CHICAGO – Adding an experimental immune-enhancing agent to a checkpoint inhibitor was safe and showed early promise of activity against advanced solid tumors in a phase I/IIa clinical trial.

BMS-986156 is a fully human immunoglobulin G1 agonist monoclonal antibody with high affinity binding for the glucorticoid-induced tumor necrosis factor receptor-related gene. The drug acts synergistically with the programmed-death 1 inhibitor (PD-1) nivolumab (Opdivo) by increasing survival of T effector cells, promoting regulatory T-cell depletion and reduction, and reducing regulatory T cell suppression of T effector cells to produce a more robust antitumor immune response.

In this video interview at the annual meeting of the American Society of Clinical Oncology, Lillian Siu, MD, from the Princess Margaret Hospital, Toronto, describes how the combination has induced durable partial responses in patients with tumors thought to be insensitive to immunotherapy, as well as patients who had disease progression while on a PD-1 inhibitor.

CHICAGO – Adding an experimental immune-enhancing agent to a checkpoint inhibitor was safe and showed early promise of activity against advanced solid tumors in a phase I/IIa clinical trial.

BMS-986156 is a fully human immunoglobulin G1 agonist monoclonal antibody with high affinity binding for the glucorticoid-induced tumor necrosis factor receptor-related gene. The drug acts synergistically with the programmed-death 1 inhibitor (PD-1) nivolumab (Opdivo) by increasing survival of T effector cells, promoting regulatory T-cell depletion and reduction, and reducing regulatory T cell suppression of T effector cells to produce a more robust antitumor immune response.

In this video interview at the annual meeting of the American Society of Clinical Oncology, Lillian Siu, MD, from the Princess Margaret Hospital, Toronto, describes how the combination has induced durable partial responses in patients with tumors thought to be insensitive to immunotherapy, as well as patients who had disease progression while on a PD-1 inhibitor.

CHICAGO – Adding an experimental immune-enhancing agent to a checkpoint inhibitor was safe and showed early promise of activity against advanced solid tumors in a phase I/IIa clinical trial.

BMS-986156 is a fully human immunoglobulin G1 agonist monoclonal antibody with high affinity binding for the glucorticoid-induced tumor necrosis factor receptor-related gene. The drug acts synergistically with the programmed-death 1 inhibitor (PD-1) nivolumab (Opdivo) by increasing survival of T effector cells, promoting regulatory T-cell depletion and reduction, and reducing regulatory T cell suppression of T effector cells to produce a more robust antitumor immune response.

In this video interview at the annual meeting of the American Society of Clinical Oncology, Lillian Siu, MD, from the Princess Margaret Hospital, Toronto, describes how the combination has induced durable partial responses in patients with tumors thought to be insensitive to immunotherapy, as well as patients who had disease progression while on a PD-1 inhibitor.

Bob Wachter, MD, created buzz in March 2016 when, at the SHM annual meeting in San Diego, he displayed a slide titled “What did we get wrong?” The slide contained the copy, “Hospitalist shifts run 7 a.m.-7 p.m.; 10 a.m.-10 p.m. 7on/7off” circled in bold red.

Over the last several years, thought leaders in the hospital medicine field have expressed concern that this one-size-fits-all schedule model is a threat to the well-being of many physicians and, by extension, the sustainability of their hospital medicine groups. Despite this, the 2016 State of Hospital Medicine Report reveals relatively little change in the way hospital medicine groups schedule their physicians.

Dr. Eisenstock, MD, FHM, is clinical chief, division of hospital medicine, at the University of Massachusetts Memorial Health Care, Worcester.

Bob Wachter, MD, created buzz in March 2016 when, at the SHM annual meeting in San Diego, he displayed a slide titled “What did we get wrong?” The slide contained the copy, “Hospitalist shifts run 7 a.m.-7 p.m.; 10 a.m.-10 p.m. 7on/7off” circled in bold red.

