A surge in elderly patients with diabetes has placed a large burden on extended-care facilities. According to the Centers for Medicare and Medicaid Services, the prevalence of diabetes among nursing home residents is 33.3%.¹ Between 1995 and 2004, the estimated number of long-term care residents with diabetes mellitus (DM) grew by 7.1%, from approximately 242,000 to 329,000.² The increase adds to the challenge extended-care facilities face in attempting to provide high-quality care to patients with diabetes. No well-accepted management guidelines exist for nursing home residents with DM.³

Frail older adults with DM are more likely to suffer from cardiovascular conditions than younger patients, and are at greater risk for hypoglycemic coma and serious hyperglycemia.^4,5 A high frequency of hypoglycemia, especially nocturnal hypoglycemia, has been reported among nursing home residents with diabetes.⁶ Intensive insulin therapy is associated with hypoglycemia and increased mortality.⁷ However, hyperglycemia also must be considered because it significantly impairs quality of life. Uncontrolled hyperglycemia causes osmotic diuresis, leading to polyuria, nocturia, aggravated incontinence, and disrupted sleep, as well as contributing to dehydration.⁴ All of these problems have serious implications for quality of life and overall health.

Although studies have identified poor glycemic control and hypertension as the major problems facing nursing home patients with DM,^2,6 little research has examined how therapies targeting these problems help the elderly. Solid evidence supports the effectiveness of controlling hyperglycemia, lipid levels, and blood pressure (BP), along with aspirin therapy, in preventing microvascular disease, but does not reflect research involving older patients.⁸

A study of nursing homes found that health care teams did not respond to half of all significantly abnormal laboratory test results.⁹ Physicians who are aware of the problems associated with DM in elderly patients may hesitate to treat them because of the lack of guidelines for this patient population or concerns about adverse effects. Because of the deficiency of clinical trial data in elderly patients and the heterogenicity of the population, the American Diabetes Association (ADA) suggests that “less stringent treatment goals” may be appropriate.¹⁰

A central conflict in diabetes care for nursing home residents revolves around the need for guidelines that are both generalizable and easily individualized. Some studies support the need for individualized care, particularly with regard to A1c goals, because residents vary greatly in both disease burden and frailty.^8,11 Yet individualized treatment could increase the complexity of care for nurses who must manage many patients, potentially having a negative effect on patient care.

Implementation of a treatment protocol for residents with DM is associated with a decrease in the number of hospital days for acute and chronic complications,¹² but one study found that only 15% of nursing homes had such a protocol.¹³ Ultimately, long-term care facilities may benefit from an approach that strikes a balance between individualized care and generalized goals and does not closely mimic either acute hospital care or outpatient management of diabetes.³

In the absence of specific recommendations for extended-care residents with diabetes, our study evaluated the status of care in this population on the basis of pharmacotherapy and standards of care recommended by the ADA for ambulatory adults with DM.

Methods

Data collection
We reviewed the charts of 245 patients in 14 long-term care facilities in Ohio and West Virginia. All participating facilities signed a letter of agreement to take part in the study. The study was approved by the Ohio University Institutional Review Board.

At each facility, the director of nursing supplied a list of residents with DM. To be eligible for chart review, residents had to have a physician-documented diagnosis of type 1 or type 2 DM and have lived at the facility for at least 3 of the previous 12 months. Residents in both skilled nursing care and assisted living facilities were able to participate; short-term rehabilitation residents were not.

We performed a comprehensive review of each chart, examining the medical diagnoses, medication lists, laboratory reports, and physician and consultation notes for a one-year period. Data collection focused on diabetes-related intermediate outcomes and processes of care. Intermediate outcomes included A1c tests, lipid panels, and BP readings. Processes of care included aspirin therapy, use of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers, use of statins, eye exams, foot exams, and microalbumin tests. The data collected omitted information identifying the patient, physician, or facility.

We compared the collected data with the 2011 ADA standards of care: blood glucose (fasting 80-120 mg/dL; postprandial 100-140 mg/dL), A1c (<7%), BP (<130/80 mm Hg), and lipid levels (low-density lipoprotein [LDL] <100 mg/dL; high-density lipoprotein [HDL] >40 mg/dL in men and >50 mg/dL in women; triglycerides <150 mg/dL).

Data analysis
We entered the data into an Excel database by type and key format and analyzed results using SPSS software, version 14.0 (SPSS, Chicago, IL). We used percentages and means±standard deviation to describe the data.

Results

TABLE 1 lists characteristics of the patients in the study: 24.5% were male and 75.5% were female; 9 (3.7%) were diagnosed with type 1 DM; 236 (96.3%) had type 2 DM. The mean age was 81±9 years, with a range of 44 to 103 years. Approximately 96% were Caucasian. The residents’ medical care was managed by family physicians (66.1%), internists (25.7%), geriatricians (6.9%), endocrinologists (0.8%), and other physicians (0.4%). The findings that follow are all based on a one-year period unless otherwise specified.

TABLE 1
Study population profile

Diabetes management
Most of the residents (211 [86.1%]) underwent glucose monitoring. The proportion of residents who received specific diabetes interventions is detailed in TABLE 2.

Hypoglycemia. Fifty-two residents (24.6% of those receiving glucose monitoring and 21.2% of the total) experienced a hypoglycemic event; 103 (representing 48.8% of the monitored patients and 42% of the total) had hyperglycemic events. On average, each resident experienced 1±2 mild hypoglycemic episodes per month, with a maximum of 13 mild episodes for one resident. Severe hypoglycemia (< 50 mg/dL) occurred less often, on average 0.24±1 time per resident. One resident had 15 severe hypoglycemic events in a month. The mean low hypoglycemic episode was at a glucose level of 52±16 mg/dL.

Hyperglycemia occurred more often than hypoglycemia (8±14 times per month), with a mean high glucose level of 352±89 mg/dL. This study used a generous range for normal glucose readings (70-249 mg/dL), and 89% of blood glucose readings were within that range. Thirty-seven percent of residents had an A1c <7.0%.

Medication. Thirty-two (13.1%) patients received no oral medication or insulin, and were managed with lifestyle interventions alone. Sixty-four patients (26.1%) used only oral medications, 64 (26.1%) received only insulin, and 85 (34.7%) were treated with both. Of the patients receiving insulin, 108 (72%) were on a sliding scale regimen. Seventy-seven (51.7%) of the patients on insulin experienced hypoglycemia, vs 30 (20%) of those taking oral medication. Twenty-seven (31.8%) patients in the combined therapy group had hypoglycemic events.

TABLE 2
Interventions received by the study population

Preventive care
Foot and eye care. Dilated eye examinations were provided for 133 residents (54.3%). Most (76.3%) received foot examinations, and 69.4% were seen by a podiatrist.

Blood pressure. Of the 240 residents (98%) whose BP was monitored, 107 (43.7%) had readings lower than 125/85 mm Hg, a goal set by a team of diabetologists, endocrinologists, and geriatricians at Ohio University. One hundred residents (40.8%) were taking an angiotensin-converting enzyme inhibitor or an angiotensin II receptor blocker; 122 (49.8%) were receiving aspirin therapy. In the total population, 110 patients (44.9%) were prescribed a statin.

Lipid monitoring. Of the 190 residents (77.6%) whose lipids were monitored, only 89 (46.8%) met the LDL goal suggested by the ADA. Fifty-six (29.5%) had triglycerides <150 mg/dL.

The HDL goal recommended by the ADA is >40 mg/dL for men and >50 mg/dL for women. Three of the 24 men and 16 of the 91 women whose lipids were monitored met the HDL goal.

Discussion

Although several components of diabetes management in our study population failed to meet the ADA standards of care for ambulatory adults, some elements of care were well managed. Monthly foot exams were performed on 76.3% of patients; 69.4% were seen by a podiatrist. While the number of residents receiving foot exams had decreased by 10.7% since a previous study by our research group, the number of podiatric consults increased by 11.4%.¹⁴

Dilated eye exams were given to 54.3% of residents. More patients should be given the opportunity to have an annual eye exam. Diabetes is the leading cause of new cases of blindness among adults 20 to 74 years of age,¹⁵ and impaired vision affects patient activity levels, susceptibility to falls, and quality of life.

In addition to a good record of preventive exams, physicians were proficient in monitoring residents with diabetes with regular testing regimens. Eighty-six percent of patients underwent regular blood glucose monitoring; 84% had had their A1c tested in the past year, and 36.7% achieved the A1c goal of <7%. The average A1c reading was 6.7±1%.

While these A1c values would seem to reflect well-managed diabetes, blood glucose readings tell a different story. A comparison of A1c values and hyperglycemic events revealed a disparity between the estimated average glucose reading and the actual readings. Of the patients who underwent scheduled fingersticks, 24.6% experienced a hypoglycemic event and 48.8% had hyperglycemic events. On average, each patient had 8 hyperglycemic episodes per month. The average highest glucose reading was >350 mg/dL.

A1c is only part of the story. While A1c can be a marker of sustained hyperglycemia, it does not reflect the stability of glycemic control.¹⁶ A study by Löfgren and colleagues confirmed that elderly diabetic patients in nursing homes who have low A1c levels often suffer from hypoglycemia.⁶ Patients receiving insulin therapy are more likely to experience hypoglycemia.⁷

The mismatch between A1c and glucose readings reveals an important point about the management of diabetes in long-term care patients: A1c values do not tell the entire story about a patient’s blood glucose; thus, a physician cannot look only at A1c to assess a patient’s diabetes management. A previous study demonstrated that when physicians base treatment plans solely on A1c without consulting glucose logs or being familiar with newer treatments, adherence to evidence-based algorithms is unlikely.¹⁷

While A1c does provide information about average blood glucose levels, it does not offer perspective on hypoglycemia or glucose variability. It is vital that physicians screen the glucose log for evidence of hypo- and hyperglycemia before adjusting the patient’s treatment plan. Physicians must also keep in mind that A1c may be falsely low in elderly patients who have concomitant anemia, which lowers the value.

Controlling BP and lipids helps prevent complications. In addition to diabetes management, our study evaluated regulation of the complications of diabetes, particularly cardiovascular complications. Evidence suggests that people with DM derive the greatest mortality benefit from a treatment plan centered first on hypertension, then lipids, and finally, glycemic control.¹⁸ A renewed focus on the BP and lipid aspects of diabetes care is needed.

Our data demonstrate that, of the 240 patients who met the ADA goal of <130/80 mm Hg, only 100 (40.8%) were taking an angiotensin-converting enzyme inhibitor or an angiotensin II receptor blocker. Lowering BP to <130/80 mm Hg may provide further benefit in preventing diabetes-related macrovascular complications.⁸

Lipid levels are a critical gauge of cardiovascular risk. Previous studies of patients with type 2 DM have shown that treating hyperlipidemia can produce a mortality benefit within 2 to 4 years, whereas aggressive glucose management takes approximately 8 years.¹⁸

A lipid panel was performed for 77.6% of the patients in our study—an improvement over a previous study by our team in which only 33% of patients received lipid checks.¹⁴ In the current study, a mere 2.9% of patients met the ADA’s combined lipid goals (LDL <100 mg/dL; HDL >40 mg/dL in men and >50 mg/dL in women; and triglycerides<150 mg/dL). Considering the LDL goal alone, 46.8% of the 190 patients whose lipids were monitored achieved it.

One hundred ten (44.9%) of the 245 patients in our study were prescribed a statin. Various studies support the use of lipid-lowering medications to increase HDL in elderly patients with DM.⁸ Yet data suggest that the rate of statin use among older adults is suboptimal.¹⁹ Our study highlights the limited prescription of statins for elderly nursing home patients who need them.

The ADA lipid goals are reasonable for this patient population, especially considering the potential mortality benefit. Rather than adjust lipid and BP goals, standards of care should emphasize the importance of meeting these objectives and suggest means to achieve them, including greater use of statins.

One set of standards does not work for all patients. Our study demonstrates that the ADA standards of care for ambulatory adults with diabetes are not acceptable for long-term care residents with DM. Although stringent A1c goals are appropriate for ambulatory adults, the risk of hypoglycemic episodes among the older and frailer nursing home population is too great to adhere to such a strict approach.

We recommend new guidelines be established. Guidelines developed specifically for residents in extended care are necessary to ensure the proper care of these patients, particularly in the face of a steady increase in their number.

Study limitations. Future inquiries into this subject should take into account the weaknesses of this study. First, it was conducted solely in Ohio and West Virginia. A chart review covering more territory could explore regional differences in diabetes care provided by long-term facilities and provide more evidence of the need for a population-specific standards of care.

The study also failed to account for comorbid conditions, including dementia, and code status, and followed residents for only one year. More extensive reviews could examine the effects of therapy in this patient population and the relationship between mortality and treatment plan, spurring movement toward more uniform and effective care of patients with diabetes in the long-term care setting.

CORRESPONDENCE Jay Shubrook Jr, DO, Department of Family Medicine, Ohio University Heritage College of Osteopathic Medicine, Grosvenor Hall, Athens, OH 45701; [email protected]

A surge in elderly patients with diabetes has placed a large burden on extended-care facilities. According to the Centers for Medicare and Medicaid Services, the prevalence of diabetes among nursing home residents is 33.3%.¹ Between 1995 and 2004, the estimated number of long-term care residents with diabetes mellitus (DM) grew by 7.1%, from approximately 242,000 to 329,000.² The increase adds to the challenge extended-care facilities face in attempting to provide high-quality care to patients with diabetes. No well-accepted management guidelines exist for nursing home residents with DM.³

Frail older adults with DM are more likely to suffer from cardiovascular conditions than younger patients, and are at greater risk for hypoglycemic coma and serious hyperglycemia.^4,5 A high frequency of hypoglycemia, especially nocturnal hypoglycemia, has been reported among nursing home residents with diabetes.⁶ Intensive insulin therapy is associated with hypoglycemia and increased mortality.⁷ However, hyperglycemia also must be considered because it significantly impairs quality of life. Uncontrolled hyperglycemia causes osmotic diuresis, leading to polyuria, nocturia, aggravated incontinence, and disrupted sleep, as well as contributing to dehydration.⁴ All of these problems have serious implications for quality of life and overall health.

Although studies have identified poor glycemic control and hypertension as the major problems facing nursing home patients with DM,^2,6 little research has examined how therapies targeting these problems help the elderly. Solid evidence supports the effectiveness of controlling hyperglycemia, lipid levels, and blood pressure (BP), along with aspirin therapy, in preventing microvascular disease, but does not reflect research involving older patients.⁸

A study of nursing homes found that health care teams did not respond to half of all significantly abnormal laboratory test results.⁹ Physicians who are aware of the problems associated with DM in elderly patients may hesitate to treat them because of the lack of guidelines for this patient population or concerns about adverse effects. Because of the deficiency of clinical trial data in elderly patients and the heterogenicity of the population, the American Diabetes Association (ADA) suggests that “less stringent treatment goals” may be appropriate.¹⁰

A central conflict in diabetes care for nursing home residents revolves around the need for guidelines that are both generalizable and easily individualized. Some studies support the need for individualized care, particularly with regard to A1c goals, because residents vary greatly in both disease burden and frailty.^8,11 Yet individualized treatment could increase the complexity of care for nurses who must manage many patients, potentially having a negative effect on patient care.

Implementation of a treatment protocol for residents with DM is associated with a decrease in the number of hospital days for acute and chronic complications,¹² but one study found that only 15% of nursing homes had such a protocol.¹³ Ultimately, long-term care facilities may benefit from an approach that strikes a balance between individualized care and generalized goals and does not closely mimic either acute hospital care or outpatient management of diabetes.³

In the absence of specific recommendations for extended-care residents with diabetes, our study evaluated the status of care in this population on the basis of pharmacotherapy and standards of care recommended by the ADA for ambulatory adults with DM.

Methods

Data collection
We reviewed the charts of 245 patients in 14 long-term care facilities in Ohio and West Virginia. All participating facilities signed a letter of agreement to take part in the study. The study was approved by the Ohio University Institutional Review Board.

At each facility, the director of nursing supplied a list of residents with DM. To be eligible for chart review, residents had to have a physician-documented diagnosis of type 1 or type 2 DM and have lived at the facility for at least 3 of the previous 12 months. Residents in both skilled nursing care and assisted living facilities were able to participate; short-term rehabilitation residents were not.

We performed a comprehensive review of each chart, examining the medical diagnoses, medication lists, laboratory reports, and physician and consultation notes for a one-year period. Data collection focused on diabetes-related intermediate outcomes and processes of care. Intermediate outcomes included A1c tests, lipid panels, and BP readings. Processes of care included aspirin therapy, use of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers, use of statins, eye exams, foot exams, and microalbumin tests. The data collected omitted information identifying the patient, physician, or facility.

We compared the collected data with the 2011 ADA standards of care: blood glucose (fasting 80-120 mg/dL; postprandial 100-140 mg/dL), A1c (<7%), BP (<130/80 mm Hg), and lipid levels (low-density lipoprotein [LDL] <100 mg/dL; high-density lipoprotein [HDL] >40 mg/dL in men and >50 mg/dL in women; triglycerides <150 mg/dL).

Data analysis
We entered the data into an Excel database by type and key format and analyzed results using SPSS software, version 14.0 (SPSS, Chicago, IL). We used percentages and means±standard deviation to describe the data.

Results

TABLE 1 lists characteristics of the patients in the study: 24.5% were male and 75.5% were female; 9 (3.7%) were diagnosed with type 1 DM; 236 (96.3%) had type 2 DM. The mean age was 81±9 years, with a range of 44 to 103 years. Approximately 96% were Caucasian. The residents’ medical care was managed by family physicians (66.1%), internists (25.7%), geriatricians (6.9%), endocrinologists (0.8%), and other physicians (0.4%). The findings that follow are all based on a one-year period unless otherwise specified.

TABLE 1
Study population profile

Diabetes management
Most of the residents (211 [86.1%]) underwent glucose monitoring. The proportion of residents who received specific diabetes interventions is detailed in TABLE 2.

Hypoglycemia. Fifty-two residents (24.6% of those receiving glucose monitoring and 21.2% of the total) experienced a hypoglycemic event; 103 (representing 48.8% of the monitored patients and 42% of the total) had hyperglycemic events. On average, each resident experienced 1±2 mild hypoglycemic episodes per month, with a maximum of 13 mild episodes for one resident. Severe hypoglycemia (< 50 mg/dL) occurred less often, on average 0.24±1 time per resident. One resident had 15 severe hypoglycemic events in a month. The mean low hypoglycemic episode was at a glucose level of 52±16 mg/dL.

Hyperglycemia occurred more often than hypoglycemia (8±14 times per month), with a mean high glucose level of 352±89 mg/dL. This study used a generous range for normal glucose readings (70-249 mg/dL), and 89% of blood glucose readings were within that range. Thirty-seven percent of residents had an A1c <7.0%.

Medication. Thirty-two (13.1%) patients received no oral medication or insulin, and were managed with lifestyle interventions alone. Sixty-four patients (26.1%) used only oral medications, 64 (26.1%) received only insulin, and 85 (34.7%) were treated with both. Of the patients receiving insulin, 108 (72%) were on a sliding scale regimen. Seventy-seven (51.7%) of the patients on insulin experienced hypoglycemia, vs 30 (20%) of those taking oral medication. Twenty-seven (31.8%) patients in the combined therapy group had hypoglycemic events.

TABLE 2
Interventions received by the study population

Preventive care
Foot and eye care. Dilated eye examinations were provided for 133 residents (54.3%). Most (76.3%) received foot examinations, and 69.4% were seen by a podiatrist.

Blood pressure. Of the 240 residents (98%) whose BP was monitored, 107 (43.7%) had readings lower than 125/85 mm Hg, a goal set by a team of diabetologists, endocrinologists, and geriatricians at Ohio University. One hundred residents (40.8%) were taking an angiotensin-converting enzyme inhibitor or an angiotensin II receptor blocker; 122 (49.8%) were receiving aspirin therapy. In the total population, 110 patients (44.9%) were prescribed a statin.

Lipid monitoring. Of the 190 residents (77.6%) whose lipids were monitored, only 89 (46.8%) met the LDL goal suggested by the ADA. Fifty-six (29.5%) had triglycerides <150 mg/dL.

The HDL goal recommended by the ADA is >40 mg/dL for men and >50 mg/dL for women. Three of the 24 men and 16 of the 91 women whose lipids were monitored met the HDL goal.

Discussion

Although several components of diabetes management in our study population failed to meet the ADA standards of care for ambulatory adults, some elements of care were well managed. Monthly foot exams were performed on 76.3% of patients; 69.4% were seen by a podiatrist. While the number of residents receiving foot exams had decreased by 10.7% since a previous study by our research group, the number of podiatric consults increased by 11.4%.¹⁴

Dilated eye exams were given to 54.3% of residents. More patients should be given the opportunity to have an annual eye exam. Diabetes is the leading cause of new cases of blindness among adults 20 to 74 years of age,¹⁵ and impaired vision affects patient activity levels, susceptibility to falls, and quality of life.

In addition to a good record of preventive exams, physicians were proficient in monitoring residents with diabetes with regular testing regimens. Eighty-six percent of patients underwent regular blood glucose monitoring; 84% had had their A1c tested in the past year, and 36.7% achieved the A1c goal of <7%. The average A1c reading was 6.7±1%.

While these A1c values would seem to reflect well-managed diabetes, blood glucose readings tell a different story. A comparison of A1c values and hyperglycemic events revealed a disparity between the estimated average glucose reading and the actual readings. Of the patients who underwent scheduled fingersticks, 24.6% experienced a hypoglycemic event and 48.8% had hyperglycemic events. On average, each patient had 8 hyperglycemic episodes per month. The average highest glucose reading was >350 mg/dL.

A1c is only part of the story. While A1c can be a marker of sustained hyperglycemia, it does not reflect the stability of glycemic control.¹⁶ A study by Löfgren and colleagues confirmed that elderly diabetic patients in nursing homes who have low A1c levels often suffer from hypoglycemia.⁶ Patients receiving insulin therapy are more likely to experience hypoglycemia.⁷

The mismatch between A1c and glucose readings reveals an important point about the management of diabetes in long-term care patients: A1c values do not tell the entire story about a patient’s blood glucose; thus, a physician cannot look only at A1c to assess a patient’s diabetes management. A previous study demonstrated that when physicians base treatment plans solely on A1c without consulting glucose logs or being familiar with newer treatments, adherence to evidence-based algorithms is unlikely.¹⁷

While A1c does provide information about average blood glucose levels, it does not offer perspective on hypoglycemia or glucose variability. It is vital that physicians screen the glucose log for evidence of hypo- and hyperglycemia before adjusting the patient’s treatment plan. Physicians must also keep in mind that A1c may be falsely low in elderly patients who have concomitant anemia, which lowers the value.

Controlling BP and lipids helps prevent complications. In addition to diabetes management, our study evaluated regulation of the complications of diabetes, particularly cardiovascular complications. Evidence suggests that people with DM derive the greatest mortality benefit from a treatment plan centered first on hypertension, then lipids, and finally, glycemic control.¹⁸ A renewed focus on the BP and lipid aspects of diabetes care is needed.

Our data demonstrate that, of the 240 patients who met the ADA goal of <130/80 mm Hg, only 100 (40.8%) were taking an angiotensin-converting enzyme inhibitor or an angiotensin II receptor blocker. Lowering BP to <130/80 mm Hg may provide further benefit in preventing diabetes-related macrovascular complications.⁸

Lipid levels are a critical gauge of cardiovascular risk. Previous studies of patients with type 2 DM have shown that treating hyperlipidemia can produce a mortality benefit within 2 to 4 years, whereas aggressive glucose management takes approximately 8 years.¹⁸

A lipid panel was performed for 77.6% of the patients in our study—an improvement over a previous study by our team in which only 33% of patients received lipid checks.¹⁴ In the current study, a mere 2.9% of patients met the ADA’s combined lipid goals (LDL <100 mg/dL; HDL >40 mg/dL in men and >50 mg/dL in women; and triglycerides<150 mg/dL). Considering the LDL goal alone, 46.8% of the 190 patients whose lipids were monitored achieved it.

One hundred ten (44.9%) of the 245 patients in our study were prescribed a statin. Various studies support the use of lipid-lowering medications to increase HDL in elderly patients with DM.⁸ Yet data suggest that the rate of statin use among older adults is suboptimal.¹⁹ Our study highlights the limited prescription of statins for elderly nursing home patients who need them.

The ADA lipid goals are reasonable for this patient population, especially considering the potential mortality benefit. Rather than adjust lipid and BP goals, standards of care should emphasize the importance of meeting these objectives and suggest means to achieve them, including greater use of statins.

One set of standards does not work for all patients. Our study demonstrates that the ADA standards of care for ambulatory adults with diabetes are not acceptable for long-term care residents with DM. Although stringent A1c goals are appropriate for ambulatory adults, the risk of hypoglycemic episodes among the older and frailer nursing home population is too great to adhere to such a strict approach.

We recommend new guidelines be established. Guidelines developed specifically for residents in extended care are necessary to ensure the proper care of these patients, particularly in the face of a steady increase in their number.

