to remove all the cyst wall if possible, but absolutely to minimize ovarian tissue damage, because reduced ovarian reserve is a possible major negative consequence of ovarian surgery. 

Recommendations

While endometriosis is often a cause of infertility, often infertile patients do not have endometriosis. A careful history, physical examination, and ultrasonography, and possibly other imaging studies, are prerequisites to careful clinical judgment in diagnosing and treating infertile patients who might or do have endometriosis.

When pelvic pain is present, initially nonsteroidal anti-inflammatory drugs (NSAIDs), oral contraceptives (OCs), progestational agents, or an intrauterine device can be helpful. These ovarian suppression medications do not increase fertility, however, and should be stopped in any patient who desires to get pregnant.

When pelvic and male fertility factors appear reasonably normal (even if minimal or mild endometriosis is suspected), treatment with clomiphene 100 mg on cycle days 3 through 7 and IUI for 3 to 6 cycles is an effective first step. However, if the patient has persistent pain and/or infertility without other significant infertility factors, then diagnostic laparoscopy with intraoperative treatment of disease is indicated.

Surgery well performed is effective treatment for all stages of endometriosis and endometriomas, both for infertility and for pain. Repeat surgery, however, is rarely indicated because of limited results, so it is important to obtain the best possible result on the first surgery. Surgery is indicated for large endometriomas (>4 cm). Endometriosis has almost no effect on the IVF live birth rate unless ovarian reserve has been reduced by endometriomas or surgery, so endometriosis surgery should be performed by skilled and experienced surgeons.

Read about why oil-based contrast may be better than water-based contrast with HSG.

Oil-based contrast medium use in hysterosalpingography is associated with higher pregnancy rates compared with water-based contrast

Dreyer K, van Rijswijk J, Mijatovic V, et al. Oil-based or water-based contrast for hysterosalpingography in infertile women. N Engl J Med. 2017;376(21):2043-2052.

Hysterosalpingography (HSG) to assess tubal patency has been a mainstay of infertility diagnosis for decades. Some, but not all, studies also have suggested that pregnancy rates are higher after this tubal flushing procedure, especially if performed with oil contrast.^7,8 A recent multicenter, randomized, controlled trial by Dreyer and colleagues that compared ongoing pregnancy rates and other outcomes among women who had HSG with oil contrast versus with water contrast provides additional valuable information.⁹

Trial details

In this study, 1,294 infertile women in 27 academic, teaching and nonteaching hospitals were screened for trial eligibility; 1,119 women provided written informed consent. Of these, 557 women were randomly assigned to HSG with oil contrast and 562 to water contrast. The women had spontaneous menstrual cycles, had been attempting pregnancy for at least 1 year, and had indications for HSG.

Exclusion criteria were known endocrine disorders, fewer than 8 menstrual cycles per year, a high risk of tubal disease, iodine allergy, and a total motile sperm count after sperm wash of less than 3 million/mL in the male partner (or a total motile sperm count of less than 1 million/mL when an analysis after sperm wash was not performed).

Just prior to undergoing HSG, the women were randomly assigned to receive either oil contrast or water contrast medium. (The trial was not blinded to participants or caregivers.) HSG was performed according to local protocols using cervical vacuum cup, metal cannula (hysterophore), or balloon catheter and approximately 5 to 10 mL of contrast medium.

After HSG, couples received expectant management when the predicted likelihood of pregnancy within 12 months, based on the prognostic model of Hunault, was 30% or greater.¹⁰ IUI was offered for pregnancy likelihood less than 30%, mild male infertility, or failure after a period of expectant management. IUI with or without mild ovarian stimulation (2-3 follicles) with clomiphene or gonadotropins was initiated after a minimum of 2 months of expectant management after HSG.

The primary outcome measure was ongoing pregnancy, defined as a positive fetal heartbeat on ultrasonographic examination after 12 weeks of gestation, with the first day of the last menstrual cycle for the pregnancy within 6 months after randomization. Secondary outcome measures were clinical pregnancy, live birth, miscarriage, ectopic pregnancy, time to pregnancy, and pain scores after HSG. All data were analyzed according to intention-to-treat.

Pregnancy rates increased with oil-contrast HSG

The baseline characteristics of the 2 groups were similar. HSG showed bilateral tubal patency in 477 of 554 women (86.1%) in the oil contrast group and in 491 of 554 women (88.6%) who received the water contrast (rate ratio, 0.97; 95% confidence interval [CI], 0.93-1.02). Bilateral tubal occlusion occurred in 9 women in the oil group (1.6%) and in 13 in the water group (2.3%) (relative risk, 0.69; 95% CI, 0.30-1.61).

A total of 58.3% of the women assigned to oil contrast and 57.2% of those assigned to water contrast received expectant management. Similar percentages of women in the oil group and in the water group underwent IUI (39.7% and 41.0%, respectively), IVF or intracytoplasmic sperm injection (ICSI) (2.3% and 2.2%), laparoscopy (6.2% in each group), and hysteroscopy (4.4% and 4.2%).

Ongoing pregnancy occurred in 220 of 554 women (39.7%) in the oil contrast group and in 161 of 554 women (29.1%) in the water contrast group (rate ratio, 1.37; 95% CI, 1.16-1.61; P<.001). The median time to the onset of pregnancy in the oil group was 2.7 months (interquartile range, 1.5-4.7) (FIGURE 2), while in the water group it was 3.1 months (interquartile range, 1.6-4.8) (P = .44).

While the proportion of women getting pregnant with or without the different interventions was similar in both groups, the live birth rate was 38.8% in the oil group versus 28.1% in the water group (rate ratio, 1.38; 95% CI, 1.17-1.64; P<.001). Three of 554 women (0.5%) assigned to oil contrast and 4 of  554 women (0.7%) in the water contrast group had an adverse event during the trial period. Three women (1.4%), all in the oil group, delivered a child with a congenital anomaly.

Why this study is important

This is the largest and best methodologic study on this clinical issue. It showed higher pregnancy and live birth rates within 6 months of HSG performed with oil compared with water. Although the study was not blinded, the group similarities and objective outcomes support minimal bias. Importantly, these results can be generalized only to women with similar inclusion characteristics. 

It is unclear why oil HSG might enhance fertility. Suggested mechanisms include flushing of debris and/or mucous plugs or an effect on peritoneal macrophages or endometrial receptivity. Since HSG is minimally invasive and inexpensive, and the 10% increase in pregnancy rates corresponds to an NNT of 10, it is reasonable to consider, although formal cost-effectiveness data are lacking.

Concerns include the rare theoretical risk of intravasation with subsequent allergic  reaction or fat embolism. Three infants in the oil group and none in the water group had congenital anomalies. This is likely due to chance, since this rate is not higher than that in the general population and no other data suggest an increased risk. Comparison of these results with other new techniques, such as sonohysterography (saline infusion sonogram), awaits further studies.

Recommendation

HSG with oil contrast should be considered a potential therapeutic as well as diagnostic intervention in selected patients.

Read about new definitions of infertility terminology you should know.

Infertility glossary is newly updated

Zegers-Hochchild F, Adamson GD, Dyer S, et al. The International Glossary on Infertility and Fertility Care, 2017. Fertil Steril. 2017;108(3):393-406.

Terms and definitions used in infertility and fertility care frequently have had different meanings for different stakeholders, especially on a global basis. This can result in misunderstandings and inappropriate interpretation and comparison of published information and research. To help address these issues, international fertility organizations recently developed an updated glossary on infertilityterminology.

The consensus process for updating the glossary

The International Glossary on Infertility and Fertility Care, 2017, was recently published simultaneously in Fertility and Sterility and Human Reproduction. This is the second revision; the first glossary was published in 2006 and revised in 2009. This revision's 25 lead experts began work in 2014. Their teams of professionals interacted by electronic mail, at international and regional society meetings, and at 2 consultations held in Geneva, Switzerland. This glossary represents consensus agreement reached on 283 evidence-driven terms and definitions.

The work was led by the International Committee for Monitoring Assisted Reproductive Technologies in partnership with the American Society for Reproductive Medicine, European Society of Human Reproduction and Embryology, International Federation of Fertility Societies, March of Dimes, African Fertility Society, Groupe Inter-africain d'Etude de Recherche et d'Application sur la Fertilité, Asian Pacific Initiative on Reproduction, Middle East Fertility Society, Red Latinoamericana de Reproducción Asistida, and the International Federation of Gynecology and Obstetrics.

All together, 108 international professional experts (clinicians, basic scientists, epidemiologists, and social scientists), along with national and regional representatives of infertile persons, participated in the development of this evidence-base driven glossary. As such, these definitions now set the standard for international communication among clinicians, scientists, and policymakers.

Definition of infertility is broadened

The definitions take account of ethics, human rights, cultural sensitivities, ethnic minorities, and gender equality. For example, the first modification included broadening the concept of infertility to be an "impairment of individuals" in their capacity to reproduce, irrespective of whether the individual has a partner. (See “Broadened definition of infertility” below). Reproductive rights are individual human rights and do not depend on a relationship with another individual. The revised definition also reinforces the concept of infertility as a disease that can generate an impairment of function. 

New--and changed--definitions

Certain terms need to be consistent with those used currently internationally, for example, at which gestational age a miscarriage/abortion becomes a stillbirth.

Some terms are confusing, such as subfertility, which does not define a different or less severe fertility status than infertility, does not exist before infertility is diagnosed, and should not be confused with sterility, which is a permanent state of infertility. The term subfertility therefore is redundant and has been removed and replaced by infertility (See “Some terms with an important new definition” below).

In a different context, the term conception, and its derivatives such as conceiving or conceived, was removed because it cannot be described biologically during the process of reproduction. Instead, terms such as fertilization, implantation, pregnancy, and live birth should be used.

Important male terms also changed: oligospermia is a term for low semen volume that is now replaced by hypospermia to avoid confusion with oligozoospermia, which is low concentration of spermatozoa in the ejaculate below the lower reference limit. When reporting results, the reference criteria should be specified.

Lastly, owing to the lack of standardization in determining the burden of infertility, and to better ensure comparability of prevalence data published globally, this glossary includes definitions for terms frequently used in epidemiology and public health. Examples include voluntary and involuntary childlessness, primary and secondary infertility, fertility care, fecundity, and fecundability, among others. 

Getting the word out

The glossary has been approved by all of the participating organizations who are assisting in its distribution. It is being presented at national and international meetings and is used in The FIGO Fertility Toolbox (www.fertilitytool.com). It is hoped that all professionals and other stakeholders will begin to use its terminology globally to provide quality care and ensure consistency in registering specific fertility care interventions and more accurate reporting of their outcomes.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Chronic pelvic pain (CPP) is defined as noncyclic pain in the pelvis, anterior abdominal wall, back, or buttocks that has been present for at least 6 months and is severe enough to cause functional disability or require medical care.¹ CPP is very common, with an estimated prevalence of 15% to 20%. It accounts for 20% of gynecology visits and 15% of hysterectomies in the United States, and it is believed to account for $2.8 billion in direct health care spending annually.^2–5

Caring for patients with CPP can be very challenging. They often arrive at your office frustrated, having seen multiple providers or having undergone multiple surgeries. They may come to you whether you are a general ObGyn or subspecialize in maternal-fetal medicine, oncology, reproductive endocrinology, urogynecology, or adolescent gynecology. From interactions with other providers or their own family members, these patients may have received the message—either subtly or overtly—that their pain is “all in their head.” As such, some patients may resist any implication that their pain does not have an anatomic source. It is therefore critical to have appropriate tools for evaluating and managing the complex problem of CPP.

Perform a thorough and thoughtful assessment

Chronic pelvic pain often presents as a constellation of symptoms with contributions from multiple sources, as opposed to a single disease entity. Occasionally there is a single cause of pain, such as a large endometrioma or degenerating fibroid, where surgery can be curative. But more commonly the pain arises from multiple organ systems. In such cases, surgery may be unnecessary and, often, can worsen pain.

Thoughtful evaluation is critical in the CPP population. Take a thorough patient history to determine the characteristics of pain (cyclic or constant, widespread or localized), exacerbating factors, sleep disturbances, fatigue, and current coping strategies. Focus a comprehensive physical examination on identifying the maneuvers that reproduce the patient’s pain, and include an examination of the pelvic floor muscles.⁶ In most cases, pelvic ultrasonography provides adequate evaluation for anatomic sources of pain.

Chronic pain does not behave like acute injury or postsurgical pain. Continuous peripheral pain signals for a prolonged period can lead to changes in how the brain processes pain; specifically, the brain can begin to amplify pain signals. This “central pain amplification” is characterized clinically by widespread pain, fatigue, sleep disturbances, memory difficulties, and somatic symptoms. Central pain amplification occurs in many chronic pain conditions, including fibromyalgia, interstitial cystitis, irritable bowel syndrome, low back pain, chronic headaches, and temporomandibular joint disorder.^7,8 Recent clinical and functional magnetic resonance imaging (MRI) studies demonstrate central pain amplification in many patients with CPP.^9–12 Notably, these findings are independent of the presence or severity of endometriosis.

In this article we discuss many therapies that have not been specifically studied in patients with CPP, and treatment efficacy is extrapolated from other conditions with chronic pain amplification, such as fibromyalgia or interstitial cystitis. Additionally, many treatments for conditions associated with central pain amplification are used off-label, that is, the US Food and Drug Administration (FDA) has not approved the medication for treatment of these specific conditions. This should be disclosed to patients during counseling.

Discuss treatment expectations with patients

Educating patients regarding the pathophysiology of chronic pain and setting reasonable expectations is the cornerstone of providing patient-centered care for this complex condition. We start most of our discussions about treatment options by telling patients that while we may not cure their pain, we will provide them with medical, surgical, and behavioral strategies that will reduce their pain, improve their function, and enhance their quality of life.

Surprisingly, most patients say that a cure is not their goal. They just want to feel better so they can return to work or activities, fully participate in family life, or not feel exhausted all the time. As such, a multimodal treatment plan is generally the best strategy for achieving a satisfactory improvement in symptoms.

Read about treating a case of continued pain after endometriosis treatment.

CASE 1 Patient’s pain continues after endometriosis excision

A 32-year-old woman (G1P1) reports having CPP for 8 years. She underwent excision of stage 1 endometriosis last year, which resulted in a modest improvement in pain for 6 months. Her pain is worse during menses, at the end of the day, and with vaginal intercourse (both during and lasting for 1 to 2 days after). On examination, you find diffuse pelvic floor tenderness but no adnexal masses or rectovaginal nodularity on palpation.

What treatment options would you consider for this patient?

Multimodal treatment often needed to manage CPP symptoms

The patient described in Case 1 may benefit from a combination of therapies that include analgesics, hormone suppression agents, and physical therapy (PT) (TABLE).

Analgesics

Nonsteroidal anti-inflammatory drugs (NSAIDs), including ibuprofen and naproxen, work by inhibiting cyclooxygenase enzyme, which decreases assembly of peripheral prostaglandins and thromboxane. In a large Cochrane review, NSAIDs were associated with moderate or excellent pain relief for approximately 50% of patients with dysmenorrhea, and they have been shown to reduce menstrual flow due to decreased production of uterine prostaglandins.¹³ There is little evidence for use of NSAIDs in chronic pain conditions.

Acetaminophen’s mechanism of action is unclear, but the drug likely inhibits central prostaglandin synthesis, and it works synergistically with other analgesics.

Opioids act on μ and δ opioid receptors in the central and peripheral nervous systems as well as in the gastrointestinal system. No evidence supports opioid use in CPP or other chronic pain conditions. Long-term opioid use is associated with a multitude of adverse effects, risk for dependence, and the induction of opioid-induced hyperalgesia (in which patients develop greater sensitivity to pain stimuli).

Analgesics, specifically NSAIDs, can be considered for use in patients with dysmenorrhea, cyclic pain exacerbation, or a suspected inflammatory component of pain. Best practices include scheduling NSAID use before the onset of menses and continuing the drugs on a scheduled basis throughout. NSAIDs should be used for a brief period, and regular use on an empty stomach should be avoided.

Hormone suppression

Many types of hormone suppression therapy are available, including combined estrogen-progestin medications, progestin-only medications, and gonadotropin-releasing hormone (GnRH) agonists and antagonists.

Combined estrogen-progestin medications include oral contraceptive pills (OCPs), vaginal rings, and transdermal patches. Combined estrogen-progestin methods cause atrophy of eutopic and ectopic endometrium and suppress GnRH.

Progestin-only methods include oral formulations, the levonorgestrel intrauterine device, intramuscular and subcuticular injections, and subdermal implants. Progestin-only methods lead to atrophy of eutopic and ectopic endometrium.

A GnRH agonist, leuprolide depot works by downregulating luteinizing hormone and follicle stimulating hormone release from the pituitary, causing suppression of ovarian follicular development and ovulation, leading to a hypoestrogenic state.

Combined estrogen-progestin formulations and progestin-only options are often considered first-line therapy for dysmenorrhea and endometriosis.¹³ Continuous administration, with the goal of inducing amenorrhea, is effective in the treatment of dysmenorrhea. Several randomized controlled trials have shown that different types of hormone suppression agents are, essentially, equally effective.^13–15 Treatment recommendations therefore should focus on adverse effects, cost, and patient preference. GnRH agonists and norethindrone are not FDA approved for the treatment of endometriosis.

It may be appropriate to consider use of hormone suppression therapy in patients with menstrual exacerbation of pain symptoms, including those with a history of endometriosis. We generally advise patients that the goal is amenorrhea and that achieving it often involves a process of trying different formulations to find the best fit. Remember that GnRH agonists are dependent on a functional hypothalamic-pituitary-ovarian axis, and they are unlikely to be effective in women with suspected residual endometriosis who have had a bilateral oophorectomy.

Physical therapy

For CPP, PT typically targets musculoskeletal dysfunction in the pelvic floor, abdominal wall, hips, and back. Interventions include muscle control, mobilization, and biofeedback. Pelvic PT has been shown to improve pain and dyspareunia in patients with CPP, coccydynia, and vestibulodynia.^16–18 One large study found a significant, patient-directed decrease in pain medication use after pelvic floor PT.¹⁹ Pelvic PT for patients with interstitial cystitis and pelvic floor tenderness resulted in improved pain and bladder symptoms.²⁰

Pelvic PT can be considered for patients with pain reproducible with palpation of the pelvic floor, abdominal wall, paraspinal-lumbar muscles, or sacroiliac joints. Best practices include referral to a therapist who has specialized training in CPP, including pelvic floor therapy. It is important to clearly list the indication for referral, as many of these therapists also treat stress urinary incontinence. The wrong exercises can result in increased hypercontractility of pelvic floor muscles, which can worsen pelvic pain.

It is also critical to clarify expectations with your patient at the time of PT referral. Specifically, advise patients that when beginning therapy, it is common to experience a temporary increase in discomfort of the pelvic muscles. Inform patients also to expect that their therapist will perform internal manipulation of the pelvic floor muscles through the vagina, as this can be surprising for some patients. Finally, counsel patients that their adherence to daily home exercises improves their chance of a durable, long-term successful response.²¹

CASE 1 Treatment recommendations

For treatment of this patient’s CPP, consider scheduled naproxen therapy during menses, continuous OCPs, and referral for pelvic floor PT.

Read about treating a case of pain, sleep disturbance, and depression.

CASE 2 Patient with long-standing CPP, multiple diagnoses, and sleep problems

A 30-year-old woman (G2P2) reports having had CPP for 17 years. She is amenorrheic with continuous OCP treatment. She had experienced some improvement with pelvic PT. The patient reports that she has daily pain with intermittent pain flares and that she is exhausted and has poor sleep quality, which she attributes to pain. She has been diagnosed with interstitial cystitis, irritable bowel syndrome, and temporomandibular joint disorder. She has a history of depression, which she feels is well controlled with bupropion. Physical examination reveals that the patient has diffuse but mild pain in the pelvic floor and abdominal wall muscles.

What further pain management options can you offer for this patient?

Managing pain, sleep disturbance, and depression

This patient has been living with CPP for many years, and she has sleep difficulties that might be exacerbating pain or result from pain (or both). She is already on continuous OCPs and has had some relief with pelvic PT. Other options that may help with her multiple issues include antidepressants, cyclobenzaprine, and calcium channel blockers.

Antidepressants

Several classes of antidepressants have been used in the treatment of chronic pain conditions, specifically, tricyclic antidepressants (TCAs) and serotonin-norepinephrine reuptake inhibitors (SNRIs). Commonly used TCAs include amitriptyline, nortriptyline, desipramine, and doxepin. Commonly used SNRIs are duloxetine and milnacipran. Both TCAs and SNRIs increase the availability of norepinephrine and serotonin, which are thought to act on the descending pain inhibitory systems to decrease pain sensitivity. Of note, most selective serotonin reuptake inhibitors (SSRIs) at typical doses do not exert a significant enough impact on norepinephrine to be useful for chronic pain.²²

Evidence is limited on the use of antidepressants for treating CPP. Amitriptyline is the most extensively studied antidepressant. Amitriptyline treatment resulted in modest pain improvement in patients with CPP and fibromyalgia.^23,24 Bothersome anticholinergic effects, including fatigue, dry mouth, and constipation, often are reported with TCAs. Adverse effects tend to be less with nortriptyline or desipramine compared with amitriptyline, but possibly at the expense of efficacy.

While SNRIs have not yet been studied in CPP, several investigations have shown that they improve pain and quality of life in fibromyalgia patients.^22,25

Antidepressant therapy may be appropriate for patients with suspected central pain amplification, widespread pain, and sleep disturbances. Best practices include patient education and careful discussion of this option with your patient. We suggest that clinicians explain that antidepressant medications alter the function of neurotransmitters, which modulate pain signals. While neurotransmitters also are involved in mood modulation, this is not the therapeutic goal in this circumstance. In addition, the doses used for the effective treatment of chronic pain are significantly lower than those needed to treat depression effectively.

Patients often need to hear that you believe that their pain is real and is not a manifestation of depression or another mood disorder. If you suspect that the patient also has untreated depression, address this as its own issue and use medications that have greater efficacy for mood symptoms.

Because many antidepressants can cause sedation, they are best taken before bedtime. Also, slow dose titration over several weeks will reduce the chance of bothersome adverse effects. Counsel patients that efficacy is not generally seen until at goal dose for several weeks. Be aware of interactions with other medications that can cause serotonin syndrome.

Cyclobenzaprine

Cyclobenzaprine is a muscle relaxant that also has activity in the central nervous system. The drug’s precise mechanism of action is not known, but it appears to potentiate norepinephrine and bind to serotonin receptors. Thus, it also likely has some TCA-like activity.

Cyclobenzaprine has not been studied in patients with CPP. In fibromyalgia patients, however, it produced significant improvements in pain, sleep, fatigue, and tenderness.^26,27 In our anecdotal experience with CPP patients, cyclobenzaprine has been one of the most impactful therapies. It hits the “chronic pain triad,” meaning that it helps with myofascial pain, neuropathic pain, and sleep disturbances.

Cyclobenzaprine treatment may be considered for patients with myofascial pain, sleep disturbances, and clinical symptoms of central pain amplification. Best practices include starting with low (5 mg) scheduled doses at bedtime and slowly titrating the dose. Drowsiness is a very common side effect, so we try to use that to the patient’s advantage to help with sleep quality.

Notably, sleep disturbances are highly prevalent in patients with chronic pain.²⁸ The relationship appears to be bidirectional, meaning that chronic pain negatively impacts sleep quality, and poor sleep quality causes amplified perception of pain.^28–30 Interventions that improve sleep quality have been associated with improvements in pain, coping, mood, and functional status.³¹ Helping a patient to improve her sleep generally requires a multifaceted approach. It always involves “sleep hygiene” or a behavioral component, and pharmacologic assistance may be considered when improved sleep hygiene does not provide adequately improved sleep quality.

Calcium channel blockers

Gabapentin and pregabalin are calcium channel blockers that inhibit the reuptake of glutamate, norepinephrine, and substance P, which helps to decrease pain sensitivity. They also act as membrane stabilizers, reducing hyperexcitability of peripheral and central nerves. Studies have shown that in patients with CPP, gabapentin resulted in improved pain and mood symptoms with few adverse effects.^23,32 Patients with fibromyalgia had improvements in pain, sleep, quality of life, fatigue, and anxiety with both gabapentin and pregabalin.³³

It is appropriate to consider use of gabapentin or pregabalin in patients with central pain amplification and sleep disturbances. Best practices include starting with a low dose at bedtime. Traditionally, gabapentin is given in 3 equal doses throughout the day. In our experience, patients report less daytime drowsiness and better sleep quality if two-thirds of the daily dose is given at night, with the remaining daily dose broken up into 2 smaller daytime doses. Slow titration over several weeks will reduce risk of bothersome adverse effects. Patients should be counseled that efficacy is not generally seen until treatment is at goal dose for several weeks.

CASE 2 Treatment recommendations

For this patient with daily pelvic pain, multiple diagnoses that have a pain component, and poor sleep quality, consider a treatment plan that includes scheduled cyclobenzaprine, improved sleep hygiene, and, if needed, gabapentin.

Read about treating a case of focal pain.

CASE 3 Cesarean delivery, hysterectomy, and continued pelvic pain

A 38-year-old woman (G2P2) has had CPP for the past 10 years. She developed persistent left lower-quadrant pain after cesarean delivery of her son. She had a hysterectomy 2 years ago for CPP, after which her pain worsened. She describes daily pain with intermittent flares. On examination, the patient has focal left lower-quadrant pain lateral to the left apex of her Pfannenstiel incision.

What treatment approach would be appropriate for this patient?

Focal pain requires a precisely targeted treatment

This patient with focal left lower-quadrant pain is a candidate for anesthetic trigger point injections in the affected area near her Pfannenstiel incision.

Anesthetic injections

Consider the presence of trigger points and peripheral neuropathy in patients with focal abdominal wall pain. Trigger points are focal, palpable nodules within muscles. They are markedly painful to palpation and are associated with referred pain, motor dysfunction, and occasionally autonomic symptoms. They frequently are seen in abdominal wall or pelvic floor muscles in patients with CPP and are caused by abnormal neuromuscular depolarization.

The ilioinguinal, iliohypogastric, and genitofemoral nerves are in close proximity to Pfannenstiel and laparoscopic port site incisions. These nerves may be injured directly during surgery, but they also may be compressed by postoperative scarring.

Anesthetics, such as lidocaine and bupivacaine, which act as sodium channel blockers, can be injected into this area, and improvement often substantially outlasts the anesthetic’s duration of action. While these drugs’ mechanism of action is not clear, theories include altered function of sodium channels on sensory nerves with repeated anesthetic exposure, dry needling that occurs during injection, hydrodissection of tight connective tissue bands surrounding neuromuscular bundles, or depletion of substance P and neuropeptides as a result of injection.^34,35

In several studies, patients with CPP reported decreased pain with lidocaine injections in pelvic floor or abdominal wall trigger points.^36–38 Patients with fibromyalgia reported improvement in pain and a decreased need for NSAIDs with bupivacaine trigger point injections.³⁹ While abdominal wall nerve blocks have not been extensively studied in patients with chronic neuropathic pain following gynecologic surgery, they have been shown to substantially improve chronic neuropathic pain following inguinal hernia repair.⁴⁰

Anesthetic injections appropriately may be considered in patients with focal pain in a muscle or in the distribution of abdominal wall nerves, palpation of which reproduces pain symptoms. Patients with diffuse pain are less likely to benefit from anesthetic injections. Best practices include careful examination with attention to areas of prior abdominal incisions.

Our practice is to inject each affected area with a mix of 9 mL of 1% lidocaine and 1 mL of sodium bicarbonate. If a patient reports at least 24 hours of improvement, we repeat the injection in 2 to 4 weeks. The goal is for the patient to experience a progressively longer duration of benefit with subsequent injections. We perform repeat injections shortly after pain begins to recur at that site. The patient should eventually graduate from receiving regular injections and may return for a remedial injection if pain recurs.

CASE 3 Treatment recommendations

For this patient with persistent focal left-lower quadrant pain and a defined trigger point near her Pfannenstiel incision, consider anesthetic injection in the left lower quadrant.

Work toward realistic symptom improvement

Remember that living with chronic pain is exhausting, and empathy with a patient-centered approach is the most important ingredient for patient improvement and satisfaction. Discuss realistic expectations with patients. Remind them that there is no magic bullet for the complex problem of CPP, and that chronic conditions generally do not improve overnight. Focus on improving the patient’s function and quality of life, and applaud symptom improvement rather than focusing on complete pain resolution.

As these visits often require a good deal of patient education, budget more appointment time if feasible. We find that scheduling frequent return visits (approximately every 3 to 4 months) allows timely treatment follow-up so that changes may be made if needed. If you have maximized your available treatment options, referring the patient to a specialist with additional training in CPP is a sensible next step.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Chronic pelvic pain (CPP) is defined as noncyclic pain in the pelvis, anterior abdominal wall, back, or buttocks that has been present for at least 6 months and is severe enough to cause functional disability or require medical care.¹ CPP is very common, with an estimated prevalence of 15% to 20%. It accounts for 20% of gynecology visits and 15% of hysterectomies in the United States, and it is believed to account for $2.8 billion in direct health care spending annually.^2–5

Caring for patients with CPP can be very challenging. They often arrive at your office frustrated, having seen multiple providers or having undergone multiple surgeries. They may come to you whether you are a general ObGyn or subspecialize in maternal-fetal medicine, oncology, reproductive endocrinology, urogynecology, or adolescent gynecology. From interactions with other providers or their own family members, these patients may have received the message—either subtly or overtly—that their pain is “all in their head.” As such, some patients may resist any implication that their pain does not have an anatomic source. It is therefore critical to have appropriate tools for evaluating and managing the complex problem of CPP.

Perform a thorough and thoughtful assessment

Chronic pelvic pain often presents as a constellation of symptoms with contributions from multiple sources, as opposed to a single disease entity. Occasionally there is a single cause of pain, such as a large endometrioma or degenerating fibroid, where surgery can be curative. But more commonly the pain arises from multiple organ systems. In such cases, surgery may be unnecessary and, often, can worsen pain.