Over the last several years, thought leaders in the hospital medicine field have expressed concern that this one-size-fits-all schedule model is a threat to the well-being of many physicians and, by extension, the sustainability of their hospital medicine groups. Despite this, the 2016 State of Hospital Medicine Report reveals relatively little change in the way hospital medicine groups schedule their physicians.

Dr. Eisenstock, MD, FHM, is clinical chief, division of hospital medicine, at the University of Massachusetts Memorial Health Care, Worcester.

Bob Wachter, MD, created buzz in March 2016 when, at the SHM annual meeting in San Diego, he displayed a slide titled “What did we get wrong?” The slide contained the copy, “Hospitalist shifts run 7 a.m.-7 p.m.; 10 a.m.-10 p.m. 7on/7off” circled in bold red.

Over the last several years, thought leaders in the hospital medicine field have expressed concern that this one-size-fits-all schedule model is a threat to the well-being of many physicians and, by extension, the sustainability of their hospital medicine groups. Despite this, the 2016 State of Hospital Medicine Report reveals relatively little change in the way hospital medicine groups schedule their physicians.

Dr. Eisenstock, MD, FHM, is clinical chief, division of hospital medicine, at the University of Massachusetts Memorial Health Care, Worcester.

PARIS – Undetected diabetes and prediabetes are pervasive in patients undergoing percutaneous coronary intervention, and they’re associated with a sharply increased risk of major adverse cardiovascular events, according to the results of the potentially practice-changing BIO-RESORT Silent Diabetes Study, Clemens von Birgelen, MD, PhD, reported at the annual congress of the European Association of Percutaneous Cardiovascular Interventions.

“Our data support screening PCI all-comers for silent diabetes, which may help identify patients with an increased event risk and improve their therapy,” said Dr. von Birgelen, professor of cardiology at the Thoraxcentrum of Twente, a high-volume center for cardiac interventions in Enschede, the Netherlands.

Bruce Jancin/Frontline Medical News

[email protected]

PARIS – Undetected diabetes and prediabetes are pervasive in patients undergoing percutaneous coronary intervention, and they’re associated with a sharply increased risk of major adverse cardiovascular events, according to the results of the potentially practice-changing BIO-RESORT Silent Diabetes Study, Clemens von Birgelen, MD, PhD, reported at the annual congress of the European Association of Percutaneous Cardiovascular Interventions.

“Our data support screening PCI all-comers for silent diabetes, which may help identify patients with an increased event risk and improve their therapy,” said Dr. von Birgelen, professor of cardiology at the Thoraxcentrum of Twente, a high-volume center for cardiac interventions in Enschede, the Netherlands.

Bruce Jancin/Frontline Medical News

[email protected]

PARIS – Undetected diabetes and prediabetes are pervasive in patients undergoing percutaneous coronary intervention, and they’re associated with a sharply increased risk of major adverse cardiovascular events, according to the results of the potentially practice-changing BIO-RESORT Silent Diabetes Study, Clemens von Birgelen, MD, PhD, reported at the annual congress of the European Association of Percutaneous Cardiovascular Interventions.

“Our data support screening PCI all-comers for silent diabetes, which may help identify patients with an increased event risk and improve their therapy,” said Dr. von Birgelen, professor of cardiology at the Thoraxcentrum of Twente, a high-volume center for cardiac interventions in Enschede, the Netherlands.

Bruce Jancin/Frontline Medical News

[email protected]

The use of opioids to treat chronic noncancer pain (CNCP) has become increasingly common over the previous 2 decades. The Office of National Drug Control Policy (ONDCP) reported that from 1997 to 2007, there was a 4-fold increase in the mg per person per year sale of prescription opioids, from 74 mg to 369 mg.¹ The number of opioid prescriptions dispensed by pharmacies also has increased by 48% from 2000 to 2009.² Within the VA population, about half of the 1.44 million patients with a diagnosis of pain (excluding cancer pain) received opioids during 2011, and 57% of these patients received chronic opioid therapy (COT), which is at least 90 days of opioid use in a year.³