Study limitations. Future inquiries into this subject should take into account the weaknesses of this study. First, it was conducted solely in Ohio and West Virginia. A chart review covering more territory could explore regional differences in diabetes care provided by long-term facilities and provide more evidence of the need for a population-specific standards of care.

The study also failed to account for comorbid conditions, including dementia, and code status, and followed residents for only one year. More extensive reviews could examine the effects of therapy in this patient population and the relationship between mortality and treatment plan, spurring movement toward more uniform and effective care of patients with diabetes in the long-term care setting.

CORRESPONDENCE Jay Shubrook Jr, DO, Department of Family Medicine, Ohio University Heritage College of Osteopathic Medicine, Grosvenor Hall, Athens, OH 45701; [email protected]

A surge in elderly patients with diabetes has placed a large burden on extended-care facilities. According to the Centers for Medicare and Medicaid Services, the prevalence of diabetes among nursing home residents is 33.3%.¹ Between 1995 and 2004, the estimated number of long-term care residents with diabetes mellitus (DM) grew by 7.1%, from approximately 242,000 to 329,000.² The increase adds to the challenge extended-care facilities face in attempting to provide high-quality care to patients with diabetes. No well-accepted management guidelines exist for nursing home residents with DM.³

Frail older adults with DM are more likely to suffer from cardiovascular conditions than younger patients, and are at greater risk for hypoglycemic coma and serious hyperglycemia.^4,5 A high frequency of hypoglycemia, especially nocturnal hypoglycemia, has been reported among nursing home residents with diabetes.⁶ Intensive insulin therapy is associated with hypoglycemia and increased mortality.⁷ However, hyperglycemia also must be considered because it significantly impairs quality of life. Uncontrolled hyperglycemia causes osmotic diuresis, leading to polyuria, nocturia, aggravated incontinence, and disrupted sleep, as well as contributing to dehydration.⁴ All of these problems have serious implications for quality of life and overall health.

Although studies have identified poor glycemic control and hypertension as the major problems facing nursing home patients with DM,^2,6 little research has examined how therapies targeting these problems help the elderly. Solid evidence supports the effectiveness of controlling hyperglycemia, lipid levels, and blood pressure (BP), along with aspirin therapy, in preventing microvascular disease, but does not reflect research involving older patients.⁸

A study of nursing homes found that health care teams did not respond to half of all significantly abnormal laboratory test results.⁹ Physicians who are aware of the problems associated with DM in elderly patients may hesitate to treat them because of the lack of guidelines for this patient population or concerns about adverse effects. Because of the deficiency of clinical trial data in elderly patients and the heterogenicity of the population, the American Diabetes Association (ADA) suggests that “less stringent treatment goals” may be appropriate.¹⁰

A central conflict in diabetes care for nursing home residents revolves around the need for guidelines that are both generalizable and easily individualized. Some studies support the need for individualized care, particularly with regard to A1c goals, because residents vary greatly in both disease burden and frailty.^8,11 Yet individualized treatment could increase the complexity of care for nurses who must manage many patients, potentially having a negative effect on patient care.

Implementation of a treatment protocol for residents with DM is associated with a decrease in the number of hospital days for acute and chronic complications,¹² but one study found that only 15% of nursing homes had such a protocol.¹³ Ultimately, long-term care facilities may benefit from an approach that strikes a balance between individualized care and generalized goals and does not closely mimic either acute hospital care or outpatient management of diabetes.³

In the absence of specific recommendations for extended-care residents with diabetes, our study evaluated the status of care in this population on the basis of pharmacotherapy and standards of care recommended by the ADA for ambulatory adults with DM.

Methods

Data collection
We reviewed the charts of 245 patients in 14 long-term care facilities in Ohio and West Virginia. All participating facilities signed a letter of agreement to take part in the study. The study was approved by the Ohio University Institutional Review Board.

At each facility, the director of nursing supplied a list of residents with DM. To be eligible for chart review, residents had to have a physician-documented diagnosis of type 1 or type 2 DM and have lived at the facility for at least 3 of the previous 12 months. Residents in both skilled nursing care and assisted living facilities were able to participate; short-term rehabilitation residents were not.

We performed a comprehensive review of each chart, examining the medical diagnoses, medication lists, laboratory reports, and physician and consultation notes for a one-year period. Data collection focused on diabetes-related intermediate outcomes and processes of care. Intermediate outcomes included A1c tests, lipid panels, and BP readings. Processes of care included aspirin therapy, use of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers, use of statins, eye exams, foot exams, and microalbumin tests. The data collected omitted information identifying the patient, physician, or facility.

We compared the collected data with the 2011 ADA standards of care: blood glucose (fasting 80-120 mg/dL; postprandial 100-140 mg/dL), A1c (<7%), BP (<130/80 mm Hg), and lipid levels (low-density lipoprotein [LDL] <100 mg/dL; high-density lipoprotein [HDL] >40 mg/dL in men and >50 mg/dL in women; triglycerides <150 mg/dL).

Data analysis
We entered the data into an Excel database by type and key format and analyzed results using SPSS software, version 14.0 (SPSS, Chicago, IL). We used percentages and means±standard deviation to describe the data.

Results

TABLE 1 lists characteristics of the patients in the study: 24.5% were male and 75.5% were female; 9 (3.7%) were diagnosed with type 1 DM; 236 (96.3%) had type 2 DM. The mean age was 81±9 years, with a range of 44 to 103 years. Approximately 96% were Caucasian. The residents’ medical care was managed by family physicians (66.1%), internists (25.7%), geriatricians (6.9%), endocrinologists (0.8%), and other physicians (0.4%). The findings that follow are all based on a one-year period unless otherwise specified.

TABLE 1
Study population profile

Diabetes management
Most of the residents (211 [86.1%]) underwent glucose monitoring. The proportion of residents who received specific diabetes interventions is detailed in TABLE 2.

Hypoglycemia. Fifty-two residents (24.6% of those receiving glucose monitoring and 21.2% of the total) experienced a hypoglycemic event; 103 (representing 48.8% of the monitored patients and 42% of the total) had hyperglycemic events. On average, each resident experienced 1±2 mild hypoglycemic episodes per month, with a maximum of 13 mild episodes for one resident. Severe hypoglycemia (< 50 mg/dL) occurred less often, on average 0.24±1 time per resident. One resident had 15 severe hypoglycemic events in a month. The mean low hypoglycemic episode was at a glucose level of 52±16 mg/dL.

Hyperglycemia occurred more often than hypoglycemia (8±14 times per month), with a mean high glucose level of 352±89 mg/dL. This study used a generous range for normal glucose readings (70-249 mg/dL), and 89% of blood glucose readings were within that range. Thirty-seven percent of residents had an A1c <7.0%.

Medication. Thirty-two (13.1%) patients received no oral medication or insulin, and were managed with lifestyle interventions alone. Sixty-four patients (26.1%) used only oral medications, 64 (26.1%) received only insulin, and 85 (34.7%) were treated with both. Of the patients receiving insulin, 108 (72%) were on a sliding scale regimen. Seventy-seven (51.7%) of the patients on insulin experienced hypoglycemia, vs 30 (20%) of those taking oral medication. Twenty-seven (31.8%) patients in the combined therapy group had hypoglycemic events.

TABLE 2
Interventions received by the study population

Preventive care
Foot and eye care. Dilated eye examinations were provided for 133 residents (54.3%). Most (76.3%) received foot examinations, and 69.4% were seen by a podiatrist.

Blood pressure. Of the 240 residents (98%) whose BP was monitored, 107 (43.7%) had readings lower than 125/85 mm Hg, a goal set by a team of diabetologists, endocrinologists, and geriatricians at Ohio University. One hundred residents (40.8%) were taking an angiotensin-converting enzyme inhibitor or an angiotensin II receptor blocker; 122 (49.8%) were receiving aspirin therapy. In the total population, 110 patients (44.9%) were prescribed a statin.

Lipid monitoring. Of the 190 residents (77.6%) whose lipids were monitored, only 89 (46.8%) met the LDL goal suggested by the ADA. Fifty-six (29.5%) had triglycerides <150 mg/dL.

The HDL goal recommended by the ADA is >40 mg/dL for men and >50 mg/dL for women. Three of the 24 men and 16 of the 91 women whose lipids were monitored met the HDL goal.

Discussion

Although several components of diabetes management in our study population failed to meet the ADA standards of care for ambulatory adults, some elements of care were well managed. Monthly foot exams were performed on 76.3% of patients; 69.4% were seen by a podiatrist. While the number of residents receiving foot exams had decreased by 10.7% since a previous study by our research group, the number of podiatric consults increased by 11.4%.¹⁴

Dilated eye exams were given to 54.3% of residents. More patients should be given the opportunity to have an annual eye exam. Diabetes is the leading cause of new cases of blindness among adults 20 to 74 years of age,¹⁵ and impaired vision affects patient activity levels, susceptibility to falls, and quality of life.

In addition to a good record of preventive exams, physicians were proficient in monitoring residents with diabetes with regular testing regimens. Eighty-six percent of patients underwent regular blood glucose monitoring; 84% had had their A1c tested in the past year, and 36.7% achieved the A1c goal of <7%. The average A1c reading was 6.7±1%.

While these A1c values would seem to reflect well-managed diabetes, blood glucose readings tell a different story. A comparison of A1c values and hyperglycemic events revealed a disparity between the estimated average glucose reading and the actual readings. Of the patients who underwent scheduled fingersticks, 24.6% experienced a hypoglycemic event and 48.8% had hyperglycemic events. On average, each patient had 8 hyperglycemic episodes per month. The average highest glucose reading was >350 mg/dL.

A1c is only part of the story. While A1c can be a marker of sustained hyperglycemia, it does not reflect the stability of glycemic control.¹⁶ A study by Löfgren and colleagues confirmed that elderly diabetic patients in nursing homes who have low A1c levels often suffer from hypoglycemia.⁶ Patients receiving insulin therapy are more likely to experience hypoglycemia.⁷

The mismatch between A1c and glucose readings reveals an important point about the management of diabetes in long-term care patients: A1c values do not tell the entire story about a patient’s blood glucose; thus, a physician cannot look only at A1c to assess a patient’s diabetes management. A previous study demonstrated that when physicians base treatment plans solely on A1c without consulting glucose logs or being familiar with newer treatments, adherence to evidence-based algorithms is unlikely.¹⁷

While A1c does provide information about average blood glucose levels, it does not offer perspective on hypoglycemia or glucose variability. It is vital that physicians screen the glucose log for evidence of hypo- and hyperglycemia before adjusting the patient’s treatment plan. Physicians must also keep in mind that A1c may be falsely low in elderly patients who have concomitant anemia, which lowers the value.

Controlling BP and lipids helps prevent complications. In addition to diabetes management, our study evaluated regulation of the complications of diabetes, particularly cardiovascular complications. Evidence suggests that people with DM derive the greatest mortality benefit from a treatment plan centered first on hypertension, then lipids, and finally, glycemic control.¹⁸ A renewed focus on the BP and lipid aspects of diabetes care is needed.

Our data demonstrate that, of the 240 patients who met the ADA goal of <130/80 mm Hg, only 100 (40.8%) were taking an angiotensin-converting enzyme inhibitor or an angiotensin II receptor blocker. Lowering BP to <130/80 mm Hg may provide further benefit in preventing diabetes-related macrovascular complications.⁸

Lipid levels are a critical gauge of cardiovascular risk. Previous studies of patients with type 2 DM have shown that treating hyperlipidemia can produce a mortality benefit within 2 to 4 years, whereas aggressive glucose management takes approximately 8 years.¹⁸

A lipid panel was performed for 77.6% of the patients in our study—an improvement over a previous study by our team in which only 33% of patients received lipid checks.¹⁴ In the current study, a mere 2.9% of patients met the ADA’s combined lipid goals (LDL <100 mg/dL; HDL >40 mg/dL in men and >50 mg/dL in women; and triglycerides<150 mg/dL). Considering the LDL goal alone, 46.8% of the 190 patients whose lipids were monitored achieved it.

One hundred ten (44.9%) of the 245 patients in our study were prescribed a statin. Various studies support the use of lipid-lowering medications to increase HDL in elderly patients with DM.⁸ Yet data suggest that the rate of statin use among older adults is suboptimal.¹⁹ Our study highlights the limited prescription of statins for elderly nursing home patients who need them.

The ADA lipid goals are reasonable for this patient population, especially considering the potential mortality benefit. Rather than adjust lipid and BP goals, standards of care should emphasize the importance of meeting these objectives and suggest means to achieve them, including greater use of statins.

One set of standards does not work for all patients. Our study demonstrates that the ADA standards of care for ambulatory adults with diabetes are not acceptable for long-term care residents with DM. Although stringent A1c goals are appropriate for ambulatory adults, the risk of hypoglycemic episodes among the older and frailer nursing home population is too great to adhere to such a strict approach.

We recommend new guidelines be established. Guidelines developed specifically for residents in extended care are necessary to ensure the proper care of these patients, particularly in the face of a steady increase in their number.

Study limitations. Future inquiries into this subject should take into account the weaknesses of this study. First, it was conducted solely in Ohio and West Virginia. A chart review covering more territory could explore regional differences in diabetes care provided by long-term facilities and provide more evidence of the need for a population-specific standards of care.

The study also failed to account for comorbid conditions, including dementia, and code status, and followed residents for only one year. More extensive reviews could examine the effects of therapy in this patient population and the relationship between mortality and treatment plan, spurring movement toward more uniform and effective care of patients with diabetes in the long-term care setting.

CORRESPONDENCE Jay Shubrook Jr, DO, Department of Family Medicine, Ohio University Heritage College of Osteopathic Medicine, Grosvenor Hall, Athens, OH 45701; [email protected]

What to include in the workup

Whether you’re doing an initial evaluation of a patient with high blood pressure (BP) or examining a patient with resistant hypertension, the history should focus on the duration of hypertension, previous BP levels, and comorbid conditions. It is also important to take a targeted family history, inquiring about hypertension as well as genetic disorders that increase the likelihood of secondary hypertension.

Inherited diseases associated with secondary hypertension include polycystic kidney disease, multiple endocrine neoplasia type 2 (MEN2), and von Hippel-Lindau syndrome.^12,13 All are inherited in an autosomal dominant pattern. Patients with von Hippel-Lindau syndrome may present with multiple tumors, which can develop in the eyes, brain, adrenal glands, pancreas, liver, spinal cord, kidneys, or other parts of the body. Pheochromocytoma is a manifestation of both MEN2 and von Hippel-Lindau syndrome, and some specialists recommend that everyone with a family history of either condition undergo screening for pheochromocytoma.¹⁴

Table
Secondary hypertension: What you’ll see, what to test for^8-11

BP measurement is key
The physical examination should start with a calculation of body mass index, as well as a careful measurement of BP. The patient should be seated quietly in a chair for ≥5 minutes, with both feet on the floor and the arm being tested supported at heart level.

Unfortunately, reliability on the office BP measurement can be a confounding factor in the diagnosis of hypertension. “White coat hypertension”—in which BP is persistently elevated in the office and persistently normal in nonclinical settings—should be considered in patients who have high BP but no other signs or symptoms, and ambulatory monitoring used to rule out hypertension.^15,16

Physicians also need to consider the opposite effect: Masked hypertension, characterized by normal office readings and elevated ambulatory readings, is more serious, of course, with patients at higher risk for end organ damage from unrecognized hypertension.^17,18 Asking patients who self-monitor what type of BP readings they’re getting can be helpful in identifying masked hypertension. Ambulatory monitoring may be used to identify this condition, as well.

Other components in the physical workup include a fundoscopic exam; assessment of the thorax for murmurs and the abdomen for enlarged kidneys, masses, and abnormal aortic pulsation; auscultation for abdominal and carotid bruits; palpation of the thyroid gland; and palpation of the lower extremities for edema and pulses.

Include these tests in the workup
Routine tests for a patient with hypertension include:

• electrocardiogram
• blood glucose and hematocrit
• serum potassium, creatinine, and fasting lipid profiles
• urinalysis with measurement of microalbumin.

Microalbuminuria, a sensitive marker of early renal disease, is defined as a urinary albumin excretion between 30 and 300 mg/d.¹⁹ The albumin-creatinine ratio (30-300 mcg/mg), measured in spot urine specimens, is a more convenient way to detect it.²⁰

Suspicious findings prompt further testing. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) recommends specific testing—much of it detailed below—if any aspect of the initial evaluation raises suspicion of a secondary cause or the patient has hypertension that’s of sudden onset or hard to control.²¹ (According to the National Heart, Lung, and Blood Institute, JNC 8 is due for release later this year.)

Kidney disease may be a consequence or a cause

The overall prevalence of hypertension in patients with renal disease is 60%,²² but varies according to the type of nephropathy. Eighty-seven percent of patients with diabetic nephropathy also have hypertension, and hypertension and diabetes are the 2 most common causes of end-stage renal disease.^23,24

A combination of 2 or more drugs is usually needed to achieve the target BP of <130/80 mm Hg in patients with diabetes.²¹ ACE inhibitors and angiotensin receptor blockers have been found to slow the progression of diabetic nephropathy.^25-27

Is renal artery stenosis to blame?
Renal artery stenosis is the most common form of secondary hypertension that’s reversible, affecting about 0.2% to 3.1% of hypertensive patients.^5,6,28 The condition leads to renal ischemia, thereby stimulating the renin-angiotensin-aldosterone axis and causing secondary hyperaldosteronism.

In younger patients, especially women between 15 and 50 years of age, fibromuscular disease is the most common cause of renovascular hypertension.^29,30 In older patients, atherosclerosis (which accounts for 90% of renovascular hypertension) is more likely.^29,30

The choice of initial imaging tests includes duplex renal ultrasonography, magnetic resonance angiography (MRA), and spiral computed tomographic angiography. Contrast angiography is the gold standard, but it carries a risk of contrast-induced nephropathy. Duplex ultrasonography and MRA do not use iodinated contrast media, and are safe for patients with chronic kidney disease.⁸

Treatment. Percutaneous transluminal renal artery angioplasty is a treatment option for patients with renal artery stenosis. Angioplasty achieves higher cure rates for patients with fibromuscular dysplasia than for those with atherosclerotic renal artery stenosis.³¹ Most patients referred for renal artery revascularization have atherosclerosis. Because they’re generally older individuals with comorbidities, the benefits of stent revascularization for this group is controversial. Such patients require antihypertensive therapy with drugs that block the renin-angiotensin system.³²

Endocrine disorders must be ruled out

Primary hyperaldosteronism is thought to be present in 0.3% to 1.4% of patients with hypertension.^5,6 The prevalence varies widely from one source to another, however, and may be as high as 5% to 20% among patients with resistant hypertension.^33,34

Hyperaldosteronism is related to either an aldosterone-secreting adrenal adenoma (in about 40% of cases) or bilateral adrenal hyperplasia (in the remaining 60%), and leads to increased sodium reabsorption and, typically, to a loss of potassium.³⁵

Renin-secreting tumor, which usually arises from the juxtaglomerular cells of the kidney, is a rare cause of hyperaldosteronism. Extrarenal renin-secreting tumors have also been reported.³⁶

What should raise your suspicion. Suspect hyperaldosteronism in patients who have both hypertension and hypokalemia, but keep in mind that not all patients with hyperaldosteronism have low serum potassium.³⁷ Further laboratory evaluation should include a simultaneous measurement of plasma aldosterone (PA) and plasma renin activity (PRA). Patients with hyperaldosteronism will have elevated PA and suppressed PRA.

Testing considerations. It is important to ensure that the PA/PRA test is performed in the morning, with the patient in an upright position.³⁶ He or she should be on a high sodium diet in preparation for the test, consuming 2 to 3 grams of sodium per meal for ≥2 days.³⁷

In patients with a positive PA/PRA ratio (≥20), a 24-hour urinary aldosterone excretion test should be performed. A finding >12 to 14 mcg, along with a PRA <1.0 ng/mL per hour, confirms the diagnosis of primary hyperaldosteronism.^18,37 Computed tomography or magnetic resonance imaging of the adrenal glands will distinguish between aldosterone-producing adenoma and bilateral adrenal hyperplasia.

Treatment. Laparoscopic adrenalectomy is the accepted surgical treatment of primary hyperaldosteronism.³⁷ Patients with bilateral disease due to idiopathic hyperaldosteronism are not candidates for surgery and should be treated medically, with potassium-sparing diuretics such as spironolactone.

Cushing’s syndrome is marked by rapid weight gain
High BP may be a manifestation of Cushing’s syndrome, which affects 0.1% to 0.5% of patients with hypertension.^5-7 Other signs and symptoms of Cushing’s syndrome include fatigue, weakness, hirsutism, amenorrhea, moon facies, dorsal hump, purple striae, truncal obesity, and hypokalemia. Rapid weight gain is the most common manifestation, and typically the one for which patients seek medical attention.³⁸

The most widely used screening test for Cushing’s syndrome is a 24-hour urine collection measuring urinary-free cortisol.⁹ Normal urinary cortisol excretion is 20 to 100 mcg/dL in 24 hours; most patients with Cushing’s syndrome produce >250 mcg/dL in that time frame.⁹

Once hypercortisolism is established, determination of the cause is the next step. A serum adrenocorticotropic hormone (ACTH) level is needed to localize it. Normal (9-52 pg/mL) or elevated ACTH indicates a pituitary or ectopic source, while low levels of ACTH are an indication of an adrenal source.^9,39

Treatment. Surgical resection of the tumor is often curative. For pituitary tumors (Cushing’s disease), transsphenoidal resection is the standard of care.³⁹ For adrenal adenomas, unilateral adrenalectomy is the best option.³⁹

Pheochromocytomas: Most are adrenal, sporadic, and benign
Pheochromocytomas—neuroendocrine, catecholamine-secreting tumors that develop from the adrenal medulla—are another cause of secondary hypertension. Catecholamines include norepinephrine and epinephrine and, rarely, dopamine secreted either intermittently or continuously. The prevalence of pheochromocytoma is 0.1% to 0.3% among patients with hypertension.^5,6,28 A “rule of 10” (90:10 ratio) is often applied to pheochromocytomas because of the following:

• 90% of pheochromocytomas are located in the adrenal glands; the remaining 10% are extra-adrenal and can occur anywhere along the sympathetic chain⁴⁰
• 90% are sporadic; 10% are familial⁴¹
• 90% are benign; 10% are malignant⁴⁰
• 90% are found in adults; 10% affect children.⁴²

Signs and symptoms of pheochromocytomas include palpitations, headache, dyspnea, diaphoresis, and flushing, as well as paroxysmal hypertension.⁴⁰ Measurement of 24-hour urinary catecholamines and their metabolites has been the screening test of choice,⁴³ but recent evidence suggests that measurement of plasma metanephrine and normetanephrine is a far more sensitive screen.¹⁰

Treatment. Surgical resection is the treatment of choice. Alpha blockade is started 7 to 10 days preoperatively;^44,45 a beta-blocker is added only after an adequate alpha blockade has been established, as unopposed alpha stimulation could precipitate a hypertensive crisis. Laparoscopic adrenalectomy is routinely performed for small (<5 cm) pheochromocytomas.^46,47

Don’t forget these (relatively) common secondary causes

Obstructive sleep apnea (OSA) is one of the most common conditions associated with resistant hypertension.⁴⁸ Signs and symptoms include snoring, daytime somnolence, and obesity (body mass index ≥30 kg/m²).

OSA involves upper airway collapse during inspiration, causing intermittent hypoxemia with resultant sympathetic nervous system activation.¹¹ The underlying mechanism of OSA-induced hypertension is strongly related to sympathetic activation.⁴⁹ Overnight polysomnography is required for diagnosis.¹¹

Continuous positive airway pressure is the treatment of choice for patients unable to lose weight.¹¹

Pregnancy-induced hypertension is the most common medical problem encountered in pregnancy. It occurs in up to 15% of pregnancies, either during the pregnancy itself or postpartum. Postpartum hypertension may be related to preexisting chronic hypertension or to the persistence of gestational hypertension or preeclampsia, which usually occurs after 20 weeks’ gestation and is characterized by the presence of hypertension and proteinuria.⁵⁰ Methyldopa and labetalol are commonly used treatments for hypertension during pregnancy.⁵¹

Drug-induced hypertension. Several drugs can cause or exacerbate hypertension, rendering it resistant to therapy. A careful review of the patient’s medication regimen is essential. Generally, drug-induced hypertension falls into 2 broad categories based on mechanism of action: volume overload and sympathetic activity.^52,53

Corticosteroids can elevate BP in a dose-dependent manner, as a result of volume overload. Glycyrrhizic acid, the main ingredient in licorice, produces a state of excess mineralocorticoid, with a similar effect. Estrogen-containing oral contraceptives can cause an increased synthesis of angiotensin in the liver, resulting in greater aldosterone secretion and volume overload.

Drugs that stimulate sympathetic activity include cocaine, ephedrine, amphetamine, phenylephrine, phenylpropanolamine, caffeine, and alcohol. Nonsteroidal anti-inflammatory drugs may interfere with the action of ACE inhibitors and cause renal vasoconstriction, leading to sodium and water retention and hypertension.⁵⁴

Discontinuation of the medication in question is preferable. In many cases, an agent that does not affect BP can be found to replace it.