Thoughtful evaluation is critical in the CPP population. Take a thorough patient history to determine the characteristics of pain (cyclic or constant, widespread or localized), exacerbating factors, sleep disturbances, fatigue, and current coping strategies. Focus a comprehensive physical examination on identifying the maneuvers that reproduce the patient’s pain, and include an examination of the pelvic floor muscles.⁶ In most cases, pelvic ultrasonography provides adequate evaluation for anatomic sources of pain.

Chronic pain does not behave like acute injury or postsurgical pain. Continuous peripheral pain signals for a prolonged period can lead to changes in how the brain processes pain; specifically, the brain can begin to amplify pain signals. This “central pain amplification” is characterized clinically by widespread pain, fatigue, sleep disturbances, memory difficulties, and somatic symptoms. Central pain amplification occurs in many chronic pain conditions, including fibromyalgia, interstitial cystitis, irritable bowel syndrome, low back pain, chronic headaches, and temporomandibular joint disorder.^7,8 Recent clinical and functional magnetic resonance imaging (MRI) studies demonstrate central pain amplification in many patients with CPP.^9–12 Notably, these findings are independent of the presence or severity of endometriosis.

In this article we discuss many therapies that have not been specifically studied in patients with CPP, and treatment efficacy is extrapolated from other conditions with chronic pain amplification, such as fibromyalgia or interstitial cystitis. Additionally, many treatments for conditions associated with central pain amplification are used off-label, that is, the US Food and Drug Administration (FDA) has not approved the medication for treatment of these specific conditions. This should be disclosed to patients during counseling.

Discuss treatment expectations with patients

Educating patients regarding the pathophysiology of chronic pain and setting reasonable expectations is the cornerstone of providing patient-centered care for this complex condition. We start most of our discussions about treatment options by telling patients that while we may not cure their pain, we will provide them with medical, surgical, and behavioral strategies that will reduce their pain, improve their function, and enhance their quality of life.

Surprisingly, most patients say that a cure is not their goal. They just want to feel better so they can return to work or activities, fully participate in family life, or not feel exhausted all the time. As such, a multimodal treatment plan is generally the best strategy for achieving a satisfactory improvement in symptoms.

Read about treating a case of continued pain after endometriosis treatment.

CASE 1 Patient’s pain continues after endometriosis excision

A 32-year-old woman (G1P1) reports having CPP for 8 years. She underwent excision of stage 1 endometriosis last year, which resulted in a modest improvement in pain for 6 months. Her pain is worse during menses, at the end of the day, and with vaginal intercourse (both during and lasting for 1 to 2 days after). On examination, you find diffuse pelvic floor tenderness but no adnexal masses or rectovaginal nodularity on palpation.

What treatment options would you consider for this patient?

Multimodal treatment often needed to manage CPP symptoms

The patient described in Case 1 may benefit from a combination of therapies that include analgesics, hormone suppression agents, and physical therapy (PT) (TABLE).

Analgesics

Nonsteroidal anti-inflammatory drugs (NSAIDs), including ibuprofen and naproxen, work by inhibiting cyclooxygenase enzyme, which decreases assembly of peripheral prostaglandins and thromboxane. In a large Cochrane review, NSAIDs were associated with moderate or excellent pain relief for approximately 50% of patients with dysmenorrhea, and they have been shown to reduce menstrual flow due to decreased production of uterine prostaglandins.¹³ There is little evidence for use of NSAIDs in chronic pain conditions.

Acetaminophen’s mechanism of action is unclear, but the drug likely inhibits central prostaglandin synthesis, and it works synergistically with other analgesics.

Opioids act on μ and δ opioid receptors in the central and peripheral nervous systems as well as in the gastrointestinal system. No evidence supports opioid use in CPP or other chronic pain conditions. Long-term opioid use is associated with a multitude of adverse effects, risk for dependence, and the induction of opioid-induced hyperalgesia (in which patients develop greater sensitivity to pain stimuli).

Analgesics, specifically NSAIDs, can be considered for use in patients with dysmenorrhea, cyclic pain exacerbation, or a suspected inflammatory component of pain. Best practices include scheduling NSAID use before the onset of menses and continuing the drugs on a scheduled basis throughout. NSAIDs should be used for a brief period, and regular use on an empty stomach should be avoided.

Hormone suppression

Many types of hormone suppression therapy are available, including combined estrogen-progestin medications, progestin-only medications, and gonadotropin-releasing hormone (GnRH) agonists and antagonists.

Combined estrogen-progestin medications include oral contraceptive pills (OCPs), vaginal rings, and transdermal patches. Combined estrogen-progestin methods cause atrophy of eutopic and ectopic endometrium and suppress GnRH.

Progestin-only methods include oral formulations, the levonorgestrel intrauterine device, intramuscular and subcuticular injections, and subdermal implants. Progestin-only methods lead to atrophy of eutopic and ectopic endometrium.

A GnRH agonist, leuprolide depot works by downregulating luteinizing hormone and follicle stimulating hormone release from the pituitary, causing suppression of ovarian follicular development and ovulation, leading to a hypoestrogenic state.

Combined estrogen-progestin formulations and progestin-only options are often considered first-line therapy for dysmenorrhea and endometriosis.¹³ Continuous administration, with the goal of inducing amenorrhea, is effective in the treatment of dysmenorrhea. Several randomized controlled trials have shown that different types of hormone suppression agents are, essentially, equally effective.^13–15 Treatment recommendations therefore should focus on adverse effects, cost, and patient preference. GnRH agonists and norethindrone are not FDA approved for the treatment of endometriosis.

It may be appropriate to consider use of hormone suppression therapy in patients with menstrual exacerbation of pain symptoms, including those with a history of endometriosis. We generally advise patients that the goal is amenorrhea and that achieving it often involves a process of trying different formulations to find the best fit. Remember that GnRH agonists are dependent on a functional hypothalamic-pituitary-ovarian axis, and they are unlikely to be effective in women with suspected residual endometriosis who have had a bilateral oophorectomy.

Physical therapy

For CPP, PT typically targets musculoskeletal dysfunction in the pelvic floor, abdominal wall, hips, and back. Interventions include muscle control, mobilization, and biofeedback. Pelvic PT has been shown to improve pain and dyspareunia in patients with CPP, coccydynia, and vestibulodynia.^16–18 One large study found a significant, patient-directed decrease in pain medication use after pelvic floor PT.¹⁹ Pelvic PT for patients with interstitial cystitis and pelvic floor tenderness resulted in improved pain and bladder symptoms.²⁰

Pelvic PT can be considered for patients with pain reproducible with palpation of the pelvic floor, abdominal wall, paraspinal-lumbar muscles, or sacroiliac joints. Best practices include referral to a therapist who has specialized training in CPP, including pelvic floor therapy. It is important to clearly list the indication for referral, as many of these therapists also treat stress urinary incontinence. The wrong exercises can result in increased hypercontractility of pelvic floor muscles, which can worsen pelvic pain.

It is also critical to clarify expectations with your patient at the time of PT referral. Specifically, advise patients that when beginning therapy, it is common to experience a temporary increase in discomfort of the pelvic muscles. Inform patients also to expect that their therapist will perform internal manipulation of the pelvic floor muscles through the vagina, as this can be surprising for some patients. Finally, counsel patients that their adherence to daily home exercises improves their chance of a durable, long-term successful response.²¹

CASE 1 Treatment recommendations

For treatment of this patient’s CPP, consider scheduled naproxen therapy during menses, continuous OCPs, and referral for pelvic floor PT.

Read about treating a case of pain, sleep disturbance, and depression.

CASE 2 Patient with long-standing CPP, multiple diagnoses, and sleep problems

A 30-year-old woman (G2P2) reports having had CPP for 17 years. She is amenorrheic with continuous OCP treatment. She had experienced some improvement with pelvic PT. The patient reports that she has daily pain with intermittent pain flares and that she is exhausted and has poor sleep quality, which she attributes to pain. She has been diagnosed with interstitial cystitis, irritable bowel syndrome, and temporomandibular joint disorder. She has a history of depression, which she feels is well controlled with bupropion. Physical examination reveals that the patient has diffuse but mild pain in the pelvic floor and abdominal wall muscles.

What further pain management options can you offer for this patient?

Managing pain, sleep disturbance, and depression

This patient has been living with CPP for many years, and she has sleep difficulties that might be exacerbating pain or result from pain (or both). She is already on continuous OCPs and has had some relief with pelvic PT. Other options that may help with her multiple issues include antidepressants, cyclobenzaprine, and calcium channel blockers.

Antidepressants

Several classes of antidepressants have been used in the treatment of chronic pain conditions, specifically, tricyclic antidepressants (TCAs) and serotonin-norepinephrine reuptake inhibitors (SNRIs). Commonly used TCAs include amitriptyline, nortriptyline, desipramine, and doxepin. Commonly used SNRIs are duloxetine and milnacipran. Both TCAs and SNRIs increase the availability of norepinephrine and serotonin, which are thought to act on the descending pain inhibitory systems to decrease pain sensitivity. Of note, most selective serotonin reuptake inhibitors (SSRIs) at typical doses do not exert a significant enough impact on norepinephrine to be useful for chronic pain.²²

Evidence is limited on the use of antidepressants for treating CPP. Amitriptyline is the most extensively studied antidepressant. Amitriptyline treatment resulted in modest pain improvement in patients with CPP and fibromyalgia.^23,24 Bothersome anticholinergic effects, including fatigue, dry mouth, and constipation, often are reported with TCAs. Adverse effects tend to be less with nortriptyline or desipramine compared with amitriptyline, but possibly at the expense of efficacy.

While SNRIs have not yet been studied in CPP, several investigations have shown that they improve pain and quality of life in fibromyalgia patients.^22,25

Antidepressant therapy may be appropriate for patients with suspected central pain amplification, widespread pain, and sleep disturbances. Best practices include patient education and careful discussion of this option with your patient. We suggest that clinicians explain that antidepressant medications alter the function of neurotransmitters, which modulate pain signals. While neurotransmitters also are involved in mood modulation, this is not the therapeutic goal in this circumstance. In addition, the doses used for the effective treatment of chronic pain are significantly lower than those needed to treat depression effectively.

Patients often need to hear that you believe that their pain is real and is not a manifestation of depression or another mood disorder. If you suspect that the patient also has untreated depression, address this as its own issue and use medications that have greater efficacy for mood symptoms.

Because many antidepressants can cause sedation, they are best taken before bedtime. Also, slow dose titration over several weeks will reduce the chance of bothersome adverse effects. Counsel patients that efficacy is not generally seen until at goal dose for several weeks. Be aware of interactions with other medications that can cause serotonin syndrome.

Cyclobenzaprine

Cyclobenzaprine is a muscle relaxant that also has activity in the central nervous system. The drug’s precise mechanism of action is not known, but it appears to potentiate norepinephrine and bind to serotonin receptors. Thus, it also likely has some TCA-like activity.

Cyclobenzaprine has not been studied in patients with CPP. In fibromyalgia patients, however, it produced significant improvements in pain, sleep, fatigue, and tenderness.^26,27 In our anecdotal experience with CPP patients, cyclobenzaprine has been one of the most impactful therapies. It hits the “chronic pain triad,” meaning that it helps with myofascial pain, neuropathic pain, and sleep disturbances.

Cyclobenzaprine treatment may be considered for patients with myofascial pain, sleep disturbances, and clinical symptoms of central pain amplification. Best practices include starting with low (5 mg) scheduled doses at bedtime and slowly titrating the dose. Drowsiness is a very common side effect, so we try to use that to the patient’s advantage to help with sleep quality.

Notably, sleep disturbances are highly prevalent in patients with chronic pain.²⁸ The relationship appears to be bidirectional, meaning that chronic pain negatively impacts sleep quality, and poor sleep quality causes amplified perception of pain.^28–30 Interventions that improve sleep quality have been associated with improvements in pain, coping, mood, and functional status.³¹ Helping a patient to improve her sleep generally requires a multifaceted approach. It always involves “sleep hygiene” or a behavioral component, and pharmacologic assistance may be considered when improved sleep hygiene does not provide adequately improved sleep quality.

Calcium channel blockers

Gabapentin and pregabalin are calcium channel blockers that inhibit the reuptake of glutamate, norepinephrine, and substance P, which helps to decrease pain sensitivity. They also act as membrane stabilizers, reducing hyperexcitability of peripheral and central nerves. Studies have shown that in patients with CPP, gabapentin resulted in improved pain and mood symptoms with few adverse effects.^23,32 Patients with fibromyalgia had improvements in pain, sleep, quality of life, fatigue, and anxiety with both gabapentin and pregabalin.³³

It is appropriate to consider use of gabapentin or pregabalin in patients with central pain amplification and sleep disturbances. Best practices include starting with a low dose at bedtime. Traditionally, gabapentin is given in 3 equal doses throughout the day. In our experience, patients report less daytime drowsiness and better sleep quality if two-thirds of the daily dose is given at night, with the remaining daily dose broken up into 2 smaller daytime doses. Slow titration over several weeks will reduce risk of bothersome adverse effects. Patients should be counseled that efficacy is not generally seen until treatment is at goal dose for several weeks.

CASE 2 Treatment recommendations

For this patient with daily pelvic pain, multiple diagnoses that have a pain component, and poor sleep quality, consider a treatment plan that includes scheduled cyclobenzaprine, improved sleep hygiene, and, if needed, gabapentin.

Read about treating a case of focal pain.

CASE 3 Cesarean delivery, hysterectomy, and continued pelvic pain

A 38-year-old woman (G2P2) has had CPP for the past 10 years. She developed persistent left lower-quadrant pain after cesarean delivery of her son. She had a hysterectomy 2 years ago for CPP, after which her pain worsened. She describes daily pain with intermittent flares. On examination, the patient has focal left lower-quadrant pain lateral to the left apex of her Pfannenstiel incision.

What treatment approach would be appropriate for this patient?

Focal pain requires a precisely targeted treatment

This patient with focal left lower-quadrant pain is a candidate for anesthetic trigger point injections in the affected area near her Pfannenstiel incision.

Anesthetic injections

Consider the presence of trigger points and peripheral neuropathy in patients with focal abdominal wall pain. Trigger points are focal, palpable nodules within muscles. They are markedly painful to palpation and are associated with referred pain, motor dysfunction, and occasionally autonomic symptoms. They frequently are seen in abdominal wall or pelvic floor muscles in patients with CPP and are caused by abnormal neuromuscular depolarization.

The ilioinguinal, iliohypogastric, and genitofemoral nerves are in close proximity to Pfannenstiel and laparoscopic port site incisions. These nerves may be injured directly during surgery, but they also may be compressed by postoperative scarring.

Anesthetics, such as lidocaine and bupivacaine, which act as sodium channel blockers, can be injected into this area, and improvement often substantially outlasts the anesthetic’s duration of action. While these drugs’ mechanism of action is not clear, theories include altered function of sodium channels on sensory nerves with repeated anesthetic exposure, dry needling that occurs during injection, hydrodissection of tight connective tissue bands surrounding neuromuscular bundles, or depletion of substance P and neuropeptides as a result of injection.^34,35

In several studies, patients with CPP reported decreased pain with lidocaine injections in pelvic floor or abdominal wall trigger points.^36–38 Patients with fibromyalgia reported improvement in pain and a decreased need for NSAIDs with bupivacaine trigger point injections.³⁹ While abdominal wall nerve blocks have not been extensively studied in patients with chronic neuropathic pain following gynecologic surgery, they have been shown to substantially improve chronic neuropathic pain following inguinal hernia repair.⁴⁰

Anesthetic injections appropriately may be considered in patients with focal pain in a muscle or in the distribution of abdominal wall nerves, palpation of which reproduces pain symptoms. Patients with diffuse pain are less likely to benefit from anesthetic injections. Best practices include careful examination with attention to areas of prior abdominal incisions.

Our practice is to inject each affected area with a mix of 9 mL of 1% lidocaine and 1 mL of sodium bicarbonate. If a patient reports at least 24 hours of improvement, we repeat the injection in 2 to 4 weeks. The goal is for the patient to experience a progressively longer duration of benefit with subsequent injections. We perform repeat injections shortly after pain begins to recur at that site. The patient should eventually graduate from receiving regular injections and may return for a remedial injection if pain recurs.

CASE 3 Treatment recommendations

For this patient with persistent focal left-lower quadrant pain and a defined trigger point near her Pfannenstiel incision, consider anesthetic injection in the left lower quadrant.

Work toward realistic symptom improvement

Remember that living with chronic pain is exhausting, and empathy with a patient-centered approach is the most important ingredient for patient improvement and satisfaction. Discuss realistic expectations with patients. Remind them that there is no magic bullet for the complex problem of CPP, and that chronic conditions generally do not improve overnight. Focus on improving the patient’s function and quality of life, and applaud symptom improvement rather than focusing on complete pain resolution.

As these visits often require a good deal of patient education, budget more appointment time if feasible. We find that scheduling frequent return visits (approximately every 3 to 4 months) allows timely treatment follow-up so that changes may be made if needed. If you have maximized your available treatment options, referring the patient to a specialist with additional training in CPP is a sensible next step.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Chronic pelvic pain (CPP) is defined as noncyclic pain in the pelvis, anterior abdominal wall, back, or buttocks that has been present for at least 6 months and is severe enough to cause functional disability or require medical care.¹ CPP is very common, with an estimated prevalence of 15% to 20%. It accounts for 20% of gynecology visits and 15% of hysterectomies in the United States, and it is believed to account for $2.8 billion in direct health care spending annually.^2–5

Caring for patients with CPP can be very challenging. They often arrive at your office frustrated, having seen multiple providers or having undergone multiple surgeries. They may come to you whether you are a general ObGyn or subspecialize in maternal-fetal medicine, oncology, reproductive endocrinology, urogynecology, or adolescent gynecology. From interactions with other providers or their own family members, these patients may have received the message—either subtly or overtly—that their pain is “all in their head.” As such, some patients may resist any implication that their pain does not have an anatomic source. It is therefore critical to have appropriate tools for evaluating and managing the complex problem of CPP.

Perform a thorough and thoughtful assessment

Chronic pelvic pain often presents as a constellation of symptoms with contributions from multiple sources, as opposed to a single disease entity. Occasionally there is a single cause of pain, such as a large endometrioma or degenerating fibroid, where surgery can be curative. But more commonly the pain arises from multiple organ systems. In such cases, surgery may be unnecessary and, often, can worsen pain.

Thoughtful evaluation is critical in the CPP population. Take a thorough patient history to determine the characteristics of pain (cyclic or constant, widespread or localized), exacerbating factors, sleep disturbances, fatigue, and current coping strategies. Focus a comprehensive physical examination on identifying the maneuvers that reproduce the patient’s pain, and include an examination of the pelvic floor muscles.⁶ In most cases, pelvic ultrasonography provides adequate evaluation for anatomic sources of pain.

Chronic pain does not behave like acute injury or postsurgical pain. Continuous peripheral pain signals for a prolonged period can lead to changes in how the brain processes pain; specifically, the brain can begin to amplify pain signals. This “central pain amplification” is characterized clinically by widespread pain, fatigue, sleep disturbances, memory difficulties, and somatic symptoms. Central pain amplification occurs in many chronic pain conditions, including fibromyalgia, interstitial cystitis, irritable bowel syndrome, low back pain, chronic headaches, and temporomandibular joint disorder.^7,8 Recent clinical and functional magnetic resonance imaging (MRI) studies demonstrate central pain amplification in many patients with CPP.^9–12 Notably, these findings are independent of the presence or severity of endometriosis.

In this article we discuss many therapies that have not been specifically studied in patients with CPP, and treatment efficacy is extrapolated from other conditions with chronic pain amplification, such as fibromyalgia or interstitial cystitis. Additionally, many treatments for conditions associated with central pain amplification are used off-label, that is, the US Food and Drug Administration (FDA) has not approved the medication for treatment of these specific conditions. This should be disclosed to patients during counseling.

Discuss treatment expectations with patients

Educating patients regarding the pathophysiology of chronic pain and setting reasonable expectations is the cornerstone of providing patient-centered care for this complex condition. We start most of our discussions about treatment options by telling patients that while we may not cure their pain, we will provide them with medical, surgical, and behavioral strategies that will reduce their pain, improve their function, and enhance their quality of life.

Surprisingly, most patients say that a cure is not their goal. They just want to feel better so they can return to work or activities, fully participate in family life, or not feel exhausted all the time. As such, a multimodal treatment plan is generally the best strategy for achieving a satisfactory improvement in symptoms.

Read about treating a case of continued pain after endometriosis treatment.

CASE 1 Patient’s pain continues after endometriosis excision

A 32-year-old woman (G1P1) reports having CPP for 8 years. She underwent excision of stage 1 endometriosis last year, which resulted in a modest improvement in pain for 6 months. Her pain is worse during menses, at the end of the day, and with vaginal intercourse (both during and lasting for 1 to 2 days after). On examination, you find diffuse pelvic floor tenderness but no adnexal masses or rectovaginal nodularity on palpation.

What treatment options would you consider for this patient?

Multimodal treatment often needed to manage CPP symptoms

The patient described in Case 1 may benefit from a combination of therapies that include analgesics, hormone suppression agents, and physical therapy (PT) (TABLE).

Analgesics

Nonsteroidal anti-inflammatory drugs (NSAIDs), including ibuprofen and naproxen, work by inhibiting cyclooxygenase enzyme, which decreases assembly of peripheral prostaglandins and thromboxane. In a large Cochrane review, NSAIDs were associated with moderate or excellent pain relief for approximately 50% of patients with dysmenorrhea, and they have been shown to reduce menstrual flow due to decreased production of uterine prostaglandins.¹³ There is little evidence for use of NSAIDs in chronic pain conditions.

Acetaminophen’s mechanism of action is unclear, but the drug likely inhibits central prostaglandin synthesis, and it works synergistically with other analgesics.

Opioids act on μ and δ opioid receptors in the central and peripheral nervous systems as well as in the gastrointestinal system. No evidence supports opioid use in CPP or other chronic pain conditions. Long-term opioid use is associated with a multitude of adverse effects, risk for dependence, and the induction of opioid-induced hyperalgesia (in which patients develop greater sensitivity to pain stimuli).

Analgesics, specifically NSAIDs, can be considered for use in patients with dysmenorrhea, cyclic pain exacerbation, or a suspected inflammatory component of pain. Best practices include scheduling NSAID use before the onset of menses and continuing the drugs on a scheduled basis throughout. NSAIDs should be used for a brief period, and regular use on an empty stomach should be avoided.

Hormone suppression

Many types of hormone suppression therapy are available, including combined estrogen-progestin medications, progestin-only medications, and gonadotropin-releasing hormone (GnRH) agonists and antagonists.

Combined estrogen-progestin medications include oral contraceptive pills (OCPs), vaginal rings, and transdermal patches. Combined estrogen-progestin methods cause atrophy of eutopic and ectopic endometrium and suppress GnRH.

Progestin-only methods include oral formulations, the levonorgestrel intrauterine device, intramuscular and subcuticular injections, and subdermal implants. Progestin-only methods lead to atrophy of eutopic and ectopic endometrium.

A GnRH agonist, leuprolide depot works by downregulating luteinizing hormone and follicle stimulating hormone release from the pituitary, causing suppression of ovarian follicular development and ovulation, leading to a hypoestrogenic state.

Combined estrogen-progestin formulations and progestin-only options are often considered first-line therapy for dysmenorrhea and endometriosis.¹³ Continuous administration, with the goal of inducing amenorrhea, is effective in the treatment of dysmenorrhea. Several randomized controlled trials have shown that different types of hormone suppression agents are, essentially, equally effective.^13–15 Treatment recommendations therefore should focus on adverse effects, cost, and patient preference. GnRH agonists and norethindrone are not FDA approved for the treatment of endometriosis.

It may be appropriate to consider use of hormone suppression therapy in patients with menstrual exacerbation of pain symptoms, including those with a history of endometriosis. We generally advise patients that the goal is amenorrhea and that achieving it often involves a process of trying different formulations to find the best fit. Remember that GnRH agonists are dependent on a functional hypothalamic-pituitary-ovarian axis, and they are unlikely to be effective in women with suspected residual endometriosis who have had a bilateral oophorectomy.

Physical therapy

For CPP, PT typically targets musculoskeletal dysfunction in the pelvic floor, abdominal wall, hips, and back. Interventions include muscle control, mobilization, and biofeedback. Pelvic PT has been shown to improve pain and dyspareunia in patients with CPP, coccydynia, and vestibulodynia.^16–18 One large study found a significant, patient-directed decrease in pain medication use after pelvic floor PT.¹⁹ Pelvic PT for patients with interstitial cystitis and pelvic floor tenderness resulted in improved pain and bladder symptoms.²⁰

Pelvic PT can be considered for patients with pain reproducible with palpation of the pelvic floor, abdominal wall, paraspinal-lumbar muscles, or sacroiliac joints. Best practices include referral to a therapist who has specialized training in CPP, including pelvic floor therapy. It is important to clearly list the indication for referral, as many of these therapists also treat stress urinary incontinence. The wrong exercises can result in increased hypercontractility of pelvic floor muscles, which can worsen pelvic pain.

It is also critical to clarify expectations with your patient at the time of PT referral. Specifically, advise patients that when beginning therapy, it is common to experience a temporary increase in discomfort of the pelvic muscles. Inform patients also to expect that their therapist will perform internal manipulation of the pelvic floor muscles through the vagina, as this can be surprising for some patients. Finally, counsel patients that their adherence to daily home exercises improves their chance of a durable, long-term successful response.²¹

CASE 1 Treatment recommendations

For treatment of this patient’s CPP, consider scheduled naproxen therapy during menses, continuous OCPs, and referral for pelvic floor PT.

Read about treating a case of pain, sleep disturbance, and depression.

CASE 2 Patient with long-standing CPP, multiple diagnoses, and sleep problems

A 30-year-old woman (G2P2) reports having had CPP for 17 years. She is amenorrheic with continuous OCP treatment. She had experienced some improvement with pelvic PT. The patient reports that she has daily pain with intermittent pain flares and that she is exhausted and has poor sleep quality, which she attributes to pain. She has been diagnosed with interstitial cystitis, irritable bowel syndrome, and temporomandibular joint disorder. She has a history of depression, which she feels is well controlled with bupropion. Physical examination reveals that the patient has diffuse but mild pain in the pelvic floor and abdominal wall muscles.

What further pain management options can you offer for this patient?

Managing pain, sleep disturbance, and depression

This patient has been living with CPP for many years, and she has sleep difficulties that might be exacerbating pain or result from pain (or both). She is already on continuous OCPs and has had some relief with pelvic PT. Other options that may help with her multiple issues include antidepressants, cyclobenzaprine, and calcium channel blockers.

Antidepressants

Several classes of antidepressants have been used in the treatment of chronic pain conditions, specifically, tricyclic antidepressants (TCAs) and serotonin-norepinephrine reuptake inhibitors (SNRIs). Commonly used TCAs include amitriptyline, nortriptyline, desipramine, and doxepin. Commonly used SNRIs are duloxetine and milnacipran. Both TCAs and SNRIs increase the availability of norepinephrine and serotonin, which are thought to act on the descending pain inhibitory systems to decrease pain sensitivity. Of note, most selective serotonin reuptake inhibitors (SSRIs) at typical doses do not exert a significant enough impact on norepinephrine to be useful for chronic pain.²²

Evidence is limited on the use of antidepressants for treating CPP. Amitriptyline is the most extensively studied antidepressant. Amitriptyline treatment resulted in modest pain improvement in patients with CPP and fibromyalgia.^23,24 Bothersome anticholinergic effects, including fatigue, dry mouth, and constipation, often are reported with TCAs. Adverse effects tend to be less with nortriptyline or desipramine compared with amitriptyline, but possibly at the expense of efficacy.

While SNRIs have not yet been studied in CPP, several investigations have shown that they improve pain and quality of life in fibromyalgia patients.^22,25

Antidepressant therapy may be appropriate for patients with suspected central pain amplification, widespread pain, and sleep disturbances. Best practices include patient education and careful discussion of this option with your patient. We suggest that clinicians explain that antidepressant medications alter the function of neurotransmitters, which modulate pain signals. While neurotransmitters also are involved in mood modulation, this is not the therapeutic goal in this circumstance. In addition, the doses used for the effective treatment of chronic pain are significantly lower than those needed to treat depression effectively.

Patients often need to hear that you believe that their pain is real and is not a manifestation of depression or another mood disorder. If you suspect that the patient also has untreated depression, address this as its own issue and use medications that have greater efficacy for mood symptoms.

Because many antidepressants can cause sedation, they are best taken before bedtime. Also, slow dose titration over several weeks will reduce the chance of bothersome adverse effects. Counsel patients that efficacy is not generally seen until at goal dose for several weeks. Be aware of interactions with other medications that can cause serotonin syndrome.

Cyclobenzaprine

Cyclobenzaprine is a muscle relaxant that also has activity in the central nervous system. The drug’s precise mechanism of action is not known, but it appears to potentiate norepinephrine and bind to serotonin receptors. Thus, it also likely has some TCA-like activity.

Cyclobenzaprine has not been studied in patients with CPP. In fibromyalgia patients, however, it produced significant improvements in pain, sleep, fatigue, and tenderness.^26,27 In our anecdotal experience with CPP patients, cyclobenzaprine has been one of the most impactful therapies. It hits the “chronic pain triad,” meaning that it helps with myofascial pain, neuropathic pain, and sleep disturbances.

Cyclobenzaprine treatment may be considered for patients with myofascial pain, sleep disturbances, and clinical symptoms of central pain amplification. Best practices include starting with low (5 mg) scheduled doses at bedtime and slowly titrating the dose. Drowsiness is a very common side effect, so we try to use that to the patient’s advantage to help with sleep quality.

Notably, sleep disturbances are highly prevalent in patients with chronic pain.²⁸ The relationship appears to be bidirectional, meaning that chronic pain negatively impacts sleep quality, and poor sleep quality causes amplified perception of pain.^28–30 Interventions that improve sleep quality have been associated with improvements in pain, coping, mood, and functional status.³¹ Helping a patient to improve her sleep generally requires a multifaceted approach. It always involves “sleep hygiene” or a behavioral component, and pharmacologic assistance may be considered when improved sleep hygiene does not provide adequately improved sleep quality.