Despite this increased use of opioids, data regarding the efficacy of long-term opioid use for noncancer pain remain limited.^1,4-8 Instead, there is a growing body of evidence describing potential adverse effects (AEs) of long-term opioid use at even relatively modest doses, including sexual dysfunction, hyperalgesia, and altered brain structure.^9-11 Additionally, increases in the misuse and abuse of opioids as well as mortality associated with opioid toxicity have been observed.^12-14 Opioid pain relievers were involved in nearly 17,000 deaths in the U.S. in 2010, which represents a 3-fold increase since 1999. This number also represents 75% of all deaths that were attributed to prescription drug poisoning in 2010.¹³ Unfortunately, this alarming trend parallels the aforementioned increases in the utilization of prescription opioids for CNCP.

Given this accumulating data regarding the profound risks and limited benefit of COT, many organizations have advocated a reassessment of the upward trajectory of opioid utilization. In 2009, the American Pain Society (APS) in partnership with the American Academy of Pain Medicine (AAPM) released clinical guidelines for the use of COT in CNCP.⁶ In this guideline, the authors advocate a balanced approach to opioid use: Clinicians consider both the legitimate medical need for opioids in some patients with CNCP as well as the serious public health problem of abuse, addiction, and diversion.⁶ In 2011, the FDA, Drug Enforcement Agency (DEA), and ONDCP enacted the Prescription Drug Abuse Prevention Plan, which focused on 4 major areas: education, prescription monitoring, proper medication disposal, and law enforcement.⁴

In March 2016, the CDC released a new guideline for prescribing opioids for chronic pain that included 12 recommendations based on 3 key principles. First, nonopioids are preferred for chronic pain in all settings except for active cancer, palliative, and end-of-life care. Next, when opioids are used for chronic pain, they always should be prescribed at the lowest possible effective dose to reduce the risk of opioid use disorder and overdose. Finally, clinicians should exercise caution when prescribing opioids and monitor all patients closely for opioid-related risk.¹⁵

Recently, an August 2016 FDA review found that the combined use of opioids and benzodiazepines (BZDs) resulted in serious AEs, including respiratory depression and death. Based on these findings, the FDA requires that updated boxed warnings be added to the labeling of prescription opioid and BZDs.¹⁶

The VHA also has been at the forefront of this national movement to promote the appropriate use of opioids. In 2009, the VHA released a pain management directive that highlighted the risks of COT and required adoption of a stepped-care approach to opioid prescribing that focused on quality of life as the primary determinant of treatment quality.¹⁷ In 2010, the VHA released its guideline on opioid therapy for chronic pain, which also included tools for providers, such as a sample opioid therapy agreement, equivalent potency tables, and a urine drug screening guide.¹⁸ In 2014, the VHA released the Opioid Safety Initiative (OSI), which advocates for a team-based approach to reduce the use of opioids for veterans through a focus on alternate methods to alleviate pain.

At the Ralph H. Johnson VAMC (RHJVAMC) in Charleston, South Carolina, a multidisciplinary pain oversight committee (POC) was tasked with assisting in achieving the goals set forth in the VHA OSI. To reach these goals, the POC sought to develop and implement a population-based initiative targeting modifiable factors that are known to increase the risk of opioid-related toxicity and overdose. These factors included patient utilization of multiple prescribers or multiple pharmacies, high-dose COT (defined in the APS/AAPM guidelines as a morphine equivalent daily dose [MEDD] > 200 mg⁶), and use of concomitant central nervous system-active medications, chiefly BZDs.^19-23 The POC consisted of the RHJVAMC chiefs of mental health, primary care, and pharmacy; a physician specializing in pain and addiction medicine; a pharmacist specializing in pain and palliative care; quality management personnel; a patient advocate; and multiple physicians from the mental health and primary care departments.