If the patient is a child
Hypertension is uncommon in young people. However, coarctation of the aorta, a congenital narrowing associated with secondary hypertension, is typically diagnosed in childhood. In rare cases, the condition remains undetected well into adulthood.⁵⁵ Clinical signs include weak femoral pulses, visible pulsations in the neck, a systolic murmur of the anterior and posterior thorax, and elevated BP in the upper extremities with low BP in the lower extremities.

Thus, once hypertension is confirmed in a young patient, BP should be measured in both arms and legs.⁵⁶ Delayed or absent femoral pulses and a difference in systolic BP of ≥20 mm Hg between the arms and legs provide evidence of aortic coarctation.⁵⁷ In adults, stenting is the initial treatment for this condition because of the morbidity associated with surgery.⁵⁷ Stenting is an option for children with this condition, as well.⁵⁸

CORRESPONDENCE Bernard M. Karnath, MD, University of Texas Medical Branch at Galveston, 301 University Boulevard, Galveston, TX 77555; [email protected]

What to include in the workup

Whether you’re doing an initial evaluation of a patient with high blood pressure (BP) or examining a patient with resistant hypertension, the history should focus on the duration of hypertension, previous BP levels, and comorbid conditions. It is also important to take a targeted family history, inquiring about hypertension as well as genetic disorders that increase the likelihood of secondary hypertension.

Inherited diseases associated with secondary hypertension include polycystic kidney disease, multiple endocrine neoplasia type 2 (MEN2), and von Hippel-Lindau syndrome.^12,13 All are inherited in an autosomal dominant pattern. Patients with von Hippel-Lindau syndrome may present with multiple tumors, which can develop in the eyes, brain, adrenal glands, pancreas, liver, spinal cord, kidneys, or other parts of the body. Pheochromocytoma is a manifestation of both MEN2 and von Hippel-Lindau syndrome, and some specialists recommend that everyone with a family history of either condition undergo screening for pheochromocytoma.¹⁴

Table
Secondary hypertension: What you’ll see, what to test for^8-11

BP measurement is key
The physical examination should start with a calculation of body mass index, as well as a careful measurement of BP. The patient should be seated quietly in a chair for ≥5 minutes, with both feet on the floor and the arm being tested supported at heart level.

Unfortunately, reliability on the office BP measurement can be a confounding factor in the diagnosis of hypertension. “White coat hypertension”—in which BP is persistently elevated in the office and persistently normal in nonclinical settings—should be considered in patients who have high BP but no other signs or symptoms, and ambulatory monitoring used to rule out hypertension.^15,16

Physicians also need to consider the opposite effect: Masked hypertension, characterized by normal office readings and elevated ambulatory readings, is more serious, of course, with patients at higher risk for end organ damage from unrecognized hypertension.^17,18 Asking patients who self-monitor what type of BP readings they’re getting can be helpful in identifying masked hypertension. Ambulatory monitoring may be used to identify this condition, as well.

Other components in the physical workup include a fundoscopic exam; assessment of the thorax for murmurs and the abdomen for enlarged kidneys, masses, and abnormal aortic pulsation; auscultation for abdominal and carotid bruits; palpation of the thyroid gland; and palpation of the lower extremities for edema and pulses.

Include these tests in the workup
Routine tests for a patient with hypertension include:

• electrocardiogram
• blood glucose and hematocrit
• serum potassium, creatinine, and fasting lipid profiles
• urinalysis with measurement of microalbumin.

Microalbuminuria, a sensitive marker of early renal disease, is defined as a urinary albumin excretion between 30 and 300 mg/d.¹⁹ The albumin-creatinine ratio (30-300 mcg/mg), measured in spot urine specimens, is a more convenient way to detect it.²⁰

Suspicious findings prompt further testing. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) recommends specific testing—much of it detailed below—if any aspect of the initial evaluation raises suspicion of a secondary cause or the patient has hypertension that’s of sudden onset or hard to control.²¹ (According to the National Heart, Lung, and Blood Institute, JNC 8 is due for release later this year.)

Kidney disease may be a consequence or a cause

The overall prevalence of hypertension in patients with renal disease is 60%,²² but varies according to the type of nephropathy. Eighty-seven percent of patients with diabetic nephropathy also have hypertension, and hypertension and diabetes are the 2 most common causes of end-stage renal disease.^23,24

A combination of 2 or more drugs is usually needed to achieve the target BP of <130/80 mm Hg in patients with diabetes.²¹ ACE inhibitors and angiotensin receptor blockers have been found to slow the progression of diabetic nephropathy.^25-27

Is renal artery stenosis to blame?
Renal artery stenosis is the most common form of secondary hypertension that’s reversible, affecting about 0.2% to 3.1% of hypertensive patients.^5,6,28 The condition leads to renal ischemia, thereby stimulating the renin-angiotensin-aldosterone axis and causing secondary hyperaldosteronism.

In younger patients, especially women between 15 and 50 years of age, fibromuscular disease is the most common cause of renovascular hypertension.^29,30 In older patients, atherosclerosis (which accounts for 90% of renovascular hypertension) is more likely.^29,30

The choice of initial imaging tests includes duplex renal ultrasonography, magnetic resonance angiography (MRA), and spiral computed tomographic angiography. Contrast angiography is the gold standard, but it carries a risk of contrast-induced nephropathy. Duplex ultrasonography and MRA do not use iodinated contrast media, and are safe for patients with chronic kidney disease.⁸

Treatment. Percutaneous transluminal renal artery angioplasty is a treatment option for patients with renal artery stenosis. Angioplasty achieves higher cure rates for patients with fibromuscular dysplasia than for those with atherosclerotic renal artery stenosis.³¹ Most patients referred for renal artery revascularization have atherosclerosis. Because they’re generally older individuals with comorbidities, the benefits of stent revascularization for this group is controversial. Such patients require antihypertensive therapy with drugs that block the renin-angiotensin system.³²

Endocrine disorders must be ruled out

Primary hyperaldosteronism is thought to be present in 0.3% to 1.4% of patients with hypertension.^5,6 The prevalence varies widely from one source to another, however, and may be as high as 5% to 20% among patients with resistant hypertension.^33,34

Hyperaldosteronism is related to either an aldosterone-secreting adrenal adenoma (in about 40% of cases) or bilateral adrenal hyperplasia (in the remaining 60%), and leads to increased sodium reabsorption and, typically, to a loss of potassium.³⁵

Renin-secreting tumor, which usually arises from the juxtaglomerular cells of the kidney, is a rare cause of hyperaldosteronism. Extrarenal renin-secreting tumors have also been reported.³⁶

What should raise your suspicion. Suspect hyperaldosteronism in patients who have both hypertension and hypokalemia, but keep in mind that not all patients with hyperaldosteronism have low serum potassium.³⁷ Further laboratory evaluation should include a simultaneous measurement of plasma aldosterone (PA) and plasma renin activity (PRA). Patients with hyperaldosteronism will have elevated PA and suppressed PRA.

Testing considerations. It is important to ensure that the PA/PRA test is performed in the morning, with the patient in an upright position.³⁶ He or she should be on a high sodium diet in preparation for the test, consuming 2 to 3 grams of sodium per meal for ≥2 days.³⁷

In patients with a positive PA/PRA ratio (≥20), a 24-hour urinary aldosterone excretion test should be performed. A finding >12 to 14 mcg, along with a PRA <1.0 ng/mL per hour, confirms the diagnosis of primary hyperaldosteronism.^18,37 Computed tomography or magnetic resonance imaging of the adrenal glands will distinguish between aldosterone-producing adenoma and bilateral adrenal hyperplasia.

Treatment. Laparoscopic adrenalectomy is the accepted surgical treatment of primary hyperaldosteronism.³⁷ Patients with bilateral disease due to idiopathic hyperaldosteronism are not candidates for surgery and should be treated medically, with potassium-sparing diuretics such as spironolactone.

Cushing’s syndrome is marked by rapid weight gain
High BP may be a manifestation of Cushing’s syndrome, which affects 0.1% to 0.5% of patients with hypertension.^5-7 Other signs and symptoms of Cushing’s syndrome include fatigue, weakness, hirsutism, amenorrhea, moon facies, dorsal hump, purple striae, truncal obesity, and hypokalemia. Rapid weight gain is the most common manifestation, and typically the one for which patients seek medical attention.³⁸

The most widely used screening test for Cushing’s syndrome is a 24-hour urine collection measuring urinary-free cortisol.⁹ Normal urinary cortisol excretion is 20 to 100 mcg/dL in 24 hours; most patients with Cushing’s syndrome produce >250 mcg/dL in that time frame.⁹

Once hypercortisolism is established, determination of the cause is the next step. A serum adrenocorticotropic hormone (ACTH) level is needed to localize it. Normal (9-52 pg/mL) or elevated ACTH indicates a pituitary or ectopic source, while low levels of ACTH are an indication of an adrenal source.^9,39

Treatment. Surgical resection of the tumor is often curative. For pituitary tumors (Cushing’s disease), transsphenoidal resection is the standard of care.³⁹ For adrenal adenomas, unilateral adrenalectomy is the best option.³⁹

Pheochromocytomas: Most are adrenal, sporadic, and benign
Pheochromocytomas—neuroendocrine, catecholamine-secreting tumors that develop from the adrenal medulla—are another cause of secondary hypertension. Catecholamines include norepinephrine and epinephrine and, rarely, dopamine secreted either intermittently or continuously. The prevalence of pheochromocytoma is 0.1% to 0.3% among patients with hypertension.^5,6,28 A “rule of 10” (90:10 ratio) is often applied to pheochromocytomas because of the following:

• 90% of pheochromocytomas are located in the adrenal glands; the remaining 10% are extra-adrenal and can occur anywhere along the sympathetic chain⁴⁰
• 90% are sporadic; 10% are familial⁴¹
• 90% are benign; 10% are malignant⁴⁰
• 90% are found in adults; 10% affect children.⁴²

Signs and symptoms of pheochromocytomas include palpitations, headache, dyspnea, diaphoresis, and flushing, as well as paroxysmal hypertension.⁴⁰ Measurement of 24-hour urinary catecholamines and their metabolites has been the screening test of choice,⁴³ but recent evidence suggests that measurement of plasma metanephrine and normetanephrine is a far more sensitive screen.¹⁰

Treatment. Surgical resection is the treatment of choice. Alpha blockade is started 7 to 10 days preoperatively;^44,45 a beta-blocker is added only after an adequate alpha blockade has been established, as unopposed alpha stimulation could precipitate a hypertensive crisis. Laparoscopic adrenalectomy is routinely performed for small (<5 cm) pheochromocytomas.^46,47

Don’t forget these (relatively) common secondary causes

Obstructive sleep apnea (OSA) is one of the most common conditions associated with resistant hypertension.⁴⁸ Signs and symptoms include snoring, daytime somnolence, and obesity (body mass index ≥30 kg/m²).

OSA involves upper airway collapse during inspiration, causing intermittent hypoxemia with resultant sympathetic nervous system activation.¹¹ The underlying mechanism of OSA-induced hypertension is strongly related to sympathetic activation.⁴⁹ Overnight polysomnography is required for diagnosis.¹¹

Continuous positive airway pressure is the treatment of choice for patients unable to lose weight.¹¹

Pregnancy-induced hypertension is the most common medical problem encountered in pregnancy. It occurs in up to 15% of pregnancies, either during the pregnancy itself or postpartum. Postpartum hypertension may be related to preexisting chronic hypertension or to the persistence of gestational hypertension or preeclampsia, which usually occurs after 20 weeks’ gestation and is characterized by the presence of hypertension and proteinuria.⁵⁰ Methyldopa and labetalol are commonly used treatments for hypertension during pregnancy.⁵¹

Drug-induced hypertension. Several drugs can cause or exacerbate hypertension, rendering it resistant to therapy. A careful review of the patient’s medication regimen is essential. Generally, drug-induced hypertension falls into 2 broad categories based on mechanism of action: volume overload and sympathetic activity.^52,53

Corticosteroids can elevate BP in a dose-dependent manner, as a result of volume overload. Glycyrrhizic acid, the main ingredient in licorice, produces a state of excess mineralocorticoid, with a similar effect. Estrogen-containing oral contraceptives can cause an increased synthesis of angiotensin in the liver, resulting in greater aldosterone secretion and volume overload.

Drugs that stimulate sympathetic activity include cocaine, ephedrine, amphetamine, phenylephrine, phenylpropanolamine, caffeine, and alcohol. Nonsteroidal anti-inflammatory drugs may interfere with the action of ACE inhibitors and cause renal vasoconstriction, leading to sodium and water retention and hypertension.⁵⁴

Discontinuation of the medication in question is preferable. In many cases, an agent that does not affect BP can be found to replace it.

If the patient is a child
Hypertension is uncommon in young people. However, coarctation of the aorta, a congenital narrowing associated with secondary hypertension, is typically diagnosed in childhood. In rare cases, the condition remains undetected well into adulthood.⁵⁵ Clinical signs include weak femoral pulses, visible pulsations in the neck, a systolic murmur of the anterior and posterior thorax, and elevated BP in the upper extremities with low BP in the lower extremities.

Thus, once hypertension is confirmed in a young patient, BP should be measured in both arms and legs.⁵⁶ Delayed or absent femoral pulses and a difference in systolic BP of ≥20 mm Hg between the arms and legs provide evidence of aortic coarctation.⁵⁷ In adults, stenting is the initial treatment for this condition because of the morbidity associated with surgery.⁵⁷ Stenting is an option for children with this condition, as well.⁵⁸

CORRESPONDENCE Bernard M. Karnath, MD, University of Texas Medical Branch at Galveston, 301 University Boulevard, Galveston, TX 77555; [email protected]

What to include in the workup

Whether you’re doing an initial evaluation of a patient with high blood pressure (BP) or examining a patient with resistant hypertension, the history should focus on the duration of hypertension, previous BP levels, and comorbid conditions. It is also important to take a targeted family history, inquiring about hypertension as well as genetic disorders that increase the likelihood of secondary hypertension.

Inherited diseases associated with secondary hypertension include polycystic kidney disease, multiple endocrine neoplasia type 2 (MEN2), and von Hippel-Lindau syndrome.^12,13 All are inherited in an autosomal dominant pattern. Patients with von Hippel-Lindau syndrome may present with multiple tumors, which can develop in the eyes, brain, adrenal glands, pancreas, liver, spinal cord, kidneys, or other parts of the body. Pheochromocytoma is a manifestation of both MEN2 and von Hippel-Lindau syndrome, and some specialists recommend that everyone with a family history of either condition undergo screening for pheochromocytoma.¹⁴

Table
Secondary hypertension: What you’ll see, what to test for^8-11

BP measurement is key
The physical examination should start with a calculation of body mass index, as well as a careful measurement of BP. The patient should be seated quietly in a chair for ≥5 minutes, with both feet on the floor and the arm being tested supported at heart level.

Unfortunately, reliability on the office BP measurement can be a confounding factor in the diagnosis of hypertension. “White coat hypertension”—in which BP is persistently elevated in the office and persistently normal in nonclinical settings—should be considered in patients who have high BP but no other signs or symptoms, and ambulatory monitoring used to rule out hypertension.^15,16

Physicians also need to consider the opposite effect: Masked hypertension, characterized by normal office readings and elevated ambulatory readings, is more serious, of course, with patients at higher risk for end organ damage from unrecognized hypertension.^17,18 Asking patients who self-monitor what type of BP readings they’re getting can be helpful in identifying masked hypertension. Ambulatory monitoring may be used to identify this condition, as well.

Other components in the physical workup include a fundoscopic exam; assessment of the thorax for murmurs and the abdomen for enlarged kidneys, masses, and abnormal aortic pulsation; auscultation for abdominal and carotid bruits; palpation of the thyroid gland; and palpation of the lower extremities for edema and pulses.

Include these tests in the workup
Routine tests for a patient with hypertension include:

• electrocardiogram
• blood glucose and hematocrit
• serum potassium, creatinine, and fasting lipid profiles
• urinalysis with measurement of microalbumin.

Microalbuminuria, a sensitive marker of early renal disease, is defined as a urinary albumin excretion between 30 and 300 mg/d.¹⁹ The albumin-creatinine ratio (30-300 mcg/mg), measured in spot urine specimens, is a more convenient way to detect it.²⁰

Suspicious findings prompt further testing. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) recommends specific testing—much of it detailed below—if any aspect of the initial evaluation raises suspicion of a secondary cause or the patient has hypertension that’s of sudden onset or hard to control.²¹ (According to the National Heart, Lung, and Blood Institute, JNC 8 is due for release later this year.)

Kidney disease may be a consequence or a cause

The overall prevalence of hypertension in patients with renal disease is 60%,²² but varies according to the type of nephropathy. Eighty-seven percent of patients with diabetic nephropathy also have hypertension, and hypertension and diabetes are the 2 most common causes of end-stage renal disease.^23,24

A combination of 2 or more drugs is usually needed to achieve the target BP of <130/80 mm Hg in patients with diabetes.²¹ ACE inhibitors and angiotensin receptor blockers have been found to slow the progression of diabetic nephropathy.^25-27

Is renal artery stenosis to blame?
Renal artery stenosis is the most common form of secondary hypertension that’s reversible, affecting about 0.2% to 3.1% of hypertensive patients.^5,6,28 The condition leads to renal ischemia, thereby stimulating the renin-angiotensin-aldosterone axis and causing secondary hyperaldosteronism.

In younger patients, especially women between 15 and 50 years of age, fibromuscular disease is the most common cause of renovascular hypertension.^29,30 In older patients, atherosclerosis (which accounts for 90% of renovascular hypertension) is more likely.^29,30

The choice of initial imaging tests includes duplex renal ultrasonography, magnetic resonance angiography (MRA), and spiral computed tomographic angiography. Contrast angiography is the gold standard, but it carries a risk of contrast-induced nephropathy. Duplex ultrasonography and MRA do not use iodinated contrast media, and are safe for patients with chronic kidney disease.⁸

Treatment. Percutaneous transluminal renal artery angioplasty is a treatment option for patients with renal artery stenosis. Angioplasty achieves higher cure rates for patients with fibromuscular dysplasia than for those with atherosclerotic renal artery stenosis.³¹ Most patients referred for renal artery revascularization have atherosclerosis. Because they’re generally older individuals with comorbidities, the benefits of stent revascularization for this group is controversial. Such patients require antihypertensive therapy with drugs that block the renin-angiotensin system.³²

Endocrine disorders must be ruled out

Primary hyperaldosteronism is thought to be present in 0.3% to 1.4% of patients with hypertension.^5,6 The prevalence varies widely from one source to another, however, and may be as high as 5% to 20% among patients with resistant hypertension.^33,34

Hyperaldosteronism is related to either an aldosterone-secreting adrenal adenoma (in about 40% of cases) or bilateral adrenal hyperplasia (in the remaining 60%), and leads to increased sodium reabsorption and, typically, to a loss of potassium.³⁵

Renin-secreting tumor, which usually arises from the juxtaglomerular cells of the kidney, is a rare cause of hyperaldosteronism. Extrarenal renin-secreting tumors have also been reported.³⁶

What should raise your suspicion. Suspect hyperaldosteronism in patients who have both hypertension and hypokalemia, but keep in mind that not all patients with hyperaldosteronism have low serum potassium.³⁷ Further laboratory evaluation should include a simultaneous measurement of plasma aldosterone (PA) and plasma renin activity (PRA). Patients with hyperaldosteronism will have elevated PA and suppressed PRA.

Testing considerations. It is important to ensure that the PA/PRA test is performed in the morning, with the patient in an upright position.³⁶ He or she should be on a high sodium diet in preparation for the test, consuming 2 to 3 grams of sodium per meal for ≥2 days.³⁷

In patients with a positive PA/PRA ratio (≥20), a 24-hour urinary aldosterone excretion test should be performed. A finding >12 to 14 mcg, along with a PRA <1.0 ng/mL per hour, confirms the diagnosis of primary hyperaldosteronism.^18,37 Computed tomography or magnetic resonance imaging of the adrenal glands will distinguish between aldosterone-producing adenoma and bilateral adrenal hyperplasia.

Treatment. Laparoscopic adrenalectomy is the accepted surgical treatment of primary hyperaldosteronism.³⁷ Patients with bilateral disease due to idiopathic hyperaldosteronism are not candidates for surgery and should be treated medically, with potassium-sparing diuretics such as spironolactone.

Cushing’s syndrome is marked by rapid weight gain
High BP may be a manifestation of Cushing’s syndrome, which affects 0.1% to 0.5% of patients with hypertension.^5-7 Other signs and symptoms of Cushing’s syndrome include fatigue, weakness, hirsutism, amenorrhea, moon facies, dorsal hump, purple striae, truncal obesity, and hypokalemia. Rapid weight gain is the most common manifestation, and typically the one for which patients seek medical attention.³⁸

The most widely used screening test for Cushing’s syndrome is a 24-hour urine collection measuring urinary-free cortisol.⁹ Normal urinary cortisol excretion is 20 to 100 mcg/dL in 24 hours; most patients with Cushing’s syndrome produce >250 mcg/dL in that time frame.⁹

Once hypercortisolism is established, determination of the cause is the next step. A serum adrenocorticotropic hormone (ACTH) level is needed to localize it. Normal (9-52 pg/mL) or elevated ACTH indicates a pituitary or ectopic source, while low levels of ACTH are an indication of an adrenal source.^9,39

Treatment. Surgical resection of the tumor is often curative. For pituitary tumors (Cushing’s disease), transsphenoidal resection is the standard of care.³⁹ For adrenal adenomas, unilateral adrenalectomy is the best option.³⁹

Pheochromocytomas: Most are adrenal, sporadic, and benign
Pheochromocytomas—neuroendocrine, catecholamine-secreting tumors that develop from the adrenal medulla—are another cause of secondary hypertension. Catecholamines include norepinephrine and epinephrine and, rarely, dopamine secreted either intermittently or continuously. The prevalence of pheochromocytoma is 0.1% to 0.3% among patients with hypertension.^5,6,28 A “rule of 10” (90:10 ratio) is often applied to pheochromocytomas because of the following:

• 90% of pheochromocytomas are located in the adrenal glands; the remaining 10% are extra-adrenal and can occur anywhere along the sympathetic chain⁴⁰
• 90% are sporadic; 10% are familial⁴¹
• 90% are benign; 10% are malignant⁴⁰
• 90% are found in adults; 10% affect children.⁴²

Signs and symptoms of pheochromocytomas include palpitations, headache, dyspnea, diaphoresis, and flushing, as well as paroxysmal hypertension.⁴⁰ Measurement of 24-hour urinary catecholamines and their metabolites has been the screening test of choice,⁴³ but recent evidence suggests that measurement of plasma metanephrine and normetanephrine is a far more sensitive screen.¹⁰

Treatment. Surgical resection is the treatment of choice. Alpha blockade is started 7 to 10 days preoperatively;^44,45 a beta-blocker is added only after an adequate alpha blockade has been established, as unopposed alpha stimulation could precipitate a hypertensive crisis. Laparoscopic adrenalectomy is routinely performed for small (<5 cm) pheochromocytomas.^46,47

Don’t forget these (relatively) common secondary causes

Obstructive sleep apnea (OSA) is one of the most common conditions associated with resistant hypertension.⁴⁸ Signs and symptoms include snoring, daytime somnolence, and obesity (body mass index ≥30 kg/m²).

OSA involves upper airway collapse during inspiration, causing intermittent hypoxemia with resultant sympathetic nervous system activation.¹¹ The underlying mechanism of OSA-induced hypertension is strongly related to sympathetic activation.⁴⁹ Overnight polysomnography is required for diagnosis.¹¹

Continuous positive airway pressure is the treatment of choice for patients unable to lose weight.¹¹

Pregnancy-induced hypertension is the most common medical problem encountered in pregnancy. It occurs in up to 15% of pregnancies, either during the pregnancy itself or postpartum. Postpartum hypertension may be related to preexisting chronic hypertension or to the persistence of gestational hypertension or preeclampsia, which usually occurs after 20 weeks’ gestation and is characterized by the presence of hypertension and proteinuria.⁵⁰ Methyldopa and labetalol are commonly used treatments for hypertension during pregnancy.⁵¹

Drug-induced hypertension. Several drugs can cause or exacerbate hypertension, rendering it resistant to therapy. A careful review of the patient’s medication regimen is essential. Generally, drug-induced hypertension falls into 2 broad categories based on mechanism of action: volume overload and sympathetic activity.^52,53

Corticosteroids can elevate BP in a dose-dependent manner, as a result of volume overload. Glycyrrhizic acid, the main ingredient in licorice, produces a state of excess mineralocorticoid, with a similar effect. Estrogen-containing oral contraceptives can cause an increased synthesis of angiotensin in the liver, resulting in greater aldosterone secretion and volume overload.