Calcium channel blockers

Gabapentin and pregabalin are calcium channel blockers that inhibit the reuptake of glutamate, norepinephrine, and substance P, which helps to decrease pain sensitivity. They also act as membrane stabilizers, reducing hyperexcitability of peripheral and central nerves. Studies have shown that in patients with CPP, gabapentin resulted in improved pain and mood symptoms with few adverse effects.^23,32 Patients with fibromyalgia had improvements in pain, sleep, quality of life, fatigue, and anxiety with both gabapentin and pregabalin.³³

It is appropriate to consider use of gabapentin or pregabalin in patients with central pain amplification and sleep disturbances. Best practices include starting with a low dose at bedtime. Traditionally, gabapentin is given in 3 equal doses throughout the day. In our experience, patients report less daytime drowsiness and better sleep quality if two-thirds of the daily dose is given at night, with the remaining daily dose broken up into 2 smaller daytime doses. Slow titration over several weeks will reduce risk of bothersome adverse effects. Patients should be counseled that efficacy is not generally seen until treatment is at goal dose for several weeks.

CASE 2 Treatment recommendations

For this patient with daily pelvic pain, multiple diagnoses that have a pain component, and poor sleep quality, consider a treatment plan that includes scheduled cyclobenzaprine, improved sleep hygiene, and, if needed, gabapentin.

Read about treating a case of focal pain.

CASE 3 Cesarean delivery, hysterectomy, and continued pelvic pain

A 38-year-old woman (G2P2) has had CPP for the past 10 years. She developed persistent left lower-quadrant pain after cesarean delivery of her son. She had a hysterectomy 2 years ago for CPP, after which her pain worsened. She describes daily pain with intermittent flares. On examination, the patient has focal left lower-quadrant pain lateral to the left apex of her Pfannenstiel incision.

What treatment approach would be appropriate for this patient?

Focal pain requires a precisely targeted treatment

This patient with focal left lower-quadrant pain is a candidate for anesthetic trigger point injections in the affected area near her Pfannenstiel incision.

Anesthetic injections

Consider the presence of trigger points and peripheral neuropathy in patients with focal abdominal wall pain. Trigger points are focal, palpable nodules within muscles. They are markedly painful to palpation and are associated with referred pain, motor dysfunction, and occasionally autonomic symptoms. They frequently are seen in abdominal wall or pelvic floor muscles in patients with CPP and are caused by abnormal neuromuscular depolarization.

The ilioinguinal, iliohypogastric, and genitofemoral nerves are in close proximity to Pfannenstiel and laparoscopic port site incisions. These nerves may be injured directly during surgery, but they also may be compressed by postoperative scarring.

Anesthetics, such as lidocaine and bupivacaine, which act as sodium channel blockers, can be injected into this area, and improvement often substantially outlasts the anesthetic’s duration of action. While these drugs’ mechanism of action is not clear, theories include altered function of sodium channels on sensory nerves with repeated anesthetic exposure, dry needling that occurs during injection, hydrodissection of tight connective tissue bands surrounding neuromuscular bundles, or depletion of substance P and neuropeptides as a result of injection.^34,35

In several studies, patients with CPP reported decreased pain with lidocaine injections in pelvic floor or abdominal wall trigger points.^36–38 Patients with fibromyalgia reported improvement in pain and a decreased need for NSAIDs with bupivacaine trigger point injections.³⁹ While abdominal wall nerve blocks have not been extensively studied in patients with chronic neuropathic pain following gynecologic surgery, they have been shown to substantially improve chronic neuropathic pain following inguinal hernia repair.⁴⁰

Anesthetic injections appropriately may be considered in patients with focal pain in a muscle or in the distribution of abdominal wall nerves, palpation of which reproduces pain symptoms. Patients with diffuse pain are less likely to benefit from anesthetic injections. Best practices include careful examination with attention to areas of prior abdominal incisions.

Our practice is to inject each affected area with a mix of 9 mL of 1% lidocaine and 1 mL of sodium bicarbonate. If a patient reports at least 24 hours of improvement, we repeat the injection in 2 to 4 weeks. The goal is for the patient to experience a progressively longer duration of benefit with subsequent injections. We perform repeat injections shortly after pain begins to recur at that site. The patient should eventually graduate from receiving regular injections and may return for a remedial injection if pain recurs.

CASE 3 Treatment recommendations

For this patient with persistent focal left-lower quadrant pain and a defined trigger point near her Pfannenstiel incision, consider anesthetic injection in the left lower quadrant.

Work toward realistic symptom improvement

Remember that living with chronic pain is exhausting, and empathy with a patient-centered approach is the most important ingredient for patient improvement and satisfaction. Discuss realistic expectations with patients. Remind them that there is no magic bullet for the complex problem of CPP, and that chronic conditions generally do not improve overnight. Focus on improving the patient’s function and quality of life, and applaud symptom improvement rather than focusing on complete pain resolution.

As these visits often require a good deal of patient education, budget more appointment time if feasible. We find that scheduling frequent return visits (approximately every 3 to 4 months) allows timely treatment follow-up so that changes may be made if needed. If you have maximized your available treatment options, referring the patient to a specialist with additional training in CPP is a sensible next step.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

The prevalence of psoriasis among human immunodeficiency virus (HIV)–positive patients in the United States is reported to be approximately 1% to 3%, which is similar to the rates reported for the general population.¹ Recalcitrant cases of psoriasis in patients with no history of the condition can be the initial manifestation of HIV infection. In patients with preexisting psoriasis, a flare of their disease can be seen following infection, and progression of HIV correlates with worsening psoriasis.² Psoriatic arthropathy also affects 23% to 50% of HIV-positive patients with psoriasis worldwide, which may be higher than the general population,¹ with more severe joint disease.

The management of psoriatic disease in the HIV-positive population is challenging. The current first-line recommendations for treatment include topical therapies, phototherapy, and highly active antiretroviral therapy (HAART), followed by oral retinoids as second-line agents.³ However, the clinical course of psoriasis in HIV-positive patients often is progressive and refractory²; therefore, these therapies often are inadequate to control both skin and joint manifestations. Most other currently available systemic therapies for psoriatic disease are immunosuppressive, which poses a distinct clinical challenge because HIV-positive patients are already immunocompromised.

There currently are many systemic immunosuppressive agents used for the treatment of psoriatic disease, including oral agents (eg, methotrexate, hydroxyurea, cyclosporine), as well as newer biologic medications, including tumor necrosis factor (TNF) α inhibitors etanercept, adalimumab, infliximab, golimumab, and certolizumab pegol. Golimumab and certolizumab pegol currently are indicated for psoriatic arthritis only. Other newer biologic therapies include ustekinumab, which inhibits IL-12 and IL-23, and secukinumab, which inhibits IL-17A. The purpose of this systematic review is to evaluate the most current literature to explore the efficacy and safety data as they pertain to systemic immunosuppressive therapies for the treatment of psoriatic disease in HIV-positive individuals.

Methods

To investigate the efficacy and safety of systemic immunosuppressive therapies for psoriatic disease in HIV-positive individuals, a PubMed search of articles indexed for MEDLINE (1985-2015) was conducted using the terms psoriasis and HIV and psoriatic arthritis and HIV combined with each of the following systemic immunosuppressive agents: methotrexate, hydroxyurea, cyclosporine, etanercept, adalimumab, infliximab, golimumab, certolizumab pegol, ustekinumab, and secukinumab. Pediatric cases and articles that were not available in the English language were excluded.

For each case, patient demographic information (ie, age, sex), prior failed psoriasis treatments, and history of HAART were documented. The dosing regimen of the systemic agent was noted when different from the US Food and Drug administration–approved dosage for psoriasis or psoriatic arthritis. The duration of immunosuppressive therapy as well as pretreatment and posttreatment CD4 and viral counts (when available) were collected. The response to treatment and adverse effects were summarized.

Results

Our review of the literature yielded a total of 25 reported cases of systemic immunosuppressive therapies used to treat psoriatic disease in HIV-positive patients, including methotrexate, cyclosporine, etanercept, adalimumab, in-fliximab, and ustekinumab (Table). There were no reports of the use of hydroxyurea, golimumab, certolizumab pegol, or secukinumab to treat psoriatic disease in this patient population.

Methotrexate
Eight individual cases of methotrexate used to treat psoriasis and/or psoriatic arthritis in HIV-positive patients were reported.^4-6 Duvic et al⁶ described 4 patients with psoriatic disease that was treated with methotrexate with varying efficacy. One patient developed toxic encephalopathy, which improved after discontinuation of methotrexate; however, he died 5 months later from pneumocystis pneumonia. In this early study, none of the 4 patients were on antiretroviral therapy for HIV.⁶

In the cases reported by Masson et al⁴ and Maurer et al,⁵ 4 patients were treated with a single antiretroviral agent and received appropriate prophylaxis against opportunistic infections. In 1 case, methotrexate was given at a chemotherapeutic dose of 525 mg once weekly for Kaposi sarcoma.⁴ In 2 of 4 cases, the patients developed pneumocystis pneumonia.^4,5

Cyclosporine
There were 2 case reports of successful treatment of psoriatic disease with cyclosporine in HIV-positive patients.^7,8 Skin and joint manifestations improved rapidly without reports of infection for 2⁷ and 8 years.⁸ Both patients were treated with one antiretroviral agent.^7,8

Etanercept
There were 5 case reports of successful treatment of psoriatic disease with etanercept. In all 5 cases the patients were on HAART, and the CD4 count increased or remained stable and viral count became undetectable or remained stable following treatment.^9-13 In 2 cases, the patient also had hepatitis C virus, which remained stable throughout the treatment period.^9,12 The maximum duration of treatment was 6 years, with only 1 reported adverse event.¹³ In this case reported by Aboulafia et al,¹³ the patient experienced recurrent polymicrobial infections, including enterococcal cellulitis, cystitis, and bacteremia, as well as pseudomonas pneumonia and septic arthritis. Therapy was discontinued at 6 months. Four months after discontinuation of etanercept, the patient died from infectious causes.¹³

Adalimumab
There was 1 case of successful treatment of psoriatic disease with adalimumab in an HIV-positive patient. In this case, the patient was on HAART, and CD4 and viral counts improved substantially after 30 months of treatment.¹⁴

Infliximab
Six individual cases of successful treatment of psoriatic disease with infliximab were reported.^15-17 In a report by Cepeda et al,¹⁵ HIV-positive patients with various rheumatologic diseases were chosen to receive etanercept followed by adalimumab and/or infliximab if clinical improvement was not observed on etanercept. In 3 patients with psoriasis and psoriatic arthritis, inadequate response was observed on etanercept. Two of these 3 patients received adalimumab with only partial response. All 3 were treated with infliximab in the end and showed excellent response. One of the patients experienced facial abscess responsive to antibiotics and was continued on infliximab therapy without further complications. In all 6 cases of infliximab therapy, the patients were on HAART, and CD4 and viral counts improved or remained stable.¹⁵

Ustekinumab
There were 3 case reports of successful treatment of psoriatic disease with ustekinumab in HIV-positive patients on HAART. CD4 and viral counts improved or remained stable.^18-20

Comment

Currently, all of the systemic immunosuppressive therapies approved for psoriatic disease have a warning by the US Food and Drug Administration for increased risk of serious infection. Given such labels, these therapies are not routinely prescribed for HIV-positive patients who are already immunocompromised; however, many HIV-positive patients have severe psoriatic disease that cannot be adequately treated with first- and second-line therapies including topical agents, phototherapy, or oral retinoids.

Our comprehensive review yielded a total of 25 reported cases of systemic immunosuppressive therapies used to treat psoriatic disease in HIV-positive patients including methotrexate, cyclosporine, etanercept, adalimumab, in-fliximab, and ustekinumab. Although data are limited to case reports and case series, some trends were observed.

Efficacy
In most of the cases reviewed, the patients had inadequate improvement of psoriatic disease with first- and second-line therapies, which included antiretrovirals alone, topical agents, phototherapy, and oral retinoids. Some cases reported poor response to methotrexate and cyclosporine.^4-8 Biologic agents were effective in many such cases.

Safety
Overall, there were 11 cases in which the patient was not on adequate HAART while being treated with systemic immunosuppressive therapy for psoriatic disease.^4-8,15 Of them, 3 were associated with serious infection while on methotrexate.^5,6 There was only 1 report of serious infection¹³ of 14 cases in which the patient was on concomitant HAART. In this case, which reported polymicrobial infections and subsequent death of the patient, the infections continued after discontinuing etanercept; thus, the association is unclear. Interestingly, despite multiple infections, the CD4 and viral counts were stable throughout treatment with etanercept.¹³

From reviewing the 4 total cases^5,6,13 of serious infection, HAART appears to be a valuable concomitant treatment during systemic immunosuppressive therapy for HIV-positive patients; however, it does not necessarily prevent serious infections from occurring, and thus the clinician’s diligence in monitoring for signs and symptoms of infection remains important.

CD4 and Viral Counts
Although reports of CD4 and viral counts were not available in earlier studies,^4-8 there were 15 cases that reported consistent pretreatment and posttreatment CD4 and viral counts during treatment with etanercept, adalimumab, infliximab, and ustekinumab.^9-20 In all cases, the CD4 count was stable or increased. Similarly, the viral count was stable or decreased. All patients, except 1 by Cepeda et al,¹⁵ were on concomitant HAART.^9-14,16-20

Although data are limited, treatment of psoriatic disease with biologic agents when used in combination with HAART may have beneficial effects on CD4 and viral counts. Tumor necrosis factor has a role in HIV expression through the action of nuclear factor κβ.²¹ An increase in TNF levels is shown to be associated with increased viral count, decreased CD4 count, and increased symptoms of HIV progression, such as fever, fatigue, cachexia, and dementia.²² Although more studies are necessary, TNF-α inhibitors may have a positive effect on HIV while simultaneously treating psoriatic disease. Other cytokines (eg, IL-12, IL-23, IL-17) involved in the mechanism of action of other biologic agents (ustekinumab and secukinumab) have not been shown to be directly associated with HIV activity; however, studies have shown that IL-10 has a role in inhibiting HIV-1 replication and inhibits secretion of proinflammatory cytokines such as IL-12 and TNF-α.²¹ It may be speculated that the inhibition of IL-12 and TNF-α may create a positive feedback effect to increase IL-10, which in turn inhibits HIV replication.

Conclusion

Although there are limited data on the efficacy and safety of systemic immunosuppressive therapies for the treatment of psoriatic disease in HIV-positive patients, a review of 25 individual cases suggest that these treatments are not only required but also are sufficient to treat some of the most resistant cases. It is possible that with adequate concomitant HAART and monitoring for signs and symptoms of infection, the likelihood of serious infection may be low. Furthermore, biologic agents may have a positive effect over other systemic immunosuppressive agents, such as methotrexate and cyclosporine, in improving CD4 and viral counts when used in combination with HAART. Although randomized controlled trials are necessary, current biologic therapies such as etanercept, adalimumab, infliximab, and ustekinumab may be safe viable options as third-line treatment of severe psoriasis in the HIV-positive population.

The prevalence of psoriasis among human immunodeficiency virus (HIV)–positive patients in the United States is reported to be approximately 1% to 3%, which is similar to the rates reported for the general population.¹ Recalcitrant cases of psoriasis in patients with no history of the condition can be the initial manifestation of HIV infection. In patients with preexisting psoriasis, a flare of their disease can be seen following infection, and progression of HIV correlates with worsening psoriasis.² Psoriatic arthropathy also affects 23% to 50% of HIV-positive patients with psoriasis worldwide, which may be higher than the general population,¹ with more severe joint disease.

The management of psoriatic disease in the HIV-positive population is challenging. The current first-line recommendations for treatment include topical therapies, phototherapy, and highly active antiretroviral therapy (HAART), followed by oral retinoids as second-line agents.³ However, the clinical course of psoriasis in HIV-positive patients often is progressive and refractory²; therefore, these therapies often are inadequate to control both skin and joint manifestations. Most other currently available systemic therapies for psoriatic disease are immunosuppressive, which poses a distinct clinical challenge because HIV-positive patients are already immunocompromised.

There currently are many systemic immunosuppressive agents used for the treatment of psoriatic disease, including oral agents (eg, methotrexate, hydroxyurea, cyclosporine), as well as newer biologic medications, including tumor necrosis factor (TNF) α inhibitors etanercept, adalimumab, infliximab, golimumab, and certolizumab pegol. Golimumab and certolizumab pegol currently are indicated for psoriatic arthritis only. Other newer biologic therapies include ustekinumab, which inhibits IL-12 and IL-23, and secukinumab, which inhibits IL-17A. The purpose of this systematic review is to evaluate the most current literature to explore the efficacy and safety data as they pertain to systemic immunosuppressive therapies for the treatment of psoriatic disease in HIV-positive individuals.

Methods

To investigate the efficacy and safety of systemic immunosuppressive therapies for psoriatic disease in HIV-positive individuals, a PubMed search of articles indexed for MEDLINE (1985-2015) was conducted using the terms psoriasis and HIV and psoriatic arthritis and HIV combined with each of the following systemic immunosuppressive agents: methotrexate, hydroxyurea, cyclosporine, etanercept, adalimumab, infliximab, golimumab, certolizumab pegol, ustekinumab, and secukinumab. Pediatric cases and articles that were not available in the English language were excluded.

For each case, patient demographic information (ie, age, sex), prior failed psoriasis treatments, and history of HAART were documented. The dosing regimen of the systemic agent was noted when different from the US Food and Drug administration–approved dosage for psoriasis or psoriatic arthritis. The duration of immunosuppressive therapy as well as pretreatment and posttreatment CD4 and viral counts (when available) were collected. The response to treatment and adverse effects were summarized.

Results

Our review of the literature yielded a total of 25 reported cases of systemic immunosuppressive therapies used to treat psoriatic disease in HIV-positive patients, including methotrexate, cyclosporine, etanercept, adalimumab, in-fliximab, and ustekinumab (Table). There were no reports of the use of hydroxyurea, golimumab, certolizumab pegol, or secukinumab to treat psoriatic disease in this patient population.

Methotrexate
Eight individual cases of methotrexate used to treat psoriasis and/or psoriatic arthritis in HIV-positive patients were reported.^4-6 Duvic et al⁶ described 4 patients with psoriatic disease that was treated with methotrexate with varying efficacy. One patient developed toxic encephalopathy, which improved after discontinuation of methotrexate; however, he died 5 months later from pneumocystis pneumonia. In this early study, none of the 4 patients were on antiretroviral therapy for HIV.⁶

In the cases reported by Masson et al⁴ and Maurer et al,⁵ 4 patients were treated with a single antiretroviral agent and received appropriate prophylaxis against opportunistic infections. In 1 case, methotrexate was given at a chemotherapeutic dose of 525 mg once weekly for Kaposi sarcoma.⁴ In 2 of 4 cases, the patients developed pneumocystis pneumonia.^4,5

Cyclosporine
There were 2 case reports of successful treatment of psoriatic disease with cyclosporine in HIV-positive patients.^7,8 Skin and joint manifestations improved rapidly without reports of infection for 2⁷ and 8 years.⁸ Both patients were treated with one antiretroviral agent.^7,8

Etanercept
There were 5 case reports of successful treatment of psoriatic disease with etanercept. In all 5 cases the patients were on HAART, and the CD4 count increased or remained stable and viral count became undetectable or remained stable following treatment.^9-13 In 2 cases, the patient also had hepatitis C virus, which remained stable throughout the treatment period.^9,12 The maximum duration of treatment was 6 years, with only 1 reported adverse event.¹³ In this case reported by Aboulafia et al,¹³ the patient experienced recurrent polymicrobial infections, including enterococcal cellulitis, cystitis, and bacteremia, as well as pseudomonas pneumonia and septic arthritis. Therapy was discontinued at 6 months. Four months after discontinuation of etanercept, the patient died from infectious causes.¹³

Adalimumab
There was 1 case of successful treatment of psoriatic disease with adalimumab in an HIV-positive patient. In this case, the patient was on HAART, and CD4 and viral counts improved substantially after 30 months of treatment.¹⁴

Infliximab
Six individual cases of successful treatment of psoriatic disease with infliximab were reported.^15-17 In a report by Cepeda et al,¹⁵ HIV-positive patients with various rheumatologic diseases were chosen to receive etanercept followed by adalimumab and/or infliximab if clinical improvement was not observed on etanercept. In 3 patients with psoriasis and psoriatic arthritis, inadequate response was observed on etanercept. Two of these 3 patients received adalimumab with only partial response. All 3 were treated with infliximab in the end and showed excellent response. One of the patients experienced facial abscess responsive to antibiotics and was continued on infliximab therapy without further complications. In all 6 cases of infliximab therapy, the patients were on HAART, and CD4 and viral counts improved or remained stable.¹⁵

Ustekinumab
There were 3 case reports of successful treatment of psoriatic disease with ustekinumab in HIV-positive patients on HAART. CD4 and viral counts improved or remained stable.^18-20

Comment

Currently, all of the systemic immunosuppressive therapies approved for psoriatic disease have a warning by the US Food and Drug Administration for increased risk of serious infection. Given such labels, these therapies are not routinely prescribed for HIV-positive patients who are already immunocompromised; however, many HIV-positive patients have severe psoriatic disease that cannot be adequately treated with first- and second-line therapies including topical agents, phototherapy, or oral retinoids.

Our comprehensive review yielded a total of 25 reported cases of systemic immunosuppressive therapies used to treat psoriatic disease in HIV-positive patients including methotrexate, cyclosporine, etanercept, adalimumab, in-fliximab, and ustekinumab. Although data are limited to case reports and case series, some trends were observed.

Efficacy
In most of the cases reviewed, the patients had inadequate improvement of psoriatic disease with first- and second-line therapies, which included antiretrovirals alone, topical agents, phototherapy, and oral retinoids. Some cases reported poor response to methotrexate and cyclosporine.^4-8 Biologic agents were effective in many such cases.

Safety
Overall, there were 11 cases in which the patient was not on adequate HAART while being treated with systemic immunosuppressive therapy for psoriatic disease.^4-8,15 Of them, 3 were associated with serious infection while on methotrexate.^5,6 There was only 1 report of serious infection¹³ of 14 cases in which the patient was on concomitant HAART. In this case, which reported polymicrobial infections and subsequent death of the patient, the infections continued after discontinuing etanercept; thus, the association is unclear. Interestingly, despite multiple infections, the CD4 and viral counts were stable throughout treatment with etanercept.¹³

From reviewing the 4 total cases^5,6,13 of serious infection, HAART appears to be a valuable concomitant treatment during systemic immunosuppressive therapy for HIV-positive patients; however, it does not necessarily prevent serious infections from occurring, and thus the clinician’s diligence in monitoring for signs and symptoms of infection remains important.

CD4 and Viral Counts
Although reports of CD4 and viral counts were not available in earlier studies,^4-8 there were 15 cases that reported consistent pretreatment and posttreatment CD4 and viral counts during treatment with etanercept, adalimumab, infliximab, and ustekinumab.^9-20 In all cases, the CD4 count was stable or increased. Similarly, the viral count was stable or decreased. All patients, except 1 by Cepeda et al,¹⁵ were on concomitant HAART.^9-14,16-20

Although data are limited, treatment of psoriatic disease with biologic agents when used in combination with HAART may have beneficial effects on CD4 and viral counts. Tumor necrosis factor has a role in HIV expression through the action of nuclear factor κβ.²¹ An increase in TNF levels is shown to be associated with increased viral count, decreased CD4 count, and increased symptoms of HIV progression, such as fever, fatigue, cachexia, and dementia.²² Although more studies are necessary, TNF-α inhibitors may have a positive effect on HIV while simultaneously treating psoriatic disease. Other cytokines (eg, IL-12, IL-23, IL-17) involved in the mechanism of action of other biologic agents (ustekinumab and secukinumab) have not been shown to be directly associated with HIV activity; however, studies have shown that IL-10 has a role in inhibiting HIV-1 replication and inhibits secretion of proinflammatory cytokines such as IL-12 and TNF-α.²¹ It may be speculated that the inhibition of IL-12 and TNF-α may create a positive feedback effect to increase IL-10, which in turn inhibits HIV replication.

Conclusion

Although there are limited data on the efficacy and safety of systemic immunosuppressive therapies for the treatment of psoriatic disease in HIV-positive patients, a review of 25 individual cases suggest that these treatments are not only required but also are sufficient to treat some of the most resistant cases. It is possible that with adequate concomitant HAART and monitoring for signs and symptoms of infection, the likelihood of serious infection may be low. Furthermore, biologic agents may have a positive effect over other systemic immunosuppressive agents, such as methotrexate and cyclosporine, in improving CD4 and viral counts when used in combination with HAART. Although randomized controlled trials are necessary, current biologic therapies such as etanercept, adalimumab, infliximab, and ustekinumab may be safe viable options as third-line treatment of severe psoriasis in the HIV-positive population.

The prevalence of psoriasis among human immunodeficiency virus (HIV)–positive patients in the United States is reported to be approximately 1% to 3%, which is similar to the rates reported for the general population.¹ Recalcitrant cases of psoriasis in patients with no history of the condition can be the initial manifestation of HIV infection. In patients with preexisting psoriasis, a flare of their disease can be seen following infection, and progression of HIV correlates with worsening psoriasis.² Psoriatic arthropathy also affects 23% to 50% of HIV-positive patients with psoriasis worldwide, which may be higher than the general population,¹ with more severe joint disease.

The management of psoriatic disease in the HIV-positive population is challenging. The current first-line recommendations for treatment include topical therapies, phototherapy, and highly active antiretroviral therapy (HAART), followed by oral retinoids as second-line agents.³ However, the clinical course of psoriasis in HIV-positive patients often is progressive and refractory²; therefore, these therapies often are inadequate to control both skin and joint manifestations. Most other currently available systemic therapies for psoriatic disease are immunosuppressive, which poses a distinct clinical challenge because HIV-positive patients are already immunocompromised.

There currently are many systemic immunosuppressive agents used for the treatment of psoriatic disease, including oral agents (eg, methotrexate, hydroxyurea, cyclosporine), as well as newer biologic medications, including tumor necrosis factor (TNF) α inhibitors etanercept, adalimumab, infliximab, golimumab, and certolizumab pegol. Golimumab and certolizumab pegol currently are indicated for psoriatic arthritis only. Other newer biologic therapies include ustekinumab, which inhibits IL-12 and IL-23, and secukinumab, which inhibits IL-17A. The purpose of this systematic review is to evaluate the most current literature to explore the efficacy and safety data as they pertain to systemic immunosuppressive therapies for the treatment of psoriatic disease in HIV-positive individuals.

Methods

To investigate the efficacy and safety of systemic immunosuppressive therapies for psoriatic disease in HIV-positive individuals, a PubMed search of articles indexed for MEDLINE (1985-2015) was conducted using the terms psoriasis and HIV and psoriatic arthritis and HIV combined with each of the following systemic immunosuppressive agents: methotrexate, hydroxyurea, cyclosporine, etanercept, adalimumab, infliximab, golimumab, certolizumab pegol, ustekinumab, and secukinumab. Pediatric cases and articles that were not available in the English language were excluded.

For each case, patient demographic information (ie, age, sex), prior failed psoriasis treatments, and history of HAART were documented. The dosing regimen of the systemic agent was noted when different from the US Food and Drug administration–approved dosage for psoriasis or psoriatic arthritis. The duration of immunosuppressive therapy as well as pretreatment and posttreatment CD4 and viral counts (when available) were collected. The response to treatment and adverse effects were summarized.

Results

Our review of the literature yielded a total of 25 reported cases of systemic immunosuppressive therapies used to treat psoriatic disease in HIV-positive patients, including methotrexate, cyclosporine, etanercept, adalimumab, in-fliximab, and ustekinumab (Table). There were no reports of the use of hydroxyurea, golimumab, certolizumab pegol, or secukinumab to treat psoriatic disease in this patient population.

Methotrexate
Eight individual cases of methotrexate used to treat psoriasis and/or psoriatic arthritis in HIV-positive patients were reported.^4-6 Duvic et al⁶ described 4 patients with psoriatic disease that was treated with methotrexate with varying efficacy. One patient developed toxic encephalopathy, which improved after discontinuation of methotrexate; however, he died 5 months later from pneumocystis pneumonia. In this early study, none of the 4 patients were on antiretroviral therapy for HIV.⁶

In the cases reported by Masson et al⁴ and Maurer et al,⁵ 4 patients were treated with a single antiretroviral agent and received appropriate prophylaxis against opportunistic infections. In 1 case, methotrexate was given at a chemotherapeutic dose of 525 mg once weekly for Kaposi sarcoma.⁴ In 2 of 4 cases, the patients developed pneumocystis pneumonia.^4,5

Cyclosporine
There were 2 case reports of successful treatment of psoriatic disease with cyclosporine in HIV-positive patients.^7,8 Skin and joint manifestations improved rapidly without reports of infection for 2⁷ and 8 years.⁸ Both patients were treated with one antiretroviral agent.^7,8

Etanercept
There were 5 case reports of successful treatment of psoriatic disease with etanercept. In all 5 cases the patients were on HAART, and the CD4 count increased or remained stable and viral count became undetectable or remained stable following treatment.^9-13 In 2 cases, the patient also had hepatitis C virus, which remained stable throughout the treatment period.^9,12 The maximum duration of treatment was 6 years, with only 1 reported adverse event.¹³ In this case reported by Aboulafia et al,¹³ the patient experienced recurrent polymicrobial infections, including enterococcal cellulitis, cystitis, and bacteremia, as well as pseudomonas pneumonia and septic arthritis. Therapy was discontinued at 6 months. Four months after discontinuation of etanercept, the patient died from infectious causes.¹³

Adalimumab
There was 1 case of successful treatment of psoriatic disease with adalimumab in an HIV-positive patient. In this case, the patient was on HAART, and CD4 and viral counts improved substantially after 30 months of treatment.¹⁴

Infliximab
Six individual cases of successful treatment of psoriatic disease with infliximab were reported.^15-17 In a report by Cepeda et al,¹⁵ HIV-positive patients with various rheumatologic diseases were chosen to receive etanercept followed by adalimumab and/or infliximab if clinical improvement was not observed on etanercept. In 3 patients with psoriasis and psoriatic arthritis, inadequate response was observed on etanercept. Two of these 3 patients received adalimumab with only partial response. All 3 were treated with infliximab in the end and showed excellent response. One of the patients experienced facial abscess responsive to antibiotics and was continued on infliximab therapy without further complications. In all 6 cases of infliximab therapy, the patients were on HAART, and CD4 and viral counts improved or remained stable.¹⁵

Ustekinumab
There were 3 case reports of successful treatment of psoriatic disease with ustekinumab in HIV-positive patients on HAART. CD4 and viral counts improved or remained stable.^18-20

Comment

Currently, all of the systemic immunosuppressive therapies approved for psoriatic disease have a warning by the US Food and Drug Administration for increased risk of serious infection. Given such labels, these therapies are not routinely prescribed for HIV-positive patients who are already immunocompromised; however, many HIV-positive patients have severe psoriatic disease that cannot be adequately treated with first- and second-line therapies including topical agents, phototherapy, or oral retinoids.