Previous studies have described the successful implementation of opioid management initiatives in a variety of health care settings.^2,21,24-27 However, most of this work focused only on strategies to decrease prescribing of high-dose and long-acting opioid formulations. The study presented here sought to add to the existing body of knowledge through evaluation of an initiative aimed at increasing appropriate monitoring as a tool to decrease opioid-related patient risk. The primary aim of this study was to describe the types of interventions implemented by the POC during the study period. The secondary aim was to evaluate the effect of these interventions on the appropriate monitoring of COT as well as the appropriate management of high-risk COT > 200 mg MEDD.

Methods

This study involved a qualitative description of individual POC interventions as well as a retrospective data analysis that examined the clinical impact of these interventions during the study period from April 1, 2012 to September 30, 2015. This study was reviewed and approved by the Medical University of South Carolina Institutional Review Board and the RHJVAMC Research and Development Committee.

Setting

The RHJVAMC is a tertiary care teaching hospital with primary and specialized outpatient services that are provided at the main medical center in Charleston, South Carolina, and at 6 community-based outpatient clinics (CBOCs) located throughout southeastern South Carolina and parts of Georgia. Primary care is delivered by patient aligned care teams (PACTs) based on the patient-centered medical home model.²⁸ The PACT consists of a primary care provider (PCP) who is aided by dedicated nursing, pharmacy, and mental health care providers. In most cases, COT is prescribed and managed in the PACT setting. At the time of this initiative, a broad range of specialty services were available, including a multidisciplinary pain management team, orthopedics, and physical medicine and rehabilitation. In 2012, about 55,000 patients were enrolled and received care at RHJVAMC. The POC interventions were carried out at all clinic sites.

Patients

The study population included all patients prescribed COT at RHJVAMC during the study period. A patient was considered to be prescribed COT if at least 1 opioid-containing medication was dispensed to the patient in a selected fiscal quarter during the study period and the total cumulative supply of opioid-containing medications was ≥ 90 days for both the selected quarter and the prior quarter.

Furthermore, a high-risk COT subpopulation included any patient who satisfied either of the following criteria: (1) Receipt of outpatient prescription(s) for opioid-containing medication(s) (including tramadol) and a benzodiazepine derivative in the same fiscal quarter; patients were included in this subpopulation regardless of whether they met COT criteria; (2) Receipt of outpatient prescription(s) for opioid-containing medication(s) with at least 1 instance in which the MEDD was ≥ 200 mg in the designated quarter (Table 1). The MEDD was calculated for each fill in the fiscal quarter using the following equation:

If medication fills were within 3 days of each other, the prescriptions were considered to be taken together and the MEDD was summed. 

Intervention Descriptions

The primary aim of this study was to qualitatively describe each intervention implemented by the POC. The POC monthly meeting minutes were recorded and reviewed for the study period, and descriptive information regarding each intervention was extracted. Extracted information included implementation date(s), the responsible POC member, and a general description of each intervention. Interventions were then categorized as informatics tool, targeted patient intervention, provider education, or patient education.

Impact of Interventions on Monitoring

In order to characterize the impact of POC interventions on appropriate monitoring of COT, the electronic medical record (EMR) of each patient satisfying COT criteria was queried for the presence of an annual urine drug screen (UDS) result and a note in the chart signaling that a prescription drug monitoring program (PDMP) review had been performed. The authors defined appropriate UDS monitoring and PDMP review as the presence of a UDS result and a PDMP review note in the EMR in the year prior to the query date.

Prior to the start of the POC interventions, 4.1% of RJVAMC patients had an annual PDMP review and 47.8% had an annual UDS. Although more frequent UDS results and PDMP reviews are appropriate in most cases, yearly monitoring was considered by the POC to be a reasonable initial goal. The percentage of veterans receiving COT who had received appropriate monitoring for each measure was collected for each fiscal quarter during the study period. In addition, the difference between the initial and final fiscal quarter during the study period was calculated for each measure.