Drugs that stimulate sympathetic activity include cocaine, ephedrine, amphetamine, phenylephrine, phenylpropanolamine, caffeine, and alcohol. Nonsteroidal anti-inflammatory drugs may interfere with the action of ACE inhibitors and cause renal vasoconstriction, leading to sodium and water retention and hypertension.⁵⁴

Discontinuation of the medication in question is preferable. In many cases, an agent that does not affect BP can be found to replace it.

If the patient is a child
Hypertension is uncommon in young people. However, coarctation of the aorta, a congenital narrowing associated with secondary hypertension, is typically diagnosed in childhood. In rare cases, the condition remains undetected well into adulthood.⁵⁵ Clinical signs include weak femoral pulses, visible pulsations in the neck, a systolic murmur of the anterior and posterior thorax, and elevated BP in the upper extremities with low BP in the lower extremities.

Thus, once hypertension is confirmed in a young patient, BP should be measured in both arms and legs.⁵⁶ Delayed or absent femoral pulses and a difference in systolic BP of ≥20 mm Hg between the arms and legs provide evidence of aortic coarctation.⁵⁷ In adults, stenting is the initial treatment for this condition because of the morbidity associated with surgery.⁵⁷ Stenting is an option for children with this condition, as well.⁵⁸

CORRESPONDENCE Bernard M. Karnath, MD, University of Texas Medical Branch at Galveston, 301 University Boulevard, Galveston, TX 77555; [email protected]

With all of the discussion about a truly comprehensive and inclusive psychiatry, it was sad to see the emptiness and one-sidedness of Dr. Nasrallah’s June editorial (“Innovative approaches to treatment-resistant depression,” From the Editor, Current Psychiatry, June 2012, p. 4-5; http://bit.ly/1GM92oV). Depression certainly is not a unified diagnosis such as measles or appendicitis. In the face of so-called treatment-resistance, the first step is to review the psychological and biologic formulation of the patient and the reasons for his or her depression. Dr. Nasrallah does not mention the need for a review of all aspects of the patient’s life. The approaches he suggests are dreary, dull, ineffective, and unchanging. It proves that patients are best cared for by psychiatrists who practice biopsychosocial psychiatry and not merely to pay lip service to it.

Arnold Robbins, MD
Private Practice
Cambridge, MA
Clinical Professor of Psychiatry
Boston University School of Medicine
Boston, MA

Dr. Nasrallah responds

I thank Dr. Robbins for his letter. As someone trained by the father of biopsychosocial psychiatry—George Engel, MD, at the University of Rochester—I agree that it is the optimal practice of psychiatry and I practice that approach with all my patients. However, I was describing innovative interventions and paradigm shifts for truly end-of-the-road refractory depression, where all psychosocial and pharmacotherapy treatments have failed and the patient is desperate, disabled, and at high risk for suicide. None of the available interventions work with such individuals and that’s why I regard the innovative breakthroughs I described in my editorial as a promise of hope, thanks to dedicated psychiatric neuroscientists. I hope psychotherapy researchers can achieve breakthroughs for these patients as well.

Henry A. Nasrallah, MD
Editor-in-Chief

Psychotherapy for GAD

I appreciated Dr. Barry’s in-depth review of current diagnostic criteria and therapy for generalized anxiety disorder (GAD) (“Generalized anxiety disorder: Helping patients overcome worry,” Current Psychiatry, May 2012, p. 40-44; http://bit.ly/1oUymyJ). However, I want to point out an error under the “Evidence-based treatments” section labeled “Psychotherapy.” Dr. Barry states that cognitive-behavioral therapy (CBT) is the preferred form of psychotherapy for GAD. In my 40 years of practice, I have found a combination of medication—preferably selective serotonin reuptake inhibitors—and psychodynamic psychotherapy is the most effective treatment for GAD and provides more enduring relief.

Jonathan Shedler, PhD, of the University of Colorado Denver School of Medicine reported on the efficacy of psychodynamic psychotherapy vs behavioral therapy.¹ He compiled the results of meta-analyses of psychotherapy efficacy by 18 investigators covering 792 studies. The findings show a superior result for psychodynamic psychotherapy over behavioral therapy and the effects are more lasting.

Edward L. Parsons, MD
Private Practice
Westfield, NJ

The author responds

I appreciate Dr. Parsons’ comments and his valuable contribution to the dialogue on GAD. Dr. Parsons reemphasizes the importance of psychotherapy in this chronic condition. As demonstrated by the meta-analyses reviewed by Dr. Shedler, there is sufficient evidence in the medical literature to support either psychodynamic psychotherapy or CBT. The specific therapeutic recommendation should consider unique patient variables, such as therapist availability and expertise, the presence of co-occurring conditions or dynamics that would better align with a specific modality, and patient preference and psychological mindedness, to name a few. Regardless, psychotherapy is indicated in the treatment of GAD, and both CBT and psychodynamic psychotherapy are well-supported interventions.

Matthew J. Barry, DO
Lead Psychiatrist
Rochester Veterans Affairs Outpatient Clinic
Canandaigua Veterans Affairs Medical Center
Canandaigua, NY

Caution with prazosin

We welcome the article discussing the use of prazosin and antipsychotics for posttraumatic stress disorder (PTSD)-related nightmares (Graham RL, Leckband SG, Endow-Eyer RA. “PTSD nightmares: Prazosin and atypical antipsychotics,” Current Psychiatry, June 2012, p. 59-62; http://bit.ly/LVAlSo). The favorable outcomes associated with prazosin use combined with its low cost and general tolerability give it considerable potential. Prazosin may be particularly valuable given the unfavorable cardiometabolic risks associated with antipsychotic use, especially because evidence suggests individuals with PTSD have higher rates of cardiovascular disease.¹

We believe the occurrence of adverse cardiovascular effects when starting prazosin requires further attention. As an α1-adrenergic receptor antagonist, it has been linked to orthostatic hypotension and syncope.^2,3 Its cardiovascular effects may be further complicated by concomitant use of other antihypertensive medications. Therefore, we suggest a low initiation dose and gradual titration of prazosin. In individuals who initially were normotensive but then experienced hypotension following prazosin administration, we successfully used short-term sodium chloride tablets, 4 g/d. We discontinued sodium chloride after titration was completed and no postural hypotension was evident.

To minimize polypharmacy, individuals on multiple agents for hypertension may benefit from substituting prazosin for 1 of their regular anti- hypertensives. Despite the mounting evidence supporting prazosin use, it is not indicated for PTSD.

This material is the result of work supported with resources and the use of facilities of the Mental Health and Research and Development Service Lines, Atlanta Veterans Affairs Medical Center, Decatur, GA.

Arshya Vahabzadeh, MD
PGY-2, Resident Psychiatrist
Emory University School of Medicine

Erica Duncan, MD
Attending Psychiatrist
and Associate Professor
Mental Health Service Line
Atlanta Veterans Affairs Medical Center
Decatur, GA
Department of Psychiatry and Behavioral
Sciences
Emory University School of Medicine
Atlanta, GA

The authors respond

We agree with the comments by Drs. Vahabzadeh and Duncan regarding the cardiovascular adverse effects of prazosin. It is important to assess the hemodynamic status of the patient before initiating prazosin therapy, and usually, initiation is attempted only if a patient is normotensive or hypertensive because of potential orthostatic hypotension and syncope, which can occur in up to 4% of patients.¹ As noted by Drs. Vahabzadeh and Duncan, prazosin often is viewed as a dual treatment for both nightmares and blood pressure in individuals who are hypertensive prior to initiation. Prazosin therapy usually is initiated at 1 mg at bedtime and titrated by 1 to 2 mg every 3 to 5 days.² The average dose was approximately 3 mg in studies evaluating prazosin for treating PTSD-associated nightmares (dose range: 1 to 10 mg).² Until the patient is stabilized on a prazosin dose, blood pressure should be monitored daily for inpatients. Outpatients should be educated regarding the signs and symptoms of hypotension, especially dizziness and light-headedness upon standing, along with monitoring blood pressure at his or her next clinic appointment.

Prazosin does not carry an FDA indication for PTSD. Although this is important to consider, the level of evidence in terms of treatment of nightmares also is key. Aurora et al found prazosin was the only medication with a level A rating for treating PTSD-associated nightmares, indicating it as a recommended therapy option.² Because we do not have any medications indicated for PTSD-associated nightmares, it is crucial to practice evidence-based medicine and base therapy choices on available literature supporting the most effective and safe options.

Safety is an issue in many clinicians’ minds, especially when treating geriatric patients with PTSD because of the risk of hypotensive effects with prazosin leading to negative outcomes, such as falls. In Peskind et al’s open-label study of 9 older patients (mean age: 76) with intractable PTSD-associated nightmares treated with prazosin (mean dose: 2.3 mg; increased by 1 mg per week to a maximum dose of 4 mg), 8 patients experienced >50% reduction in nightmares after 8 weeks of treatment, and 1 patient experienced transient orthostasis when starting prazosin that resolved spontaneously with only mild decreases in blood pressure noted otherwise (<20 mm Hg decrease in systolic blood pressure upon standing).³ Although this study was small, it provides evidence that prazosin can be an effective and safe treatment option in geriatric patients and is devoid of the highly sedating side effects of some other treatment options.

Rebecca L. Graham, PharmD
Second-Year Psychiatric Pharmacy Resident
Veterans Affairs San Diego Healthcare System
(VASDHS)

Susan G. Leckband, RPh, BCPP
Clinical Psychiatric Pharmacist Specialist
VASDHS
Assistant Clinical Professor
Skaggs School of Pharmacy and
Pharmaceutical Sciences
Department of Psychiatry
University of California, San Diego

Rene A. Endow-Eyer, PharmD, BCPP
Psychiatric Clinical Pharmacy Specialist
VASDHS
Assistant Clinical Professor
Skaggs School of Pharmacy and
Pharmaceutical Sciences
Department of Psychiatry
University of California, San Diego
San Diego, CA

With all of the discussion about a truly comprehensive and inclusive psychiatry, it was sad to see the emptiness and one-sidedness of Dr. Nasrallah’s June editorial (“Innovative approaches to treatment-resistant depression,” From the Editor, Current Psychiatry, June 2012, p. 4-5; http://bit.ly/1GM92oV). Depression certainly is not a unified diagnosis such as measles or appendicitis. In the face of so-called treatment-resistance, the first step is to review the psychological and biologic formulation of the patient and the reasons for his or her depression. Dr. Nasrallah does not mention the need for a review of all aspects of the patient’s life. The approaches he suggests are dreary, dull, ineffective, and unchanging. It proves that patients are best cared for by psychiatrists who practice biopsychosocial psychiatry and not merely to pay lip service to it.

Arnold Robbins, MD
Private Practice
Cambridge, MA
Clinical Professor of Psychiatry
Boston University School of Medicine
Boston, MA

Dr. Nasrallah responds

I thank Dr. Robbins for his letter. As someone trained by the father of biopsychosocial psychiatry—George Engel, MD, at the University of Rochester—I agree that it is the optimal practice of psychiatry and I practice that approach with all my patients. However, I was describing innovative interventions and paradigm shifts for truly end-of-the-road refractory depression, where all psychosocial and pharmacotherapy treatments have failed and the patient is desperate, disabled, and at high risk for suicide. None of the available interventions work with such individuals and that’s why I regard the innovative breakthroughs I described in my editorial as a promise of hope, thanks to dedicated psychiatric neuroscientists. I hope psychotherapy researchers can achieve breakthroughs for these patients as well.

Henry A. Nasrallah, MD
Editor-in-Chief

Psychotherapy for GAD

I appreciated Dr. Barry’s in-depth review of current diagnostic criteria and therapy for generalized anxiety disorder (GAD) (“Generalized anxiety disorder: Helping patients overcome worry,” Current Psychiatry, May 2012, p. 40-44; http://bit.ly/1oUymyJ). However, I want to point out an error under the “Evidence-based treatments” section labeled “Psychotherapy.” Dr. Barry states that cognitive-behavioral therapy (CBT) is the preferred form of psychotherapy for GAD. In my 40 years of practice, I have found a combination of medication—preferably selective serotonin reuptake inhibitors—and psychodynamic psychotherapy is the most effective treatment for GAD and provides more enduring relief.

Jonathan Shedler, PhD, of the University of Colorado Denver School of Medicine reported on the efficacy of psychodynamic psychotherapy vs behavioral therapy.¹ He compiled the results of meta-analyses of psychotherapy efficacy by 18 investigators covering 792 studies. The findings show a superior result for psychodynamic psychotherapy over behavioral therapy and the effects are more lasting.

Edward L. Parsons, MD
Private Practice
Westfield, NJ

The author responds

I appreciate Dr. Parsons’ comments and his valuable contribution to the dialogue on GAD. Dr. Parsons reemphasizes the importance of psychotherapy in this chronic condition. As demonstrated by the meta-analyses reviewed by Dr. Shedler, there is sufficient evidence in the medical literature to support either psychodynamic psychotherapy or CBT. The specific therapeutic recommendation should consider unique patient variables, such as therapist availability and expertise, the presence of co-occurring conditions or dynamics that would better align with a specific modality, and patient preference and psychological mindedness, to name a few. Regardless, psychotherapy is indicated in the treatment of GAD, and both CBT and psychodynamic psychotherapy are well-supported interventions.

Matthew J. Barry, DO
Lead Psychiatrist
Rochester Veterans Affairs Outpatient Clinic
Canandaigua Veterans Affairs Medical Center
Canandaigua, NY

Caution with prazosin

We welcome the article discussing the use of prazosin and antipsychotics for posttraumatic stress disorder (PTSD)-related nightmares (Graham RL, Leckband SG, Endow-Eyer RA. “PTSD nightmares: Prazosin and atypical antipsychotics,” Current Psychiatry, June 2012, p. 59-62; http://bit.ly/LVAlSo). The favorable outcomes associated with prazosin use combined with its low cost and general tolerability give it considerable potential. Prazosin may be particularly valuable given the unfavorable cardiometabolic risks associated with antipsychotic use, especially because evidence suggests individuals with PTSD have higher rates of cardiovascular disease.¹

We believe the occurrence of adverse cardiovascular effects when starting prazosin requires further attention. As an α1-adrenergic receptor antagonist, it has been linked to orthostatic hypotension and syncope.^2,3 Its cardiovascular effects may be further complicated by concomitant use of other antihypertensive medications. Therefore, we suggest a low initiation dose and gradual titration of prazosin. In individuals who initially were normotensive but then experienced hypotension following prazosin administration, we successfully used short-term sodium chloride tablets, 4 g/d. We discontinued sodium chloride after titration was completed and no postural hypotension was evident.

To minimize polypharmacy, individuals on multiple agents for hypertension may benefit from substituting prazosin for 1 of their regular anti- hypertensives. Despite the mounting evidence supporting prazosin use, it is not indicated for PTSD.

This material is the result of work supported with resources and the use of facilities of the Mental Health and Research and Development Service Lines, Atlanta Veterans Affairs Medical Center, Decatur, GA.

Arshya Vahabzadeh, MD
PGY-2, Resident Psychiatrist
Emory University School of Medicine

Erica Duncan, MD
Attending Psychiatrist
and Associate Professor
Mental Health Service Line
Atlanta Veterans Affairs Medical Center
Decatur, GA
Department of Psychiatry and Behavioral
Sciences
Emory University School of Medicine
Atlanta, GA

The authors respond

We agree with the comments by Drs. Vahabzadeh and Duncan regarding the cardiovascular adverse effects of prazosin. It is important to assess the hemodynamic status of the patient before initiating prazosin therapy, and usually, initiation is attempted only if a patient is normotensive or hypertensive because of potential orthostatic hypotension and syncope, which can occur in up to 4% of patients.¹ As noted by Drs. Vahabzadeh and Duncan, prazosin often is viewed as a dual treatment for both nightmares and blood pressure in individuals who are hypertensive prior to initiation. Prazosin therapy usually is initiated at 1 mg at bedtime and titrated by 1 to 2 mg every 3 to 5 days.² The average dose was approximately 3 mg in studies evaluating prazosin for treating PTSD-associated nightmares (dose range: 1 to 10 mg).² Until the patient is stabilized on a prazosin dose, blood pressure should be monitored daily for inpatients. Outpatients should be educated regarding the signs and symptoms of hypotension, especially dizziness and light-headedness upon standing, along with monitoring blood pressure at his or her next clinic appointment.

Prazosin does not carry an FDA indication for PTSD. Although this is important to consider, the level of evidence in terms of treatment of nightmares also is key. Aurora et al found prazosin was the only medication with a level A rating for treating PTSD-associated nightmares, indicating it as a recommended therapy option.² Because we do not have any medications indicated for PTSD-associated nightmares, it is crucial to practice evidence-based medicine and base therapy choices on available literature supporting the most effective and safe options.

Safety is an issue in many clinicians’ minds, especially when treating geriatric patients with PTSD because of the risk of hypotensive effects with prazosin leading to negative outcomes, such as falls. In Peskind et al’s open-label study of 9 older patients (mean age: 76) with intractable PTSD-associated nightmares treated with prazosin (mean dose: 2.3 mg; increased by 1 mg per week to a maximum dose of 4 mg), 8 patients experienced >50% reduction in nightmares after 8 weeks of treatment, and 1 patient experienced transient orthostasis when starting prazosin that resolved spontaneously with only mild decreases in blood pressure noted otherwise (<20 mm Hg decrease in systolic blood pressure upon standing).³ Although this study was small, it provides evidence that prazosin can be an effective and safe treatment option in geriatric patients and is devoid of the highly sedating side effects of some other treatment options.

Rebecca L. Graham, PharmD
Second-Year Psychiatric Pharmacy Resident
Veterans Affairs San Diego Healthcare System
(VASDHS)

Susan G. Leckband, RPh, BCPP
Clinical Psychiatric Pharmacist Specialist
VASDHS
Assistant Clinical Professor
Skaggs School of Pharmacy and
Pharmaceutical Sciences
Department of Psychiatry
University of California, San Diego

Rene A. Endow-Eyer, PharmD, BCPP
Psychiatric Clinical Pharmacy Specialist
VASDHS
Assistant Clinical Professor
Skaggs School of Pharmacy and
Pharmaceutical Sciences
Department of Psychiatry
University of California, San Diego
San Diego, CA

With all of the discussion about a truly comprehensive and inclusive psychiatry, it was sad to see the emptiness and one-sidedness of Dr. Nasrallah’s June editorial (“Innovative approaches to treatment-resistant depression,” From the Editor, Current Psychiatry, June 2012, p. 4-5; http://bit.ly/1GM92oV). Depression certainly is not a unified diagnosis such as measles or appendicitis. In the face of so-called treatment-resistance, the first step is to review the psychological and biologic formulation of the patient and the reasons for his or her depression. Dr. Nasrallah does not mention the need for a review of all aspects of the patient’s life. The approaches he suggests are dreary, dull, ineffective, and unchanging. It proves that patients are best cared for by psychiatrists who practice biopsychosocial psychiatry and not merely to pay lip service to it.

Arnold Robbins, MD
Private Practice
Cambridge, MA
Clinical Professor of Psychiatry
Boston University School of Medicine
Boston, MA

Dr. Nasrallah responds

I thank Dr. Robbins for his letter. As someone trained by the father of biopsychosocial psychiatry—George Engel, MD, at the University of Rochester—I agree that it is the optimal practice of psychiatry and I practice that approach with all my patients. However, I was describing innovative interventions and paradigm shifts for truly end-of-the-road refractory depression, where all psychosocial and pharmacotherapy treatments have failed and the patient is desperate, disabled, and at high risk for suicide. None of the available interventions work with such individuals and that’s why I regard the innovative breakthroughs I described in my editorial as a promise of hope, thanks to dedicated psychiatric neuroscientists. I hope psychotherapy researchers can achieve breakthroughs for these patients as well.

Henry A. Nasrallah, MD
Editor-in-Chief

Psychotherapy for GAD

I appreciated Dr. Barry’s in-depth review of current diagnostic criteria and therapy for generalized anxiety disorder (GAD) (“Generalized anxiety disorder: Helping patients overcome worry,” Current Psychiatry, May 2012, p. 40-44; http://bit.ly/1oUymyJ). However, I want to point out an error under the “Evidence-based treatments” section labeled “Psychotherapy.” Dr. Barry states that cognitive-behavioral therapy (CBT) is the preferred form of psychotherapy for GAD. In my 40 years of practice, I have found a combination of medication—preferably selective serotonin reuptake inhibitors—and psychodynamic psychotherapy is the most effective treatment for GAD and provides more enduring relief.

Jonathan Shedler, PhD, of the University of Colorado Denver School of Medicine reported on the efficacy of psychodynamic psychotherapy vs behavioral therapy.¹ He compiled the results of meta-analyses of psychotherapy efficacy by 18 investigators covering 792 studies. The findings show a superior result for psychodynamic psychotherapy over behavioral therapy and the effects are more lasting.

Edward L. Parsons, MD
Private Practice
Westfield, NJ

The author responds

I appreciate Dr. Parsons’ comments and his valuable contribution to the dialogue on GAD. Dr. Parsons reemphasizes the importance of psychotherapy in this chronic condition. As demonstrated by the meta-analyses reviewed by Dr. Shedler, there is sufficient evidence in the medical literature to support either psychodynamic psychotherapy or CBT. The specific therapeutic recommendation should consider unique patient variables, such as therapist availability and expertise, the presence of co-occurring conditions or dynamics that would better align with a specific modality, and patient preference and psychological mindedness, to name a few. Regardless, psychotherapy is indicated in the treatment of GAD, and both CBT and psychodynamic psychotherapy are well-supported interventions.

Matthew J. Barry, DO
Lead Psychiatrist
Rochester Veterans Affairs Outpatient Clinic
Canandaigua Veterans Affairs Medical Center
Canandaigua, NY

Caution with prazosin

We welcome the article discussing the use of prazosin and antipsychotics for posttraumatic stress disorder (PTSD)-related nightmares (Graham RL, Leckband SG, Endow-Eyer RA. “PTSD nightmares: Prazosin and atypical antipsychotics,” Current Psychiatry, June 2012, p. 59-62; http://bit.ly/LVAlSo). The favorable outcomes associated with prazosin use combined with its low cost and general tolerability give it considerable potential. Prazosin may be particularly valuable given the unfavorable cardiometabolic risks associated with antipsychotic use, especially because evidence suggests individuals with PTSD have higher rates of cardiovascular disease.¹

We believe the occurrence of adverse cardiovascular effects when starting prazosin requires further attention. As an α1-adrenergic receptor antagonist, it has been linked to orthostatic hypotension and syncope.^2,3 Its cardiovascular effects may be further complicated by concomitant use of other antihypertensive medications. Therefore, we suggest a low initiation dose and gradual titration of prazosin. In individuals who initially were normotensive but then experienced hypotension following prazosin administration, we successfully used short-term sodium chloride tablets, 4 g/d. We discontinued sodium chloride after titration was completed and no postural hypotension was evident.

To minimize polypharmacy, individuals on multiple agents for hypertension may benefit from substituting prazosin for 1 of their regular anti- hypertensives. Despite the mounting evidence supporting prazosin use, it is not indicated for PTSD.

This material is the result of work supported with resources and the use of facilities of the Mental Health and Research and Development Service Lines, Atlanta Veterans Affairs Medical Center, Decatur, GA.

Arshya Vahabzadeh, MD
PGY-2, Resident Psychiatrist
Emory University School of Medicine

Erica Duncan, MD
Attending Psychiatrist
and Associate Professor
Mental Health Service Line
Atlanta Veterans Affairs Medical Center
Decatur, GA
Department of Psychiatry and Behavioral
Sciences
Emory University School of Medicine
Atlanta, GA

The authors respond

We agree with the comments by Drs. Vahabzadeh and Duncan regarding the cardiovascular adverse effects of prazosin. It is important to assess the hemodynamic status of the patient before initiating prazosin therapy, and usually, initiation is attempted only if a patient is normotensive or hypertensive because of potential orthostatic hypotension and syncope, which can occur in up to 4% of patients.¹ As noted by Drs. Vahabzadeh and Duncan, prazosin often is viewed as a dual treatment for both nightmares and blood pressure in individuals who are hypertensive prior to initiation. Prazosin therapy usually is initiated at 1 mg at bedtime and titrated by 1 to 2 mg every 3 to 5 days.² The average dose was approximately 3 mg in studies evaluating prazosin for treating PTSD-associated nightmares (dose range: 1 to 10 mg).² Until the patient is stabilized on a prazosin dose, blood pressure should be monitored daily for inpatients. Outpatients should be educated regarding the signs and symptoms of hypotension, especially dizziness and light-headedness upon standing, along with monitoring blood pressure at his or her next clinic appointment.

Prazosin does not carry an FDA indication for PTSD. Although this is important to consider, the level of evidence in terms of treatment of nightmares also is key. Aurora et al found prazosin was the only medication with a level A rating for treating PTSD-associated nightmares, indicating it as a recommended therapy option.² Because we do not have any medications indicated for PTSD-associated nightmares, it is crucial to practice evidence-based medicine and base therapy choices on available literature supporting the most effective and safe options.