Our comprehensive review yielded a total of 25 reported cases of systemic immunosuppressive therapies used to treat psoriatic disease in HIV-positive patients including methotrexate, cyclosporine, etanercept, adalimumab, in-fliximab, and ustekinumab. Although data are limited to case reports and case series, some trends were observed.

Efficacy
In most of the cases reviewed, the patients had inadequate improvement of psoriatic disease with first- and second-line therapies, which included antiretrovirals alone, topical agents, phototherapy, and oral retinoids. Some cases reported poor response to methotrexate and cyclosporine.^4-8 Biologic agents were effective in many such cases.

Safety
Overall, there were 11 cases in which the patient was not on adequate HAART while being treated with systemic immunosuppressive therapy for psoriatic disease.^4-8,15 Of them, 3 were associated with serious infection while on methotrexate.^5,6 There was only 1 report of serious infection¹³ of 14 cases in which the patient was on concomitant HAART. In this case, which reported polymicrobial infections and subsequent death of the patient, the infections continued after discontinuing etanercept; thus, the association is unclear. Interestingly, despite multiple infections, the CD4 and viral counts were stable throughout treatment with etanercept.¹³

From reviewing the 4 total cases^5,6,13 of serious infection, HAART appears to be a valuable concomitant treatment during systemic immunosuppressive therapy for HIV-positive patients; however, it does not necessarily prevent serious infections from occurring, and thus the clinician’s diligence in monitoring for signs and symptoms of infection remains important.

CD4 and Viral Counts
Although reports of CD4 and viral counts were not available in earlier studies,^4-8 there were 15 cases that reported consistent pretreatment and posttreatment CD4 and viral counts during treatment with etanercept, adalimumab, infliximab, and ustekinumab.^9-20 In all cases, the CD4 count was stable or increased. Similarly, the viral count was stable or decreased. All patients, except 1 by Cepeda et al,¹⁵ were on concomitant HAART.^9-14,16-20

Although data are limited, treatment of psoriatic disease with biologic agents when used in combination with HAART may have beneficial effects on CD4 and viral counts. Tumor necrosis factor has a role in HIV expression through the action of nuclear factor κβ.²¹ An increase in TNF levels is shown to be associated with increased viral count, decreased CD4 count, and increased symptoms of HIV progression, such as fever, fatigue, cachexia, and dementia.²² Although more studies are necessary, TNF-α inhibitors may have a positive effect on HIV while simultaneously treating psoriatic disease. Other cytokines (eg, IL-12, IL-23, IL-17) involved in the mechanism of action of other biologic agents (ustekinumab and secukinumab) have not been shown to be directly associated with HIV activity; however, studies have shown that IL-10 has a role in inhibiting HIV-1 replication and inhibits secretion of proinflammatory cytokines such as IL-12 and TNF-α.²¹ It may be speculated that the inhibition of IL-12 and TNF-α may create a positive feedback effect to increase IL-10, which in turn inhibits HIV replication.

Conclusion

Although there are limited data on the efficacy and safety of systemic immunosuppressive therapies for the treatment of psoriatic disease in HIV-positive patients, a review of 25 individual cases suggest that these treatments are not only required but also are sufficient to treat some of the most resistant cases. It is possible that with adequate concomitant HAART and monitoring for signs and symptoms of infection, the likelihood of serious infection may be low. Furthermore, biologic agents may have a positive effect over other systemic immunosuppressive agents, such as methotrexate and cyclosporine, in improving CD4 and viral counts when used in combination with HAART. Although randomized controlled trials are necessary, current biologic therapies such as etanercept, adalimumab, infliximab, and ustekinumab may be safe viable options as third-line treatment of severe psoriasis in the HIV-positive population.

Biologic agents have provided patients with moderate to severe psoriasis with treatment alternatives that have improved systemic safety profiles and disease control¹; however, case reports of associated neurologic complications have been emerging. Tumor necrosis factor α (TNF-α) inhibitors have been associated with central and peripheral demyelinating disorders. Notably, efalizumab was withdrawn from the market for its association with fatal cases of progressive multifocal leukoencephalopathy (PML).^2,3 It is imperative for dermatologists to be familiar with the clinical presentation, evaluation, and diagnostic criteria of neurologic complications of biologic agents used in the treatment of psoriasis.

Leukoencephalopathy

Progressive multifocal leukoencephalopathy is a fatal demyelinating neurodegenerative disease caused by reactivation of the ubiquitous John Cunningham virus. Primary asymptomatic infection is thought to occur during childhood, then the virus remains latent. Reactivation usually occurs during severe immunosuppression and is classically described in human immunodeficiency virus infection, lymphoproliferative disorders, and other forms of cancer.⁴ A summary of PML and its association with biologics is found in Table 1.^5-13 Few case reports of TNF-α inhibitor–associated PML exist, mostly in the presence of confounding factors such as immunosuppression or underlying autoimmune disease.^10-13 Presenting symptoms of PML often are subacute, rapidly progressive, and can be focal or multifocal and include motor, cognitive, and visual deficits. Of note, there are 2 reported cases of ustekinumab associated with reversible posterior leukoencephalopathy syndrome, which is a hypertensive encephalopathy characterized by headache, altered mental status, vision abnormalities, and seizures.^14,15 Fortunately, this disease is reversible with blood pressure control and removal of the immunosuppressive agent.¹⁶

Demyelinating Disorders

Clinical presentation of demyelinating events associated with biologic agents are varied but include optic neuritis, multiple sclerosis, transverse myelitis, and Guillain-Barré syndrome, among others.^17-28 These demyelinating disorders with their salient features and associated biologics are summarized in Table 2.^17-20,22-28 Patients on biologic agents, especially TNF-α inhibitors, with new-onset visual, motor, or sensory changes warrant closer inspection. Currently, there are no data on any neurologic side effects occurring with the new biologic secukinumab.²⁹

Conclusion

Biologic agents are effective in treating moderate to severe plaque psoriasis, but awareness of associated neurological adverse effects, though rare, is important to consider. Physicians need to be able to counsel patients concerning these risks and promote informed decision-making prior to initiating biologics. Patients with a personal or strong family history of demyelinating disease should be considered for alternative treatment options before initiating anti–TNF-α therapy. Since the withdrawal of efalizumab, no new cases of PML have been reported in patients who were previously on a long-term course. Dermatologists should be vigilant in detecting signs of neurological complications so that an expedited evaluation and neurology referral may prevent progression of disease.

Biologic agents have provided patients with moderate to severe psoriasis with treatment alternatives that have improved systemic safety profiles and disease control¹; however, case reports of associated neurologic complications have been emerging. Tumor necrosis factor α (TNF-α) inhibitors have been associated with central and peripheral demyelinating disorders. Notably, efalizumab was withdrawn from the market for its association with fatal cases of progressive multifocal leukoencephalopathy (PML).^2,3 It is imperative for dermatologists to be familiar with the clinical presentation, evaluation, and diagnostic criteria of neurologic complications of biologic agents used in the treatment of psoriasis.

Leukoencephalopathy

Progressive multifocal leukoencephalopathy is a fatal demyelinating neurodegenerative disease caused by reactivation of the ubiquitous John Cunningham virus. Primary asymptomatic infection is thought to occur during childhood, then the virus remains latent. Reactivation usually occurs during severe immunosuppression and is classically described in human immunodeficiency virus infection, lymphoproliferative disorders, and other forms of cancer.⁴ A summary of PML and its association with biologics is found in Table 1.^5-13 Few case reports of TNF-α inhibitor–associated PML exist, mostly in the presence of confounding factors such as immunosuppression or underlying autoimmune disease.^10-13 Presenting symptoms of PML often are subacute, rapidly progressive, and can be focal or multifocal and include motor, cognitive, and visual deficits. Of note, there are 2 reported cases of ustekinumab associated with reversible posterior leukoencephalopathy syndrome, which is a hypertensive encephalopathy characterized by headache, altered mental status, vision abnormalities, and seizures.^14,15 Fortunately, this disease is reversible with blood pressure control and removal of the immunosuppressive agent.¹⁶

Demyelinating Disorders

Clinical presentation of demyelinating events associated with biologic agents are varied but include optic neuritis, multiple sclerosis, transverse myelitis, and Guillain-Barré syndrome, among others.^17-28 These demyelinating disorders with their salient features and associated biologics are summarized in Table 2.^17-20,22-28 Patients on biologic agents, especially TNF-α inhibitors, with new-onset visual, motor, or sensory changes warrant closer inspection. Currently, there are no data on any neurologic side effects occurring with the new biologic secukinumab.²⁹

Conclusion

Biologic agents are effective in treating moderate to severe plaque psoriasis, but awareness of associated neurological adverse effects, though rare, is important to consider. Physicians need to be able to counsel patients concerning these risks and promote informed decision-making prior to initiating biologics. Patients with a personal or strong family history of demyelinating disease should be considered for alternative treatment options before initiating anti–TNF-α therapy. Since the withdrawal of efalizumab, no new cases of PML have been reported in patients who were previously on a long-term course. Dermatologists should be vigilant in detecting signs of neurological complications so that an expedited evaluation and neurology referral may prevent progression of disease.

Biologic agents have provided patients with moderate to severe psoriasis with treatment alternatives that have improved systemic safety profiles and disease control¹; however, case reports of associated neurologic complications have been emerging. Tumor necrosis factor α (TNF-α) inhibitors have been associated with central and peripheral demyelinating disorders. Notably, efalizumab was withdrawn from the market for its association with fatal cases of progressive multifocal leukoencephalopathy (PML).^2,3 It is imperative for dermatologists to be familiar with the clinical presentation, evaluation, and diagnostic criteria of neurologic complications of biologic agents used in the treatment of psoriasis.

Leukoencephalopathy

Progressive multifocal leukoencephalopathy is a fatal demyelinating neurodegenerative disease caused by reactivation of the ubiquitous John Cunningham virus. Primary asymptomatic infection is thought to occur during childhood, then the virus remains latent. Reactivation usually occurs during severe immunosuppression and is classically described in human immunodeficiency virus infection, lymphoproliferative disorders, and other forms of cancer.⁴ A summary of PML and its association with biologics is found in Table 1.^5-13 Few case reports of TNF-α inhibitor–associated PML exist, mostly in the presence of confounding factors such as immunosuppression or underlying autoimmune disease.^10-13 Presenting symptoms of PML often are subacute, rapidly progressive, and can be focal or multifocal and include motor, cognitive, and visual deficits. Of note, there are 2 reported cases of ustekinumab associated with reversible posterior leukoencephalopathy syndrome, which is a hypertensive encephalopathy characterized by headache, altered mental status, vision abnormalities, and seizures.^14,15 Fortunately, this disease is reversible with blood pressure control and removal of the immunosuppressive agent.¹⁶

Demyelinating Disorders

Clinical presentation of demyelinating events associated with biologic agents are varied but include optic neuritis, multiple sclerosis, transverse myelitis, and Guillain-Barré syndrome, among others.^17-28 These demyelinating disorders with their salient features and associated biologics are summarized in Table 2.^17-20,22-28 Patients on biologic agents, especially TNF-α inhibitors, with new-onset visual, motor, or sensory changes warrant closer inspection. Currently, there are no data on any neurologic side effects occurring with the new biologic secukinumab.²⁹

Conclusion

Biologic agents are effective in treating moderate to severe plaque psoriasis, but awareness of associated neurological adverse effects, though rare, is important to consider. Physicians need to be able to counsel patients concerning these risks and promote informed decision-making prior to initiating biologics. Patients with a personal or strong family history of demyelinating disease should be considered for alternative treatment options before initiating anti–TNF-α therapy. Since the withdrawal of efalizumab, no new cases of PML have been reported in patients who were previously on a long-term course. Dermatologists should be vigilant in detecting signs of neurological complications so that an expedited evaluation and neurology referral may prevent progression of disease.

IN THIS ARTICLE

• Presenting symptoms
• Diagnostic tests
• Differential diagnostic criteria

Multiple myeloma (MM) is a fatal, malignant neoplasm that originates in the plasma cells of bone marrow. A genetic mutation in the plasma cells creates myeloma cells, which replicate and produce monoclonal protein (M-protein). This accumulation of cells and abnormal protein can result in destruction and eventual marrow failure.^1,2

MM’s insidious nature means it often goes undetected or misdiagnosed in its early stages; this delayed diagnosis can cause sequelae that limit quality of life. Furthermore, the five-year survival rate for myeloma varies by stage at which the disease is diagnosed: from 48% for distant (metastasized) myeloma to 71% for localized disease.³ It has also been noted that, in the past two decades, improvements in available treatment options and supportive care have contributed to a doubling of median survival time (from three years to six years).⁴ It is therefore paramount that providers be aware of MM and its signs to facilitate early diagnosis and treatment.

INCIDENCE AND EPIDEMIOLOGY

MM accounts for 1% of all cancers and about 10% of all hematologic malignancies.⁵ In 2017, the American Cancer Society estimated that more than 30,000 new cases of MM would be diagnosed in the United States.⁶ Additionally, MM was expected to cause more than 12,000 deaths last year.⁶

Median age at diagnosis is 69.³ In fact, 75% of men are older than 75 and 79% of women are older than 70 at diagnosis.¹

Apart from age, other risk factors for MM have been identified but not fully explicated. For example, the disease is more common in men than in women (with men comprising two-thirds of new cases per year).³ MM is also two to three times more common in black than in white persons, making it the most common hematologic malignancy in this demographic group.^3,7

The possibility of a genetic predisposition has also been studied. Several analyses have indicated an increased risk for MM in patients with a family history of the disease—as much as four times higher in those with an affected first-degree relative. This risk was further elevated in black compared with white patients (odds ratios, 17.4 and 1.5, respectively).⁷ However, many patients with MM have no relatives with this disorder.^6,8

DISEASE PROGRESSION

Almost all patients who develop MM also experience an asymptomatic premalignant stage called monoclonal gammopathy of undetermined significance (MGUS). MGUS is present in 3% to 4% of the general population older than 50 and is often an incidental finding. This stage almost always precedes MM—but because it is asymptomatic, only 10% of individuals diagnosed with MM have a known history of MGUS.⁸

In some patients, an asymptomatic intermediate stage called smoldering multiple myeloma (SMM) can be identified. SMM progresses to MM at a rate of 10% per year for the first five years; the rate decreases to 3% per year over the following five years, and 1% per year after that.⁸

MM is not curable, but as noted, the survival rate is steadily increasing due to rapidly evolving treatment regimens. Discussion of treatment is outside the scope of this article, but early diagnosis can improve quality of life and clinical outcomes and prolong life expectancy.

SYMPTOMS

The initial symptoms of MM can be nonspecific and may lead the provider to suspect a host of other conditions.^2,6 (Those for advanced disease are also vague but tend to be more pronounced.) These may include fatigue, weakness, easy bruising or bleeding, and bone pain. Other common clinical manifestations of MM are anemia, chronic infection, bone disease, and/or renal failure.^1,4 Patients may also experience loss of appetite, nausea, vomiting, increased thirst, and increased urination.⁹

Recent studies have shown that patients with SMM and/or MGUS also exhibit early signs of bone disease and increased risk for fracture.¹⁰ Eighty percent of patients who progress to MM have evidence of pathologic bone fractures.¹⁰ It is also possible for bones in the spine to weaken and collapse, pressing on the spinal nerves. This is known as spinal cord compression, which can manifest with sudden, severe back pain or numbness and/or muscle weakness (most often in the legs).⁶

MM must be included in the differential diagnosis, particularly when symptoms do not point to one specific disease process. Without early diagnosis, disease progression can result in complications such as bone fracture and osteoporosis, reduced kidney function, peripheral neuropathy, chronic anemia, and ultimately, death.^2,6 The presence of bone fractures increases mortality risk by 20%.¹⁰

Evidence of MM may be discovered during routine bloodwork and screening tests, while presenting symptoms or subtle changes in lab results can raise suspicion for the disease. Initial bloodwork abnormalities include anemia, elevated calcium levels, renal insufficiency, and/or elevated protein levels.⁸

A combination of abnormalities in the complete blood count (CBC) and complete metabolic panel (CMP), along with symptoms, should alert the provider to the possibility of MM, prompting additional workup. Table 1 outlines suggested diagnostic tests; the possible findings are discussed below.

CBC. The CBC may reveal abnormalities including anemia (which occurs in 75% of patients with MM), thrombocytopenia, and leukopenia.^1,8 These findings can contribute to fatigue, increased incidence of infection, and abnormal bruising of the skin.^2,8

CMP. A CMP may show increases in ­serum calcium or protein. Hypercalcemia occurs in 15% of patients with MM, leading to symptoms such as loss of appetite, nausea, vomiting, increased urination, weakness, and confusion.⁸ An increase in protein may alter the albumin/globulin ratio, which should raise suspicion for MM. A decrease in albumin can signify disease severity. Also, the CMP may show worsening renal function and elevated serum creatinine, which occurs in 20% of patients with MM.⁸

Serum protein electrophoresis (SPEP). Suspicion of MM should prompt the clinician to evaluate proteins via SPEP. This test may be indicated for patients with anemia, hypercalcemia, bone pain, and unexplained neuropathy.⁹ The electrophoresis separates proteins based on their physical properties. This identifies the presence and amount of M-protein, which can determine the extent of the disease.¹ M-protein is identified in approximately 82% of patients with MM using this test.⁸

Serum free light chain (FLC) assay. This diagnostic test can identify MM in individuals with high clinical suspicion for the disease but no discernible M-protein on SPEP; it increases sensitivity to 97%.⁸ The serum FLC assay evaluates for presence and ratio of free light chains—proteins produced by plasma cells. This test is also useful for monitoring treatment response and disease progression.¹

Urine protein electrophoresis (UPEP). The UPEP separates proteins according to charge, which is helpful for classifying renal injury. Protein patterns are interpreted and may be reported as glomerular, tubular, or mixed. UPEP also tests for M-protein in the urine.^1,11

24-hour urine. The 24-h urine test quantifies the amount and type of protein excreted in the urine and helps determine the extent of kidney disease.¹

Skeletal survey. MM causes significant bone changes that can be identified with radiographic studies. The most common locations for fractures are the vertebral, pelvic, and clavicular areas.¹⁰ Currently, the skeletal survey is the gold standard for detecting fractures and osteolytic lesions associated with MM.¹⁰ Radiographic films ordered for other purposes may uncover abnormalities in bones.

Bone mineral density (BMD) test. Most often, BMD testing is used to evaluate treatment and progression of bone involvement. Because it can uncover osteopenia or osteoporosis, however, it can also be used to corroborate the diagnosis of MM.¹⁰

Once the presence of M-protein is identified, patients are referred for specialty care. At that time, further workup will include a bone marrow biopsy and imaging studies, such as additional radiographic films, CT scans (without contrast, as contrast dye can damage frail kidneys), and MRI.^1,8 These diagnostic tests provide useful information for the classification of the disease and guide initiation of treatment.

CLASSIFICATION OF DISEASE

MM can be classified into three stages—MGUS, SMM, and MM—based on recommendations from the International Myeloma Working Group.¹² Table 2 outlines the diagnostic criteria for each stage.

Individuals with MGUS and SMM are considered asymptomatic; guidelines do not recommend treatment for these patients. Those who are diagnosed with MM are referred to oncologists and treated based on current clinical practice guidelines.¹

CONCLUSION

Multiple myeloma is a malignant neoplasm without a cure. Presenting symptoms may include anemia, bone pain, elevated creatinine or serum protein, fatigue, and hypercalcemia. Early diagnosis is key to early intervention and treatment, which can improve quality of life and clinical outcomes for those affected. Primary care providers play a major role in recognizing the subtle symptoms and ordering the appropriate diagnostic tests.

IN THIS ARTICLE

• Presenting symptoms
• Diagnostic tests
• Differential diagnostic criteria

Multiple myeloma (MM) is a fatal, malignant neoplasm that originates in the plasma cells of bone marrow. A genetic mutation in the plasma cells creates myeloma cells, which replicate and produce monoclonal protein (M-protein). This accumulation of cells and abnormal protein can result in destruction and eventual marrow failure.^1,2

MM’s insidious nature means it often goes undetected or misdiagnosed in its early stages; this delayed diagnosis can cause sequelae that limit quality of life. Furthermore, the five-year survival rate for myeloma varies by stage at which the disease is diagnosed: from 48% for distant (metastasized) myeloma to 71% for localized disease.³ It has also been noted that, in the past two decades, improvements in available treatment options and supportive care have contributed to a doubling of median survival time (from three years to six years).⁴ It is therefore paramount that providers be aware of MM and its signs to facilitate early diagnosis and treatment.

INCIDENCE AND EPIDEMIOLOGY

MM accounts for 1% of all cancers and about 10% of all hematologic malignancies.⁵ In 2017, the American Cancer Society estimated that more than 30,000 new cases of MM would be diagnosed in the United States.⁶ Additionally, MM was expected to cause more than 12,000 deaths last year.⁶

Median age at diagnosis is 69.³ In fact, 75% of men are older than 75 and 79% of women are older than 70 at diagnosis.¹

Apart from age, other risk factors for MM have been identified but not fully explicated. For example, the disease is more common in men than in women (with men comprising two-thirds of new cases per year).³ MM is also two to three times more common in black than in white persons, making it the most common hematologic malignancy in this demographic group.^3,7

The possibility of a genetic predisposition has also been studied. Several analyses have indicated an increased risk for MM in patients with a family history of the disease—as much as four times higher in those with an affected first-degree relative. This risk was further elevated in black compared with white patients (odds ratios, 17.4 and 1.5, respectively).⁷ However, many patients with MM have no relatives with this disorder.^6,8

DISEASE PROGRESSION

Almost all patients who develop MM also experience an asymptomatic premalignant stage called monoclonal gammopathy of undetermined significance (MGUS). MGUS is present in 3% to 4% of the general population older than 50 and is often an incidental finding. This stage almost always precedes MM—but because it is asymptomatic, only 10% of individuals diagnosed with MM have a known history of MGUS.⁸

In some patients, an asymptomatic intermediate stage called smoldering multiple myeloma (SMM) can be identified. SMM progresses to MM at a rate of 10% per year for the first five years; the rate decreases to 3% per year over the following five years, and 1% per year after that.⁸

MM is not curable, but as noted, the survival rate is steadily increasing due to rapidly evolving treatment regimens. Discussion of treatment is outside the scope of this article, but early diagnosis can improve quality of life and clinical outcomes and prolong life expectancy.

SYMPTOMS

The initial symptoms of MM can be nonspecific and may lead the provider to suspect a host of other conditions.^2,6 (Those for advanced disease are also vague but tend to be more pronounced.) These may include fatigue, weakness, easy bruising or bleeding, and bone pain. Other common clinical manifestations of MM are anemia, chronic infection, bone disease, and/or renal failure.^1,4 Patients may also experience loss of appetite, nausea, vomiting, increased thirst, and increased urination.⁹

Recent studies have shown that patients with SMM and/or MGUS also exhibit early signs of bone disease and increased risk for fracture.¹⁰ Eighty percent of patients who progress to MM have evidence of pathologic bone fractures.¹⁰ It is also possible for bones in the spine to weaken and collapse, pressing on the spinal nerves. This is known as spinal cord compression, which can manifest with sudden, severe back pain or numbness and/or muscle weakness (most often in the legs).⁶

MM must be included in the differential diagnosis, particularly when symptoms do not point to one specific disease process. Without early diagnosis, disease progression can result in complications such as bone fracture and osteoporosis, reduced kidney function, peripheral neuropathy, chronic anemia, and ultimately, death.^2,6 The presence of bone fractures increases mortality risk by 20%.¹⁰

Evidence of MM may be discovered during routine bloodwork and screening tests, while presenting symptoms or subtle changes in lab results can raise suspicion for the disease. Initial bloodwork abnormalities include anemia, elevated calcium levels, renal insufficiency, and/or elevated protein levels.⁸

A combination of abnormalities in the complete blood count (CBC) and complete metabolic panel (CMP), along with symptoms, should alert the provider to the possibility of MM, prompting additional workup. Table 1 outlines suggested diagnostic tests; the possible findings are discussed below.

CBC. The CBC may reveal abnormalities including anemia (which occurs in 75% of patients with MM), thrombocytopenia, and leukopenia.^1,8 These findings can contribute to fatigue, increased incidence of infection, and abnormal bruising of the skin.^2,8

CMP. A CMP may show increases in ­serum calcium or protein. Hypercalcemia occurs in 15% of patients with MM, leading to symptoms such as loss of appetite, nausea, vomiting, increased urination, weakness, and confusion.⁸ An increase in protein may alter the albumin/globulin ratio, which should raise suspicion for MM. A decrease in albumin can signify disease severity. Also, the CMP may show worsening renal function and elevated serum creatinine, which occurs in 20% of patients with MM.⁸

Serum protein electrophoresis (SPEP). Suspicion of MM should prompt the clinician to evaluate proteins via SPEP. This test may be indicated for patients with anemia, hypercalcemia, bone pain, and unexplained neuropathy.⁹ The electrophoresis separates proteins based on their physical properties. This identifies the presence and amount of M-protein, which can determine the extent of the disease.¹ M-protein is identified in approximately 82% of patients with MM using this test.⁸

Serum free light chain (FLC) assay. This diagnostic test can identify MM in individuals with high clinical suspicion for the disease but no discernible M-protein on SPEP; it increases sensitivity to 97%.⁸ The serum FLC assay evaluates for presence and ratio of free light chains—proteins produced by plasma cells. This test is also useful for monitoring treatment response and disease progression.¹

Urine protein electrophoresis (UPEP). The UPEP separates proteins according to charge, which is helpful for classifying renal injury. Protein patterns are interpreted and may be reported as glomerular, tubular, or mixed. UPEP also tests for M-protein in the urine.^1,11

24-hour urine. The 24-h urine test quantifies the amount and type of protein excreted in the urine and helps determine the extent of kidney disease.¹

Skeletal survey. MM causes significant bone changes that can be identified with radiographic studies. The most common locations for fractures are the vertebral, pelvic, and clavicular areas.¹⁰ Currently, the skeletal survey is the gold standard for detecting fractures and osteolytic lesions associated with MM.¹⁰ Radiographic films ordered for other purposes may uncover abnormalities in bones.

Bone mineral density (BMD) test. Most often, BMD testing is used to evaluate treatment and progression of bone involvement. Because it can uncover osteopenia or osteoporosis, however, it can also be used to corroborate the diagnosis of MM.¹⁰

Once the presence of M-protein is identified, patients are referred for specialty care. At that time, further workup will include a bone marrow biopsy and imaging studies, such as additional radiographic films, CT scans (without contrast, as contrast dye can damage frail kidneys), and MRI.^1,8 These diagnostic tests provide useful information for the classification of the disease and guide initiation of treatment.

CLASSIFICATION OF DISEASE

MM can be classified into three stages—MGUS, SMM, and MM—based on recommendations from the International Myeloma Working Group.¹² Table 2 outlines the diagnostic criteria for each stage.

Individuals with MGUS and SMM are considered asymptomatic; guidelines do not recommend treatment for these patients. Those who are diagnosed with MM are referred to oncologists and treated based on current clinical practice guidelines.¹

CONCLUSION

Multiple myeloma is a malignant neoplasm without a cure. Presenting symptoms may include anemia, bone pain, elevated creatinine or serum protein, fatigue, and hypercalcemia. Early diagnosis is key to early intervention and treatment, which can improve quality of life and clinical outcomes for those affected. Primary care providers play a major role in recognizing the subtle symptoms and ordering the appropriate diagnostic tests.

IN THIS ARTICLE

• Presenting symptoms
• Diagnostic tests
• Differential diagnostic criteria

Multiple myeloma (MM) is a fatal, malignant neoplasm that originates in the plasma cells of bone marrow. A genetic mutation in the plasma cells creates myeloma cells, which replicate and produce monoclonal protein (M-protein). This accumulation of cells and abnormal protein can result in destruction and eventual marrow failure.^1,2

MM’s insidious nature means it often goes undetected or misdiagnosed in its early stages; this delayed diagnosis can cause sequelae that limit quality of life. Furthermore, the five-year survival rate for myeloma varies by stage at which the disease is diagnosed: from 48% for distant (metastasized) myeloma to 71% for localized disease.³ It has also been noted that, in the past two decades, improvements in available treatment options and supportive care have contributed to a doubling of median survival time (from three years to six years).⁴ It is therefore paramount that providers be aware of MM and its signs to facilitate early diagnosis and treatment.

INCIDENCE AND EPIDEMIOLOGY

MM accounts for 1% of all cancers and about 10% of all hematologic malignancies.⁵ In 2017, the American Cancer Society estimated that more than 30,000 new cases of MM would be diagnosed in the United States.⁶ Additionally, MM was expected to cause more than 12,000 deaths last year.⁶

Median age at diagnosis is 69.³ In fact, 75% of men are older than 75 and 79% of women are older than 70 at diagnosis.¹

Apart from age, other risk factors for MM have been identified but not fully explicated. For example, the disease is more common in men than in women (with men comprising two-thirds of new cases per year).³ MM is also two to three times more common in black than in white persons, making it the most common hematologic malignancy in this demographic group.^3,7

The possibility of a genetic predisposition has also been studied. Several analyses have indicated an increased risk for MM in patients with a family history of the disease—as much as four times higher in those with an affected first-degree relative. This risk was further elevated in black compared with white patients (odds ratios, 17.4 and 1.5, respectively).⁷ However, many patients with MM have no relatives with this disorder.^6,8

DISEASE PROGRESSION

Almost all patients who develop MM also experience an asymptomatic premalignant stage called monoclonal gammopathy of undetermined significance (MGUS). MGUS is present in 3% to 4% of the general population older than 50 and is often an incidental finding. This stage almost always precedes MM—but because it is asymptomatic, only 10% of individuals diagnosed with MM have a known history of MGUS.⁸

In some patients, an asymptomatic intermediate stage called smoldering multiple myeloma (SMM) can be identified. SMM progresses to MM at a rate of 10% per year for the first five years; the rate decreases to 3% per year over the following five years, and 1% per year after that.⁸

MM is not curable, but as noted, the survival rate is steadily increasing due to rapidly evolving treatment regimens. Discussion of treatment is outside the scope of this article, but early diagnosis can improve quality of life and clinical outcomes and prolong life expectancy.

SYMPTOMS

The initial symptoms of MM can be nonspecific and may lead the provider to suspect a host of other conditions.^2,6 (Those for advanced disease are also vague but tend to be more pronounced.) These may include fatigue, weakness, easy bruising or bleeding, and bone pain. Other common clinical manifestations of MM are anemia, chronic infection, bone disease, and/or renal failure.^1,4 Patients may also experience loss of appetite, nausea, vomiting, increased thirst, and increased urination.⁹

Recent studies have shown that patients with SMM and/or MGUS also exhibit early signs of bone disease and increased risk for fracture.¹⁰ Eighty percent of patients who progress to MM have evidence of pathologic bone fractures.¹⁰ It is also possible for bones in the spine to weaken and collapse, pressing on the spinal nerves. This is known as spinal cord compression, which can manifest with sudden, severe back pain or numbness and/or muscle weakness (most often in the legs).⁶

MM must be included in the differential diagnosis, particularly when symptoms do not point to one specific disease process. Without early diagnosis, disease progression can result in complications such as bone fracture and osteoporosis, reduced kidney function, peripheral neuropathy, chronic anemia, and ultimately, death.^2,6 The presence of bone fractures increases mortality risk by 20%.¹⁰

Evidence of MM may be discovered during routine bloodwork and screening tests, while presenting symptoms or subtle changes in lab results can raise suspicion for the disease. Initial bloodwork abnormalities include anemia, elevated calcium levels, renal insufficiency, and/or elevated protein levels.⁸

A combination of abnormalities in the complete blood count (CBC) and complete metabolic panel (CMP), along with symptoms, should alert the provider to the possibility of MM, prompting additional workup. Table 1 outlines suggested diagnostic tests; the possible findings are discussed below.

CBC. The CBC may reveal abnormalities including anemia (which occurs in 75% of patients with MM), thrombocytopenia, and leukopenia.^1,8 These findings can contribute to fatigue, increased incidence of infection, and abnormal bruising of the skin.^2,8

CMP. A CMP may show increases in ­serum calcium or protein. Hypercalcemia occurs in 15% of patients with MM, leading to symptoms such as loss of appetite, nausea, vomiting, increased urination, weakness, and confusion.⁸ An increase in protein may alter the albumin/globulin ratio, which should raise suspicion for MM. A decrease in albumin can signify disease severity. Also, the CMP may show worsening renal function and elevated serum creatinine, which occurs in 20% of patients with MM.⁸

Serum protein electrophoresis (SPEP). Suspicion of MM should prompt the clinician to evaluate proteins via SPEP. This test may be indicated for patients with anemia, hypercalcemia, bone pain, and unexplained neuropathy.⁹ The electrophoresis separates proteins based on their physical properties. This identifies the presence and amount of M-protein, which can determine the extent of the disease.¹ M-protein is identified in approximately 82% of patients with MM using this test.⁸

Serum free light chain (FLC) assay. This diagnostic test can identify MM in individuals with high clinical suspicion for the disease but no discernible M-protein on SPEP; it increases sensitivity to 97%.⁸ The serum FLC assay evaluates for presence and ratio of free light chains—proteins produced by plasma cells. This test is also useful for monitoring treatment response and disease progression.¹

Urine protein electrophoresis (UPEP). The UPEP separates proteins according to charge, which is helpful for classifying renal injury. Protein patterns are interpreted and may be reported as glomerular, tubular, or mixed. UPEP also tests for M-protein in the urine.^1,11

24-hour urine. The 24-h urine test quantifies the amount and type of protein excreted in the urine and helps determine the extent of kidney disease.¹

Skeletal survey. MM causes significant bone changes that can be identified with radiographic studies. The most common locations for fractures are the vertebral, pelvic, and clavicular areas.¹⁰ Currently, the skeletal survey is the gold standard for detecting fractures and osteolytic lesions associated with MM.¹⁰ Radiographic films ordered for other purposes may uncover abnormalities in bones.

Bone mineral density (BMD) test. Most often, BMD testing is used to evaluate treatment and progression of bone involvement. Because it can uncover osteopenia or osteoporosis, however, it can also be used to corroborate the diagnosis of MM.¹⁰

Once the presence of M-protein is identified, patients are referred for specialty care. At that time, further workup will include a bone marrow biopsy and imaging studies, such as additional radiographic films, CT scans (without contrast, as contrast dye can damage frail kidneys), and MRI.^1,8 These diagnostic tests provide useful information for the classification of the disease and guide initiation of treatment.

CLASSIFICATION OF DISEASE

MM can be classified into three stages—MGUS, SMM, and MM—based on recommendations from the International Myeloma Working Group.¹² Table 2 outlines the diagnostic criteria for each stage.

Individuals with MGUS and SMM are considered asymptomatic; guidelines do not recommend treatment for these patients. Those who are diagnosed with MM are referred to oncologists and treated based on current clinical practice guidelines.¹

CONCLUSION

Multiple myeloma is a malignant neoplasm without a cure. Presenting symptoms may include anemia, bone pain, elevated creatinine or serum protein, fatigue, and hypercalcemia. Early diagnosis is key to early intervention and treatment, which can improve quality of life and clinical outcomes for those affected. Primary care providers play a major role in recognizing the subtle symptoms and ordering the appropriate diagnostic tests.

From the Geriatric Education and Research in Aging Sciences Centre, McMaster University Hamilton, ON (Dr. McArthur) and the University of Waterloo and Research Institute for Aging, Waterloo, ON (Dr. Giangregorio), Canada

Abstract

• Objective: To synthesize the available literature on exercise and falls reduction interventions in long-term care (LTC) and provide practical information for clinicians and other decision makers.
• Methods: Review of positive trials included in systematic reviews.
• Results: Falls are a major concern for residents, families, clinicians, and decision-makers in LTC. Exercise is recommended as part of a multifactorial falls prevention program for residents in LTC. Strength and balance exercises should be incorporated into the multifactorial falls prevention program. They should be challenging and progressed as the residents’ abilities improve. Evidence suggests that exercises should be completed 2 to 3 times per week for a period longer than 6 months. Exercise programs in LTC should be resident-centered and should consider residents’ potential physical and cognitive impairments. Exercises in standing should be prioritized where appropriate.
• Conclusion: Appropriately challenging and progressive strength and balance exercises should be included in a multifactorial falls prevention program for residents in LTC.

Key words: long-term care; nursing homes; falls reduction; exercise.

Falls are common in long-term care (LTC) homes: the estimated falls rate is 1.5 falls per bed per year, which is 3 times greater than that for older adults living in the community [1]. Falls can have significant consequences for residents in LTC, including functional disability, fractures, pain, reduced quality of life, and death [1–6]. Indeed, 25% of residents who are hospitalized after a fall die within 1 year [3]. Consequently, falls prevention programs are important to help in reducing falls and averting the associated negative consequences.

Exercise may address the circumstances and physical deconditioning that often contribute to falls in LTC residents. Weight shifting [7], walking, and transferring [8–10], are common activities that precede falls, suggesting that balance, gait, and functional mobility training may be possible targets for prevention. Additionally, it is estimated that LTC residents spend three quarters of their waking time in sedentary activities [11,12] and have a high prevalence of sarcopenia [13–16]. Challenging balance training and resistance exercise are well-known intervention for reducing falls [17] and improving muscle strength for community-dwelling older adults [18]. However, evidence around balance and strength training for preventing falls in LTC is mixed [17,19,20], and careful planning and modification of exercises is necessary to meet the needs of LTC residents.

Residents in LTC are often medically complex, with multiple comorbidities [21] that can affect their ability to meaningfully participate in exercise. In Canada, 56.3% of residents have a diagnosis of Alzheimer’s or other dementias, 25.0% have diabetes, 14.4% have chronic obstructive pulmonary disease, and 21.2% have experienced a stroke [21]. Residents also often have significant functional impairments. For example, 97% of residents require assistance with basic activities of daily living [21]. Therefore, the lack of effect of exercise as a single falls prevention strategy observed in previous studies may be because the often complex, multimorbid LTC population likely requires a multifactorial approach to fall prevention [17]. Additionally, organizational aspects of LTC homes (eg, specific funds dedicated to employing exercise professionals and to support exercise programming) can affect residents’ engagement in exercise [22,23]. Subsequently, prescribing exercises in the LTC context must consider both resident characteristics and organizational features of the LTC home (eg, professionals available to support exercise programming).

A comprehensive exercise prescription describes the elements of an appropriate exercise program to facilitate implementation of that program. The exercise prescription should include a description of the type (eg, balance, strength) and intensity of exercises (eg, subjective or objective measurement of how hard the resident is working) included in the program [24]. The prescription should also include a description of the dose of exercise: frequency of exercise participation (eg, 2 days per week), duration of individual exercise sessions (eg, 30-minute sessions), and duration of exercise program (eg, 12-week program) [24]. Lastly, the prescription should describe the setting of the exercise program (eg, group or individual basis) and the professional delivering the program (eg, physiotherapist, fitness instructor) [24].

Therefore, the objectives of this article are to (1) synthesize studies demonstrating a positive effect of exercise on reducing falls for residents in LTC; (2) provide an overview of the principles of balance and strength training to guide clinicians in designing appropriate exercise prescription; and (3) make suggestions for clinical practice regarding an appropriate strength and balance exercise protocol by considering the influence of the LTC context.

Methods

To provide clinicians and other policy-makers with a description of which balance and strength exercises may be effective for preventing falls, we synthesized trials that demonstrated a positive effect on reducing falls or falls risk for residents in LTC. Studies were identified through a database search for systematic reviews in PubMed, Ovid, and Google Scholar using the keywords falls, long-term care, nursing homes, exercise, strength, balance, and systematic reviews. Our purpose was to provide practical information on what works to prevent falls through balance and strength training for residents in LTC rather than to evaluate the available evidence. Therefore, only positive trials from systematic reviews were discussed, as we wanted to present exercises that seem to have a positive effect on decreasing falls. Positive trials were defined as those included in identified systematic reviews with a risk or rate ratio and confidence intervals below 1.0.

We first provide an overview of the conclusions of the systematic reviews found in our search. Next, for each positive trial we describe the following elements of the exercise component of the intervention: frequency, time of sessions, length of program, intensity, type of exercise including a description of the specific exercises performed, whether the intervention was delivered in a group or on an individual basis, the professional delivering the intervention, and any other features of the intervention aside from the exercise component. We used the ProFaNE taxonomy definitions [25] to identify and describe each element of the exercise interventions. Frequency is the number of times per week that residents engage in sessions, time of sessions is the amount allocated to each exercise session, duration of program is how long the resident participates in the exercise program, and intensity is the subjective or objective report of how hard the resident is working [25]. The types of exercises described were those targeting balance defined as “...the efficient transfer of bodyweight from one part of the body to another or challenges specific aspects of the balance systems (eg, vestibular system)” [25], and strength defined as “...contracting the muscles against a resistance to ‘overload’ and bring about a training effect in the muscular system” [25]. Strength could be either an external resistance (eg, dumbbell) or using body weight against gravity (eg, squat) [25].

Results

We found 3 systematic reviews that include exercise programs to reduce falls in LTC homes [17,19,20]. Overall, evidence suggests that exercise should be included as part of a multifactorial falls prevention program for residents in LTC. There is limited evidence that exercise as a single intervention prevents falls, and some trials, albeit underpowered, even demonstrate an increased risk of falling in the exercise group compared to control [19]. With regards to specific exercise programs, the Cochrane review found that gait, balance, and functional training decrease the rate of falls but not the risk of falling [26–28], and the 2013 review by Silva et al [20] concluded that combined exercise programs (ie, multiple types of exercise) that include balance tasks, are completed frequently (2–3 times per week), and over a long term (greater than 6 months) were most effective at preventing falls [20].

A more recent systematic review and meta-analysis [17] also concluded that there was no evidence that exercise as a single intervention can prevent falls for residents in LTC. Table 1 provides a description of the exercise component of the seven positive trials [29–35] that were included in the 3 systematic reviews we identified in our search.

Type of Exercise

Balance Exercises

There were 4 positive trials that included balance exercises in their intervention [31,33–35]. Trials that had a positive effect on reducing falls and included balance training employed mostly dynamic balance exercises in standing (Table 1). However, only 2 of the 7 trials provided a detailed description of their balance exercises (Table 1) [26,34]. Jensen et al [30] and Dyer et al [31] did not include a description of the balance training performed but stated that balance was part of the multicomponent exercise program. Becker et al [36] stated that participants performed standing balance exercises, while Schnelle et al [39] and Huang et al [32] did not include balance training in their trial.

Strength Exercises

Of the 7 positive trials included in this review, 6 included strength exercises [29–32,34,35]. The strength activities used in trials where exercise had a positive effect on decreasing falls included functional activities [29,31] and progressive resistance training [31,36] (Table 1). Functional activities are those that replicate what a resident might be required to do in their everyday life, such as performing sit-to-stands out of a chair (Figure) 

Frequency, Time of Sessions, Duration of Program

In our description of positive trials, exercise was performed on 2 to 3 days per week for 20 to 75 minutes per session, for periods ranging from 4 to 52 weeks (Table 1).

Intensity

For the trials including balance exercises, one trial described the intensity as resident-specific [37] and another as individualized [33]. Two studies did not describe the intensity of their balance exercises [31,34]. The intensity of strength exercises included in the positive trials was individualized for one of the trial [29]. Two trials had participants complete 2 to 3 sets of 10 repetitions [32,35], with one indicating an intensity of 12–13 or “somewhat difficult” on the Borg Rating of Perceived Exertion Scale [32] and the other using a 10-rep max [35]. Two studies described their strength exercises as progressive [31,37], and one at a moderate to high intensity [30]. Lord et al prescribed 30 repetitions of each strength exercise [34].

Delivery of Intervention

Exercise was delivered in a group setting for 4 of the trials [31,32,34,36], individually for 2 of the trials [26,29], and the setting was not described for one of the trials (Table 1) [30]. Finally, only 3 of the 7 articles reported the professional delivering the intervention: one was research staff [29], one was geriatric nurses [32], and one was exercise assistants supported by a physiotherapist [31].

Discussion

There is limited evidence to support the use of strength and balance exercise as a single intervention to prevent falls in LTC. However, exercise should be included as part of a multifactorial falls prevention program. Trials that had a positive effect on decreasing falls training used dynamic balance exercises in standing, functional training, and progressive resistance training on 2 to 3 days per week, for 20 to 75 minutes per session, over 4 to 52 weeks. The intensity of balance exercises was individualized, and strength exercises were described as somewhat difficult or performed at a moderate to high intensity. Exercise was performed in a group or individually, and was delivered by research staff, geriatric nurses, exercise assistants supervised by physiotherapists, or more frequently, it was not reported who delivered the intervention.

Balance Training

Our work suggests that standing, dynamic balance exercises may be best to decrease falls. Example balance exercises include reducing the base of support (eg, standing with feet together instead of apart, or tandem with one foot in front), moving the center of gravity and control body position while standing (eg, reaching, weight shifting, stepping up or down), and standing without using arms for support or reducing reliance on the upper limbs for support (eg, use one hand on a handrail instead of two, or two fingers instead of the whole hand) [17]. It is well established that balance training programs, especially those including challenging exercises, can prevent falls in community-dwelling older adults [17]. However, the relationship is not as clear in LTC.

Strength Training

Reduced muscle strength has been identified as an important risk factor for falls [38]. There are also many psychological and metabolic benefits to strength training [39]. To induce change in muscular strength, resistance exercises need to be challenging and progressive. Our work suggests that strength training that is effective at decreasing falls is functional and progressive, and is completed at a moderate to high intensity. A resident should be able to do a strength exercise for one to two sets of 6 to 8 repetitions before being fatigued [40]. Once the resident can complete two sets of 13 to 15 repetitions easily the exercise should be progressed. Residents who are particularly deconditioned may need to begin with lower intensity strength exercises (eg, only do one set, with a lower resistance and progress to a higher resistance) [40]. Residents should perform resistance exercises for all major muscle groups [40]. Progression could include increasing the number of sets (eg, increase from one to two sets), the resistance (eg, holding dumbbells while squatting), or the intensity of the exercise (eg, squat lower or faster) [41].

Implementing Exercise Programs in LTC

Implementation of exercise programs into LTC homes should consider the dose of exercise (eg, time and frequency of sessions, duration of program), if they are delivered in a group or individual setting, and who is delivering them. First, trials included in this paper suggest that strength and balance exercises to prevent falls were delivered 2 to 3 times per week, for 20 to 75 minutes per session, over 4 to 52 weeks. Second, previous work has established that exercise programs delivered on 2 to 3 days per week over a period of more than 6 months are most effective at reducing falls in LTC [20]. Finally, a recent task force report from an international group of clinician researchers in LTC recommends twice weekly exercise sessions lasting 35 to 45 minutes each [40]. Therefore, strength and balance exercises to prevent falls in LTC should be delivered at least twice per week, for at least 20 minutes, for greater than 6 weeks’ duration.

Whether exercise should be performed in a group or individual setting remains unclear. Two of the 6 positive trials in this paper were completed individually, while 3 were in a group. The aforementioned task force also recommended that every resident who does not have contraindications to exercise must have an individualized exercise program as part of their health care plan [40]. However, whether the exercise program is provided on an individual basis or in a group setting was not delineated. Indeed, there are currently no recommendations concerning prioritizing group or individual exercise programs. Therefore, exercise programs being implemented into LTC homes should consider the residents’ preferences, the social benefits of group exercise, and the feasibility of individualizing exercises for the complex needs of residents in LTC in large group settings.

Finally, which professionals should deliver the exercise program is also uncertain. Only 3 of the positive trials in this paper described the professional delivering the intervention, with one being research staff, one geriatric nurses, and one exercise assistants supported by a physiotherapist. We suggest that professionals delivering an exercise program should be trained in exercise planning, delivery, and progression, be familiar with the principles of balance and strength training, and have training in working with older adults in LTC.

Modifications for Physical Impairments

Residents in LTC often have complex health needs, with multiple comorbidities (eg, stroke, Parkinson’s disease, multiple sclerosis) [21]. Modifications of strength and balance exercises may be required to accommodate for physical impairments (eg, hemiplegia, drop foot, freezing gait). For example, if a resident has hemiplegia and cannot fully activate the muscles of one arm, one can do resistance exercises with a dumbbell on the functioning side and active assisted range of motion (ie, the exercise provider assists the resident to achieve full range of motion against gravity) on the hemiparetic side. A resident with Parkinson’s disease who has freezing gait may need visual or rhythmical verbal cues to be able to accomplish standing balance tasks such as altered walking patterns (eg, wide or narrow stepping) [42].

Modifications for Cognitive Impairments

More than 80% of residents in LTC have some degree of cognitive impairment [21]. Cognitive impairment may be the result of stroke, depression, traumatic injuries, medications, and degenerative diseases such as Parkinson’s and Alzheimer’s disease [43]. A common misconception is that residents with cognitive impairment cannot benefit from exercise because they cannot learn new skills and have difficulty following directions. On the contrary, evidence suggests that exercise can improve functional mobility for residents with cognitive impairment [44,45].

Residents with cognitive impairment may require a different approach to facilitate participation in the desired exercises because of difficulty following multi-step directions, responsive behaviors, or increased distractibility [46]. Clear communication is key in improving the quality of interaction for residents with cognitive impairment. The Alzheimer Society of Ontario suggests 10 strategies for communicating with people with dementia [47], and we have provided suggestions of how to apply these communication strategies to the exercise context in LTC (Table 2). Other suggestions for engaging residents with cognitive impairment in strength and balance training include making the exercises functional (eg, ask them to pick something up of the floor to perform a squat, or reach a point on the wall to do calf raises) and playful (eg, toss a ball back and forth or sing a song about rowing to promote weight shifting) [48].

Standing versus Seated Exercises

Residents may not be able to participate in standing exercises for several reasons: perhaps the resident cannot stand or has severe balance impairments and a high falls risk; the resident may have poor insight into which exercises are safe to perform in standing versus sitting; or there may be limited supervision of a large group exercise class where the risk of falls is a concern. If balance impairments are a concern, where the risk of injury or falling while completing exercises in standing outweighs the benefit of doing the exercises, then seated exercises are appropriate. However, when residents are able, we recommend encouraging some or all exercises in standing, to facilitate carry over of strength gains into functional tasks such as being able to rise from a chair and walking. A recent study, comparing standing versus seated exercises for community dwelling older adults, saw greater functional gains for those who completed the standing exercises [49]. Therefore, strength and balance exercises should be performed in standing, where appropriate.

Resident-Centered Exercise for Falls Prevention

Putting the resident at the center of falls prevention is important. Previous work has found that older adults have expressed a strong preference for care that transcends traditional biomedical care and that values efficiency, consistency, and hierarchical decision making [50]. On the contrary, resident-centered care emphasizes well-being and quality of life as defined by the resident, values giving residents greater control over the nature of services they receive, and respects their rights to be involved in every day decision making [51,52]. Indeed, residents may choose to engage in risky behaviors that increase their risk of falls but also increases their quality of life. Previous work has found disconnects between residents’ perceived frailty and the potential ability of protective devices to prevent adverse events, such as falls and fractures [53]. Additionally, one study identified that older residents feared being labelled, so instead hid impairments and chose to refuse assistance and assistive devices [54]. For example, a resident with impaired balance and gait may choose to walk independently when they have been deemed as requiring a gait aid (eg, rollator walker). However, they may value walking without a gait aid and accept the increased risk of falling. Therefore, it is essential to find the delicate balance between respecting a resident’s right to make their own decisions and preventing adverse events, such as falls [52]. An example of this would be respecting a resident’s right to refuse to attend exercise programming even though the team may think they can benefit from strength and balance training.

There is limited evidence around falls prevention and resident-centered care. A recent systematic review [55] revealed that resident-centered care may increase falls rates [56,57]. However, the authors of the review attributed the increase in falls to differences in frailty between the control and intervention group [56], and to environmental factors (eg, slippery flooring material, lack of handrails) [57]. Additionally, these trials did not include an exercise program as part of the resident-centered care program. On the other hand, resident-centered care has been associated with reduction of boredom, helplessness, and depression [58,59]. Most studies included in the review were quasi-experimental, which significantly limits the evidence quality [55]. At this point in time, the evidence suggests that resident-centered care is important for mood and quality of life but may have a negative or no effect on reducing falls.

Multifactorial Falls Prevention Programs

While there are mixed results about the effect of exercise as a single intervention for reducing falls for residents in LTC, the literature clearly supports exercise as part of a multifactorial falls prevention program [17,20,60–62]. A 2015 umbrella review [62] of meta-analyses of randomized controlled trials of falls prevention interventions in LTC concluded that multifactorial interventions were the most effective at preventing falls in LTC. Additionally, recently developed recommendations for fracture prevention in LTC [61] suggest that balance, strength, and functional training should be included for residents who are not at high risk of fracture, while for those at high risk, exercise should be provided as part of a multifactorial falls prevention intervention. Clinicians must therefore incorporate elements aside from exercise into their falls prevention strategies. Interventions that have shown positive effects on reducing falls when delivered as part of multifactorial interventions include: staff and resident education [31,35,37], environmental modifications [31,35], supply/repair/provision of assistive devices [30], falls problem-solving conferences [30], urinary incontinence management [29], medication review [30], optician review [31], and cognitive behavioral therapy [32].

Conclusion and Suggestions for Clinical Practice

We suggest incorporating strength and balance exercises as part of a multifactorial falls prevention program for residents in LTC. Balance exercises should be challenging and dynamic (eg, weight shifting). Strength exercises should be of a moderate to high intensity (eg, can complete one to sets of 6 to 8 repetitions) and need to be progressed as the residents’ abilities improve. Residents should participate in strength and balance training on 2 to 3 days per week, for 30- to 45-minute sessions, for at least 6 months. Exercises in standing should be prioritized where appropriate. Exercise could be delivered in a group or individual format, but should consider the residents’ preferences, the social benefits of group exercise, and the feasibility of individualizing exercises for the complex needs of residents in LTC in large group settings. Professionals delivering an exercise program should be trained in exercise planning, delivery, and progression, be familiar with the principles of balance and strength training, and have training in working with older adults in LTC. Exercise programs in LTC should be resident-centered and consider residents’ potential physical and cognitive impairments.

Funding/support: Dr. Giangregorio was supported by grants from the Canadian Frailty Network and Canadian Institutes of Health Research.

From the Geriatric Education and Research in Aging Sciences Centre, McMaster University Hamilton, ON (Dr. McArthur) and the University of Waterloo and Research Institute for Aging, Waterloo, ON (Dr. Giangregorio), Canada

Abstract

• Objective: To synthesize the available literature on exercise and falls reduction interventions in long-term care (LTC) and provide practical information for clinicians and other decision makers.
• Methods: Review of positive trials included in systematic reviews.
• Results: Falls are a major concern for residents, families, clinicians, and decision-makers in LTC. Exercise is recommended as part of a multifactorial falls prevention program for residents in LTC. Strength and balance exercises should be incorporated into the multifactorial falls prevention program. They should be challenging and progressed as the residents’ abilities improve. Evidence suggests that exercises should be completed 2 to 3 times per week for a period longer than 6 months. Exercise programs in LTC should be resident-centered and should consider residents’ potential physical and cognitive impairments. Exercises in standing should be prioritized where appropriate.
• Conclusion: Appropriately challenging and progressive strength and balance exercises should be included in a multifactorial falls prevention program for residents in LTC.

Key words: long-term care; nursing homes; falls reduction; exercise.

Falls are common in long-term care (LTC) homes: the estimated falls rate is 1.5 falls per bed per year, which is 3 times greater than that for older adults living in the community [1]. Falls can have significant consequences for residents in LTC, including functional disability, fractures, pain, reduced quality of life, and death [1–6]. Indeed, 25% of residents who are hospitalized after a fall die within 1 year [3]. Consequently, falls prevention programs are important to help in reducing falls and averting the associated negative consequences.

Exercise may address the circumstances and physical deconditioning that often contribute to falls in LTC residents. Weight shifting [7], walking, and transferring [8–10], are common activities that precede falls, suggesting that balance, gait, and functional mobility training may be possible targets for prevention. Additionally, it is estimated that LTC residents spend three quarters of their waking time in sedentary activities [11,12] and have a high prevalence of sarcopenia [13–16]. Challenging balance training and resistance exercise are well-known intervention for reducing falls [17] and improving muscle strength for community-dwelling older adults [18]. However, evidence around balance and strength training for preventing falls in LTC is mixed [17,19,20], and careful planning and modification of exercises is necessary to meet the needs of LTC residents.

Residents in LTC are often medically complex, with multiple comorbidities [21] that can affect their ability to meaningfully participate in exercise. In Canada, 56.3% of residents have a diagnosis of Alzheimer’s or other dementias, 25.0% have diabetes, 14.4% have chronic obstructive pulmonary disease, and 21.2% have experienced a stroke [21]. Residents also often have significant functional impairments. For example, 97% of residents require assistance with basic activities of daily living [21]. Therefore, the lack of effect of exercise as a single falls prevention strategy observed in previous studies may be because the often complex, multimorbid LTC population likely requires a multifactorial approach to fall prevention [17]. Additionally, organizational aspects of LTC homes (eg, specific funds dedicated to employing exercise professionals and to support exercise programming) can affect residents’ engagement in exercise [22,23]. Subsequently, prescribing exercises in the LTC context must consider both resident characteristics and organizational features of the LTC home (eg, professionals available to support exercise programming).

A comprehensive exercise prescription describes the elements of an appropriate exercise program to facilitate implementation of that program. The exercise prescription should include a description of the type (eg, balance, strength) and intensity of exercises (eg, subjective or objective measurement of how hard the resident is working) included in the program [24]. The prescription should also include a description of the dose of exercise: frequency of exercise participation (eg, 2 days per week), duration of individual exercise sessions (eg, 30-minute sessions), and duration of exercise program (eg, 12-week program) [24]. Lastly, the prescription should describe the setting of the exercise program (eg, group or individual basis) and the professional delivering the program (eg, physiotherapist, fitness instructor) [24].

Therefore, the objectives of this article are to (1) synthesize studies demonstrating a positive effect of exercise on reducing falls for residents in LTC; (2) provide an overview of the principles of balance and strength training to guide clinicians in designing appropriate exercise prescription; and (3) make suggestions for clinical practice regarding an appropriate strength and balance exercise protocol by considering the influence of the LTC context.

Methods

To provide clinicians and other policy-makers with a description of which balance and strength exercises may be effective for preventing falls, we synthesized trials that demonstrated a positive effect on reducing falls or falls risk for residents in LTC. Studies were identified through a database search for systematic reviews in PubMed, Ovid, and Google Scholar using the keywords falls, long-term care, nursing homes, exercise, strength, balance, and systematic reviews. Our purpose was to provide practical information on what works to prevent falls through balance and strength training for residents in LTC rather than to evaluate the available evidence. Therefore, only positive trials from systematic reviews were discussed, as we wanted to present exercises that seem to have a positive effect on decreasing falls. Positive trials were defined as those included in identified systematic reviews with a risk or rate ratio and confidence intervals below 1.0.