Safety is an issue in many clinicians’ minds, especially when treating geriatric patients with PTSD because of the risk of hypotensive effects with prazosin leading to negative outcomes, such as falls. In Peskind et al’s open-label study of 9 older patients (mean age: 76) with intractable PTSD-associated nightmares treated with prazosin (mean dose: 2.3 mg; increased by 1 mg per week to a maximum dose of 4 mg), 8 patients experienced >50% reduction in nightmares after 8 weeks of treatment, and 1 patient experienced transient orthostasis when starting prazosin that resolved spontaneously with only mild decreases in blood pressure noted otherwise (<20 mm Hg decrease in systolic blood pressure upon standing).³ Although this study was small, it provides evidence that prazosin can be an effective and safe treatment option in geriatric patients and is devoid of the highly sedating side effects of some other treatment options.

Rebecca L. Graham, PharmD
Second-Year Psychiatric Pharmacy Resident
Veterans Affairs San Diego Healthcare System
(VASDHS)

Susan G. Leckband, RPh, BCPP
Clinical Psychiatric Pharmacist Specialist
VASDHS
Assistant Clinical Professor
Skaggs School of Pharmacy and
Pharmaceutical Sciences
Department of Psychiatry
University of California, San Diego

Rene A. Endow-Eyer, PharmD, BCPP
Psychiatric Clinical Pharmacy Specialist
VASDHS
Assistant Clinical Professor
Skaggs School of Pharmacy and
Pharmaceutical Sciences
Department of Psychiatry
University of California, San Diego
San Diego, CA

Nearly 2.5 million persons die each year in the United States.¹ For the bereaved, these deaths may be among the most painful and disruptive events they will experience. In this article, we evaluate the growing body of research on complicated grief (CG)—which also has been called prolonged grief, chronic grief, traumatic grief, and pathological grief—with an emphasis on how to identify CG and distinguish it from other adaptive and maladaptive reactions to the loss of a loved one. In addition, we review empirical evidence on treating CG, including psychotherapy, pharmacotherapy, and combined treatment approaches.

The bereavement-specific syndrome we refer to as CG currently is being reviewed for possible inclusion in DSM-5 as an official diagnosis. At press time, proposals for DSM-5 included a bereavement-related adjustment disorder within the new Trauma- and Stressor-Related Disorders category, as well as a provisional diagnosis of CG entitled Persistent Complex Bereavement-Related Disorder, which, upon acceptance, would be listed in Section III.²

What is ‘normal’ grief?

Grief is highly variable across individuals and time and may range from an absence of distress to severe and persistent pain and anguish. There’s no simple definition of “normal grief.” However, as clinicians, it’s necessary to understand the range of usual reactions. We recommend 2 considerations when evaluating grief reactions.

First, be aware that grief encompasses a range of cognitions, emotions, and behaviors. It may range from a relative lack of painful thoughts and emotions to intense and disruptive sadness, loneliness, anger, guilt, intrusive thoughts, difficulty concentrating, preoccupation with loss, social withdrawal, and a sense of being overwhelmed by the loss and its consequences. In the months after a loss, bereaved individuals may look for the deceased in a crowd, speak to them, or even experience auditory or visual hallucinations of the deceased. Nonetheless, positive feelings such as relief, peace, and happiness also are common following a loss.³ Moreover, laughter and smiling when discussing a lost loved one predicts reductions in grief symptoms over time.⁴ Overall, grief research suggests that, far from proceeding along standard and uniform stages,⁵ grief is complex and comprises a broad spectrum of thoughts, feelings, and behaviors that vary within and among individuals.

Second, note that in the absence of complications, grief progresses. For those who experience elevated levels of distress, the pain and disruption of loss initially may feel overwhelming but will subside in intensity over time for most individuals.⁵ This is not to say that an individual will never again feel sadness or longing for the deceased; elements of grief are likely to remain. Although the trajectory of grief symptoms varies among individuals and may progress in fits and starts, over time grief becomes more intermittent, less interfering, and is balanced with a sense of interest and purpose in life.

What is CG?

As research on grief experiences has grown, there’s increasing recognition that a minority of bereaved individuals experience more extreme grief symptoms that cause substantial, persistent distress and impairment despite the passage of many months or years. Shear et al⁶ proposed a set of CG diagnostic criteria (Table) in which a cluster of symptoms of intense and persistent separation distress are defined as core symptoms. Similar to other psychiatric diagnoses, the symptoms must be associated with significant distress or impairment.

Table

Proposed diagnostic criteria for complicated grief

Assessing CG symptoms

Among those with persistent elevated distress, a CG diagnosis must be considered in the context of the individual’s social and cultural environment, time since the loss, and duration of symptoms. The hallmark symptom of CG is separation distress with a focus of cognitive, behavioral, and emotional symptoms on the loss and its consequences. CG is associated with substantial distress, functional impairment, and an increased risk for suicide. See the Box for a case study.

Many individuals with CG remain undiagnosed and untreated for years despite high levels of distress and impairment and high risk for negative consequences such as suicide.⁷ Accordingly, there’s a need for greater CG screening. Clinically useful tools for assessing CG include a brief, 5-item dimensional screening assessment⁶ and the patient-rated Inventory of Complicated Grief.⁸

Distinguishing complicated and uncomplicated grief. Exhibiting CG symptoms in the first several months after a loss does not mean an individual has or will develop CG. Most bereaved adults report painful thoughts and emotions in the weeks and months following the loss, including distressed yearning, waves of intense grief, persistent and intrusive thoughts, images related to the death, somatic distress, and a feeling of being disconnected from others. For most individuals, the intensity of this response diminishes within 6 to 18 months after the loved one’s death.⁵ Although the optimal length of time to wait before establishing a diagnosis remains debatable, the earliest CG should be diagnosed is 6 months after a loss.

It’s common for grief to occasionally rise in intensity for days or weeks. This surge may occur many months or years after the loss, even in people who exhibited relatively little distress or impairment. In particular, anniversaries, holidays, or periods of stress may trigger increased grief intensity. However, these surges typically subside naturally within a short time. Accordingly, CG should be diagnosed only when symptoms persist for >1 month.

CG vs other post-loss disorders. CG, major depressive disorder (MDD), and posttraumatic stress disorder (PTSD) often are comorbid in bereaved adults. Simon et al⁹ found 72% of CG patients in a treatment- seeking sample reported a lifetime history of MDD and 53% reported a lifetime history of PTSD. However, CG can be distinguished from these disorders. In the same study, 25% of CG patients had no other axis I diagnosis.⁹ After accounting for comorbid disorders, researchers associated CG severity with work and social impairment. These findings provide clear evidence for the incremental validity of CG—ie, a CG diagnosis gives clinicians additional information that predicts impairment above and beyond other disorders. However, future research needs to further examine CG and its overlap and differentiation from MDD and PTSD.

Distinguishing CG and MDD. Intense yearning or preoccupation with the deceased is a common symptom of CG but not MDD. In addition, CG symptoms possess intentionality. For example, emotional distress such as sadness and anger are prominent features of both CG and MDD. However, in CG, these symptoms are specific to the loss or circumstances of the loss, whereas in MDD they generally are more nebulous and generalized. Similarly, CG entails proximity seeking related to the deceased, and avoidance of reminders of the deceased, whereas MDD includes a more general social withdrawal and anhedonia.

Distinguishing CG and PTSD. CG and loss-related PTSD are distinguished by the predominant emotions and focus of concern associated with each disorder. The predominant emotion in PTSD is fear, whereas in CG it is sadness and longing. In PTSD, intrusive thoughts and memories associated with the trauma generally are associated with the event itself and produce an ongoing sense of threat.¹⁰ Avoidance in PTSD is intended to reduce this threat feeling. By contrast, in CG, intrusive memories focus on the deceased or the circumstances of the death, and avoidance is aimed at preventing painful reminders of the loss or its permanence. Importantly, both syndromes may be present.

Box

Treating CG

When is treatment indicated? For years, bereavement theorists emphasized the need to work through emotions and memories related to the deceased with particular focus on negative material. However, evidence suggests that universal application of treatment to all bereaved individuals is unhelpful. In a recent meta-analysis, Neimeyer et al¹¹ found that the outcomes of grief therapy applied indiscriminately to all bereaved adults or all members of high-risk populations—such as parents whose child experienced a violent death—were no better than would be expected by the passage of time. In contrast, grief therapy applied only to those who develop elevated and persistent distress (eg, CG) led to greater and more enduring improvement in post-loss distress than was observed in control conditions.

These results suggest that most grieving individuals who do not meet criteria for CG (or other psychiatric disorders) will not require intervention. Those who do seek treatment for grief-related distress in the acute grief period should be assessed for bereavement-related depression, anxiety, and suicidality, and treated or referred to professional or community-based resources for support or counseling as clinically indicated.

Evidence for psychotherapy. For those who meet CG criteria, psychotherapy targeting the specific symptoms of CG is helpful. The evidence is strongest for CG treatment (CGT), a 16-session, manualized psychotherapy developed by M. Katherine Shear, MD.¹² CGT is based on an attachment model and cognitive-behavioral therapy (CBT) principles, and is informed by the dual-process theory proposed by Stroebe et al.¹³ According to this theory, natural healing following loss comprises 2 processes:

• a loss-oriented process in which the patient comes to terms with the loss, and
• a restoration-oriented process in which the patient reinvigorates a sense of purpose and meaning in life without the deceased.

CGT focuses on both processes. To address the former, it includes clinician-guided exercises in which the patient revisits the time of the death and planned activities in which the patient reengages with people, places, or thoughts that remind him or her of the deceased. CGT aims to allow the patient to gain an increased tolerance of the distressing thoughts and emotions associated with the loss so that these thoughts can be processed and the finality of the death and its circumstances can be accepted.

The restoration process is addressed by having patients generate and discuss personal goals and aspirations for the near and distant future, as well as scheduling pleasurable and rewarding events. This is accomplished by having patients imagine what they would want for themselves if their grief was less intense and planning concrete steps to take toward these goals. The restoration-oriented process is addressed concurrent with the loss-oriented process to encourage the oscillation between processes thought to be characteristic of a natural healing process following the loss of a loved one.

Other psychotherapy approaches (eg, support groups) may have a role for some individuals, and future research may suggest alternative approaches to CGT. To date, CGT is the most targeted evidence-based psychotherapy with randomized controlled data supporting its use in CG.

Pharmacotherapy for CG. Early research suggested that antidepressants—in particular tricyclics—may effectively reduce depressive symptoms in bereavement-related depression; their effect on CG symptoms, however, may not be as strong.¹⁴ Research on pharmacologic treatment that targets CG symptoms is developing. Because of the overlap between CG, PTSD, and MDD, researchers have hypothesized that antidepressants may be effective. Two open-label studies reported that the selective serotonin reuptake inhibitor (SSRI) escitalopram may be effective for CG.^15,16 Although a post-hoc comparison of paroxetine and nortriptyline¹⁷ showed significant reduction in CG and depressive symptoms with both agents, effects could not be separated from concomitant psychotherapy. Furthermore, an examination of naturalistic data on combining antidepressants with CGT suggested that antidepressants may improve outcomes for individuals receiving CGT.¹⁸ A multicenter, randomized controlled trial funded by the National Institute of Mental Health is examining the potential efficacy of citalopram, an SSRI, alone or in combination with CGT.¹⁹

The efficacy of benzodiazepines, which commonly are prescribed for bereaved individuals, has not been assessed in CG. However, recent research suggests they may not be useful for medically managing recent grief²⁰ and that their use in the aftermath of a loss may lead to long-term dependence in geriatric patients.²¹

Related Resources

• Center for Anxiety and Traumatic Stress Disorders. Massachusetts General Hospital. www.bostongrief.com.
• Zisook S, Shear K. Grief and bereavement: what psychiatrists need to know. World Psychiatry. 2009;8(2):67-74.
• Bonanno G. The other side of sadness: what the new science of bereavement tells us about loss. New York, NY: Basic Books; 2009.

Drug Brand Names

• Citalopram • Celexa
• Nortriptyline • Aventyl, Pamelor
• Escitalopram • Lexapro
• Paroxetine • Paxil

Disclosures

Dr. Simon receives grant or research support from the American Cancer Society, the American Foundation for Suicide Prevention, the Department of Defense, Forest Laboratories, and the National Institute of Mental Health.

Nearly 2.5 million persons die each year in the United States.¹ For the bereaved, these deaths may be among the most painful and disruptive events they will experience. In this article, we evaluate the growing body of research on complicated grief (CG)—which also has been called prolonged grief, chronic grief, traumatic grief, and pathological grief—with an emphasis on how to identify CG and distinguish it from other adaptive and maladaptive reactions to the loss of a loved one. In addition, we review empirical evidence on treating CG, including psychotherapy, pharmacotherapy, and combined treatment approaches.

The bereavement-specific syndrome we refer to as CG currently is being reviewed for possible inclusion in DSM-5 as an official diagnosis. At press time, proposals for DSM-5 included a bereavement-related adjustment disorder within the new Trauma- and Stressor-Related Disorders category, as well as a provisional diagnosis of CG entitled Persistent Complex Bereavement-Related Disorder, which, upon acceptance, would be listed in Section III.²

What is ‘normal’ grief?

Grief is highly variable across individuals and time and may range from an absence of distress to severe and persistent pain and anguish. There’s no simple definition of “normal grief.” However, as clinicians, it’s necessary to understand the range of usual reactions. We recommend 2 considerations when evaluating grief reactions.

First, be aware that grief encompasses a range of cognitions, emotions, and behaviors. It may range from a relative lack of painful thoughts and emotions to intense and disruptive sadness, loneliness, anger, guilt, intrusive thoughts, difficulty concentrating, preoccupation with loss, social withdrawal, and a sense of being overwhelmed by the loss and its consequences. In the months after a loss, bereaved individuals may look for the deceased in a crowd, speak to them, or even experience auditory or visual hallucinations of the deceased. Nonetheless, positive feelings such as relief, peace, and happiness also are common following a loss.³ Moreover, laughter and smiling when discussing a lost loved one predicts reductions in grief symptoms over time.⁴ Overall, grief research suggests that, far from proceeding along standard and uniform stages,⁵ grief is complex and comprises a broad spectrum of thoughts, feelings, and behaviors that vary within and among individuals.

Second, note that in the absence of complications, grief progresses. For those who experience elevated levels of distress, the pain and disruption of loss initially may feel overwhelming but will subside in intensity over time for most individuals.⁵ This is not to say that an individual will never again feel sadness or longing for the deceased; elements of grief are likely to remain. Although the trajectory of grief symptoms varies among individuals and may progress in fits and starts, over time grief becomes more intermittent, less interfering, and is balanced with a sense of interest and purpose in life.

What is CG?

As research on grief experiences has grown, there’s increasing recognition that a minority of bereaved individuals experience more extreme grief symptoms that cause substantial, persistent distress and impairment despite the passage of many months or years. Shear et al⁶ proposed a set of CG diagnostic criteria (Table) in which a cluster of symptoms of intense and persistent separation distress are defined as core symptoms. Similar to other psychiatric diagnoses, the symptoms must be associated with significant distress or impairment.

Table

Proposed diagnostic criteria for complicated grief

Assessing CG symptoms

Among those with persistent elevated distress, a CG diagnosis must be considered in the context of the individual’s social and cultural environment, time since the loss, and duration of symptoms. The hallmark symptom of CG is separation distress with a focus of cognitive, behavioral, and emotional symptoms on the loss and its consequences. CG is associated with substantial distress, functional impairment, and an increased risk for suicide. See the Box for a case study.

Many individuals with CG remain undiagnosed and untreated for years despite high levels of distress and impairment and high risk for negative consequences such as suicide.⁷ Accordingly, there’s a need for greater CG screening. Clinically useful tools for assessing CG include a brief, 5-item dimensional screening assessment⁶ and the patient-rated Inventory of Complicated Grief.⁸

Distinguishing complicated and uncomplicated grief. Exhibiting CG symptoms in the first several months after a loss does not mean an individual has or will develop CG. Most bereaved adults report painful thoughts and emotions in the weeks and months following the loss, including distressed yearning, waves of intense grief, persistent and intrusive thoughts, images related to the death, somatic distress, and a feeling of being disconnected from others. For most individuals, the intensity of this response diminishes within 6 to 18 months after the loved one’s death.⁵ Although the optimal length of time to wait before establishing a diagnosis remains debatable, the earliest CG should be diagnosed is 6 months after a loss.

It’s common for grief to occasionally rise in intensity for days or weeks. This surge may occur many months or years after the loss, even in people who exhibited relatively little distress or impairment. In particular, anniversaries, holidays, or periods of stress may trigger increased grief intensity. However, these surges typically subside naturally within a short time. Accordingly, CG should be diagnosed only when symptoms persist for >1 month.

CG vs other post-loss disorders. CG, major depressive disorder (MDD), and posttraumatic stress disorder (PTSD) often are comorbid in bereaved adults. Simon et al⁹ found 72% of CG patients in a treatment- seeking sample reported a lifetime history of MDD and 53% reported a lifetime history of PTSD. However, CG can be distinguished from these disorders. In the same study, 25% of CG patients had no other axis I diagnosis.⁹ After accounting for comorbid disorders, researchers associated CG severity with work and social impairment. These findings provide clear evidence for the incremental validity of CG—ie, a CG diagnosis gives clinicians additional information that predicts impairment above and beyond other disorders. However, future research needs to further examine CG and its overlap and differentiation from MDD and PTSD.

Distinguishing CG and MDD. Intense yearning or preoccupation with the deceased is a common symptom of CG but not MDD. In addition, CG symptoms possess intentionality. For example, emotional distress such as sadness and anger are prominent features of both CG and MDD. However, in CG, these symptoms are specific to the loss or circumstances of the loss, whereas in MDD they generally are more nebulous and generalized. Similarly, CG entails proximity seeking related to the deceased, and avoidance of reminders of the deceased, whereas MDD includes a more general social withdrawal and anhedonia.

Distinguishing CG and PTSD. CG and loss-related PTSD are distinguished by the predominant emotions and focus of concern associated with each disorder. The predominant emotion in PTSD is fear, whereas in CG it is sadness and longing. In PTSD, intrusive thoughts and memories associated with the trauma generally are associated with the event itself and produce an ongoing sense of threat.¹⁰ Avoidance in PTSD is intended to reduce this threat feeling. By contrast, in CG, intrusive memories focus on the deceased or the circumstances of the death, and avoidance is aimed at preventing painful reminders of the loss or its permanence. Importantly, both syndromes may be present.

Box

Treating CG

When is treatment indicated? For years, bereavement theorists emphasized the need to work through emotions and memories related to the deceased with particular focus on negative material. However, evidence suggests that universal application of treatment to all bereaved individuals is unhelpful. In a recent meta-analysis, Neimeyer et al¹¹ found that the outcomes of grief therapy applied indiscriminately to all bereaved adults or all members of high-risk populations—such as parents whose child experienced a violent death—were no better than would be expected by the passage of time. In contrast, grief therapy applied only to those who develop elevated and persistent distress (eg, CG) led to greater and more enduring improvement in post-loss distress than was observed in control conditions.

These results suggest that most grieving individuals who do not meet criteria for CG (or other psychiatric disorders) will not require intervention. Those who do seek treatment for grief-related distress in the acute grief period should be assessed for bereavement-related depression, anxiety, and suicidality, and treated or referred to professional or community-based resources for support or counseling as clinically indicated.

Evidence for psychotherapy. For those who meet CG criteria, psychotherapy targeting the specific symptoms of CG is helpful. The evidence is strongest for CG treatment (CGT), a 16-session, manualized psychotherapy developed by M. Katherine Shear, MD.¹² CGT is based on an attachment model and cognitive-behavioral therapy (CBT) principles, and is informed by the dual-process theory proposed by Stroebe et al.¹³ According to this theory, natural healing following loss comprises 2 processes:

• a loss-oriented process in which the patient comes to terms with the loss, and
• a restoration-oriented process in which the patient reinvigorates a sense of purpose and meaning in life without the deceased.

CGT focuses on both processes. To address the former, it includes clinician-guided exercises in which the patient revisits the time of the death and planned activities in which the patient reengages with people, places, or thoughts that remind him or her of the deceased. CGT aims to allow the patient to gain an increased tolerance of the distressing thoughts and emotions associated with the loss so that these thoughts can be processed and the finality of the death and its circumstances can be accepted.

The restoration process is addressed by having patients generate and discuss personal goals and aspirations for the near and distant future, as well as scheduling pleasurable and rewarding events. This is accomplished by having patients imagine what they would want for themselves if their grief was less intense and planning concrete steps to take toward these goals. The restoration-oriented process is addressed concurrent with the loss-oriented process to encourage the oscillation between processes thought to be characteristic of a natural healing process following the loss of a loved one.

Other psychotherapy approaches (eg, support groups) may have a role for some individuals, and future research may suggest alternative approaches to CGT. To date, CGT is the most targeted evidence-based psychotherapy with randomized controlled data supporting its use in CG.

Pharmacotherapy for CG. Early research suggested that antidepressants—in particular tricyclics—may effectively reduce depressive symptoms in bereavement-related depression; their effect on CG symptoms, however, may not be as strong.¹⁴ Research on pharmacologic treatment that targets CG symptoms is developing. Because of the overlap between CG, PTSD, and MDD, researchers have hypothesized that antidepressants may be effective. Two open-label studies reported that the selective serotonin reuptake inhibitor (SSRI) escitalopram may be effective for CG.^15,16 Although a post-hoc comparison of paroxetine and nortriptyline¹⁷ showed significant reduction in CG and depressive symptoms with both agents, effects could not be separated from concomitant psychotherapy. Furthermore, an examination of naturalistic data on combining antidepressants with CGT suggested that antidepressants may improve outcomes for individuals receiving CGT.¹⁸ A multicenter, randomized controlled trial funded by the National Institute of Mental Health is examining the potential efficacy of citalopram, an SSRI, alone or in combination with CGT.¹⁹

The efficacy of benzodiazepines, which commonly are prescribed for bereaved individuals, has not been assessed in CG. However, recent research suggests they may not be useful for medically managing recent grief²⁰ and that their use in the aftermath of a loss may lead to long-term dependence in geriatric patients.²¹

Related Resources

• Center for Anxiety and Traumatic Stress Disorders. Massachusetts General Hospital. www.bostongrief.com.
• Zisook S, Shear K. Grief and bereavement: what psychiatrists need to know. World Psychiatry. 2009;8(2):67-74.
• Bonanno G. The other side of sadness: what the new science of bereavement tells us about loss. New York, NY: Basic Books; 2009.

Drug Brand Names

• Citalopram • Celexa
• Nortriptyline • Aventyl, Pamelor
• Escitalopram • Lexapro
• Paroxetine • Paxil

Disclosures

Dr. Simon receives grant or research support from the American Cancer Society, the American Foundation for Suicide Prevention, the Department of Defense, Forest Laboratories, and the National Institute of Mental Health.

Nearly 2.5 million persons die each year in the United States.¹ For the bereaved, these deaths may be among the most painful and disruptive events they will experience. In this article, we evaluate the growing body of research on complicated grief (CG)—which also has been called prolonged grief, chronic grief, traumatic grief, and pathological grief—with an emphasis on how to identify CG and distinguish it from other adaptive and maladaptive reactions to the loss of a loved one. In addition, we review empirical evidence on treating CG, including psychotherapy, pharmacotherapy, and combined treatment approaches.

The bereavement-specific syndrome we refer to as CG currently is being reviewed for possible inclusion in DSM-5 as an official diagnosis. At press time, proposals for DSM-5 included a bereavement-related adjustment disorder within the new Trauma- and Stressor-Related Disorders category, as well as a provisional diagnosis of CG entitled Persistent Complex Bereavement-Related Disorder, which, upon acceptance, would be listed in Section III.²

What is ‘normal’ grief?

Grief is highly variable across individuals and time and may range from an absence of distress to severe and persistent pain and anguish. There’s no simple definition of “normal grief.” However, as clinicians, it’s necessary to understand the range of usual reactions. We recommend 2 considerations when evaluating grief reactions.

First, be aware that grief encompasses a range of cognitions, emotions, and behaviors. It may range from a relative lack of painful thoughts and emotions to intense and disruptive sadness, loneliness, anger, guilt, intrusive thoughts, difficulty concentrating, preoccupation with loss, social withdrawal, and a sense of being overwhelmed by the loss and its consequences. In the months after a loss, bereaved individuals may look for the deceased in a crowd, speak to them, or even experience auditory or visual hallucinations of the deceased. Nonetheless, positive feelings such as relief, peace, and happiness also are common following a loss.³ Moreover, laughter and smiling when discussing a lost loved one predicts reductions in grief symptoms over time.⁴ Overall, grief research suggests that, far from proceeding along standard and uniform stages,⁵ grief is complex and comprises a broad spectrum of thoughts, feelings, and behaviors that vary within and among individuals.

Second, note that in the absence of complications, grief progresses. For those who experience elevated levels of distress, the pain and disruption of loss initially may feel overwhelming but will subside in intensity over time for most individuals.⁵ This is not to say that an individual will never again feel sadness or longing for the deceased; elements of grief are likely to remain. Although the trajectory of grief symptoms varies among individuals and may progress in fits and starts, over time grief becomes more intermittent, less interfering, and is balanced with a sense of interest and purpose in life.