We first provide an overview of the conclusions of the systematic reviews found in our search. Next, for each positive trial we describe the following elements of the exercise component of the intervention: frequency, time of sessions, length of program, intensity, type of exercise including a description of the specific exercises performed, whether the intervention was delivered in a group or on an individual basis, the professional delivering the intervention, and any other features of the intervention aside from the exercise component. We used the ProFaNE taxonomy definitions [25] to identify and describe each element of the exercise interventions. Frequency is the number of times per week that residents engage in sessions, time of sessions is the amount allocated to each exercise session, duration of program is how long the resident participates in the exercise program, and intensity is the subjective or objective report of how hard the resident is working [25]. The types of exercises described were those targeting balance defined as “...the efficient transfer of bodyweight from one part of the body to another or challenges specific aspects of the balance systems (eg, vestibular system)” [25], and strength defined as “...contracting the muscles against a resistance to ‘overload’ and bring about a training effect in the muscular system” [25]. Strength could be either an external resistance (eg, dumbbell) or using body weight against gravity (eg, squat) [25].

Results

We found 3 systematic reviews that include exercise programs to reduce falls in LTC homes [17,19,20]. Overall, evidence suggests that exercise should be included as part of a multifactorial falls prevention program for residents in LTC. There is limited evidence that exercise as a single intervention prevents falls, and some trials, albeit underpowered, even demonstrate an increased risk of falling in the exercise group compared to control [19]. With regards to specific exercise programs, the Cochrane review found that gait, balance, and functional training decrease the rate of falls but not the risk of falling [26–28], and the 2013 review by Silva et al [20] concluded that combined exercise programs (ie, multiple types of exercise) that include balance tasks, are completed frequently (2–3 times per week), and over a long term (greater than 6 months) were most effective at preventing falls [20].

A more recent systematic review and meta-analysis [17] also concluded that there was no evidence that exercise as a single intervention can prevent falls for residents in LTC. Table 1 provides a description of the exercise component of the seven positive trials [29–35] that were included in the 3 systematic reviews we identified in our search.

Type of Exercise

Balance Exercises

There were 4 positive trials that included balance exercises in their intervention [31,33–35]. Trials that had a positive effect on reducing falls and included balance training employed mostly dynamic balance exercises in standing (Table 1). However, only 2 of the 7 trials provided a detailed description of their balance exercises (Table 1) [26,34]. Jensen et al [30] and Dyer et al [31] did not include a description of the balance training performed but stated that balance was part of the multicomponent exercise program. Becker et al [36] stated that participants performed standing balance exercises, while Schnelle et al [39] and Huang et al [32] did not include balance training in their trial.

Strength Exercises

Of the 7 positive trials included in this review, 6 included strength exercises [29–32,34,35]. The strength activities used in trials where exercise had a positive effect on decreasing falls included functional activities [29,31] and progressive resistance training [31,36] (Table 1). Functional activities are those that replicate what a resident might be required to do in their everyday life, such as performing sit-to-stands out of a chair (Figure) 

Frequency, Time of Sessions, Duration of Program

In our description of positive trials, exercise was performed on 2 to 3 days per week for 20 to 75 minutes per session, for periods ranging from 4 to 52 weeks (Table 1).

Intensity

For the trials including balance exercises, one trial described the intensity as resident-specific [37] and another as individualized [33]. Two studies did not describe the intensity of their balance exercises [31,34]. The intensity of strength exercises included in the positive trials was individualized for one of the trial [29]. Two trials had participants complete 2 to 3 sets of 10 repetitions [32,35], with one indicating an intensity of 12–13 or “somewhat difficult” on the Borg Rating of Perceived Exertion Scale [32] and the other using a 10-rep max [35]. Two studies described their strength exercises as progressive [31,37], and one at a moderate to high intensity [30]. Lord et al prescribed 30 repetitions of each strength exercise [34].

Delivery of Intervention

Exercise was delivered in a group setting for 4 of the trials [31,32,34,36], individually for 2 of the trials [26,29], and the setting was not described for one of the trials (Table 1) [30]. Finally, only 3 of the 7 articles reported the professional delivering the intervention: one was research staff [29], one was geriatric nurses [32], and one was exercise assistants supported by a physiotherapist [31].

Discussion

There is limited evidence to support the use of strength and balance exercise as a single intervention to prevent falls in LTC. However, exercise should be included as part of a multifactorial falls prevention program. Trials that had a positive effect on decreasing falls training used dynamic balance exercises in standing, functional training, and progressive resistance training on 2 to 3 days per week, for 20 to 75 minutes per session, over 4 to 52 weeks. The intensity of balance exercises was individualized, and strength exercises were described as somewhat difficult or performed at a moderate to high intensity. Exercise was performed in a group or individually, and was delivered by research staff, geriatric nurses, exercise assistants supervised by physiotherapists, or more frequently, it was not reported who delivered the intervention.

Balance Training

Our work suggests that standing, dynamic balance exercises may be best to decrease falls. Example balance exercises include reducing the base of support (eg, standing with feet together instead of apart, or tandem with one foot in front), moving the center of gravity and control body position while standing (eg, reaching, weight shifting, stepping up or down), and standing without using arms for support or reducing reliance on the upper limbs for support (eg, use one hand on a handrail instead of two, or two fingers instead of the whole hand) [17]. It is well established that balance training programs, especially those including challenging exercises, can prevent falls in community-dwelling older adults [17]. However, the relationship is not as clear in LTC.

Strength Training

Reduced muscle strength has been identified as an important risk factor for falls [38]. There are also many psychological and metabolic benefits to strength training [39]. To induce change in muscular strength, resistance exercises need to be challenging and progressive. Our work suggests that strength training that is effective at decreasing falls is functional and progressive, and is completed at a moderate to high intensity. A resident should be able to do a strength exercise for one to two sets of 6 to 8 repetitions before being fatigued [40]. Once the resident can complete two sets of 13 to 15 repetitions easily the exercise should be progressed. Residents who are particularly deconditioned may need to begin with lower intensity strength exercises (eg, only do one set, with a lower resistance and progress to a higher resistance) [40]. Residents should perform resistance exercises for all major muscle groups [40]. Progression could include increasing the number of sets (eg, increase from one to two sets), the resistance (eg, holding dumbbells while squatting), or the intensity of the exercise (eg, squat lower or faster) [41].

Implementing Exercise Programs in LTC

Implementation of exercise programs into LTC homes should consider the dose of exercise (eg, time and frequency of sessions, duration of program), if they are delivered in a group or individual setting, and who is delivering them. First, trials included in this paper suggest that strength and balance exercises to prevent falls were delivered 2 to 3 times per week, for 20 to 75 minutes per session, over 4 to 52 weeks. Second, previous work has established that exercise programs delivered on 2 to 3 days per week over a period of more than 6 months are most effective at reducing falls in LTC [20]. Finally, a recent task force report from an international group of clinician researchers in LTC recommends twice weekly exercise sessions lasting 35 to 45 minutes each [40]. Therefore, strength and balance exercises to prevent falls in LTC should be delivered at least twice per week, for at least 20 minutes, for greater than 6 weeks’ duration.

Whether exercise should be performed in a group or individual setting remains unclear. Two of the 6 positive trials in this paper were completed individually, while 3 were in a group. The aforementioned task force also recommended that every resident who does not have contraindications to exercise must have an individualized exercise program as part of their health care plan [40]. However, whether the exercise program is provided on an individual basis or in a group setting was not delineated. Indeed, there are currently no recommendations concerning prioritizing group or individual exercise programs. Therefore, exercise programs being implemented into LTC homes should consider the residents’ preferences, the social benefits of group exercise, and the feasibility of individualizing exercises for the complex needs of residents in LTC in large group settings.

Finally, which professionals should deliver the exercise program is also uncertain. Only 3 of the positive trials in this paper described the professional delivering the intervention, with one being research staff, one geriatric nurses, and one exercise assistants supported by a physiotherapist. We suggest that professionals delivering an exercise program should be trained in exercise planning, delivery, and progression, be familiar with the principles of balance and strength training, and have training in working with older adults in LTC.

Modifications for Physical Impairments

Residents in LTC often have complex health needs, with multiple comorbidities (eg, stroke, Parkinson’s disease, multiple sclerosis) [21]. Modifications of strength and balance exercises may be required to accommodate for physical impairments (eg, hemiplegia, drop foot, freezing gait). For example, if a resident has hemiplegia and cannot fully activate the muscles of one arm, one can do resistance exercises with a dumbbell on the functioning side and active assisted range of motion (ie, the exercise provider assists the resident to achieve full range of motion against gravity) on the hemiparetic side. A resident with Parkinson’s disease who has freezing gait may need visual or rhythmical verbal cues to be able to accomplish standing balance tasks such as altered walking patterns (eg, wide or narrow stepping) [42].

Modifications for Cognitive Impairments

More than 80% of residents in LTC have some degree of cognitive impairment [21]. Cognitive impairment may be the result of stroke, depression, traumatic injuries, medications, and degenerative diseases such as Parkinson’s and Alzheimer’s disease [43]. A common misconception is that residents with cognitive impairment cannot benefit from exercise because they cannot learn new skills and have difficulty following directions. On the contrary, evidence suggests that exercise can improve functional mobility for residents with cognitive impairment [44,45].

Residents with cognitive impairment may require a different approach to facilitate participation in the desired exercises because of difficulty following multi-step directions, responsive behaviors, or increased distractibility [46]. Clear communication is key in improving the quality of interaction for residents with cognitive impairment. The Alzheimer Society of Ontario suggests 10 strategies for communicating with people with dementia [47], and we have provided suggestions of how to apply these communication strategies to the exercise context in LTC (Table 2). Other suggestions for engaging residents with cognitive impairment in strength and balance training include making the exercises functional (eg, ask them to pick something up of the floor to perform a squat, or reach a point on the wall to do calf raises) and playful (eg, toss a ball back and forth or sing a song about rowing to promote weight shifting) [48].

Standing versus Seated Exercises

Residents may not be able to participate in standing exercises for several reasons: perhaps the resident cannot stand or has severe balance impairments and a high falls risk; the resident may have poor insight into which exercises are safe to perform in standing versus sitting; or there may be limited supervision of a large group exercise class where the risk of falls is a concern. If balance impairments are a concern, where the risk of injury or falling while completing exercises in standing outweighs the benefit of doing the exercises, then seated exercises are appropriate. However, when residents are able, we recommend encouraging some or all exercises in standing, to facilitate carry over of strength gains into functional tasks such as being able to rise from a chair and walking. A recent study, comparing standing versus seated exercises for community dwelling older adults, saw greater functional gains for those who completed the standing exercises [49]. Therefore, strength and balance exercises should be performed in standing, where appropriate.

Resident-Centered Exercise for Falls Prevention

Putting the resident at the center of falls prevention is important. Previous work has found that older adults have expressed a strong preference for care that transcends traditional biomedical care and that values efficiency, consistency, and hierarchical decision making [50]. On the contrary, resident-centered care emphasizes well-being and quality of life as defined by the resident, values giving residents greater control over the nature of services they receive, and respects their rights to be involved in every day decision making [51,52]. Indeed, residents may choose to engage in risky behaviors that increase their risk of falls but also increases their quality of life. Previous work has found disconnects between residents’ perceived frailty and the potential ability of protective devices to prevent adverse events, such as falls and fractures [53]. Additionally, one study identified that older residents feared being labelled, so instead hid impairments and chose to refuse assistance and assistive devices [54]. For example, a resident with impaired balance and gait may choose to walk independently when they have been deemed as requiring a gait aid (eg, rollator walker). However, they may value walking without a gait aid and accept the increased risk of falling. Therefore, it is essential to find the delicate balance between respecting a resident’s right to make their own decisions and preventing adverse events, such as falls [52]. An example of this would be respecting a resident’s right to refuse to attend exercise programming even though the team may think they can benefit from strength and balance training.

There is limited evidence around falls prevention and resident-centered care. A recent systematic review [55] revealed that resident-centered care may increase falls rates [56,57]. However, the authors of the review attributed the increase in falls to differences in frailty between the control and intervention group [56], and to environmental factors (eg, slippery flooring material, lack of handrails) [57]. Additionally, these trials did not include an exercise program as part of the resident-centered care program. On the other hand, resident-centered care has been associated with reduction of boredom, helplessness, and depression [58,59]. Most studies included in the review were quasi-experimental, which significantly limits the evidence quality [55]. At this point in time, the evidence suggests that resident-centered care is important for mood and quality of life but may have a negative or no effect on reducing falls.

Multifactorial Falls Prevention Programs

While there are mixed results about the effect of exercise as a single intervention for reducing falls for residents in LTC, the literature clearly supports exercise as part of a multifactorial falls prevention program [17,20,60–62]. A 2015 umbrella review [62] of meta-analyses of randomized controlled trials of falls prevention interventions in LTC concluded that multifactorial interventions were the most effective at preventing falls in LTC. Additionally, recently developed recommendations for fracture prevention in LTC [61] suggest that balance, strength, and functional training should be included for residents who are not at high risk of fracture, while for those at high risk, exercise should be provided as part of a multifactorial falls prevention intervention. Clinicians must therefore incorporate elements aside from exercise into their falls prevention strategies. Interventions that have shown positive effects on reducing falls when delivered as part of multifactorial interventions include: staff and resident education [31,35,37], environmental modifications [31,35], supply/repair/provision of assistive devices [30], falls problem-solving conferences [30], urinary incontinence management [29], medication review [30], optician review [31], and cognitive behavioral therapy [32].

Conclusion and Suggestions for Clinical Practice

We suggest incorporating strength and balance exercises as part of a multifactorial falls prevention program for residents in LTC. Balance exercises should be challenging and dynamic (eg, weight shifting). Strength exercises should be of a moderate to high intensity (eg, can complete one to sets of 6 to 8 repetitions) and need to be progressed as the residents’ abilities improve. Residents should participate in strength and balance training on 2 to 3 days per week, for 30- to 45-minute sessions, for at least 6 months. Exercises in standing should be prioritized where appropriate. Exercise could be delivered in a group or individual format, but should consider the residents’ preferences, the social benefits of group exercise, and the feasibility of individualizing exercises for the complex needs of residents in LTC in large group settings. Professionals delivering an exercise program should be trained in exercise planning, delivery, and progression, be familiar with the principles of balance and strength training, and have training in working with older adults in LTC. Exercise programs in LTC should be resident-centered and consider residents’ potential physical and cognitive impairments.

Funding/support: Dr. Giangregorio was supported by grants from the Canadian Frailty Network and Canadian Institutes of Health Research.

From the Geriatric Education and Research in Aging Sciences Centre, McMaster University Hamilton, ON (Dr. McArthur) and the University of Waterloo and Research Institute for Aging, Waterloo, ON (Dr. Giangregorio), Canada

Abstract

• Objective: To synthesize the available literature on exercise and falls reduction interventions in long-term care (LTC) and provide practical information for clinicians and other decision makers.
• Methods: Review of positive trials included in systematic reviews.
• Results: Falls are a major concern for residents, families, clinicians, and decision-makers in LTC. Exercise is recommended as part of a multifactorial falls prevention program for residents in LTC. Strength and balance exercises should be incorporated into the multifactorial falls prevention program. They should be challenging and progressed as the residents’ abilities improve. Evidence suggests that exercises should be completed 2 to 3 times per week for a period longer than 6 months. Exercise programs in LTC should be resident-centered and should consider residents’ potential physical and cognitive impairments. Exercises in standing should be prioritized where appropriate.
• Conclusion: Appropriately challenging and progressive strength and balance exercises should be included in a multifactorial falls prevention program for residents in LTC.

Key words: long-term care; nursing homes; falls reduction; exercise.

Falls are common in long-term care (LTC) homes: the estimated falls rate is 1.5 falls per bed per year, which is 3 times greater than that for older adults living in the community [1]. Falls can have significant consequences for residents in LTC, including functional disability, fractures, pain, reduced quality of life, and death [1–6]. Indeed, 25% of residents who are hospitalized after a fall die within 1 year [3]. Consequently, falls prevention programs are important to help in reducing falls and averting the associated negative consequences.

Exercise may address the circumstances and physical deconditioning that often contribute to falls in LTC residents. Weight shifting [7], walking, and transferring [8–10], are common activities that precede falls, suggesting that balance, gait, and functional mobility training may be possible targets for prevention. Additionally, it is estimated that LTC residents spend three quarters of their waking time in sedentary activities [11,12] and have a high prevalence of sarcopenia [13–16]. Challenging balance training and resistance exercise are well-known intervention for reducing falls [17] and improving muscle strength for community-dwelling older adults [18]. However, evidence around balance and strength training for preventing falls in LTC is mixed [17,19,20], and careful planning and modification of exercises is necessary to meet the needs of LTC residents.

Residents in LTC are often medically complex, with multiple comorbidities [21] that can affect their ability to meaningfully participate in exercise. In Canada, 56.3% of residents have a diagnosis of Alzheimer’s or other dementias, 25.0% have diabetes, 14.4% have chronic obstructive pulmonary disease, and 21.2% have experienced a stroke [21]. Residents also often have significant functional impairments. For example, 97% of residents require assistance with basic activities of daily living [21]. Therefore, the lack of effect of exercise as a single falls prevention strategy observed in previous studies may be because the often complex, multimorbid LTC population likely requires a multifactorial approach to fall prevention [17]. Additionally, organizational aspects of LTC homes (eg, specific funds dedicated to employing exercise professionals and to support exercise programming) can affect residents’ engagement in exercise [22,23]. Subsequently, prescribing exercises in the LTC context must consider both resident characteristics and organizational features of the LTC home (eg, professionals available to support exercise programming).

A comprehensive exercise prescription describes the elements of an appropriate exercise program to facilitate implementation of that program. The exercise prescription should include a description of the type (eg, balance, strength) and intensity of exercises (eg, subjective or objective measurement of how hard the resident is working) included in the program [24]. The prescription should also include a description of the dose of exercise: frequency of exercise participation (eg, 2 days per week), duration of individual exercise sessions (eg, 30-minute sessions), and duration of exercise program (eg, 12-week program) [24]. Lastly, the prescription should describe the setting of the exercise program (eg, group or individual basis) and the professional delivering the program (eg, physiotherapist, fitness instructor) [24].

Therefore, the objectives of this article are to (1) synthesize studies demonstrating a positive effect of exercise on reducing falls for residents in LTC; (2) provide an overview of the principles of balance and strength training to guide clinicians in designing appropriate exercise prescription; and (3) make suggestions for clinical practice regarding an appropriate strength and balance exercise protocol by considering the influence of the LTC context.

Methods

To provide clinicians and other policy-makers with a description of which balance and strength exercises may be effective for preventing falls, we synthesized trials that demonstrated a positive effect on reducing falls or falls risk for residents in LTC. Studies were identified through a database search for systematic reviews in PubMed, Ovid, and Google Scholar using the keywords falls, long-term care, nursing homes, exercise, strength, balance, and systematic reviews. Our purpose was to provide practical information on what works to prevent falls through balance and strength training for residents in LTC rather than to evaluate the available evidence. Therefore, only positive trials from systematic reviews were discussed, as we wanted to present exercises that seem to have a positive effect on decreasing falls. Positive trials were defined as those included in identified systematic reviews with a risk or rate ratio and confidence intervals below 1.0.

We first provide an overview of the conclusions of the systematic reviews found in our search. Next, for each positive trial we describe the following elements of the exercise component of the intervention: frequency, time of sessions, length of program, intensity, type of exercise including a description of the specific exercises performed, whether the intervention was delivered in a group or on an individual basis, the professional delivering the intervention, and any other features of the intervention aside from the exercise component. We used the ProFaNE taxonomy definitions [25] to identify and describe each element of the exercise interventions. Frequency is the number of times per week that residents engage in sessions, time of sessions is the amount allocated to each exercise session, duration of program is how long the resident participates in the exercise program, and intensity is the subjective or objective report of how hard the resident is working [25]. The types of exercises described were those targeting balance defined as “...the efficient transfer of bodyweight from one part of the body to another or challenges specific aspects of the balance systems (eg, vestibular system)” [25], and strength defined as “...contracting the muscles against a resistance to ‘overload’ and bring about a training effect in the muscular system” [25]. Strength could be either an external resistance (eg, dumbbell) or using body weight against gravity (eg, squat) [25].

Results

We found 3 systematic reviews that include exercise programs to reduce falls in LTC homes [17,19,20]. Overall, evidence suggests that exercise should be included as part of a multifactorial falls prevention program for residents in LTC. There is limited evidence that exercise as a single intervention prevents falls, and some trials, albeit underpowered, even demonstrate an increased risk of falling in the exercise group compared to control [19]. With regards to specific exercise programs, the Cochrane review found that gait, balance, and functional training decrease the rate of falls but not the risk of falling [26–28], and the 2013 review by Silva et al [20] concluded that combined exercise programs (ie, multiple types of exercise) that include balance tasks, are completed frequently (2–3 times per week), and over a long term (greater than 6 months) were most effective at preventing falls [20].

A more recent systematic review and meta-analysis [17] also concluded that there was no evidence that exercise as a single intervention can prevent falls for residents in LTC. Table 1 provides a description of the exercise component of the seven positive trials [29–35] that were included in the 3 systematic reviews we identified in our search.

Type of Exercise

Balance Exercises

There were 4 positive trials that included balance exercises in their intervention [31,33–35]. Trials that had a positive effect on reducing falls and included balance training employed mostly dynamic balance exercises in standing (Table 1). However, only 2 of the 7 trials provided a detailed description of their balance exercises (Table 1) [26,34]. Jensen et al [30] and Dyer et al [31] did not include a description of the balance training performed but stated that balance was part of the multicomponent exercise program. Becker et al [36] stated that participants performed standing balance exercises, while Schnelle et al [39] and Huang et al [32] did not include balance training in their trial.

Strength Exercises

Of the 7 positive trials included in this review, 6 included strength exercises [29–32,34,35]. The strength activities used in trials where exercise had a positive effect on decreasing falls included functional activities [29,31] and progressive resistance training [31,36] (Table 1). Functional activities are those that replicate what a resident might be required to do in their everyday life, such as performing sit-to-stands out of a chair (Figure) 

Frequency, Time of Sessions, Duration of Program

In our description of positive trials, exercise was performed on 2 to 3 days per week for 20 to 75 minutes per session, for periods ranging from 4 to 52 weeks (Table 1).

Intensity

For the trials including balance exercises, one trial described the intensity as resident-specific [37] and another as individualized [33]. Two studies did not describe the intensity of their balance exercises [31,34]. The intensity of strength exercises included in the positive trials was individualized for one of the trial [29]. Two trials had participants complete 2 to 3 sets of 10 repetitions [32,35], with one indicating an intensity of 12–13 or “somewhat difficult” on the Borg Rating of Perceived Exertion Scale [32] and the other using a 10-rep max [35]. Two studies described their strength exercises as progressive [31,37], and one at a moderate to high intensity [30]. Lord et al prescribed 30 repetitions of each strength exercise [34].

Delivery of Intervention

Exercise was delivered in a group setting for 4 of the trials [31,32,34,36], individually for 2 of the trials [26,29], and the setting was not described for one of the trials (Table 1) [30]. Finally, only 3 of the 7 articles reported the professional delivering the intervention: one was research staff [29], one was geriatric nurses [32], and one was exercise assistants supported by a physiotherapist [31].

Discussion

There is limited evidence to support the use of strength and balance exercise as a single intervention to prevent falls in LTC. However, exercise should be included as part of a multifactorial falls prevention program. Trials that had a positive effect on decreasing falls training used dynamic balance exercises in standing, functional training, and progressive resistance training on 2 to 3 days per week, for 20 to 75 minutes per session, over 4 to 52 weeks. The intensity of balance exercises was individualized, and strength exercises were described as somewhat difficult or performed at a moderate to high intensity. Exercise was performed in a group or individually, and was delivered by research staff, geriatric nurses, exercise assistants supervised by physiotherapists, or more frequently, it was not reported who delivered the intervention.

Balance Training

Our work suggests that standing, dynamic balance exercises may be best to decrease falls. Example balance exercises include reducing the base of support (eg, standing with feet together instead of apart, or tandem with one foot in front), moving the center of gravity and control body position while standing (eg, reaching, weight shifting, stepping up or down), and standing without using arms for support or reducing reliance on the upper limbs for support (eg, use one hand on a handrail instead of two, or two fingers instead of the whole hand) [17]. It is well established that balance training programs, especially those including challenging exercises, can prevent falls in community-dwelling older adults [17]. However, the relationship is not as clear in LTC.

Strength Training

Reduced muscle strength has been identified as an important risk factor for falls [38]. There are also many psychological and metabolic benefits to strength training [39]. To induce change in muscular strength, resistance exercises need to be challenging and progressive. Our work suggests that strength training that is effective at decreasing falls is functional and progressive, and is completed at a moderate to high intensity. A resident should be able to do a strength exercise for one to two sets of 6 to 8 repetitions before being fatigued [40]. Once the resident can complete two sets of 13 to 15 repetitions easily the exercise should be progressed. Residents who are particularly deconditioned may need to begin with lower intensity strength exercises (eg, only do one set, with a lower resistance and progress to a higher resistance) [40]. Residents should perform resistance exercises for all major muscle groups [40]. Progression could include increasing the number of sets (eg, increase from one to two sets), the resistance (eg, holding dumbbells while squatting), or the intensity of the exercise (eg, squat lower or faster) [41].

Implementing Exercise Programs in LTC

Implementation of exercise programs into LTC homes should consider the dose of exercise (eg, time and frequency of sessions, duration of program), if they are delivered in a group or individual setting, and who is delivering them. First, trials included in this paper suggest that strength and balance exercises to prevent falls were delivered 2 to 3 times per week, for 20 to 75 minutes per session, over 4 to 52 weeks. Second, previous work has established that exercise programs delivered on 2 to 3 days per week over a period of more than 6 months are most effective at reducing falls in LTC [20]. Finally, a recent task force report from an international group of clinician researchers in LTC recommends twice weekly exercise sessions lasting 35 to 45 minutes each [40]. Therefore, strength and balance exercises to prevent falls in LTC should be delivered at least twice per week, for at least 20 minutes, for greater than 6 weeks’ duration.

Whether exercise should be performed in a group or individual setting remains unclear. Two of the 6 positive trials in this paper were completed individually, while 3 were in a group. The aforementioned task force also recommended that every resident who does not have contraindications to exercise must have an individualized exercise program as part of their health care plan [40]. However, whether the exercise program is provided on an individual basis or in a group setting was not delineated. Indeed, there are currently no recommendations concerning prioritizing group or individual exercise programs. Therefore, exercise programs being implemented into LTC homes should consider the residents’ preferences, the social benefits of group exercise, and the feasibility of individualizing exercises for the complex needs of residents in LTC in large group settings.

Finally, which professionals should deliver the exercise program is also uncertain. Only 3 of the positive trials in this paper described the professional delivering the intervention, with one being research staff, one geriatric nurses, and one exercise assistants supported by a physiotherapist. We suggest that professionals delivering an exercise program should be trained in exercise planning, delivery, and progression, be familiar with the principles of balance and strength training, and have training in working with older adults in LTC.

Modifications for Physical Impairments

Residents in LTC often have complex health needs, with multiple comorbidities (eg, stroke, Parkinson’s disease, multiple sclerosis) [21]. Modifications of strength and balance exercises may be required to accommodate for physical impairments (eg, hemiplegia, drop foot, freezing gait). For example, if a resident has hemiplegia and cannot fully activate the muscles of one arm, one can do resistance exercises with a dumbbell on the functioning side and active assisted range of motion (ie, the exercise provider assists the resident to achieve full range of motion against gravity) on the hemiparetic side. A resident with Parkinson’s disease who has freezing gait may need visual or rhythmical verbal cues to be able to accomplish standing balance tasks such as altered walking patterns (eg, wide or narrow stepping) [42].

Modifications for Cognitive Impairments

More than 80% of residents in LTC have some degree of cognitive impairment [21]. Cognitive impairment may be the result of stroke, depression, traumatic injuries, medications, and degenerative diseases such as Parkinson’s and Alzheimer’s disease [43]. A common misconception is that residents with cognitive impairment cannot benefit from exercise because they cannot learn new skills and have difficulty following directions. On the contrary, evidence suggests that exercise can improve functional mobility for residents with cognitive impairment [44,45].

Residents with cognitive impairment may require a different approach to facilitate participation in the desired exercises because of difficulty following multi-step directions, responsive behaviors, or increased distractibility [46]. Clear communication is key in improving the quality of interaction for residents with cognitive impairment. The Alzheimer Society of Ontario suggests 10 strategies for communicating with people with dementia [47], and we have provided suggestions of how to apply these communication strategies to the exercise context in LTC (Table 2). Other suggestions for engaging residents with cognitive impairment in strength and balance training include making the exercises functional (eg, ask them to pick something up of the floor to perform a squat, or reach a point on the wall to do calf raises) and playful (eg, toss a ball back and forth or sing a song about rowing to promote weight shifting) [48].

Standing versus Seated Exercises

Residents may not be able to participate in standing exercises for several reasons: perhaps the resident cannot stand or has severe balance impairments and a high falls risk; the resident may have poor insight into which exercises are safe to perform in standing versus sitting; or there may be limited supervision of a large group exercise class where the risk of falls is a concern. If balance impairments are a concern, where the risk of injury or falling while completing exercises in standing outweighs the benefit of doing the exercises, then seated exercises are appropriate. However, when residents are able, we recommend encouraging some or all exercises in standing, to facilitate carry over of strength gains into functional tasks such as being able to rise from a chair and walking. A recent study, comparing standing versus seated exercises for community dwelling older adults, saw greater functional gains for those who completed the standing exercises [49]. Therefore, strength and balance exercises should be performed in standing, where appropriate.

Resident-Centered Exercise for Falls Prevention

Putting the resident at the center of falls prevention is important. Previous work has found that older adults have expressed a strong preference for care that transcends traditional biomedical care and that values efficiency, consistency, and hierarchical decision making [50]. On the contrary, resident-centered care emphasizes well-being and quality of life as defined by the resident, values giving residents greater control over the nature of services they receive, and respects their rights to be involved in every day decision making [51,52]. Indeed, residents may choose to engage in risky behaviors that increase their risk of falls but also increases their quality of life. Previous work has found disconnects between residents’ perceived frailty and the potential ability of protective devices to prevent adverse events, such as falls and fractures [53]. Additionally, one study identified that older residents feared being labelled, so instead hid impairments and chose to refuse assistance and assistive devices [54]. For example, a resident with impaired balance and gait may choose to walk independently when they have been deemed as requiring a gait aid (eg, rollator walker). However, they may value walking without a gait aid and accept the increased risk of falling. Therefore, it is essential to find the delicate balance between respecting a resident’s right to make their own decisions and preventing adverse events, such as falls [52]. An example of this would be respecting a resident’s right to refuse to attend exercise programming even though the team may think they can benefit from strength and balance training.