What is CG?

As research on grief experiences has grown, there’s increasing recognition that a minority of bereaved individuals experience more extreme grief symptoms that cause substantial, persistent distress and impairment despite the passage of many months or years. Shear et al⁶ proposed a set of CG diagnostic criteria (Table) in which a cluster of symptoms of intense and persistent separation distress are defined as core symptoms. Similar to other psychiatric diagnoses, the symptoms must be associated with significant distress or impairment.

Table

Proposed diagnostic criteria for complicated grief

Assessing CG symptoms

Among those with persistent elevated distress, a CG diagnosis must be considered in the context of the individual’s social and cultural environment, time since the loss, and duration of symptoms. The hallmark symptom of CG is separation distress with a focus of cognitive, behavioral, and emotional symptoms on the loss and its consequences. CG is associated with substantial distress, functional impairment, and an increased risk for suicide. See the Box for a case study.

Many individuals with CG remain undiagnosed and untreated for years despite high levels of distress and impairment and high risk for negative consequences such as suicide.⁷ Accordingly, there’s a need for greater CG screening. Clinically useful tools for assessing CG include a brief, 5-item dimensional screening assessment⁶ and the patient-rated Inventory of Complicated Grief.⁸

Distinguishing complicated and uncomplicated grief. Exhibiting CG symptoms in the first several months after a loss does not mean an individual has or will develop CG. Most bereaved adults report painful thoughts and emotions in the weeks and months following the loss, including distressed yearning, waves of intense grief, persistent and intrusive thoughts, images related to the death, somatic distress, and a feeling of being disconnected from others. For most individuals, the intensity of this response diminishes within 6 to 18 months after the loved one’s death.⁵ Although the optimal length of time to wait before establishing a diagnosis remains debatable, the earliest CG should be diagnosed is 6 months after a loss.

It’s common for grief to occasionally rise in intensity for days or weeks. This surge may occur many months or years after the loss, even in people who exhibited relatively little distress or impairment. In particular, anniversaries, holidays, or periods of stress may trigger increased grief intensity. However, these surges typically subside naturally within a short time. Accordingly, CG should be diagnosed only when symptoms persist for >1 month.

CG vs other post-loss disorders. CG, major depressive disorder (MDD), and posttraumatic stress disorder (PTSD) often are comorbid in bereaved adults. Simon et al⁹ found 72% of CG patients in a treatment- seeking sample reported a lifetime history of MDD and 53% reported a lifetime history of PTSD. However, CG can be distinguished from these disorders. In the same study, 25% of CG patients had no other axis I diagnosis.⁹ After accounting for comorbid disorders, researchers associated CG severity with work and social impairment. These findings provide clear evidence for the incremental validity of CG—ie, a CG diagnosis gives clinicians additional information that predicts impairment above and beyond other disorders. However, future research needs to further examine CG and its overlap and differentiation from MDD and PTSD.

Distinguishing CG and MDD. Intense yearning or preoccupation with the deceased is a common symptom of CG but not MDD. In addition, CG symptoms possess intentionality. For example, emotional distress such as sadness and anger are prominent features of both CG and MDD. However, in CG, these symptoms are specific to the loss or circumstances of the loss, whereas in MDD they generally are more nebulous and generalized. Similarly, CG entails proximity seeking related to the deceased, and avoidance of reminders of the deceased, whereas MDD includes a more general social withdrawal and anhedonia.

Distinguishing CG and PTSD. CG and loss-related PTSD are distinguished by the predominant emotions and focus of concern associated with each disorder. The predominant emotion in PTSD is fear, whereas in CG it is sadness and longing. In PTSD, intrusive thoughts and memories associated with the trauma generally are associated with the event itself and produce an ongoing sense of threat.¹⁰ Avoidance in PTSD is intended to reduce this threat feeling. By contrast, in CG, intrusive memories focus on the deceased or the circumstances of the death, and avoidance is aimed at preventing painful reminders of the loss or its permanence. Importantly, both syndromes may be present.

Box

Treating CG

When is treatment indicated? For years, bereavement theorists emphasized the need to work through emotions and memories related to the deceased with particular focus on negative material. However, evidence suggests that universal application of treatment to all bereaved individuals is unhelpful. In a recent meta-analysis, Neimeyer et al¹¹ found that the outcomes of grief therapy applied indiscriminately to all bereaved adults or all members of high-risk populations—such as parents whose child experienced a violent death—were no better than would be expected by the passage of time. In contrast, grief therapy applied only to those who develop elevated and persistent distress (eg, CG) led to greater and more enduring improvement in post-loss distress than was observed in control conditions.

These results suggest that most grieving individuals who do not meet criteria for CG (or other psychiatric disorders) will not require intervention. Those who do seek treatment for grief-related distress in the acute grief period should be assessed for bereavement-related depression, anxiety, and suicidality, and treated or referred to professional or community-based resources for support or counseling as clinically indicated.

Evidence for psychotherapy. For those who meet CG criteria, psychotherapy targeting the specific symptoms of CG is helpful. The evidence is strongest for CG treatment (CGT), a 16-session, manualized psychotherapy developed by M. Katherine Shear, MD.¹² CGT is based on an attachment model and cognitive-behavioral therapy (CBT) principles, and is informed by the dual-process theory proposed by Stroebe et al.¹³ According to this theory, natural healing following loss comprises 2 processes:

• a loss-oriented process in which the patient comes to terms with the loss, and
• a restoration-oriented process in which the patient reinvigorates a sense of purpose and meaning in life without the deceased.

CGT focuses on both processes. To address the former, it includes clinician-guided exercises in which the patient revisits the time of the death and planned activities in which the patient reengages with people, places, or thoughts that remind him or her of the deceased. CGT aims to allow the patient to gain an increased tolerance of the distressing thoughts and emotions associated with the loss so that these thoughts can be processed and the finality of the death and its circumstances can be accepted.

The restoration process is addressed by having patients generate and discuss personal goals and aspirations for the near and distant future, as well as scheduling pleasurable and rewarding events. This is accomplished by having patients imagine what they would want for themselves if their grief was less intense and planning concrete steps to take toward these goals. The restoration-oriented process is addressed concurrent with the loss-oriented process to encourage the oscillation between processes thought to be characteristic of a natural healing process following the loss of a loved one.

Other psychotherapy approaches (eg, support groups) may have a role for some individuals, and future research may suggest alternative approaches to CGT. To date, CGT is the most targeted evidence-based psychotherapy with randomized controlled data supporting its use in CG.

Pharmacotherapy for CG. Early research suggested that antidepressants—in particular tricyclics—may effectively reduce depressive symptoms in bereavement-related depression; their effect on CG symptoms, however, may not be as strong.¹⁴ Research on pharmacologic treatment that targets CG symptoms is developing. Because of the overlap between CG, PTSD, and MDD, researchers have hypothesized that antidepressants may be effective. Two open-label studies reported that the selective serotonin reuptake inhibitor (SSRI) escitalopram may be effective for CG.^15,16 Although a post-hoc comparison of paroxetine and nortriptyline¹⁷ showed significant reduction in CG and depressive symptoms with both agents, effects could not be separated from concomitant psychotherapy. Furthermore, an examination of naturalistic data on combining antidepressants with CGT suggested that antidepressants may improve outcomes for individuals receiving CGT.¹⁸ A multicenter, randomized controlled trial funded by the National Institute of Mental Health is examining the potential efficacy of citalopram, an SSRI, alone or in combination with CGT.¹⁹

The efficacy of benzodiazepines, which commonly are prescribed for bereaved individuals, has not been assessed in CG. However, recent research suggests they may not be useful for medically managing recent grief²⁰ and that their use in the aftermath of a loss may lead to long-term dependence in geriatric patients.²¹

Related Resources

• Center for Anxiety and Traumatic Stress Disorders. Massachusetts General Hospital. www.bostongrief.com.
• Zisook S, Shear K. Grief and bereavement: what psychiatrists need to know. World Psychiatry. 2009;8(2):67-74.
• Bonanno G. The other side of sadness: what the new science of bereavement tells us about loss. New York, NY: Basic Books; 2009.

Drug Brand Names

• Citalopram • Celexa
• Nortriptyline • Aventyl, Pamelor
• Escitalopram • Lexapro
• Paroxetine • Paxil

Disclosures

Dr. Simon receives grant or research support from the American Cancer Society, the American Foundation for Suicide Prevention, the Department of Defense, Forest Laboratories, and the National Institute of Mental Health.

There is considerable overlap between symptoms of adult attention-deficit/hyperactivity disorder (ADHD) and mild cognitive impairment (MCI), including problems with sustained attention or concentration, anterograde memory, and executive functioning. Differentiating these clinical syndromes based on symptomatic presentation alone can be difficult, but considering the following factors can help you make a more informed diagnosis:

Neurodevelopmental disorder history. DSM-IV-TR stipulates onset for some ADHD symptoms by age 7, although a DSM-5 Work Group is considering symptom onset as late as age 12.¹ Initial onset or a dramatic worsening of longstanding ADHD symptoms in middle-age or older adults is atypical for this neurodevelopmental disorder.

Detailed self-diagnosed symptoms. Patients with ADHD usually can give a satisfactory history of their symptoms. Patients with MCI often are less able to provide a useful history because they have prominent difficulties with anterograde memory, which may be associated with emerging anosognosia.

Educational learning difficulties. Patients with ADHD frequently have comorbid learning difficulties and substance abuse disorders, which are uncommon in MCI.

Rating scales. When in doubt, use rating scales to assess for ADHD.² Ask your patient to complete the rating scale based on how he or she remembers behaving in elementary through middle school, most of their adult life after age 20, and since symptom onset. Obtain collateral ratings from a reliable informant based on his or her knowledge of the patient’s long-term behavioral functioning.

Worsening symptoms. The typical ADHD patient will have a “positive” screen for symptoms, but will report fewer and less severe symptoms from childhood or adolescence through young adulthood and into middle and older age. Suspect MCI when your patient or an informant reports a clear worsening of symptoms in recent months or years despite a lack of evidence of a significant intervening psychiatric disorder.

Psychopharmacotherapy. Patients with MCI usually do not benefit from medications for ADHD. Patients with ADHD often report improvement in at least some of their symptoms with psychopharmacologic treatment.

When your patient’s history, rating scale assessment, and medication trials do not allow you to make a confident differential diagnosis, consider referring him or her for psychological or neuropsychological testing.

There can be overlap in psychometric test findings of middle-age and older adults with a history of ADHD and those who may have MCI. Still, MCI patients’ cognitive difficulties usually are more concerning and dramatic, including problems with spontaneous recall as well as “recognition memory.”

When findings from psychometric testing are equivocal because of possible co-occurrence, retesting in 12 to 18 months usually will help you make a reliable differential diagnosis. Specifically, progression of cognitive dysfunction—including evidence of worsening anterograde memory—is common in MCI but not in ADHD.

Current symptoms of major depressive disorder may further “muddy the waters.” However, parameters such as response to adequate medication trials, progression of cognitive dysfunction, and worsening of test-based cognitive or neuropsychological deficits over time can be useful in reaching a satisfactory differential diagnosis.

Disclosure

Dr. Pollak reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

There is considerable overlap between symptoms of adult attention-deficit/hyperactivity disorder (ADHD) and mild cognitive impairment (MCI), including problems with sustained attention or concentration, anterograde memory, and executive functioning. Differentiating these clinical syndromes based on symptomatic presentation alone can be difficult, but considering the following factors can help you make a more informed diagnosis:

Neurodevelopmental disorder history. DSM-IV-TR stipulates onset for some ADHD symptoms by age 7, although a DSM-5 Work Group is considering symptom onset as late as age 12.¹ Initial onset or a dramatic worsening of longstanding ADHD symptoms in middle-age or older adults is atypical for this neurodevelopmental disorder.

Detailed self-diagnosed symptoms. Patients with ADHD usually can give a satisfactory history of their symptoms. Patients with MCI often are less able to provide a useful history because they have prominent difficulties with anterograde memory, which may be associated with emerging anosognosia.

Educational learning difficulties. Patients with ADHD frequently have comorbid learning difficulties and substance abuse disorders, which are uncommon in MCI.

Rating scales. When in doubt, use rating scales to assess for ADHD.² Ask your patient to complete the rating scale based on how he or she remembers behaving in elementary through middle school, most of their adult life after age 20, and since symptom onset. Obtain collateral ratings from a reliable informant based on his or her knowledge of the patient’s long-term behavioral functioning.

Worsening symptoms. The typical ADHD patient will have a “positive” screen for symptoms, but will report fewer and less severe symptoms from childhood or adolescence through young adulthood and into middle and older age. Suspect MCI when your patient or an informant reports a clear worsening of symptoms in recent months or years despite a lack of evidence of a significant intervening psychiatric disorder.

Psychopharmacotherapy. Patients with MCI usually do not benefit from medications for ADHD. Patients with ADHD often report improvement in at least some of their symptoms with psychopharmacologic treatment.

When your patient’s history, rating scale assessment, and medication trials do not allow you to make a confident differential diagnosis, consider referring him or her for psychological or neuropsychological testing.

There can be overlap in psychometric test findings of middle-age and older adults with a history of ADHD and those who may have MCI. Still, MCI patients’ cognitive difficulties usually are more concerning and dramatic, including problems with spontaneous recall as well as “recognition memory.”

When findings from psychometric testing are equivocal because of possible co-occurrence, retesting in 12 to 18 months usually will help you make a reliable differential diagnosis. Specifically, progression of cognitive dysfunction—including evidence of worsening anterograde memory—is common in MCI but not in ADHD.

Current symptoms of major depressive disorder may further “muddy the waters.” However, parameters such as response to adequate medication trials, progression of cognitive dysfunction, and worsening of test-based cognitive or neuropsychological deficits over time can be useful in reaching a satisfactory differential diagnosis.

Disclosure

Dr. Pollak reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

There is considerable overlap between symptoms of adult attention-deficit/hyperactivity disorder (ADHD) and mild cognitive impairment (MCI), including problems with sustained attention or concentration, anterograde memory, and executive functioning. Differentiating these clinical syndromes based on symptomatic presentation alone can be difficult, but considering the following factors can help you make a more informed diagnosis:

Neurodevelopmental disorder history. DSM-IV-TR stipulates onset for some ADHD symptoms by age 7, although a DSM-5 Work Group is considering symptom onset as late as age 12.¹ Initial onset or a dramatic worsening of longstanding ADHD symptoms in middle-age or older adults is atypical for this neurodevelopmental disorder.

Detailed self-diagnosed symptoms. Patients with ADHD usually can give a satisfactory history of their symptoms. Patients with MCI often are less able to provide a useful history because they have prominent difficulties with anterograde memory, which may be associated with emerging anosognosia.

Educational learning difficulties. Patients with ADHD frequently have comorbid learning difficulties and substance abuse disorders, which are uncommon in MCI.

Rating scales. When in doubt, use rating scales to assess for ADHD.² Ask your patient to complete the rating scale based on how he or she remembers behaving in elementary through middle school, most of their adult life after age 20, and since symptom onset. Obtain collateral ratings from a reliable informant based on his or her knowledge of the patient’s long-term behavioral functioning.

Worsening symptoms. The typical ADHD patient will have a “positive” screen for symptoms, but will report fewer and less severe symptoms from childhood or adolescence through young adulthood and into middle and older age. Suspect MCI when your patient or an informant reports a clear worsening of symptoms in recent months or years despite a lack of evidence of a significant intervening psychiatric disorder.

Psychopharmacotherapy. Patients with MCI usually do not benefit from medications for ADHD. Patients with ADHD often report improvement in at least some of their symptoms with psychopharmacologic treatment.

When your patient’s history, rating scale assessment, and medication trials do not allow you to make a confident differential diagnosis, consider referring him or her for psychological or neuropsychological testing.

There can be overlap in psychometric test findings of middle-age and older adults with a history of ADHD and those who may have MCI. Still, MCI patients’ cognitive difficulties usually are more concerning and dramatic, including problems with spontaneous recall as well as “recognition memory.”

When findings from psychometric testing are equivocal because of possible co-occurrence, retesting in 12 to 18 months usually will help you make a reliable differential diagnosis. Specifically, progression of cognitive dysfunction—including evidence of worsening anterograde memory—is common in MCI but not in ADHD.

Current symptoms of major depressive disorder may further “muddy the waters.” However, parameters such as response to adequate medication trials, progression of cognitive dysfunction, and worsening of test-based cognitive or neuropsychological deficits over time can be useful in reaching a satisfactory differential diagnosis.

Disclosure

Dr. Pollak reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Discuss this article at www.facebook.com/CurrentPsychiatry

You’ve been treating Mr. H, a 54-year-old factory worker and tobacco user, for depression that developed after a work-related back injury and subsequent disability. His depression has had a fair response to an antidepressant. He also has been maintained on chronic opioids (morphine and oxycodone/acetaminophen) for 18 months by his primary care physician (PCP). At the end of your appointment, he asks you for a refill of the opioids because he “ran out” early because of increased night pain and resultant insomnia and “stress.” He clarifies he has asked for early refills before from his PCP, but lately he has been denied. Because you “seem to listen to me more,” he asks for your help. How should you manage Mr. H?

Opioids are among the most commonly misused prescription drugs in the United States.¹ In 2008, poisoning was the leading cause of death from injury in the United States; roughly 90% of poisonings resulted from drug exposure, and >40% of these drug poisonings were from prescription opioids.² The Centers for Disease Control and Prevention estimates that the number of emergency department (ED) visits for nonmedical use of opioids increased 111% between 2004 and 2008, from 144,600 to 305,900 visits.³ The highest number of visits were for use of oxycodone, hydrocodone, and methadone.³

Increased prescribing of opioids and overdose deaths attributable to prescribed opioids have raised concern among physicians about how to effectively treat pain as well as prevent, recognize, and manage aberrant medication-taking behaviors (AMTBs). Psychiatrists are well-positioned to screen and manage their own patients for prescription opioid use disorder (POUD) or collaborate with opioid prescribers to accomplish the same.

Clarifying terminology

Terminology used to describe POUD and related conditions often is poorly defined or loosely applied. Because emotions often enter discussions between patients and physicians about problems related to opioid therapy, nonstigmatizing and more objective terminology is needed, and clinicians are working toward standardizing this. Relevant terms are defined in Table 1.⁴

The DSM-5 Substance Use Disorders Work Group has proposed using the term opioid use disorder (OUD) to replace the term opioid dependence.⁵ The hope is that removing the word “dependence” from the diagnostic term will reduce confusion between “dependence” due to expected physical dependence (tolerance, withdrawal) on medically prescribed opioids vs true addiction (currently defined as “opioid dependence” in DSM-IV-TR). This Work Group also has proposed combining opioid abuse and opioid dependence criteria into a single diagnosis of OUD, and adding “craving” to the criteria. For the complete proposed criteria, see www.dsm5.org/ProposedRevisions/Pages/proposedrevision.aspx?rid=460.These changes are still under review. In this article, we use the term POUD.

Table 1

Terminology related to prescription opioid use disorder

POUD and chronic pain

The incidence of POUD during opioid therapy for pain is unknown.⁶ Some researchers have suggested it may be as low as 0.2%,⁷ while others estimate that rates of POUD in patients with chronic pain may be similar to those in the general population: 3% to 16%.⁸ When applying the proposed DSM-5 criteria to patients receiving long-term opioid therapy for noncancer pain, the lifetime prevalence of POUD may be as high as 35%.⁹

Prescribers may be contributing to POUD. Roughly 76% of opioids used for nonmedical purposes were prescribed to someone else, 20% were prescribed to the user, and 4% came from other sources.¹ Strategies to reduce POUD risk may be underused. In a retrospective cohort study of 1,612 patient electronic medical records from 8 primary care clinics that managed patients with long-term opioids for chronic noncancer pain (average prescribing duration of 2 years duration, ≥3 monthly prescriptions in 6 months), researchers evaluated how often prescribers used 3 risk reduction practices:

• urine drug tests
• regular office visits (≥1 every 6 months and within 30 days of changing opioid treatment)
• restricted early refills (≤1 opioid refill more than a week early).¹⁰

Risk factors for opioid misuse included age 1 early refill. Researchers found that even for high-risk patients, these strategies were used infrequently. Less than one-quarter of patients with ≥3 risk factors ever had a drug test, and those at increased risk were more likely to receive >1 early refill but no more likely to have more frequent visits. Issues such as patient entitlement, lack of physician education, and time constraints may explain why these strategies are not used more often.¹¹

No one procedure or set of variables is sufficient to identify chronic pain patients who may be at risk for POUD. However, a history of drug or alcohol use disorders may be a significant risk factor.^12,13

Few tools have been developed to help identify those at risk of AMTBs or POUD, and all have limitations.^4,14 Recommended self-report measures include the Current Opioid Misuse Measure and the Opioid Risk Tool.¹⁵ A review of studies in which these kinds of tools were developed revealed limited evidence for their use; most studies had methodological shortcomings, did not use standardized AMTB criteria, and provided little assessment of whether these tools changed clinician behaviors or improved patient outcomes.¹⁶

Evaluating AMTBs

Although diagnosing POUD in pain patients receiving chronic opioids can be challenging, assessing for AMTBs typically is helpful. Once AMTBs are identified, they can be examined to determine what drives their expression (Table 1⁴ and Table 2¹⁷). However, often it is easier to identify AMTBs than to interpret their origins; as much as 30% to 50% of patients who complain of chronic pain may have primary substance dependence to sedatives, opioids, or both.¹¹

Table 2

Aberrant medication-taking behaviors and POUD risk

Although AMTBs are common among chronic nonmalignant pain patients,^18,19 how often AMTBs reflect underlying POUD is uncertain.⁷ It is critical to interpret AMTBs with a balance of caution and care: “react therapeutically, not punitively.”²⁰ Categorizing a patient’s AMTB as more or less likely to support a POUD diagnosis can be helpful, but is not conclusive (Table 2).¹⁷ Clinical correlation often is required. No single AMTB alone is indicative of POUD. When evaluating AMTBs, the treating provider should use a nonjudgmental stance, and consider obtaining collateral data from people who can provide differing perspectives of the patient’s behaviors, such as other clinicians, significant others, family, etc. (a release of information from the patient may be required). Another source of collateral data is prescription monitoring databases. These databases typically are state-based and provide electronic access to prescription information, allowing you to search for patterns—ie, use of multiple prescribers or pharmacies, undisclosed prescriptions, etc. Interest in establishing a single, federal database has been increasing, but striking a balance between carefully monitoring for AMTBs and protecting privacy remains unresolved.

DSM-IV-TR diagnostic criteria for opioid dependence²¹ can be challenging to interpret in patients who are prescribed opioids for pain (Table 3

Assessment is primarily clinical and requires an awareness of appropriate terminology, an index of clinical suspicion, and expertise teasing apart pain, addiction, and pseudoaddiction. In our experience, it is helpful to ask a chronic pain patient whom you suspect might have POUD, “Have you ever used your prescribed opioids for reasons other than improving function or reducing pain, such as for getting a ‘high,’ managing stress, escaping from problems, etc.?” An affirmative response suggests an underlying problem with use of prescribed opioids, indicating a need for more careful questioning to determine if AMTBs or POUD coexist with chronic pain.

Drug testing can help determine if a patient is taking opioids that are not prescribed—as well as illicit drugs or alcohol—and confirm the presence of those that are prescribed. Toxicology screening should include opioids typically screened for (eg, morphine, codeine, heroin) and those for which additional tests may be required (eg, semi-synthetics such as oxycodone and hydrocodone and synthetics such as fentanyl).

Table 3

Identifying addiction in pain patients: Limitations of DSM-IV-TR

Table 4

Possible indicators of addiction in pain patients

Helping POUD patients

Goals of treatment include establishing a therapeutic alliance, educating patients about POUD, reducing relapse risk, and optimizing overall health (including pain and physical function). The ASAM Patient Placement Criteria²² provide guidance regarding level-of-care decisions. Treatment ideally includes a combination of education about POUD and its relationship to chronic pain, pharmacotherapy, psychotherapy—such as motivational enhancement therapy, 12-step facilitation therapy, cognitive-behavioral therapy, and relapse prevention—and referral to self-help groups such as Narcotics Anonymous or Pills Anonymous. Importantly, if pain is genuine, it requires treatment.

Pharmacotherapy. Methadone is recommended as the standard of care for OUD by the National Institutes of Health. Methadone is a full opioid agonist that decreases illicit opioid use, mortality, and related problems and requires highly structured treatment approaches under federal and state regulation. POUD patients may have higher rates of methadone maintenance treatment retention than heroin-dependent patients.²³ Published trials of buprenorphine for OUD have shown good treatment retention and reduction in illicit drug use and adverse events.²⁴ Buprenorphine also decreases mortality among OUD patients.