There is limited evidence around falls prevention and resident-centered care. A recent systematic review [55] revealed that resident-centered care may increase falls rates [56,57]. However, the authors of the review attributed the increase in falls to differences in frailty between the control and intervention group [56], and to environmental factors (eg, slippery flooring material, lack of handrails) [57]. Additionally, these trials did not include an exercise program as part of the resident-centered care program. On the other hand, resident-centered care has been associated with reduction of boredom, helplessness, and depression [58,59]. Most studies included in the review were quasi-experimental, which significantly limits the evidence quality [55]. At this point in time, the evidence suggests that resident-centered care is important for mood and quality of life but may have a negative or no effect on reducing falls.

Multifactorial Falls Prevention Programs

While there are mixed results about the effect of exercise as a single intervention for reducing falls for residents in LTC, the literature clearly supports exercise as part of a multifactorial falls prevention program [17,20,60–62]. A 2015 umbrella review [62] of meta-analyses of randomized controlled trials of falls prevention interventions in LTC concluded that multifactorial interventions were the most effective at preventing falls in LTC. Additionally, recently developed recommendations for fracture prevention in LTC [61] suggest that balance, strength, and functional training should be included for residents who are not at high risk of fracture, while for those at high risk, exercise should be provided as part of a multifactorial falls prevention intervention. Clinicians must therefore incorporate elements aside from exercise into their falls prevention strategies. Interventions that have shown positive effects on reducing falls when delivered as part of multifactorial interventions include: staff and resident education [31,35,37], environmental modifications [31,35], supply/repair/provision of assistive devices [30], falls problem-solving conferences [30], urinary incontinence management [29], medication review [30], optician review [31], and cognitive behavioral therapy [32].

Conclusion and Suggestions for Clinical Practice

We suggest incorporating strength and balance exercises as part of a multifactorial falls prevention program for residents in LTC. Balance exercises should be challenging and dynamic (eg, weight shifting). Strength exercises should be of a moderate to high intensity (eg, can complete one to sets of 6 to 8 repetitions) and need to be progressed as the residents’ abilities improve. Residents should participate in strength and balance training on 2 to 3 days per week, for 30- to 45-minute sessions, for at least 6 months. Exercises in standing should be prioritized where appropriate. Exercise could be delivered in a group or individual format, but should consider the residents’ preferences, the social benefits of group exercise, and the feasibility of individualizing exercises for the complex needs of residents in LTC in large group settings. Professionals delivering an exercise program should be trained in exercise planning, delivery, and progression, be familiar with the principles of balance and strength training, and have training in working with older adults in LTC. Exercise programs in LTC should be resident-centered and consider residents’ potential physical and cognitive impairments.

Funding/support: Dr. Giangregorio was supported by grants from the Canadian Frailty Network and Canadian Institutes of Health Research.

From the University of California San Francisco, Department of Psychiatry, Weill Institute for Neurosciences, San Francisco, CA.

Abstract

• Objective: To review screening for metabolic syndrome in people with severe mental illness (SMI).
• Methods: Review of the literature.
• Results: Despite evidence-based metabolic screening guidelines, rates of metabolic screening remain low among people with SMI. Barriers to screening exist at the individual, organizational, and systems levels. Interventions to address these barriers range from point-of-care tools to systems-level reorganization towards population-based care.
• Conclusion: Greater systems-level interventions, particularly those that improve collaboration between mental health and primary care, are needed to improve metabolic monitoring and identify cardiovascular disease risk among people with SMI.

Key words: metabolic monitoring; severe mental illness; metabolic syndrome; integrated care.

People with severe mental illness (SMI) have a life expectancy 10 to 20 years shorter than the general population, and cardiometabolic risk factors contribute significantly to the increased morbidity and mortality seen in this population. To address this health disparity, metabolic monitoring guidelines have been proposed as a mechanism to identify metabolic risk factors. This paper aims to discuss metabolic syndrome and its risk factors, describe metabolic monitoring including current rates and barriers to screening, and identify interventions that may improve rates of screening for metabolic syndrome among people with SMI.

Metabolic syndrome has been conceptualized as a state of chronic low-grade inflammation and hypercoagulation associated with hypertension, dyslipidemia, glucose intolerance, insulin resistance, and visceral adiposity [1]. Per the modified National Cholesterol Education Program Adult Treatment Plan III (NCEP ATP III) guidelines, metabolic syndrome is defined as the presence of 3 of the following 5 parameters: (1) blood glucose > 100 mg/dL (or a person is taking a hypoglycemic medication), (2) high density lipoprotein (HDL) < 40 mg/dL in men or < 50 mg/dL in women, (3) triglycerides > 150 mg/dL (or taking a lipid lowering agent), (4) waist circumference > 40 inches in men or > 35 inches in women, and/or (5) blood pressure > 130/85 mm Hg (or taking an antihypertensive medication) [2,3] (Table 1).

Epidemiology and Risk Factors

An estimated 34% of people in the United States meet criteria for metabolic syndrome, with worldwide estimates ranging widely from less than 10% to 84%. People with SMI (eg, bipolar disorder, schizoaffective disorder, schizophrenia) are at even greater risk of developing metabolic syndrome than the general population [4,5]. The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study demonstrated metabolic syndrome rates of 40.9% and 51.6% in men and women with a diagnosis of schizophrenia, respectively [6]. In a systematic review of bipolar disorder and metabolic syndrome, people with bipolar disorder showed higher rates of hypertriglyceridemia and hyperglycemia than controls [5].

People with SMI have been found to have significantly increased morbidity and mortality as compared to people without an SMI diagnosis, much of which has been attributed to increased cardiometabolic risk related to multiple factors [7]. Among adults with schizophrenia receiving Medicaid, Olfson et al found diabetes mellitus, ischemic heart disease, nonischemic heart disease, and cerebrovascular accident to be among the top 10 causes of death [7]. The mortality rate for people with SMI is estimated to be 2 to 3 times higher than the general population, and the life expectancy for people with SMI is estimated to be 10 to 20 years shorter than the general population [8–10]. Contributors to this disparity include modifiable health-related behaviors, social determinants of health, and iatrogenic sequelae of prescribed medications. Behavioral factors include poor nutrition, food insecurity, sedentary lifestyle, and smoking; side effects of commonly prescribed psychotropic medications, most notably atypical antipsychotics and mood stabilizers, also contribute to this disparity [7,11].

Both first- and second-generation antipsychotics have been shown to be associated with metabolic sequelae, including weight gain, elevated blood glucose, and insulin resistance [12–14]. Among psychotropic medications, the atypical or second-generation antipsychotics (SGAs) are a class of medications known to have significant metabolic side effects [15,16]. Studies comparing the metabolic consequences of individual SGAs have found significant variation within the class. Clozapine, olanzapine, quetiapine, and risperidone show significant likelihood of weight gain, hyperlipidemia, and hyperglycemia as well as other metabolic consequences [17]. Aripiprazole, lurasidone, and ziprasidone have shown little to no risk of metabolic sequelae [17].

Metabolic side effects of SGAs have been demonstrated in children, adolescents, and adults. There is evidence that adolescents may be particularly sensitive to these sequelae. Galling and colleagues found that adolescents treated with antipsychotics were at greater risk of developing type 2 diabetes mellitus as compared to both healthy controls and controls with psychiatric illness [18]. Kryzhanovskaya et al, looking at metabolic parameters associated with olanzapine use in adolescents and adults, found that both adolescents and adults showed metabolic sequelae and that adolescents had larger changes in weight gain and lipids compared with adults [19].

The mechanism of SGA impact on metabolic parameters remains incompletely understood, though is thought to be multifactorial, mediated primarily through weight gain with increased adiposity. SGA histamine (H1) receptor binding affinity is implicated in weight gain [20] and 5HT2C antagonism may also lead to an increase in appetite [21]. Other proposed mechanisms include changes in appetite through leptin resistance or decreased sensitivity to leptin, the hormone that mediates satiety. Zhang and colleagues found an increase in leptin levels in patients with schizophrenia prescribed antipsychotics, suggesting leptin dysregulation [21]. Additional studies suggest metabolic disturbances independent of weight gain including direct effects of SGAs on glucose and lipid metabolism [22].

If a person experiences a weight gain of 5% after starting an SGA, it is recommended that the dose be decreased or that they be switched to another psychotropic medication with lower likelihood of metabolic consequences [23]. The effectiveness of switching antipsychotic medications to one with lower metabolic risk to improve weight and lipids has been previously demonstrated [24]. If a patient develops diabetes in the context of an antipsychotic prescription, it is also recommended that the medication be switched to an antipsychotic with less risk of hyperglycemia, and if not possible, to target additional risk factors including weight, poor nutrition, and sedentary lifestyle [25]. The decision to switch medications or decrease dosage is often weighed against the psychiatric stability of the person and their overall response to the medication in the context of their treatment course [14].

Metabolic Monitoring

Given the increased risk of metabolic syndrome among people with SMI, and the association of metabolic syndrome with increased morbidity and all-cause mortality, there has been a growing awareness of the importance of screening for metabolic syndrome among people with SMI. Metabolic monitoring involves routine screening for metabolic parameters and assessment of metabolic risk factors among people with SMI who are prescribed antipsychotic medications. Various practice guidelines have been developed in the United States and internationally to assess for metabolic risk factors in people prescribed antipsychotic medications [26]. Current metabolic monitoring guidelines in the United States stem from 2004 consensus recommendations of the American Diabetes Association and American Psychiatric Association along with the American Association of Clinical Endocrinologists and the North American Association for the Study of Obesity for metabolic monitoring among people prescribed SGAs [23]. These recommendations include a time line for routine monitoring of weight/body mass index, waist circumference, blood pressure, fasting blood glucose or hemoglobin A1c, and fasting lipids (Table 2). Guidelines recommend screening at baseline, more frequently within the first 3 months, and then annually [23].

Though guidelines recommend measurement of waist circumference as a marker for metabolic health, body mass index is often used alone as a measure of obesity [27,28]. This may be due to the relative ease of obtaining weight over waist circumference. For example, weight is more likely to be part of clinic workflows and many providers may not be accustomed to measuring waist circumference. However, waist circumference does provide additional information regarding metabolic health [29], as central adiposity is a marker of cardiometabolic risk and related to insulin resistance [21]. Further modifications of the guidelines have included ethnicity-specific waist measurements [30].

There is evidence that non-fasting lipids may be substituted for fasting lipid panels, particularly for patients who may have difficulty adhering to fasting due to cognitive difficulties. Vanderlip and colleagues argue that fasting serum cholesterol panels are not necessary for screening for dyslipidemia given that non-HDL cholesterol is calculated based on total cholesterol and HDL, which do not substantially differ between fasting and non-fasting values [31]. Hemoglobin A1c is recommended as a screening test for blood glucose abnormalities given that it does not require a fasting state and can therefore be more easily obtained for many patients. The choice to obtain a fasting blood glucose versus hemoglobin A1c may depend on multiple factors, including that a person can adhere to fasting and the cost of the laboratory test.

Routine monitoring of metabolic parameters is an integral step in targeting interventions to treat metabolic syndrome. These interventions include lifestyle modifications and evidence-based treatment guidelines for management of associated dyslipidemia, hypertension, and type 2 diabetes mellitus.

Current Metabolic Screening Practices

Despite the presence of defined guidelines, estimates show persistently low rates of metabolic monitoring among adults prescribed SGAs [32]. One study of 3 state Medicaid programs showed little to no improvement in screening rates for glucose and lipids post dissemination of the 2004 APA/ADA guidelines [33]. They noted a nonsignificant change in rates of glucose testing from 27% to 30% and small change in lipid testing from 10% to 11% among patients prescribed SGAs between 2002–2005 [33]. Examining screening rates among Medicaid recipients in Missouri between 2010–2012, Morrato and colleagues found glucose testing rates of 80% with lipid testing remaining at 41% [34]. A retrospective study of adult Medicaid recipients prescribed first- and second-generation antipsychotics between 2008 and 2012 showed rates of screening for lipids and glucose to increase over time; glucose monitoring increased from 56.6% to 72.6% and lipids from 38.3% to 41.2% [35]. A review by Mangurian and colleagues suggested rates of glucose (fasting blood glucose or hemoglobin A1c) and lipid screening as low as 30% among people prescribed antipsychotic medications [14]. Furthermore, they underscore the impact of low screening rates, stating that if 20% of adults with SMI have diabetes and 70% remain unscreened, then approximately 2 million adults with SMI and diabetes in the United States would not be identified within our current system [14].

Higher rates of screening have been shown for Medicaid populations than commercially insured populations [36]. Haupt et al compared lipid and glucose testing pre- and post- ADA/APA guideline implementation among commercially insured patients. They found an increase from 8.4% to 10.5% post guideline implementation for baseline lipid testing and from 6.8% to 9.0% for lipid testing at 12 weeks post-antipsychotic initiation [36]. Baseline glucose testing increased from 17.3% to 21.8% and from 14.1% to 17.9 % at 12-week post antipsychotic initiation. In alignment with findings from other studies, testing rates were particularly low for children [36].

Low screening rates have been found among children and adolescents prescribed SGAs [37] despite evidence that youth may be at risk of developing more significant metabolic sequelae from SGAs [19]. Edelsohn and colleagues found an increase from 30% to 50% for glucose screening and from 19% to 28% for lipid screening among youth Medicaid recipients prescribed first- and second-generation antipsychotics between 2008 and 2012 [35]. Connolly and colleagues reported on metabolic screening rates for children and adolescents prescribed SGAs over the 8 years following announcement of the 2004 ADA/APA guidelines. Using insurance claims data, they found screening rates for fasting blood glucose and hemoglobin A1c temporarily increased following guideline dissemination, then dropped during the period 2004–2008, and again increased slightly [38].

Barriers to Screening

Barriers to screening exist at the level of the individual patient and provider as well as at the clinic and larger systems levels. Lack of provider awareness of evidence-based guidelines for metabolic monitoring despite the presence of the 2004 ADA/APA guidelines has been cited by researchers as an impediment to screening. In a survey of primary care clinicians in San Francisco, Mangurian et al found that 40% of primary care providers did not know about the ADA/APA consensus guidelines for metabolic monitoring. The same survey of primary care providers identified additional impediments to screening, including obstacles to collaboration with psychiatric providers and to scheduling patients for psychiatric follow-up [39]. Another clinician survey conducted by Parameswaran et al found that psychiatrists viewed psychiatric illness severity, lack of staff time, and lack of clinician time as significant barriers to metabolic screening. In addition, clinicians identified factors related to the complexity of coordinating care across systems as obstacles; these included barriers to coordinating follow-up with medical providers, long wait times for patients to see medical providers, and difficulty collaborating with medical providers [40].

Other systems-level barriers include lack of a population-based approach to screening (eg, registries) and lack of electronic record integration, which impedes the ability of primary care and psychiatry providers to share information related to the ordering of metabolic screening tests and prescribing of medications [41]. Mangurian calls for integration of electronic medical record systems between primary care and psychiatry, a population-based approach to metabolic monitoring utilizing registries and other elements of collaborative care models, and primary care consultation to aid in the treatment of metabolic abnormalities [41]. Amiel et al point to systems-level factors “including but not limited to … poor access to general medical services, inadequate medical record-keeping infrastructure, lack of in-system compliance incentives and lack of centralized oversight” [26].

Based on their experience implementing a computer-based intervention for metabolic monitoring, Lai et al propose that the following factors may influence providers’ engagement in metabolic monitoring: lack of apparent symptoms to suggest metabolic syndrome, patients’ lack of engagement in care, and poor access to care. They identify additional factors at the clinician level to include under-recognition of the need for metabolic monitoring, lack of familiarity with screening guidelines, lack of agreement with guidelines, and the potential for individual clinicians to forget to order tests [42]. At the systems-level, they identify the absence of ongoing training as a potential reason why sustained testing was not observed in their intervention [42].

In a 2011 survey of providers prescribing antipsychotic medication to Medicaid beneficiaries in Missouri, Morrato and colleagues found that factors limiting frequency of health care utilization were closely linked to lack of metabolic testing. They also noted disparities in screening guidelines may lead to lack of routine metabolic monitoring; providers may screen based on prescribed medication, diagnosis, or other risk factor based stratification depending on the guidelines followed [34].

Current Unmet Needs

Vulnerable Populations

Though rates of metabolic screening remain low for all groups prescribed antipsychotic medications, studies have consistently shown low rates of screening among children and adolescents [35,36]. Edelsohn and colleagues hypothesize that the cause of these low rates is multifactorial, including that guardians may be reluctant to have young people undergo blood draws [35]. Morrato and colleagues suggest that policymakers should focus initiatives on younger, healthier adults, who they found to have lower rates of screening [37].

Racial and ethnic minorities with SMI constitute another particularly vulnerable population, with some studies showing an increased risk of metabolic sequelae and lower likelihood of treatment for diabetes and other metabolic derangements among African American and Latino populations with SMI [14,43,44].

Integration of Care

Lack of widespread integration of care between mental health and primary care remains another unmet need [41]. Hasnain and colleagues recommend improved communication between mental health and primary care clinicians to coordinate care to improve rates of monitoring, facilitate early follow-up of metabolic abnormalities, and avoid duplication of monitoring efforts [45]. Morrato and colleagues recommend that efforts to increase rates of metabolic monitoring be targeted not only to providers practicing in community mental health centers, but also to other practice settings including primary care. They found that for 75% of people prescribed antipsychotic medications, the prescriptions were started by prescribing providers who practiced outside of a community mental health center [34] and recommend that educational initiatives and performance improvement interventions broaden to include primary care and other care settings [34].

Potential Interventions for Improvement

Early interventions to improve metabolic screening rates have included educational initiatives to teach providers about consensus guidelines. However, initiatives to educate clinicians on metabolic monitoring have shown to be inadequate to significantly improve rates of screening [33]. Therefore, subsequent initiatives have sought to influence screening rates by targeting behavior of individual clinicians with point-of-care tools, electronic reminders, or through systems-level reorganization towards population-based care [27,42,46].

A variety of clinical interventions focus on technologies that remind clinicians to order metabolic monitoring tests according to screening guidelines. One public mental health service in Queensland, Australia, created a standardized metabolic monitoring form to be uploaded to the electronic medical record. In their implementation study examining the efficacy of the metabolic monitoring form, they found that only 36% of the forms contained data. When data were recorded, there were significantly higher rates of documentation of measurements (weight, body mass index, blood pressure) rather than laboratory tests (including lipids and fasting blood glucose) [27].

Computerized reminder systems for metabolic monitoring have been studied in both outpatient and inpatient settings. Lai and colleagues studied the impact of a computerized reminder system on lab monitoring for metabolic parameters among outpatients with schizophrenia prescribed SGAs [42]. This intervention also included an educational component with discussion of metabolic monitoring for people prescribed SGAs at meetings with attending psychiatrists. Computer reminders were displayed when a provider failed to order fasting plasma glucose or lipids (cholesterol, triglyceride) for patients prescribed clozapine, olanzapine, quetiapine, or risperidone. The study found a statistically significant improvement in laboratory metabolic screening for patients prescribed SGAs after implementation, with the greatest impact 6-months post-intervention, though with subsequent decline in screening rates [42].

Psychiatric inpatient hospitalizations provide an opportunity to obtain testing at the time of treatment initiation and also for ongoing monitoring in a location where fasting laboratory tests may be more easily obtained given onsite phlebotomy. One intervention targeting psychiatric inpatients utilized a computerized physician order entry system with the goal to improve metabolic screening among patients prescribed SGAs. Set in a large academic medical setting, the study found inpatient metabolic monitoring rates did not change significantly after implementation of these pop-up computer alerts, comparing rates immediately and 4 years after implementation [46].

There has been increasing focus on integrating mental health and medical care in an effort to improve the health of people with mental illness [47]. Mangurian and colleagues found that the likelihood of diabetes mellitus screening doubled for people with severe mental illness who were seen for at least one primary care visit in addition to mental health treatment [48]. Haupt similarly found higher rates of metabolic screening among patients who had greater than one primary care visit [36]. Models of integration include both integration of medical services into mental health treatment as well as incorporation of mental health services into primary care. For people with SMI, integration efforts have largely focused on integrating primary care services into community mental health settings [49]. The Substance Abuse and Mental Health Service Administration’s (SAMHSA) Primary and Behavioral Health Care Integration (PBHCI) grants program and the Affordable Care Act’s Health Home Initiative are examples of federal incentive programs for improved integration between behavioral health and primary care [49]. In their evaluation of the PBHCI grant program, Scharf and colleagues presented findings that patients at 3 matched clinics with PCBHI grants showed improvement in some lipids, diastolic blood pressure, and fasting blood glucose, though not smoking or body mass index [50].

Conclusion

Several risk factors contribute to an increase in cardiometabolic risk for people with severe mental illness, including poor nutrition, sedentary lifestyle, social determinants of health, and prescribed antipsychotic medications. Metabolic monitoring aims to address these health disparities by screening for metabolic parameters and identifying abnormalities in order to target appropriate health interventions. Screening rates for metabolic parameters remain low for children, adolescents, and adults prescribed second-generation antipsychotics despite published guidelines and clinical interventions to improve screening. More system-wide interventions to improve collaboration between mental health and primary care are needed to enhance screening and prevent cardiovascular disease risk in this vulnerable population.

Corresponding author: Carrie Cunningham, MD, MPH, Zuckerberg San Francisco General Hospital, 1001 Potrero Ave, Suite 7M, San Francisco, CA 94110, [email protected].

Funding/support: Dr. Cunningham was supported by the UCSF-Zuckerberg San Francisco General Public Psychiatry Fellowship. Mr. Riano was supported by the NIH Center Grant from the National Institute of Diabetes and Digestive and Kidney Diseases for The Health Delivery Systems-Center for Diabetes Translational Research (CDTR) (P30DK092924) and by the UCSF-San Francisco General Hospital Public Psychiatry Fellowship. Dr. Mangurian received support from a grant from the NIH National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (R03 DK101857), as well as NIH Career Development Award (K23MH093689).

From the University of California San Francisco, Department of Psychiatry, Weill Institute for Neurosciences, San Francisco, CA.

Abstract

• Objective: To review screening for metabolic syndrome in people with severe mental illness (SMI).
• Methods: Review of the literature.
• Results: Despite evidence-based metabolic screening guidelines, rates of metabolic screening remain low among people with SMI. Barriers to screening exist at the individual, organizational, and systems levels. Interventions to address these barriers range from point-of-care tools to systems-level reorganization towards population-based care.
• Conclusion: Greater systems-level interventions, particularly those that improve collaboration between mental health and primary care, are needed to improve metabolic monitoring and identify cardiovascular disease risk among people with SMI.

Key words: metabolic monitoring; severe mental illness; metabolic syndrome; integrated care.

People with severe mental illness (SMI) have a life expectancy 10 to 20 years shorter than the general population, and cardiometabolic risk factors contribute significantly to the increased morbidity and mortality seen in this population. To address this health disparity, metabolic monitoring guidelines have been proposed as a mechanism to identify metabolic risk factors. This paper aims to discuss metabolic syndrome and its risk factors, describe metabolic monitoring including current rates and barriers to screening, and identify interventions that may improve rates of screening for metabolic syndrome among people with SMI.

Metabolic syndrome has been conceptualized as a state of chronic low-grade inflammation and hypercoagulation associated with hypertension, dyslipidemia, glucose intolerance, insulin resistance, and visceral adiposity [1]. Per the modified National Cholesterol Education Program Adult Treatment Plan III (NCEP ATP III) guidelines, metabolic syndrome is defined as the presence of 3 of the following 5 parameters: (1) blood glucose > 100 mg/dL (or a person is taking a hypoglycemic medication), (2) high density lipoprotein (HDL) < 40 mg/dL in men or < 50 mg/dL in women, (3) triglycerides > 150 mg/dL (or taking a lipid lowering agent), (4) waist circumference > 40 inches in men or > 35 inches in women, and/or (5) blood pressure > 130/85 mm Hg (or taking an antihypertensive medication) [2,3] (Table 1).

Epidemiology and Risk Factors

An estimated 34% of people in the United States meet criteria for metabolic syndrome, with worldwide estimates ranging widely from less than 10% to 84%. People with SMI (eg, bipolar disorder, schizoaffective disorder, schizophrenia) are at even greater risk of developing metabolic syndrome than the general population [4,5]. The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study demonstrated metabolic syndrome rates of 40.9% and 51.6% in men and women with a diagnosis of schizophrenia, respectively [6]. In a systematic review of bipolar disorder and metabolic syndrome, people with bipolar disorder showed higher rates of hypertriglyceridemia and hyperglycemia than controls [5].

People with SMI have been found to have significantly increased morbidity and mortality as compared to people without an SMI diagnosis, much of which has been attributed to increased cardiometabolic risk related to multiple factors [7]. Among adults with schizophrenia receiving Medicaid, Olfson et al found diabetes mellitus, ischemic heart disease, nonischemic heart disease, and cerebrovascular accident to be among the top 10 causes of death [7]. The mortality rate for people with SMI is estimated to be 2 to 3 times higher than the general population, and the life expectancy for people with SMI is estimated to be 10 to 20 years shorter than the general population [8–10]. Contributors to this disparity include modifiable health-related behaviors, social determinants of health, and iatrogenic sequelae of prescribed medications. Behavioral factors include poor nutrition, food insecurity, sedentary lifestyle, and smoking; side effects of commonly prescribed psychotropic medications, most notably atypical antipsychotics and mood stabilizers, also contribute to this disparity [7,11].

Both first- and second-generation antipsychotics have been shown to be associated with metabolic sequelae, including weight gain, elevated blood glucose, and insulin resistance [12–14]. Among psychotropic medications, the atypical or second-generation antipsychotics (SGAs) are a class of medications known to have significant metabolic side effects [15,16]. Studies comparing the metabolic consequences of individual SGAs have found significant variation within the class. Clozapine, olanzapine, quetiapine, and risperidone show significant likelihood of weight gain, hyperlipidemia, and hyperglycemia as well as other metabolic consequences [17]. Aripiprazole, lurasidone, and ziprasidone have shown little to no risk of metabolic sequelae [17].

Metabolic side effects of SGAs have been demonstrated in children, adolescents, and adults. There is evidence that adolescents may be particularly sensitive to these sequelae. Galling and colleagues found that adolescents treated with antipsychotics were at greater risk of developing type 2 diabetes mellitus as compared to both healthy controls and controls with psychiatric illness [18]. Kryzhanovskaya et al, looking at metabolic parameters associated with olanzapine use in adolescents and adults, found that both adolescents and adults showed metabolic sequelae and that adolescents had larger changes in weight gain and lipids compared with adults [19].

The mechanism of SGA impact on metabolic parameters remains incompletely understood, though is thought to be multifactorial, mediated primarily through weight gain with increased adiposity. SGA histamine (H1) receptor binding affinity is implicated in weight gain [20] and 5HT2C antagonism may also lead to an increase in appetite [21]. Other proposed mechanisms include changes in appetite through leptin resistance or decreased sensitivity to leptin, the hormone that mediates satiety. Zhang and colleagues found an increase in leptin levels in patients with schizophrenia prescribed antipsychotics, suggesting leptin dysregulation [21]. Additional studies suggest metabolic disturbances independent of weight gain including direct effects of SGAs on glucose and lipid metabolism [22].

If a person experiences a weight gain of 5% after starting an SGA, it is recommended that the dose be decreased or that they be switched to another psychotropic medication with lower likelihood of metabolic consequences [23]. The effectiveness of switching antipsychotic medications to one with lower metabolic risk to improve weight and lipids has been previously demonstrated [24]. If a patient develops diabetes in the context of an antipsychotic prescription, it is also recommended that the medication be switched to an antipsychotic with less risk of hyperglycemia, and if not possible, to target additional risk factors including weight, poor nutrition, and sedentary lifestyle [25]. The decision to switch medications or decrease dosage is often weighed against the psychiatric stability of the person and their overall response to the medication in the context of their treatment course [14].

Metabolic Monitoring

Given the increased risk of metabolic syndrome among people with SMI, and the association of metabolic syndrome with increased morbidity and all-cause mortality, there has been a growing awareness of the importance of screening for metabolic syndrome among people with SMI. Metabolic monitoring involves routine screening for metabolic parameters and assessment of metabolic risk factors among people with SMI who are prescribed antipsychotic medications. Various practice guidelines have been developed in the United States and internationally to assess for metabolic risk factors in people prescribed antipsychotic medications [26]. Current metabolic monitoring guidelines in the United States stem from 2004 consensus recommendations of the American Diabetes Association and American Psychiatric Association along with the American Association of Clinical Endocrinologists and the North American Association for the Study of Obesity for metabolic monitoring among people prescribed SGAs [23]. These recommendations include a time line for routine monitoring of weight/body mass index, waist circumference, blood pressure, fasting blood glucose or hemoglobin A1c, and fasting lipids (Table 2). Guidelines recommend screening at baseline, more frequently within the first 3 months, and then annually [23].

Though guidelines recommend measurement of waist circumference as a marker for metabolic health, body mass index is often used alone as a measure of obesity [27,28]. This may be due to the relative ease of obtaining weight over waist circumference. For example, weight is more likely to be part of clinic workflows and many providers may not be accustomed to measuring waist circumference. However, waist circumference does provide additional information regarding metabolic health [29], as central adiposity is a marker of cardiometabolic risk and related to insulin resistance [21]. Further modifications of the guidelines have included ethnicity-specific waist measurements [30].

There is evidence that non-fasting lipids may be substituted for fasting lipid panels, particularly for patients who may have difficulty adhering to fasting due to cognitive difficulties. Vanderlip and colleagues argue that fasting serum cholesterol panels are not necessary for screening for dyslipidemia given that non-HDL cholesterol is calculated based on total cholesterol and HDL, which do not substantially differ between fasting and non-fasting values [31]. Hemoglobin A1c is recommended as a screening test for blood glucose abnormalities given that it does not require a fasting state and can therefore be more easily obtained for many patients. The choice to obtain a fasting blood glucose versus hemoglobin A1c may depend on multiple factors, including that a person can adhere to fasting and the cost of the laboratory test.