The first large-scale, randomized clinical trial of buprenorphine specifically for POUD included 653 treatment-seeking outpatients.²⁵ This study was designed to approximate clinical practice and included buprenorphine/naloxone, recommended abstinence, and self-help; one-half of participants received intensive addiction counseling. POUD patients were most likely to reduce prescription opioid misuse during buprenorphine/naloxone treatment. If tapered off buprenorphine/naloxone, even after 12 weeks of treatment, the likelihood of an unsuccessful outcome was high. Moreover, opioid dependence counseling did not seem to afford any difference in outcomes. However, despite clinical effectiveness, over the last decade only 19% of patients admitted primarily for OUD treatment (other than heroin) were planned to be offered buprenorphine or methadone.²⁶

A Cochrane review of oral naltrexone for OUD found that the drug was no better than placebo but concluded that available evidence does not allow an adequate evaluation.²⁷ Opioid antagonists may be of value to patients who do not want to take agonists or partial agonists. Extended-release naltrexone also is available to treat OUD.

See the Box below that details steps the FDA and others have taken to prevent POUD and Table 5 for precautions to incorporate when prescribing opioids long-term.

Box

Table 5

Universal precautions with chronic opioid management

CASE CONTINUED: A closer evaluation

After expressing your appreciation for Mr. H’s kind words and empathy for his chronic pain, you redirect him to his PCP. You ask him to sign a release of information so you and his other clinicians can coordinate his care. When discussing Mr. H with his PCP, you learn the patient has made limited requests for early refills and dose escalation primarily in relation to inadequate pain control and function, has genuine pain pathology, and is greatly distressed over his inability to work. No other AMTBs are present, and a check of the state prescribing database reveals that Mr. H did receive a small quantity of opioids from an ED on 1 occasion.

You and Mr. H’s PCP agree this is “pseudo-addiction” but want to watch Mr. H more closely and look for ways to coordinate his care. The PCP agrees to implement a prescribing agreement, start drug testing (including for the prescribed opioids), and reassess maximizing Mr. H’s function and pain management while you address his combined pain, depression, insomnia, and tobacco use.

Related Resources

• Ries RK, Fiellin D, Miller SC, et al, eds. Principles of addiction medicine. 4th ed. Hagerstown, MD: Lippincott Williams & Wilkins; 2009.
• Department of Veterans Affairs. Department of Defense. VA/DoD clinical practice guideline for management of opioid therapy for chronic pain. Appendix C: sample opioid pain care agreement. http://www.healthquality.va.gov/COT_312_Full-er.pdf. Published May 2010. Accessed June 21, 2012.
• Weaver M, Schnoll S. Addiction issues in prescribing opioids for chronic non-malignant pain. J Addiction Med. 2007;1(1):2-10.
• Weaver M, Heit HA, Savage S, et al. Clinical case discussion: chronic pain management. J Addiction Med. 2007;1(1):11-14.

Drug Brand Names

• Buprenorphine • Subutex
• Buprenorphine/naloxone • Suboxone
• Codeine • Tylenol with codeine, others
• Fentanyl • Duragesic, Actiq
• Hydrocodone • Lortab, Vicodin, others
• Methadone • Dolophine, Methadose
• Morphine • Roxanol
• Naltrexone extended-release • Vivitrol
• Oxycodone • OxyContin, Roxicodone

Disclosures

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Frankowski’s time toward this project was provided by the American Board of Addiction Medicine-accredited Cincinnati VA Addiction Medicine Research Fellowship, affiliated with the CeTREAD, Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, OH.

The statements in this publication do not necessarily reflect the views or opinions of the Department of Veterans Affairs.

Acknowledgement

The authors thank Catherine Constance and Sandra Mason at the Cincinnati VA Medical Center for their administrative assistance.

Discuss this article at www.facebook.com/CurrentPsychiatry

You’ve been treating Mr. H, a 54-year-old factory worker and tobacco user, for depression that developed after a work-related back injury and subsequent disability. His depression has had a fair response to an antidepressant. He also has been maintained on chronic opioids (morphine and oxycodone/acetaminophen) for 18 months by his primary care physician (PCP). At the end of your appointment, he asks you for a refill of the opioids because he “ran out” early because of increased night pain and resultant insomnia and “stress.” He clarifies he has asked for early refills before from his PCP, but lately he has been denied. Because you “seem to listen to me more,” he asks for your help. How should you manage Mr. H?

Opioids are among the most commonly misused prescription drugs in the United States.¹ In 2008, poisoning was the leading cause of death from injury in the United States; roughly 90% of poisonings resulted from drug exposure, and >40% of these drug poisonings were from prescription opioids.² The Centers for Disease Control and Prevention estimates that the number of emergency department (ED) visits for nonmedical use of opioids increased 111% between 2004 and 2008, from 144,600 to 305,900 visits.³ The highest number of visits were for use of oxycodone, hydrocodone, and methadone.³

Increased prescribing of opioids and overdose deaths attributable to prescribed opioids have raised concern among physicians about how to effectively treat pain as well as prevent, recognize, and manage aberrant medication-taking behaviors (AMTBs). Psychiatrists are well-positioned to screen and manage their own patients for prescription opioid use disorder (POUD) or collaborate with opioid prescribers to accomplish the same.

Clarifying terminology

Terminology used to describe POUD and related conditions often is poorly defined or loosely applied. Because emotions often enter discussions between patients and physicians about problems related to opioid therapy, nonstigmatizing and more objective terminology is needed, and clinicians are working toward standardizing this. Relevant terms are defined in Table 1.⁴

The DSM-5 Substance Use Disorders Work Group has proposed using the term opioid use disorder (OUD) to replace the term opioid dependence.⁵ The hope is that removing the word “dependence” from the diagnostic term will reduce confusion between “dependence” due to expected physical dependence (tolerance, withdrawal) on medically prescribed opioids vs true addiction (currently defined as “opioid dependence” in DSM-IV-TR). This Work Group also has proposed combining opioid abuse and opioid dependence criteria into a single diagnosis of OUD, and adding “craving” to the criteria. For the complete proposed criteria, see www.dsm5.org/ProposedRevisions/Pages/proposedrevision.aspx?rid=460.These changes are still under review. In this article, we use the term POUD.

Table 1

Terminology related to prescription opioid use disorder

POUD and chronic pain

The incidence of POUD during opioid therapy for pain is unknown.⁶ Some researchers have suggested it may be as low as 0.2%,⁷ while others estimate that rates of POUD in patients with chronic pain may be similar to those in the general population: 3% to 16%.⁸ When applying the proposed DSM-5 criteria to patients receiving long-term opioid therapy for noncancer pain, the lifetime prevalence of POUD may be as high as 35%.⁹

Prescribers may be contributing to POUD. Roughly 76% of opioids used for nonmedical purposes were prescribed to someone else, 20% were prescribed to the user, and 4% came from other sources.¹ Strategies to reduce POUD risk may be underused. In a retrospective cohort study of 1,612 patient electronic medical records from 8 primary care clinics that managed patients with long-term opioids for chronic noncancer pain (average prescribing duration of 2 years duration, ≥3 monthly prescriptions in 6 months), researchers evaluated how often prescribers used 3 risk reduction practices:

• urine drug tests
• regular office visits (≥1 every 6 months and within 30 days of changing opioid treatment)
• restricted early refills (≤1 opioid refill more than a week early).¹⁰

Risk factors for opioid misuse included age 1 early refill. Researchers found that even for high-risk patients, these strategies were used infrequently. Less than one-quarter of patients with ≥3 risk factors ever had a drug test, and those at increased risk were more likely to receive >1 early refill but no more likely to have more frequent visits. Issues such as patient entitlement, lack of physician education, and time constraints may explain why these strategies are not used more often.¹¹

No one procedure or set of variables is sufficient to identify chronic pain patients who may be at risk for POUD. However, a history of drug or alcohol use disorders may be a significant risk factor.^12,13

Few tools have been developed to help identify those at risk of AMTBs or POUD, and all have limitations.^4,14 Recommended self-report measures include the Current Opioid Misuse Measure and the Opioid Risk Tool.¹⁵ A review of studies in which these kinds of tools were developed revealed limited evidence for their use; most studies had methodological shortcomings, did not use standardized AMTB criteria, and provided little assessment of whether these tools changed clinician behaviors or improved patient outcomes.¹⁶

Evaluating AMTBs

Although diagnosing POUD in pain patients receiving chronic opioids can be challenging, assessing for AMTBs typically is helpful. Once AMTBs are identified, they can be examined to determine what drives their expression (Table 1⁴ and Table 2¹⁷). However, often it is easier to identify AMTBs than to interpret their origins; as much as 30% to 50% of patients who complain of chronic pain may have primary substance dependence to sedatives, opioids, or both.¹¹

Table 2

Aberrant medication-taking behaviors and POUD risk

Although AMTBs are common among chronic nonmalignant pain patients,^18,19 how often AMTBs reflect underlying POUD is uncertain.⁷ It is critical to interpret AMTBs with a balance of caution and care: “react therapeutically, not punitively.”²⁰ Categorizing a patient’s AMTB as more or less likely to support a POUD diagnosis can be helpful, but is not conclusive (Table 2).¹⁷ Clinical correlation often is required. No single AMTB alone is indicative of POUD. When evaluating AMTBs, the treating provider should use a nonjudgmental stance, and consider obtaining collateral data from people who can provide differing perspectives of the patient’s behaviors, such as other clinicians, significant others, family, etc. (a release of information from the patient may be required). Another source of collateral data is prescription monitoring databases. These databases typically are state-based and provide electronic access to prescription information, allowing you to search for patterns—ie, use of multiple prescribers or pharmacies, undisclosed prescriptions, etc. Interest in establishing a single, federal database has been increasing, but striking a balance between carefully monitoring for AMTBs and protecting privacy remains unresolved.

DSM-IV-TR diagnostic criteria for opioid dependence²¹ can be challenging to interpret in patients who are prescribed opioids for pain (Table 3

Assessment is primarily clinical and requires an awareness of appropriate terminology, an index of clinical suspicion, and expertise teasing apart pain, addiction, and pseudoaddiction. In our experience, it is helpful to ask a chronic pain patient whom you suspect might have POUD, “Have you ever used your prescribed opioids for reasons other than improving function or reducing pain, such as for getting a ‘high,’ managing stress, escaping from problems, etc.?” An affirmative response suggests an underlying problem with use of prescribed opioids, indicating a need for more careful questioning to determine if AMTBs or POUD coexist with chronic pain.

Drug testing can help determine if a patient is taking opioids that are not prescribed—as well as illicit drugs or alcohol—and confirm the presence of those that are prescribed. Toxicology screening should include opioids typically screened for (eg, morphine, codeine, heroin) and those for which additional tests may be required (eg, semi-synthetics such as oxycodone and hydrocodone and synthetics such as fentanyl).

Table 3

Identifying addiction in pain patients: Limitations of DSM-IV-TR

Table 4

Possible indicators of addiction in pain patients

Helping POUD patients

Goals of treatment include establishing a therapeutic alliance, educating patients about POUD, reducing relapse risk, and optimizing overall health (including pain and physical function). The ASAM Patient Placement Criteria²² provide guidance regarding level-of-care decisions. Treatment ideally includes a combination of education about POUD and its relationship to chronic pain, pharmacotherapy, psychotherapy—such as motivational enhancement therapy, 12-step facilitation therapy, cognitive-behavioral therapy, and relapse prevention—and referral to self-help groups such as Narcotics Anonymous or Pills Anonymous. Importantly, if pain is genuine, it requires treatment.

Pharmacotherapy. Methadone is recommended as the standard of care for OUD by the National Institutes of Health. Methadone is a full opioid agonist that decreases illicit opioid use, mortality, and related problems and requires highly structured treatment approaches under federal and state regulation. POUD patients may have higher rates of methadone maintenance treatment retention than heroin-dependent patients.²³ Published trials of buprenorphine for OUD have shown good treatment retention and reduction in illicit drug use and adverse events.²⁴ Buprenorphine also decreases mortality among OUD patients.

The first large-scale, randomized clinical trial of buprenorphine specifically for POUD included 653 treatment-seeking outpatients.²⁵ This study was designed to approximate clinical practice and included buprenorphine/naloxone, recommended abstinence, and self-help; one-half of participants received intensive addiction counseling. POUD patients were most likely to reduce prescription opioid misuse during buprenorphine/naloxone treatment. If tapered off buprenorphine/naloxone, even after 12 weeks of treatment, the likelihood of an unsuccessful outcome was high. Moreover, opioid dependence counseling did not seem to afford any difference in outcomes. However, despite clinical effectiveness, over the last decade only 19% of patients admitted primarily for OUD treatment (other than heroin) were planned to be offered buprenorphine or methadone.²⁶

A Cochrane review of oral naltrexone for OUD found that the drug was no better than placebo but concluded that available evidence does not allow an adequate evaluation.²⁷ Opioid antagonists may be of value to patients who do not want to take agonists or partial agonists. Extended-release naltrexone also is available to treat OUD.

See the Box below that details steps the FDA and others have taken to prevent POUD and Table 5 for precautions to incorporate when prescribing opioids long-term.

Box

Table 5

Universal precautions with chronic opioid management

CASE CONTINUED: A closer evaluation

After expressing your appreciation for Mr. H’s kind words and empathy for his chronic pain, you redirect him to his PCP. You ask him to sign a release of information so you and his other clinicians can coordinate his care. When discussing Mr. H with his PCP, you learn the patient has made limited requests for early refills and dose escalation primarily in relation to inadequate pain control and function, has genuine pain pathology, and is greatly distressed over his inability to work. No other AMTBs are present, and a check of the state prescribing database reveals that Mr. H did receive a small quantity of opioids from an ED on 1 occasion.

You and Mr. H’s PCP agree this is “pseudo-addiction” but want to watch Mr. H more closely and look for ways to coordinate his care. The PCP agrees to implement a prescribing agreement, start drug testing (including for the prescribed opioids), and reassess maximizing Mr. H’s function and pain management while you address his combined pain, depression, insomnia, and tobacco use.

Related Resources

• Ries RK, Fiellin D, Miller SC, et al, eds. Principles of addiction medicine. 4th ed. Hagerstown, MD: Lippincott Williams & Wilkins; 2009.
• Department of Veterans Affairs. Department of Defense. VA/DoD clinical practice guideline for management of opioid therapy for chronic pain. Appendix C: sample opioid pain care agreement. http://www.healthquality.va.gov/COT_312_Full-er.pdf. Published May 2010. Accessed June 21, 2012.
• Weaver M, Schnoll S. Addiction issues in prescribing opioids for chronic non-malignant pain. J Addiction Med. 2007;1(1):2-10.
• Weaver M, Heit HA, Savage S, et al. Clinical case discussion: chronic pain management. J Addiction Med. 2007;1(1):11-14.

Drug Brand Names

• Buprenorphine • Subutex
• Buprenorphine/naloxone • Suboxone
• Codeine • Tylenol with codeine, others
• Fentanyl • Duragesic, Actiq
• Hydrocodone • Lortab, Vicodin, others
• Methadone • Dolophine, Methadose
• Morphine • Roxanol
• Naltrexone extended-release • Vivitrol
• Oxycodone • OxyContin, Roxicodone

Disclosures

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Frankowski’s time toward this project was provided by the American Board of Addiction Medicine-accredited Cincinnati VA Addiction Medicine Research Fellowship, affiliated with the CeTREAD, Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, OH.

The statements in this publication do not necessarily reflect the views or opinions of the Department of Veterans Affairs.

Acknowledgement

The authors thank Catherine Constance and Sandra Mason at the Cincinnati VA Medical Center for their administrative assistance.

Discuss this article at www.facebook.com/CurrentPsychiatry

You’ve been treating Mr. H, a 54-year-old factory worker and tobacco user, for depression that developed after a work-related back injury and subsequent disability. His depression has had a fair response to an antidepressant. He also has been maintained on chronic opioids (morphine and oxycodone/acetaminophen) for 18 months by his primary care physician (PCP). At the end of your appointment, he asks you for a refill of the opioids because he “ran out” early because of increased night pain and resultant insomnia and “stress.” He clarifies he has asked for early refills before from his PCP, but lately he has been denied. Because you “seem to listen to me more,” he asks for your help. How should you manage Mr. H?

Opioids are among the most commonly misused prescription drugs in the United States.¹ In 2008, poisoning was the leading cause of death from injury in the United States; roughly 90% of poisonings resulted from drug exposure, and >40% of these drug poisonings were from prescription opioids.² The Centers for Disease Control and Prevention estimates that the number of emergency department (ED) visits for nonmedical use of opioids increased 111% between 2004 and 2008, from 144,600 to 305,900 visits.³ The highest number of visits were for use of oxycodone, hydrocodone, and methadone.³

Increased prescribing of opioids and overdose deaths attributable to prescribed opioids have raised concern among physicians about how to effectively treat pain as well as prevent, recognize, and manage aberrant medication-taking behaviors (AMTBs). Psychiatrists are well-positioned to screen and manage their own patients for prescription opioid use disorder (POUD) or collaborate with opioid prescribers to accomplish the same.

Clarifying terminology

Terminology used to describe POUD and related conditions often is poorly defined or loosely applied. Because emotions often enter discussions between patients and physicians about problems related to opioid therapy, nonstigmatizing and more objective terminology is needed, and clinicians are working toward standardizing this. Relevant terms are defined in Table 1.⁴

The DSM-5 Substance Use Disorders Work Group has proposed using the term opioid use disorder (OUD) to replace the term opioid dependence.⁵ The hope is that removing the word “dependence” from the diagnostic term will reduce confusion between “dependence” due to expected physical dependence (tolerance, withdrawal) on medically prescribed opioids vs true addiction (currently defined as “opioid dependence” in DSM-IV-TR). This Work Group also has proposed combining opioid abuse and opioid dependence criteria into a single diagnosis of OUD, and adding “craving” to the criteria. For the complete proposed criteria, see www.dsm5.org/ProposedRevisions/Pages/proposedrevision.aspx?rid=460.These changes are still under review. In this article, we use the term POUD.

Table 1

Terminology related to prescription opioid use disorder

POUD and chronic pain

The incidence of POUD during opioid therapy for pain is unknown.⁶ Some researchers have suggested it may be as low as 0.2%,⁷ while others estimate that rates of POUD in patients with chronic pain may be similar to those in the general population: 3% to 16%.⁸ When applying the proposed DSM-5 criteria to patients receiving long-term opioid therapy for noncancer pain, the lifetime prevalence of POUD may be as high as 35%.⁹

Prescribers may be contributing to POUD. Roughly 76% of opioids used for nonmedical purposes were prescribed to someone else, 20% were prescribed to the user, and 4% came from other sources.¹ Strategies to reduce POUD risk may be underused. In a retrospective cohort study of 1,612 patient electronic medical records from 8 primary care clinics that managed patients with long-term opioids for chronic noncancer pain (average prescribing duration of 2 years duration, ≥3 monthly prescriptions in 6 months), researchers evaluated how often prescribers used 3 risk reduction practices:

• urine drug tests
• regular office visits (≥1 every 6 months and within 30 days of changing opioid treatment)
• restricted early refills (≤1 opioid refill more than a week early).¹⁰

Risk factors for opioid misuse included age 1 early refill. Researchers found that even for high-risk patients, these strategies were used infrequently. Less than one-quarter of patients with ≥3 risk factors ever had a drug test, and those at increased risk were more likely to receive >1 early refill but no more likely to have more frequent visits. Issues such as patient entitlement, lack of physician education, and time constraints may explain why these strategies are not used more often.¹¹

No one procedure or set of variables is sufficient to identify chronic pain patients who may be at risk for POUD. However, a history of drug or alcohol use disorders may be a significant risk factor.^12,13

Few tools have been developed to help identify those at risk of AMTBs or POUD, and all have limitations.^4,14 Recommended self-report measures include the Current Opioid Misuse Measure and the Opioid Risk Tool.¹⁵ A review of studies in which these kinds of tools were developed revealed limited evidence for their use; most studies had methodological shortcomings, did not use standardized AMTB criteria, and provided little assessment of whether these tools changed clinician behaviors or improved patient outcomes.¹⁶

Evaluating AMTBs

Although diagnosing POUD in pain patients receiving chronic opioids can be challenging, assessing for AMTBs typically is helpful. Once AMTBs are identified, they can be examined to determine what drives their expression (Table 1⁴ and Table 2¹⁷). However, often it is easier to identify AMTBs than to interpret their origins; as much as 30% to 50% of patients who complain of chronic pain may have primary substance dependence to sedatives, opioids, or both.¹¹

Table 2

Aberrant medication-taking behaviors and POUD risk

Although AMTBs are common among chronic nonmalignant pain patients,^18,19 how often AMTBs reflect underlying POUD is uncertain.⁷ It is critical to interpret AMTBs with a balance of caution and care: “react therapeutically, not punitively.”²⁰ Categorizing a patient’s AMTB as more or less likely to support a POUD diagnosis can be helpful, but is not conclusive (Table 2).¹⁷ Clinical correlation often is required. No single AMTB alone is indicative of POUD. When evaluating AMTBs, the treating provider should use a nonjudgmental stance, and consider obtaining collateral data from people who can provide differing perspectives of the patient’s behaviors, such as other clinicians, significant others, family, etc. (a release of information from the patient may be required). Another source of collateral data is prescription monitoring databases. These databases typically are state-based and provide electronic access to prescription information, allowing you to search for patterns—ie, use of multiple prescribers or pharmacies, undisclosed prescriptions, etc. Interest in establishing a single, federal database has been increasing, but striking a balance between carefully monitoring for AMTBs and protecting privacy remains unresolved.

DSM-IV-TR diagnostic criteria for opioid dependence²¹ can be challenging to interpret in patients who are prescribed opioids for pain (Table 3

Assessment is primarily clinical and requires an awareness of appropriate terminology, an index of clinical suspicion, and expertise teasing apart pain, addiction, and pseudoaddiction. In our experience, it is helpful to ask a chronic pain patient whom you suspect might have POUD, “Have you ever used your prescribed opioids for reasons other than improving function or reducing pain, such as for getting a ‘high,’ managing stress, escaping from problems, etc.?” An affirmative response suggests an underlying problem with use of prescribed opioids, indicating a need for more careful questioning to determine if AMTBs or POUD coexist with chronic pain.

Drug testing can help determine if a patient is taking opioids that are not prescribed—as well as illicit drugs or alcohol—and confirm the presence of those that are prescribed. Toxicology screening should include opioids typically screened for (eg, morphine, codeine, heroin) and those for which additional tests may be required (eg, semi-synthetics such as oxycodone and hydrocodone and synthetics such as fentanyl).

Table 3

Identifying addiction in pain patients: Limitations of DSM-IV-TR

Table 4

Possible indicators of addiction in pain patients

Helping POUD patients

Goals of treatment include establishing a therapeutic alliance, educating patients about POUD, reducing relapse risk, and optimizing overall health (including pain and physical function). The ASAM Patient Placement Criteria²² provide guidance regarding level-of-care decisions. Treatment ideally includes a combination of education about POUD and its relationship to chronic pain, pharmacotherapy, psychotherapy—such as motivational enhancement therapy, 12-step facilitation therapy, cognitive-behavioral therapy, and relapse prevention—and referral to self-help groups such as Narcotics Anonymous or Pills Anonymous. Importantly, if pain is genuine, it requires treatment.

Pharmacotherapy. Methadone is recommended as the standard of care for OUD by the National Institutes of Health. Methadone is a full opioid agonist that decreases illicit opioid use, mortality, and related problems and requires highly structured treatment approaches under federal and state regulation. POUD patients may have higher rates of methadone maintenance treatment retention than heroin-dependent patients.²³ Published trials of buprenorphine for OUD have shown good treatment retention and reduction in illicit drug use and adverse events.²⁴ Buprenorphine also decreases mortality among OUD patients.

The first large-scale, randomized clinical trial of buprenorphine specifically for POUD included 653 treatment-seeking outpatients.²⁵ This study was designed to approximate clinical practice and included buprenorphine/naloxone, recommended abstinence, and self-help; one-half of participants received intensive addiction counseling. POUD patients were most likely to reduce prescription opioid misuse during buprenorphine/naloxone treatment. If tapered off buprenorphine/naloxone, even after 12 weeks of treatment, the likelihood of an unsuccessful outcome was high. Moreover, opioid dependence counseling did not seem to afford any difference in outcomes. However, despite clinical effectiveness, over the last decade only 19% of patients admitted primarily for OUD treatment (other than heroin) were planned to be offered buprenorphine or methadone.²⁶

A Cochrane review of oral naltrexone for OUD found that the drug was no better than placebo but concluded that available evidence does not allow an adequate evaluation.²⁷ Opioid antagonists may be of value to patients who do not want to take agonists or partial agonists. Extended-release naltrexone also is available to treat OUD.

See the Box below that details steps the FDA and others have taken to prevent POUD and Table 5 for precautions to incorporate when prescribing opioids long-term.

Box

Table 5

Universal precautions with chronic opioid management

CASE CONTINUED: A closer evaluation

After expressing your appreciation for Mr. H’s kind words and empathy for his chronic pain, you redirect him to his PCP. You ask him to sign a release of information so you and his other clinicians can coordinate his care. When discussing Mr. H with his PCP, you learn the patient has made limited requests for early refills and dose escalation primarily in relation to inadequate pain control and function, has genuine pain pathology, and is greatly distressed over his inability to work. No other AMTBs are present, and a check of the state prescribing database reveals that Mr. H did receive a small quantity of opioids from an ED on 1 occasion.

You and Mr. H’s PCP agree this is “pseudo-addiction” but want to watch Mr. H more closely and look for ways to coordinate his care. The PCP agrees to implement a prescribing agreement, start drug testing (including for the prescribed opioids), and reassess maximizing Mr. H’s function and pain management while you address his combined pain, depression, insomnia, and tobacco use.

Related Resources

• Ries RK, Fiellin D, Miller SC, et al, eds. Principles of addiction medicine. 4th ed. Hagerstown, MD: Lippincott Williams & Wilkins; 2009.
• Department of Veterans Affairs. Department of Defense. VA/DoD clinical practice guideline for management of opioid therapy for chronic pain. Appendix C: sample opioid pain care agreement. http://www.healthquality.va.gov/COT_312_Full-er.pdf. Published May 2010. Accessed June 21, 2012.
• Weaver M, Schnoll S. Addiction issues in prescribing opioids for chronic non-malignant pain. J Addiction Med. 2007;1(1):2-10.
• Weaver M, Heit HA, Savage S, et al. Clinical case discussion: chronic pain management. J Addiction Med. 2007;1(1):11-14.

Drug Brand Names

• Buprenorphine • Subutex
• Buprenorphine/naloxone • Suboxone
• Codeine • Tylenol with codeine, others
• Fentanyl • Duragesic, Actiq
• Hydrocodone • Lortab, Vicodin, others
• Methadone • Dolophine, Methadose
• Morphine • Roxanol
• Naltrexone extended-release • Vivitrol
• Oxycodone • OxyContin, Roxicodone

Disclosures

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Frankowski’s time toward this project was provided by the American Board of Addiction Medicine-accredited Cincinnati VA Addiction Medicine Research Fellowship, affiliated with the CeTREAD, Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, OH.

The statements in this publication do not necessarily reflect the views or opinions of the Department of Veterans Affairs.

Acknowledgement

The authors thank Catherine Constance and Sandra Mason at the Cincinnati VA Medical Center for their administrative assistance.

Discuss this article at www.facebook.com/CurrentPsychiatry

The rate of off-label prescribing of second-generation antipsychotics (SGAs) is estimated to have doubled in the past decade.^1,2 In 2010, quetiapine was the most commonly used SGA in the United States with >10 million prescriptions dispensed.² Clinical experience and reports from patients indicate quetiapine may be useful for treating anxiety. When making medication choices, it can be useful to combine anecdotal evidence with the facts (or lack thereof). Does evidence support or contradict the use of quetiapine for anxiety?

What the research shows

Quetiapine is FDA-approved for treating:

• adults and adolescents with schizophrenia
• adults, children, and adolescents with acute manic episodes associated with bipolar I disorder (BDI) as monotherapy or as an adjunct to lithium or divalproex
• adults with an acute depressive episode associated with bipolar disorder
• adjunctive treatment of major depressive disorder (MDD) in adults
• maintenance treatment of BDI as an adjunct to lithium or divalproex in adults.³

In addition, quetiapine extended-release (XR) is approved as an adjunctive treatment for MDD in adults.⁴

Neither the immediate-release or XR formulation is indicated for treating anxiety, but quetiapine has been studied as a treatment for several anxiety disorders, including posttraumatic stress disorder, social phobia, obsessive-compulsive disorder, and anxiety secondary to mood disorders. It has been most extensively studied as treatment for generalized anxiety disorder (GAD).

Three trials that involved >2,100 patients found quetiapine XR monotherapy is effective for GAD in doses of 50 to 300 mg/d.^5-7 In 2 of the studies, quetiapine XR was as effective as paroxetine and escitalopram for GAD.^5,6 Reviews of off-label SGA use have found that compared with placebo, quetiapine XR monotherapy is effective for GAD (number needed to treat=8).^8,9 Side effects reported in clinical trials of quetiapine included headache, somnolence, sedation, fatigue, dizziness, dry mouth, weight gain, hyperlipidemia, and elevated glucose levels.

What did the FDA say?

In April 2009, the FDA’s Psychopharmacologic Drugs Advisory Committee reviewed whether evidence supported quetiapine XR for treating MDD and GAD.¹⁰ Although the committee found that quetiapine XR monotherapy effectively treated GAD, it concluded it was not acceptably safe.¹¹ The committee expressed concerns over exposing a greatly expanded population to a drug with substantial metabolic side effects, including weight gain (incidence 3% to 23%), increased cholesterol (incidence 7% to 18%), and hyperglycemia.^12-14 Weight gain and metabolic effects have been reported even when quetiapine is prescribed at low doses (≤100 mg/d).^15,16 The FDA did not approve expanding the indication of quetiapine XR to include treatment of GAD.

Our opinion

Quetiapine XR is effective for treating GAD. However, even at low doses, it is associated with substantial side effects and should be reserved for patients with poor response or contraindications (eg, mania) to traditional GAD treatments such as selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors. Published studies assessed quetiapine XR only when used on a scheduled basis, and did not address use of quetiapine immediate release or XR on an as-needed basis for GAD.

Related Resources

• AstraZeneca. Seroquel prescribing information. www1.astrazeneca-us.com/pi/seroquel.pdf.
• AstraZeneca. Seroquel XR prescribing information. www1.astrazeneca-us.com/pi/seroquelxr.pdf.

Drug Brand Names

• Divalproex • Depakote
• Paroxetine • Paxil
• Escitalopram • Lexapro
• Quetiapine • Seroquel
• Lithium • Eskalith, Lithobid

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Discuss this article at www.facebook.com/CurrentPsychiatry

The rate of off-label prescribing of second-generation antipsychotics (SGAs) is estimated to have doubled in the past decade.^1,2 In 2010, quetiapine was the most commonly used SGA in the United States with >10 million prescriptions dispensed.² Clinical experience and reports from patients indicate quetiapine may be useful for treating anxiety. When making medication choices, it can be useful to combine anecdotal evidence with the facts (or lack thereof). Does evidence support or contradict the use of quetiapine for anxiety?

What the research shows

Quetiapine is FDA-approved for treating:

• adults and adolescents with schizophrenia
• adults, children, and adolescents with acute manic episodes associated with bipolar I disorder (BDI) as monotherapy or as an adjunct to lithium or divalproex
• adults with an acute depressive episode associated with bipolar disorder
• adjunctive treatment of major depressive disorder (MDD) in adults
• maintenance treatment of BDI as an adjunct to lithium or divalproex in adults.³

In addition, quetiapine extended-release (XR) is approved as an adjunctive treatment for MDD in adults.⁴

Neither the immediate-release or XR formulation is indicated for treating anxiety, but quetiapine has been studied as a treatment for several anxiety disorders, including posttraumatic stress disorder, social phobia, obsessive-compulsive disorder, and anxiety secondary to mood disorders. It has been most extensively studied as treatment for generalized anxiety disorder (GAD).

Three trials that involved >2,100 patients found quetiapine XR monotherapy is effective for GAD in doses of 50 to 300 mg/d.^5-7 In 2 of the studies, quetiapine XR was as effective as paroxetine and escitalopram for GAD.^5,6 Reviews of off-label SGA use have found that compared with placebo, quetiapine XR monotherapy is effective for GAD (number needed to treat=8).^8,9 Side effects reported in clinical trials of quetiapine included headache, somnolence, sedation, fatigue, dizziness, dry mouth, weight gain, hyperlipidemia, and elevated glucose levels.

What did the FDA say?

In April 2009, the FDA’s Psychopharmacologic Drugs Advisory Committee reviewed whether evidence supported quetiapine XR for treating MDD and GAD.¹⁰ Although the committee found that quetiapine XR monotherapy effectively treated GAD, it concluded it was not acceptably safe.¹¹ The committee expressed concerns over exposing a greatly expanded population to a drug with substantial metabolic side effects, including weight gain (incidence 3% to 23%), increased cholesterol (incidence 7% to 18%), and hyperglycemia.^12-14 Weight gain and metabolic effects have been reported even when quetiapine is prescribed at low doses (≤100 mg/d).^15,16 The FDA did not approve expanding the indication of quetiapine XR to include treatment of GAD.

Our opinion

Quetiapine XR is effective for treating GAD. However, even at low doses, it is associated with substantial side effects and should be reserved for patients with poor response or contraindications (eg, mania) to traditional GAD treatments such as selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors. Published studies assessed quetiapine XR only when used on a scheduled basis, and did not address use of quetiapine immediate release or XR on an as-needed basis for GAD.

Related Resources

• AstraZeneca. Seroquel prescribing information. www1.astrazeneca-us.com/pi/seroquel.pdf.
• AstraZeneca. Seroquel XR prescribing information. www1.astrazeneca-us.com/pi/seroquelxr.pdf.

Drug Brand Names

• Divalproex • Depakote
• Paroxetine • Paxil
• Escitalopram • Lexapro
• Quetiapine • Seroquel
• Lithium • Eskalith, Lithobid

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Discuss this article at www.facebook.com/CurrentPsychiatry

The rate of off-label prescribing of second-generation antipsychotics (SGAs) is estimated to have doubled in the past decade.^1,2 In 2010, quetiapine was the most commonly used SGA in the United States with >10 million prescriptions dispensed.² Clinical experience and reports from patients indicate quetiapine may be useful for treating anxiety. When making medication choices, it can be useful to combine anecdotal evidence with the facts (or lack thereof). Does evidence support or contradict the use of quetiapine for anxiety?

What the research shows

Quetiapine is FDA-approved for treating:

• adults and adolescents with schizophrenia
• adults, children, and adolescents with acute manic episodes associated with bipolar I disorder (BDI) as monotherapy or as an adjunct to lithium or divalproex
• adults with an acute depressive episode associated with bipolar disorder
• adjunctive treatment of major depressive disorder (MDD) in adults
• maintenance treatment of BDI as an adjunct to lithium or divalproex in adults.³

In addition, quetiapine extended-release (XR) is approved as an adjunctive treatment for MDD in adults.⁴

Neither the immediate-release or XR formulation is indicated for treating anxiety, but quetiapine has been studied as a treatment for several anxiety disorders, including posttraumatic stress disorder, social phobia, obsessive-compulsive disorder, and anxiety secondary to mood disorders. It has been most extensively studied as treatment for generalized anxiety disorder (GAD).

Three trials that involved >2,100 patients found quetiapine XR monotherapy is effective for GAD in doses of 50 to 300 mg/d.^5-7 In 2 of the studies, quetiapine XR was as effective as paroxetine and escitalopram for GAD.^5,6 Reviews of off-label SGA use have found that compared with placebo, quetiapine XR monotherapy is effective for GAD (number needed to treat=8).^8,9 Side effects reported in clinical trials of quetiapine included headache, somnolence, sedation, fatigue, dizziness, dry mouth, weight gain, hyperlipidemia, and elevated glucose levels.

What did the FDA say?

In April 2009, the FDA’s Psychopharmacologic Drugs Advisory Committee reviewed whether evidence supported quetiapine XR for treating MDD and GAD.¹⁰ Although the committee found that quetiapine XR monotherapy effectively treated GAD, it concluded it was not acceptably safe.¹¹ The committee expressed concerns over exposing a greatly expanded population to a drug with substantial metabolic side effects, including weight gain (incidence 3% to 23%), increased cholesterol (incidence 7% to 18%), and hyperglycemia.^12-14 Weight gain and metabolic effects have been reported even when quetiapine is prescribed at low doses (≤100 mg/d).^15,16 The FDA did not approve expanding the indication of quetiapine XR to include treatment of GAD.

Our opinion

Quetiapine XR is effective for treating GAD. However, even at low doses, it is associated with substantial side effects and should be reserved for patients with poor response or contraindications (eg, mania) to traditional GAD treatments such as selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors. Published studies assessed quetiapine XR only when used on a scheduled basis, and did not address use of quetiapine immediate release or XR on an as-needed basis for GAD.

Related Resources

• AstraZeneca. Seroquel prescribing information. www1.astrazeneca-us.com/pi/seroquel.pdf.
• AstraZeneca. Seroquel XR prescribing information. www1.astrazeneca-us.com/pi/seroquelxr.pdf.

Drug Brand Names

• Divalproex • Depakote
• Paroxetine • Paxil
• Escitalopram • Lexapro
• Quetiapine • Seroquel
• Lithium • Eskalith, Lithobid

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

The Advisory Committee on Immunization Practices (ACIP) is evaluating whether to recommend the use of meningococcal vaccines for infants and children <2 years.¹ The decision may be made within the next 4 to 8 months. In its deliberation, ACIP must consider several issues, which I review here.

Current and impending vaccine options. Two quadrivalent meningococcal conjugate vaccines (MCV4) are licensed by the US Food and Drug Administration (FDA) for use in the United States: Men ACWY-CRM (Menveo, Novartis) and Men ACWY-D (Menactra, Sanofi Pasteur).² Both vaccines protect against 4 meningococcal serogroups (A, C, Y, and W-135) and are approved for use among those ages 2 to 55 years. In addition, Menactra was recently licensed as a 2-dose series for children ages 9 to 23 months. ACIP recommends routine use of MCV4 for adolescents ages 11 to 18 years, with a preference for the first dose at ages 11 to 12 years; and for all individuals between the ages of 2 and 55 years who are at increased risk for meningococcal disease ( TABLE ).

Complicating matters is the pending availability of more formulations. In addition to the 2-dose Menactra option for children 9 to 23 months, Novartis has an application before the FDA for a 4-dose schedule with Menveo, given at ages 2, 4, 6, and 12 months. GlaxoSmithKline has just received approval from the FDA for MenHibrix, a combination vaccine that contains antigens against Haemophilus influenzae type b (Hib) and 2 meningococcal serogroups, C and Y, licensed as a 4-dose series given at ages 2, 4, 6, and 12 months.

These vaccines have proven to be immunogenic in infants without diminishing the effectiveness of other, co-administered vaccines in normal infant populations. They also appear to be safe, although the studies to date have not been sufficiently large to detect uncommon adverse events.^3-7

Table
Patients at high risk for meningococcal disease

Meningococcal disease incidence and prevalence are declining

One major consideration for ACIP is the changing epidemiology of meningococcal disease and the low prevalence of disease in all age groups, including infants. The incidence of meningococcal disease has declined in the United States since 1980, with a marked and sustained decline since 2000 ( FIGURE 1 ).⁸ This decline has occurred in all age groups including infants, who have the highest rate of infection ( FIGURE 2 ).⁸ This decline in incidence occurred for all serogroups, including serogroup B.⁸

Serogroup B. Among children <5 years, including infants, half of meningococcal disease is caused by serogroup B,⁸ and these infections would not be prevented by any of the currently licensed vaccines or by those under review. Furthermore, half of all infections occur before age 9 months⁸ —an age range for which Menactra in not approved.

Serogroup C and Y. One-third of infections with serogroups C and Y occur before the age of 6 months⁸ and would not be prevented by any of the new products. Also of note: From 2007 to 2009, the mean number of cases of serotype A or C infection occurring each year in children <5 years was 77.⁸

The impact on children vs adults. Meningococcal disease in children is generally less severe than that occurring in older age groups. Overall case fatality in children is 6%; 10% in those with serogroup B and 1% in those with serogroup Y.⁸ The disease in children does result in significant sequelae, however, with 10% suffering hearing loss and 1% to 2% requiring amputation. From 2007 to 2009, there were 4 to 8 deaths per year among children under age 5, and 8 to 12 children per year experienced serious sequelae.⁸

FIGURE 1
The incidence of meningococcal disease has declined steadily since 2000⁸

FIGURE 2
Meningococcal disease has declined among infants and other age groups⁸

ACIP’s dilemma

The low morbidity and mortality associated with meningococcal disease is one issue to consider when deciding whether to recommend new vaccines as part of the routine infant and child immunization schedule. The vaccine schedule is already crowded and complex, and parents increasingly are questioning the need for additional antigens.

In addition, the cost of vaccines for children has escalated over the past decade due mainly to the new, more expensive formulations.

The reason for a declining incidence of meningococcal disease is not fully known. It may be partly explained by increasing rates of vaccination among adolescents. However, the overall low rate of disease in the population makes assessing herd immunity difficult.

If ACIP decides to recommend vaccinating infants against meningococcal disease, it is unclear how long immunity will last, potentially necessitating a booster dose before the currently recommended adolescent dose.

Finally, in children at high risk, it is not fully known how meningococcal vaccines will affect the immune response to pneumococcal conjugate vaccine. This is an important consideration because the incidence of pneumococcal disease among these children is much higher than that of meningococcal disease.

The Advisory Committee on Immunization Practices (ACIP) is evaluating whether to recommend the use of meningococcal vaccines for infants and children <2 years.¹ The decision may be made within the next 4 to 8 months. In its deliberation, ACIP must consider several issues, which I review here.

Current and impending vaccine options. Two quadrivalent meningococcal conjugate vaccines (MCV4) are licensed by the US Food and Drug Administration (FDA) for use in the United States: Men ACWY-CRM (Menveo, Novartis) and Men ACWY-D (Menactra, Sanofi Pasteur).² Both vaccines protect against 4 meningococcal serogroups (A, C, Y, and W-135) and are approved for use among those ages 2 to 55 years. In addition, Menactra was recently licensed as a 2-dose series for children ages 9 to 23 months. ACIP recommends routine use of MCV4 for adolescents ages 11 to 18 years, with a preference for the first dose at ages 11 to 12 years; and for all individuals between the ages of 2 and 55 years who are at increased risk for meningococcal disease ( TABLE ).

Complicating matters is the pending availability of more formulations. In addition to the 2-dose Menactra option for children 9 to 23 months, Novartis has an application before the FDA for a 4-dose schedule with Menveo, given at ages 2, 4, 6, and 12 months. GlaxoSmithKline has just received approval from the FDA for MenHibrix, a combination vaccine that contains antigens against Haemophilus influenzae type b (Hib) and 2 meningococcal serogroups, C and Y, licensed as a 4-dose series given at ages 2, 4, 6, and 12 months.

These vaccines have proven to be immunogenic in infants without diminishing the effectiveness of other, co-administered vaccines in normal infant populations. They also appear to be safe, although the studies to date have not been sufficiently large to detect uncommon adverse events.^3-7

Table
Patients at high risk for meningococcal disease

Meningococcal disease incidence and prevalence are declining

One major consideration for ACIP is the changing epidemiology of meningococcal disease and the low prevalence of disease in all age groups, including infants. The incidence of meningococcal disease has declined in the United States since 1980, with a marked and sustained decline since 2000 ( FIGURE 1 ).⁸ This decline has occurred in all age groups including infants, who have the highest rate of infection ( FIGURE 2 ).⁸ This decline in incidence occurred for all serogroups, including serogroup B.⁸

Serogroup B. Among children <5 years, including infants, half of meningococcal disease is caused by serogroup B,⁸ and these infections would not be prevented by any of the currently licensed vaccines or by those under review. Furthermore, half of all infections occur before age 9 months⁸ —an age range for which Menactra in not approved.

Serogroup C and Y. One-third of infections with serogroups C and Y occur before the age of 6 months⁸ and would not be prevented by any of the new products. Also of note: From 2007 to 2009, the mean number of cases of serotype A or C infection occurring each year in children <5 years was 77.⁸

The impact on children vs adults. Meningococcal disease in children is generally less severe than that occurring in older age groups. Overall case fatality in children is 6%; 10% in those with serogroup B and 1% in those with serogroup Y.⁸ The disease in children does result in significant sequelae, however, with 10% suffering hearing loss and 1% to 2% requiring amputation. From 2007 to 2009, there were 4 to 8 deaths per year among children under age 5, and 8 to 12 children per year experienced serious sequelae.⁸

FIGURE 1
The incidence of meningococcal disease has declined steadily since 2000⁸

FIGURE 2
Meningococcal disease has declined among infants and other age groups⁸

ACIP’s dilemma

The low morbidity and mortality associated with meningococcal disease is one issue to consider when deciding whether to recommend new vaccines as part of the routine infant and child immunization schedule. The vaccine schedule is already crowded and complex, and parents increasingly are questioning the need for additional antigens.

In addition, the cost of vaccines for children has escalated over the past decade due mainly to the new, more expensive formulations.

The reason for a declining incidence of meningococcal disease is not fully known. It may be partly explained by increasing rates of vaccination among adolescents. However, the overall low rate of disease in the population makes assessing herd immunity difficult.

If ACIP decides to recommend vaccinating infants against meningococcal disease, it is unclear how long immunity will last, potentially necessitating a booster dose before the currently recommended adolescent dose.

Finally, in children at high risk, it is not fully known how meningococcal vaccines will affect the immune response to pneumococcal conjugate vaccine. This is an important consideration because the incidence of pneumococcal disease among these children is much higher than that of meningococcal disease.

The Advisory Committee on Immunization Practices (ACIP) is evaluating whether to recommend the use of meningococcal vaccines for infants and children <2 years.¹ The decision may be made within the next 4 to 8 months. In its deliberation, ACIP must consider several issues, which I review here.

Current and impending vaccine options. Two quadrivalent meningococcal conjugate vaccines (MCV4) are licensed by the US Food and Drug Administration (FDA) for use in the United States: Men ACWY-CRM (Menveo, Novartis) and Men ACWY-D (Menactra, Sanofi Pasteur).² Both vaccines protect against 4 meningococcal serogroups (A, C, Y, and W-135) and are approved for use among those ages 2 to 55 years. In addition, Menactra was recently licensed as a 2-dose series for children ages 9 to 23 months. ACIP recommends routine use of MCV4 for adolescents ages 11 to 18 years, with a preference for the first dose at ages 11 to 12 years; and for all individuals between the ages of 2 and 55 years who are at increased risk for meningococcal disease ( TABLE ).

Complicating matters is the pending availability of more formulations. In addition to the 2-dose Menactra option for children 9 to 23 months, Novartis has an application before the FDA for a 4-dose schedule with Menveo, given at ages 2, 4, 6, and 12 months. GlaxoSmithKline has just received approval from the FDA for MenHibrix, a combination vaccine that contains antigens against Haemophilus influenzae type b (Hib) and 2 meningococcal serogroups, C and Y, licensed as a 4-dose series given at ages 2, 4, 6, and 12 months.

These vaccines have proven to be immunogenic in infants without diminishing the effectiveness of other, co-administered vaccines in normal infant populations. They also appear to be safe, although the studies to date have not been sufficiently large to detect uncommon adverse events.^3-7

Table
Patients at high risk for meningococcal disease

Meningococcal disease incidence and prevalence are declining

One major consideration for ACIP is the changing epidemiology of meningococcal disease and the low prevalence of disease in all age groups, including infants. The incidence of meningococcal disease has declined in the United States since 1980, with a marked and sustained decline since 2000 ( FIGURE 1 ).⁸ This decline has occurred in all age groups including infants, who have the highest rate of infection ( FIGURE 2 ).⁸ This decline in incidence occurred for all serogroups, including serogroup B.⁸

Serogroup B. Among children <5 years, including infants, half of meningococcal disease is caused by serogroup B,⁸ and these infections would not be prevented by any of the currently licensed vaccines or by those under review. Furthermore, half of all infections occur before age 9 months⁸ —an age range for which Menactra in not approved.

Serogroup C and Y. One-third of infections with serogroups C and Y occur before the age of 6 months⁸ and would not be prevented by any of the new products. Also of note: From 2007 to 2009, the mean number of cases of serotype A or C infection occurring each year in children <5 years was 77.⁸

The impact on children vs adults. Meningococcal disease in children is generally less severe than that occurring in older age groups. Overall case fatality in children is 6%; 10% in those with serogroup B and 1% in those with serogroup Y.⁸ The disease in children does result in significant sequelae, however, with 10% suffering hearing loss and 1% to 2% requiring amputation. From 2007 to 2009, there were 4 to 8 deaths per year among children under age 5, and 8 to 12 children per year experienced serious sequelae.⁸

FIGURE 1
The incidence of meningococcal disease has declined steadily since 2000⁸

FIGURE 2
Meningococcal disease has declined among infants and other age groups⁸

ACIP’s dilemma

The low morbidity and mortality associated with meningococcal disease is one issue to consider when deciding whether to recommend new vaccines as part of the routine infant and child immunization schedule. The vaccine schedule is already crowded and complex, and parents increasingly are questioning the need for additional antigens.

In addition, the cost of vaccines for children has escalated over the past decade due mainly to the new, more expensive formulations.

The reason for a declining incidence of meningococcal disease is not fully known. It may be partly explained by increasing rates of vaccination among adolescents. However, the overall low rate of disease in the population makes assessing herd immunity difficult.

If ACIP decides to recommend vaccinating infants against meningococcal disease, it is unclear how long immunity will last, potentially necessitating a booster dose before the currently recommended adolescent dose.

Finally, in children at high risk, it is not fully known how meningococcal vaccines will affect the immune response to pneumococcal conjugate vaccine. This is an important consideration because the incidence of pneumococcal disease among these children is much higher than that of meningococcal disease.