Routine monitoring of metabolic parameters is an integral step in targeting interventions to treat metabolic syndrome. These interventions include lifestyle modifications and evidence-based treatment guidelines for management of associated dyslipidemia, hypertension, and type 2 diabetes mellitus.

Current Metabolic Screening Practices

Despite the presence of defined guidelines, estimates show persistently low rates of metabolic monitoring among adults prescribed SGAs [32]. One study of 3 state Medicaid programs showed little to no improvement in screening rates for glucose and lipids post dissemination of the 2004 APA/ADA guidelines [33]. They noted a nonsignificant change in rates of glucose testing from 27% to 30% and small change in lipid testing from 10% to 11% among patients prescribed SGAs between 2002–2005 [33]. Examining screening rates among Medicaid recipients in Missouri between 2010–2012, Morrato and colleagues found glucose testing rates of 80% with lipid testing remaining at 41% [34]. A retrospective study of adult Medicaid recipients prescribed first- and second-generation antipsychotics between 2008 and 2012 showed rates of screening for lipids and glucose to increase over time; glucose monitoring increased from 56.6% to 72.6% and lipids from 38.3% to 41.2% [35]. A review by Mangurian and colleagues suggested rates of glucose (fasting blood glucose or hemoglobin A1c) and lipid screening as low as 30% among people prescribed antipsychotic medications [14]. Furthermore, they underscore the impact of low screening rates, stating that if 20% of adults with SMI have diabetes and 70% remain unscreened, then approximately 2 million adults with SMI and diabetes in the United States would not be identified within our current system [14].

Higher rates of screening have been shown for Medicaid populations than commercially insured populations [36]. Haupt et al compared lipid and glucose testing pre- and post- ADA/APA guideline implementation among commercially insured patients. They found an increase from 8.4% to 10.5% post guideline implementation for baseline lipid testing and from 6.8% to 9.0% for lipid testing at 12 weeks post-antipsychotic initiation [36]. Baseline glucose testing increased from 17.3% to 21.8% and from 14.1% to 17.9 % at 12-week post antipsychotic initiation. In alignment with findings from other studies, testing rates were particularly low for children [36].

Low screening rates have been found among children and adolescents prescribed SGAs [37] despite evidence that youth may be at risk of developing more significant metabolic sequelae from SGAs [19]. Edelsohn and colleagues found an increase from 30% to 50% for glucose screening and from 19% to 28% for lipid screening among youth Medicaid recipients prescribed first- and second-generation antipsychotics between 2008 and 2012 [35]. Connolly and colleagues reported on metabolic screening rates for children and adolescents prescribed SGAs over the 8 years following announcement of the 2004 ADA/APA guidelines. Using insurance claims data, they found screening rates for fasting blood glucose and hemoglobin A1c temporarily increased following guideline dissemination, then dropped during the period 2004–2008, and again increased slightly [38].

Barriers to Screening

Barriers to screening exist at the level of the individual patient and provider as well as at the clinic and larger systems levels. Lack of provider awareness of evidence-based guidelines for metabolic monitoring despite the presence of the 2004 ADA/APA guidelines has been cited by researchers as an impediment to screening. In a survey of primary care clinicians in San Francisco, Mangurian et al found that 40% of primary care providers did not know about the ADA/APA consensus guidelines for metabolic monitoring. The same survey of primary care providers identified additional impediments to screening, including obstacles to collaboration with psychiatric providers and to scheduling patients for psychiatric follow-up [39]. Another clinician survey conducted by Parameswaran et al found that psychiatrists viewed psychiatric illness severity, lack of staff time, and lack of clinician time as significant barriers to metabolic screening. In addition, clinicians identified factors related to the complexity of coordinating care across systems as obstacles; these included barriers to coordinating follow-up with medical providers, long wait times for patients to see medical providers, and difficulty collaborating with medical providers [40].

Other systems-level barriers include lack of a population-based approach to screening (eg, registries) and lack of electronic record integration, which impedes the ability of primary care and psychiatry providers to share information related to the ordering of metabolic screening tests and prescribing of medications [41]. Mangurian calls for integration of electronic medical record systems between primary care and psychiatry, a population-based approach to metabolic monitoring utilizing registries and other elements of collaborative care models, and primary care consultation to aid in the treatment of metabolic abnormalities [41]. Amiel et al point to systems-level factors “including but not limited to … poor access to general medical services, inadequate medical record-keeping infrastructure, lack of in-system compliance incentives and lack of centralized oversight” [26].

Based on their experience implementing a computer-based intervention for metabolic monitoring, Lai et al propose that the following factors may influence providers’ engagement in metabolic monitoring: lack of apparent symptoms to suggest metabolic syndrome, patients’ lack of engagement in care, and poor access to care. They identify additional factors at the clinician level to include under-recognition of the need for metabolic monitoring, lack of familiarity with screening guidelines, lack of agreement with guidelines, and the potential for individual clinicians to forget to order tests [42]. At the systems-level, they identify the absence of ongoing training as a potential reason why sustained testing was not observed in their intervention [42].

In a 2011 survey of providers prescribing antipsychotic medication to Medicaid beneficiaries in Missouri, Morrato and colleagues found that factors limiting frequency of health care utilization were closely linked to lack of metabolic testing. They also noted disparities in screening guidelines may lead to lack of routine metabolic monitoring; providers may screen based on prescribed medication, diagnosis, or other risk factor based stratification depending on the guidelines followed [34].

Current Unmet Needs

Vulnerable Populations

Though rates of metabolic screening remain low for all groups prescribed antipsychotic medications, studies have consistently shown low rates of screening among children and adolescents [35,36]. Edelsohn and colleagues hypothesize that the cause of these low rates is multifactorial, including that guardians may be reluctant to have young people undergo blood draws [35]. Morrato and colleagues suggest that policymakers should focus initiatives on younger, healthier adults, who they found to have lower rates of screening [37].

Racial and ethnic minorities with SMI constitute another particularly vulnerable population, with some studies showing an increased risk of metabolic sequelae and lower likelihood of treatment for diabetes and other metabolic derangements among African American and Latino populations with SMI [14,43,44].

Integration of Care

Lack of widespread integration of care between mental health and primary care remains another unmet need [41]. Hasnain and colleagues recommend improved communication between mental health and primary care clinicians to coordinate care to improve rates of monitoring, facilitate early follow-up of metabolic abnormalities, and avoid duplication of monitoring efforts [45]. Morrato and colleagues recommend that efforts to increase rates of metabolic monitoring be targeted not only to providers practicing in community mental health centers, but also to other practice settings including primary care. They found that for 75% of people prescribed antipsychotic medications, the prescriptions were started by prescribing providers who practiced outside of a community mental health center [34] and recommend that educational initiatives and performance improvement interventions broaden to include primary care and other care settings [34].

Potential Interventions for Improvement

Early interventions to improve metabolic screening rates have included educational initiatives to teach providers about consensus guidelines. However, initiatives to educate clinicians on metabolic monitoring have shown to be inadequate to significantly improve rates of screening [33]. Therefore, subsequent initiatives have sought to influence screening rates by targeting behavior of individual clinicians with point-of-care tools, electronic reminders, or through systems-level reorganization towards population-based care [27,42,46].

A variety of clinical interventions focus on technologies that remind clinicians to order metabolic monitoring tests according to screening guidelines. One public mental health service in Queensland, Australia, created a standardized metabolic monitoring form to be uploaded to the electronic medical record. In their implementation study examining the efficacy of the metabolic monitoring form, they found that only 36% of the forms contained data. When data were recorded, there were significantly higher rates of documentation of measurements (weight, body mass index, blood pressure) rather than laboratory tests (including lipids and fasting blood glucose) [27].

Computerized reminder systems for metabolic monitoring have been studied in both outpatient and inpatient settings. Lai and colleagues studied the impact of a computerized reminder system on lab monitoring for metabolic parameters among outpatients with schizophrenia prescribed SGAs [42]. This intervention also included an educational component with discussion of metabolic monitoring for people prescribed SGAs at meetings with attending psychiatrists. Computer reminders were displayed when a provider failed to order fasting plasma glucose or lipids (cholesterol, triglyceride) for patients prescribed clozapine, olanzapine, quetiapine, or risperidone. The study found a statistically significant improvement in laboratory metabolic screening for patients prescribed SGAs after implementation, with the greatest impact 6-months post-intervention, though with subsequent decline in screening rates [42].

Psychiatric inpatient hospitalizations provide an opportunity to obtain testing at the time of treatment initiation and also for ongoing monitoring in a location where fasting laboratory tests may be more easily obtained given onsite phlebotomy. One intervention targeting psychiatric inpatients utilized a computerized physician order entry system with the goal to improve metabolic screening among patients prescribed SGAs. Set in a large academic medical setting, the study found inpatient metabolic monitoring rates did not change significantly after implementation of these pop-up computer alerts, comparing rates immediately and 4 years after implementation [46].

There has been increasing focus on integrating mental health and medical care in an effort to improve the health of people with mental illness [47]. Mangurian and colleagues found that the likelihood of diabetes mellitus screening doubled for people with severe mental illness who were seen for at least one primary care visit in addition to mental health treatment [48]. Haupt similarly found higher rates of metabolic screening among patients who had greater than one primary care visit [36]. Models of integration include both integration of medical services into mental health treatment as well as incorporation of mental health services into primary care. For people with SMI, integration efforts have largely focused on integrating primary care services into community mental health settings [49]. The Substance Abuse and Mental Health Service Administration’s (SAMHSA) Primary and Behavioral Health Care Integration (PBHCI) grants program and the Affordable Care Act’s Health Home Initiative are examples of federal incentive programs for improved integration between behavioral health and primary care [49]. In their evaluation of the PBHCI grant program, Scharf and colleagues presented findings that patients at 3 matched clinics with PCBHI grants showed improvement in some lipids, diastolic blood pressure, and fasting blood glucose, though not smoking or body mass index [50].

Conclusion

Several risk factors contribute to an increase in cardiometabolic risk for people with severe mental illness, including poor nutrition, sedentary lifestyle, social determinants of health, and prescribed antipsychotic medications. Metabolic monitoring aims to address these health disparities by screening for metabolic parameters and identifying abnormalities in order to target appropriate health interventions. Screening rates for metabolic parameters remain low for children, adolescents, and adults prescribed second-generation antipsychotics despite published guidelines and clinical interventions to improve screening. More system-wide interventions to improve collaboration between mental health and primary care are needed to enhance screening and prevent cardiovascular disease risk in this vulnerable population.

Corresponding author: Carrie Cunningham, MD, MPH, Zuckerberg San Francisco General Hospital, 1001 Potrero Ave, Suite 7M, San Francisco, CA 94110, [email protected].

Funding/support: Dr. Cunningham was supported by the UCSF-Zuckerberg San Francisco General Public Psychiatry Fellowship. Mr. Riano was supported by the NIH Center Grant from the National Institute of Diabetes and Digestive and Kidney Diseases for The Health Delivery Systems-Center for Diabetes Translational Research (CDTR) (P30DK092924) and by the UCSF-San Francisco General Hospital Public Psychiatry Fellowship. Dr. Mangurian received support from a grant from the NIH National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (R03 DK101857), as well as NIH Career Development Award (K23MH093689).

From the University of California San Francisco, Department of Psychiatry, Weill Institute for Neurosciences, San Francisco, CA.

Abstract

• Objective: To review screening for metabolic syndrome in people with severe mental illness (SMI).
• Methods: Review of the literature.
• Results: Despite evidence-based metabolic screening guidelines, rates of metabolic screening remain low among people with SMI. Barriers to screening exist at the individual, organizational, and systems levels. Interventions to address these barriers range from point-of-care tools to systems-level reorganization towards population-based care.
• Conclusion: Greater systems-level interventions, particularly those that improve collaboration between mental health and primary care, are needed to improve metabolic monitoring and identify cardiovascular disease risk among people with SMI.

Key words: metabolic monitoring; severe mental illness; metabolic syndrome; integrated care.

People with severe mental illness (SMI) have a life expectancy 10 to 20 years shorter than the general population, and cardiometabolic risk factors contribute significantly to the increased morbidity and mortality seen in this population. To address this health disparity, metabolic monitoring guidelines have been proposed as a mechanism to identify metabolic risk factors. This paper aims to discuss metabolic syndrome and its risk factors, describe metabolic monitoring including current rates and barriers to screening, and identify interventions that may improve rates of screening for metabolic syndrome among people with SMI.

Metabolic syndrome has been conceptualized as a state of chronic low-grade inflammation and hypercoagulation associated with hypertension, dyslipidemia, glucose intolerance, insulin resistance, and visceral adiposity [1]. Per the modified National Cholesterol Education Program Adult Treatment Plan III (NCEP ATP III) guidelines, metabolic syndrome is defined as the presence of 3 of the following 5 parameters: (1) blood glucose > 100 mg/dL (or a person is taking a hypoglycemic medication), (2) high density lipoprotein (HDL) < 40 mg/dL in men or < 50 mg/dL in women, (3) triglycerides > 150 mg/dL (or taking a lipid lowering agent), (4) waist circumference > 40 inches in men or > 35 inches in women, and/or (5) blood pressure > 130/85 mm Hg (or taking an antihypertensive medication) [2,3] (Table 1).

Epidemiology and Risk Factors

An estimated 34% of people in the United States meet criteria for metabolic syndrome, with worldwide estimates ranging widely from less than 10% to 84%. People with SMI (eg, bipolar disorder, schizoaffective disorder, schizophrenia) are at even greater risk of developing metabolic syndrome than the general population [4,5]. The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study demonstrated metabolic syndrome rates of 40.9% and 51.6% in men and women with a diagnosis of schizophrenia, respectively [6]. In a systematic review of bipolar disorder and metabolic syndrome, people with bipolar disorder showed higher rates of hypertriglyceridemia and hyperglycemia than controls [5].

People with SMI have been found to have significantly increased morbidity and mortality as compared to people without an SMI diagnosis, much of which has been attributed to increased cardiometabolic risk related to multiple factors [7]. Among adults with schizophrenia receiving Medicaid, Olfson et al found diabetes mellitus, ischemic heart disease, nonischemic heart disease, and cerebrovascular accident to be among the top 10 causes of death [7]. The mortality rate for people with SMI is estimated to be 2 to 3 times higher than the general population, and the life expectancy for people with SMI is estimated to be 10 to 20 years shorter than the general population [8–10]. Contributors to this disparity include modifiable health-related behaviors, social determinants of health, and iatrogenic sequelae of prescribed medications. Behavioral factors include poor nutrition, food insecurity, sedentary lifestyle, and smoking; side effects of commonly prescribed psychotropic medications, most notably atypical antipsychotics and mood stabilizers, also contribute to this disparity [7,11].

Both first- and second-generation antipsychotics have been shown to be associated with metabolic sequelae, including weight gain, elevated blood glucose, and insulin resistance [12–14]. Among psychotropic medications, the atypical or second-generation antipsychotics (SGAs) are a class of medications known to have significant metabolic side effects [15,16]. Studies comparing the metabolic consequences of individual SGAs have found significant variation within the class. Clozapine, olanzapine, quetiapine, and risperidone show significant likelihood of weight gain, hyperlipidemia, and hyperglycemia as well as other metabolic consequences [17]. Aripiprazole, lurasidone, and ziprasidone have shown little to no risk of metabolic sequelae [17].

Metabolic side effects of SGAs have been demonstrated in children, adolescents, and adults. There is evidence that adolescents may be particularly sensitive to these sequelae. Galling and colleagues found that adolescents treated with antipsychotics were at greater risk of developing type 2 diabetes mellitus as compared to both healthy controls and controls with psychiatric illness [18]. Kryzhanovskaya et al, looking at metabolic parameters associated with olanzapine use in adolescents and adults, found that both adolescents and adults showed metabolic sequelae and that adolescents had larger changes in weight gain and lipids compared with adults [19].

The mechanism of SGA impact on metabolic parameters remains incompletely understood, though is thought to be multifactorial, mediated primarily through weight gain with increased adiposity. SGA histamine (H1) receptor binding affinity is implicated in weight gain [20] and 5HT2C antagonism may also lead to an increase in appetite [21]. Other proposed mechanisms include changes in appetite through leptin resistance or decreased sensitivity to leptin, the hormone that mediates satiety. Zhang and colleagues found an increase in leptin levels in patients with schizophrenia prescribed antipsychotics, suggesting leptin dysregulation [21]. Additional studies suggest metabolic disturbances independent of weight gain including direct effects of SGAs on glucose and lipid metabolism [22].

If a person experiences a weight gain of 5% after starting an SGA, it is recommended that the dose be decreased or that they be switched to another psychotropic medication with lower likelihood of metabolic consequences [23]. The effectiveness of switching antipsychotic medications to one with lower metabolic risk to improve weight and lipids has been previously demonstrated [24]. If a patient develops diabetes in the context of an antipsychotic prescription, it is also recommended that the medication be switched to an antipsychotic with less risk of hyperglycemia, and if not possible, to target additional risk factors including weight, poor nutrition, and sedentary lifestyle [25]. The decision to switch medications or decrease dosage is often weighed against the psychiatric stability of the person and their overall response to the medication in the context of their treatment course [14].

Metabolic Monitoring

Given the increased risk of metabolic syndrome among people with SMI, and the association of metabolic syndrome with increased morbidity and all-cause mortality, there has been a growing awareness of the importance of screening for metabolic syndrome among people with SMI. Metabolic monitoring involves routine screening for metabolic parameters and assessment of metabolic risk factors among people with SMI who are prescribed antipsychotic medications. Various practice guidelines have been developed in the United States and internationally to assess for metabolic risk factors in people prescribed antipsychotic medications [26]. Current metabolic monitoring guidelines in the United States stem from 2004 consensus recommendations of the American Diabetes Association and American Psychiatric Association along with the American Association of Clinical Endocrinologists and the North American Association for the Study of Obesity for metabolic monitoring among people prescribed SGAs [23]. These recommendations include a time line for routine monitoring of weight/body mass index, waist circumference, blood pressure, fasting blood glucose or hemoglobin A1c, and fasting lipids (Table 2). Guidelines recommend screening at baseline, more frequently within the first 3 months, and then annually [23].

Though guidelines recommend measurement of waist circumference as a marker for metabolic health, body mass index is often used alone as a measure of obesity [27,28]. This may be due to the relative ease of obtaining weight over waist circumference. For example, weight is more likely to be part of clinic workflows and many providers may not be accustomed to measuring waist circumference. However, waist circumference does provide additional information regarding metabolic health [29], as central adiposity is a marker of cardiometabolic risk and related to insulin resistance [21]. Further modifications of the guidelines have included ethnicity-specific waist measurements [30].

There is evidence that non-fasting lipids may be substituted for fasting lipid panels, particularly for patients who may have difficulty adhering to fasting due to cognitive difficulties. Vanderlip and colleagues argue that fasting serum cholesterol panels are not necessary for screening for dyslipidemia given that non-HDL cholesterol is calculated based on total cholesterol and HDL, which do not substantially differ between fasting and non-fasting values [31]. Hemoglobin A1c is recommended as a screening test for blood glucose abnormalities given that it does not require a fasting state and can therefore be more easily obtained for many patients. The choice to obtain a fasting blood glucose versus hemoglobin A1c may depend on multiple factors, including that a person can adhere to fasting and the cost of the laboratory test.

Routine monitoring of metabolic parameters is an integral step in targeting interventions to treat metabolic syndrome. These interventions include lifestyle modifications and evidence-based treatment guidelines for management of associated dyslipidemia, hypertension, and type 2 diabetes mellitus.

Current Metabolic Screening Practices

Despite the presence of defined guidelines, estimates show persistently low rates of metabolic monitoring among adults prescribed SGAs [32]. One study of 3 state Medicaid programs showed little to no improvement in screening rates for glucose and lipids post dissemination of the 2004 APA/ADA guidelines [33]. They noted a nonsignificant change in rates of glucose testing from 27% to 30% and small change in lipid testing from 10% to 11% among patients prescribed SGAs between 2002–2005 [33]. Examining screening rates among Medicaid recipients in Missouri between 2010–2012, Morrato and colleagues found glucose testing rates of 80% with lipid testing remaining at 41% [34]. A retrospective study of adult Medicaid recipients prescribed first- and second-generation antipsychotics between 2008 and 2012 showed rates of screening for lipids and glucose to increase over time; glucose monitoring increased from 56.6% to 72.6% and lipids from 38.3% to 41.2% [35]. A review by Mangurian and colleagues suggested rates of glucose (fasting blood glucose or hemoglobin A1c) and lipid screening as low as 30% among people prescribed antipsychotic medications [14]. Furthermore, they underscore the impact of low screening rates, stating that if 20% of adults with SMI have diabetes and 70% remain unscreened, then approximately 2 million adults with SMI and diabetes in the United States would not be identified within our current system [14].

Higher rates of screening have been shown for Medicaid populations than commercially insured populations [36]. Haupt et al compared lipid and glucose testing pre- and post- ADA/APA guideline implementation among commercially insured patients. They found an increase from 8.4% to 10.5% post guideline implementation for baseline lipid testing and from 6.8% to 9.0% for lipid testing at 12 weeks post-antipsychotic initiation [36]. Baseline glucose testing increased from 17.3% to 21.8% and from 14.1% to 17.9 % at 12-week post antipsychotic initiation. In alignment with findings from other studies, testing rates were particularly low for children [36].

Low screening rates have been found among children and adolescents prescribed SGAs [37] despite evidence that youth may be at risk of developing more significant metabolic sequelae from SGAs [19]. Edelsohn and colleagues found an increase from 30% to 50% for glucose screening and from 19% to 28% for lipid screening among youth Medicaid recipients prescribed first- and second-generation antipsychotics between 2008 and 2012 [35]. Connolly and colleagues reported on metabolic screening rates for children and adolescents prescribed SGAs over the 8 years following announcement of the 2004 ADA/APA guidelines. Using insurance claims data, they found screening rates for fasting blood glucose and hemoglobin A1c temporarily increased following guideline dissemination, then dropped during the period 2004–2008, and again increased slightly [38].

Barriers to Screening

Barriers to screening exist at the level of the individual patient and provider as well as at the clinic and larger systems levels. Lack of provider awareness of evidence-based guidelines for metabolic monitoring despite the presence of the 2004 ADA/APA guidelines has been cited by researchers as an impediment to screening. In a survey of primary care clinicians in San Francisco, Mangurian et al found that 40% of primary care providers did not know about the ADA/APA consensus guidelines for metabolic monitoring. The same survey of primary care providers identified additional impediments to screening, including obstacles to collaboration with psychiatric providers and to scheduling patients for psychiatric follow-up [39]. Another clinician survey conducted by Parameswaran et al found that psychiatrists viewed psychiatric illness severity, lack of staff time, and lack of clinician time as significant barriers to metabolic screening. In addition, clinicians identified factors related to the complexity of coordinating care across systems as obstacles; these included barriers to coordinating follow-up with medical providers, long wait times for patients to see medical providers, and difficulty collaborating with medical providers [40].

Other systems-level barriers include lack of a population-based approach to screening (eg, registries) and lack of electronic record integration, which impedes the ability of primary care and psychiatry providers to share information related to the ordering of metabolic screening tests and prescribing of medications [41]. Mangurian calls for integration of electronic medical record systems between primary care and psychiatry, a population-based approach to metabolic monitoring utilizing registries and other elements of collaborative care models, and primary care consultation to aid in the treatment of metabolic abnormalities [41]. Amiel et al point to systems-level factors “including but not limited to … poor access to general medical services, inadequate medical record-keeping infrastructure, lack of in-system compliance incentives and lack of centralized oversight” [26].

Based on their experience implementing a computer-based intervention for metabolic monitoring, Lai et al propose that the following factors may influence providers’ engagement in metabolic monitoring: lack of apparent symptoms to suggest metabolic syndrome, patients’ lack of engagement in care, and poor access to care. They identify additional factors at the clinician level to include under-recognition of the need for metabolic monitoring, lack of familiarity with screening guidelines, lack of agreement with guidelines, and the potential for individual clinicians to forget to order tests [42]. At the systems-level, they identify the absence of ongoing training as a potential reason why sustained testing was not observed in their intervention [42].

In a 2011 survey of providers prescribing antipsychotic medication to Medicaid beneficiaries in Missouri, Morrato and colleagues found that factors limiting frequency of health care utilization were closely linked to lack of metabolic testing. They also noted disparities in screening guidelines may lead to lack of routine metabolic monitoring; providers may screen based on prescribed medication, diagnosis, or other risk factor based stratification depending on the guidelines followed [34].

Current Unmet Needs

Vulnerable Populations

Though rates of metabolic screening remain low for all groups prescribed antipsychotic medications, studies have consistently shown low rates of screening among children and adolescents [35,36]. Edelsohn and colleagues hypothesize that the cause of these low rates is multifactorial, including that guardians may be reluctant to have young people undergo blood draws [35]. Morrato and colleagues suggest that policymakers should focus initiatives on younger, healthier adults, who they found to have lower rates of screening [37].

Racial and ethnic minorities with SMI constitute another particularly vulnerable population, with some studies showing an increased risk of metabolic sequelae and lower likelihood of treatment for diabetes and other metabolic derangements among African American and Latino populations with SMI [14,43,44].

Integration of Care

Lack of widespread integration of care between mental health and primary care remains another unmet need [41]. Hasnain and colleagues recommend improved communication between mental health and primary care clinicians to coordinate care to improve rates of monitoring, facilitate early follow-up of metabolic abnormalities, and avoid duplication of monitoring efforts [45]. Morrato and colleagues recommend that efforts to increase rates of metabolic monitoring be targeted not only to providers practicing in community mental health centers, but also to other practice settings including primary care. They found that for 75% of people prescribed antipsychotic medications, the prescriptions were started by prescribing providers who practiced outside of a community mental health center [34] and recommend that educational initiatives and performance improvement interventions broaden to include primary care and other care settings [34].

Potential Interventions for Improvement

Early interventions to improve metabolic screening rates have included educational initiatives to teach providers about consensus guidelines. However, initiatives to educate clinicians on metabolic monitoring have shown to be inadequate to significantly improve rates of screening [33]. Therefore, subsequent initiatives have sought to influence screening rates by targeting behavior of individual clinicians with point-of-care tools, electronic reminders, or through systems-level reorganization towards population-based care [27,42,46].

A variety of clinical interventions focus on technologies that remind clinicians to order metabolic monitoring tests according to screening guidelines. One public mental health service in Queensland, Australia, created a standardized metabolic monitoring form to be uploaded to the electronic medical record. In their implementation study examining the efficacy of the metabolic monitoring form, they found that only 36% of the forms contained data. When data were recorded, there were significantly higher rates of documentation of measurements (weight, body mass index, blood pressure) rather than laboratory tests (including lipids and fasting blood glucose) [27].

Computerized reminder systems for metabolic monitoring have been studied in both outpatient and inpatient settings. Lai and colleagues studied the impact of a computerized reminder system on lab monitoring for metabolic parameters among outpatients with schizophrenia prescribed SGAs [42]. This intervention also included an educational component with discussion of metabolic monitoring for people prescribed SGAs at meetings with attending psychiatrists. Computer reminders were displayed when a provider failed to order fasting plasma glucose or lipids (cholesterol, triglyceride) for patients prescribed clozapine, olanzapine, quetiapine, or risperidone. The study found a statistically significant improvement in laboratory metabolic screening for patients prescribed SGAs after implementation, with the greatest impact 6-months post-intervention, though with subsequent decline in screening rates [42].

Psychiatric inpatient hospitalizations provide an opportunity to obtain testing at the time of treatment initiation and also for ongoing monitoring in a location where fasting laboratory tests may be more easily obtained given onsite phlebotomy. One intervention targeting psychiatric inpatients utilized a computerized physician order entry system with the goal to improve metabolic screening among patients prescribed SGAs. Set in a large academic medical setting, the study found inpatient metabolic monitoring rates did not change significantly after implementation of these pop-up computer alerts, comparing rates immediately and 4 years after implementation [46].

There has been increasing focus on integrating mental health and medical care in an effort to improve the health of people with mental illness [47]. Mangurian and colleagues found that the likelihood of diabetes mellitus screening doubled for people with severe mental illness who were seen for at least one primary care visit in addition to mental health treatment [48]. Haupt similarly found higher rates of metabolic screening among patients who had greater than one primary care visit [36]. Models of integration include both integration of medical services into mental health treatment as well as incorporation of mental health services into primary care. For people with SMI, integration efforts have largely focused on integrating primary care services into community mental health settings [49]. The Substance Abuse and Mental Health Service Administration’s (SAMHSA) Primary and Behavioral Health Care Integration (PBHCI) grants program and the Affordable Care Act’s Health Home Initiative are examples of federal incentive programs for improved integration between behavioral health and primary care [49]. In their evaluation of the PBHCI grant program, Scharf and colleagues presented findings that patients at 3 matched clinics with PCBHI grants showed improvement in some lipids, diastolic blood pressure, and fasting blood glucose, though not smoking or body mass index [50].

Conclusion

Several risk factors contribute to an increase in cardiometabolic risk for people with severe mental illness, including poor nutrition, sedentary lifestyle, social determinants of health, and prescribed antipsychotic medications. Metabolic monitoring aims to address these health disparities by screening for metabolic parameters and identifying abnormalities in order to target appropriate health interventions. Screening rates for metabolic parameters remain low for children, adolescents, and adults prescribed second-generation antipsychotics despite published guidelines and clinical interventions to improve screening. More system-wide interventions to improve collaboration between mental health and primary care are needed to enhance screening and prevent cardiovascular disease risk in this vulnerable population.

Corresponding author: Carrie Cunningham, MD, MPH, Zuckerberg San Francisco General Hospital, 1001 Potrero Ave, Suite 7M, San Francisco, CA 94110, [email protected].

Funding/support: Dr. Cunningham was supported by the UCSF-Zuckerberg San Francisco General Public Psychiatry Fellowship. Mr. Riano was supported by the NIH Center Grant from the National Institute of Diabetes and Digestive and Kidney Diseases for The Health Delivery Systems-Center for Diabetes Translational Research (CDTR) (P30DK092924) and by the UCSF-San Francisco General Hospital Public Psychiatry Fellowship. Dr. Mangurian received support from a grant from the NIH National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (R03 DK101857), as well as NIH Career Development Award (K23MH093689).