Impact of Interventions on High-Risk Opioid Prescribing

To assess the impact of POC interventions on appropriate management of high-dose COT, clinical variables were collected for patients who were prescribed high-dose COT and received targeted intervention in the form of a pain clinic e-consult. These variables were MEDD, presence of annual UDS, presence of annual PDMP review, and active BZD prescription. Each variable was assessed on the date of intervention (e-consult submission) and at 6 months postintervention. Changes in each clinical variable between baseline and at 6 months postintervention were then evaluated.

Data Sources

All patient data were obtained from the VHA Corporate Data Warehouse (CDW). The CDW contains extracts from VHA clinical and administrative systems that contain complete clinical data from October 1999 to the present. Population-level data were obtained from the Opioid Safety Initiative Master Dashboard National Report where available. Data not contained in this national dashboard were obtained through local data extractions from the CDW.

Informatics Tool

In September 2014, an e-consult tool was created to enable PCPs to efficiently consult the RHJVAMC pain clinic for advice on opioid-related issues in patients who require specialized attention. On activation of this EMR-based tool, the following patient data autopopulated in the consult: recent and active opioid prescription(s), UDS data from the previous 365 days, and PDMP review data from the previous 365 days. The consulting provider was then required to enter data on concomitant mental health disorders that were deemed pertinent to opioid safety as well as obstructive sleep apnea (OSA) status (OSA diagnosis and continuous positive airway pressure machine receipt and adherence).

The consulting provider was required to indicate whether the patient had an active BZD prescription. If yes, a text field allowed the provider to enter the specific agent(s) prescribed and dose(s). Data were required in all fields for the e-consult to be considered ready for pain clinic review. Common pain clinic recommendations included orders for additional laboratory tests to assess adherence and potential toxicity, drug tapers, and consideration for complementary and alternative medicine (CAM). If a drug taper was recommended (either opioid or BZD), specific taper schedules would be provided by a pharmacist specializing in pain management.

Targeted Patient Intervention

In April 2014, the POC and Mental Health service began a targeted review of all outpatients receiving combination opioid and BZD therapy. First, the POC distributed to each mental health provider a list of patients who were receiving combination opioid and BZD therapy. An opioid/BZD combination risk assessment tool (Table 2) was developed by the POC and made available to assist with these patient reviews. This tool prompted a provider to assess a patient’s stability on the current regimen as well as the presence of any absolute or relative contraindications to concomitant BZD and opioid use. Providers documented whether a discussion regarding the risks and benefits of opioids and BZDs had occurred with the patient. The tool encouraged providers to document a continued indication for combined BZD and opioid therapy use and whether the lowest effective BZD dose was being prescribed. A standardized BZD taper protocol also was developed by the POC to assist providers if a BZD taper was indicated. A total of 222 patients were reviewed over 7 months from April 2014 to October 2015.

Following completion of this targeted review in October 2015, the POC required that starting any patients on opioid and BZD combination therapy would require a specialist consult. For existing COT patients, a mental health consult would be required to initiate BZD therapy. For stable patients on BZD therapy, a pain clinic consult was required before initiating an opioid prescription. The Pharmacy service acted as a gatekeeper for these agents and refused to dispense either new agent until the proper consults had been submitted unless clinical necessity of an agent was apparent (ie, opioid prescription following invasive surgery).

The final targeted patient intervention occurred following deployment of the opioid safety review e-consult tool in September 2015. To review the highest risk COT patients, each PCP was given a list of their patients who were taking ≥ 200 mg MEDD. With support from the primary care service chief, PCPs were required to submit an e-consult for every patient who did not meet the e-consult exclusion criteria. In the fourth quarter of fiscal year (FY) 2014, and first quarter of FY 2015, 116 RHJVAMC patients received ≥ 200 mg MEDD with 49 meeting the exclusion criteria. Of the 67 patients eligible for pain clinic review, e-consults were placed for 58 patients over a 7-month period. The remaining 9 patients did not receive an e-consult because taper was initiated by the patient’s PCP without pain clinic assistance (6), aberrant patient behavior was identified during data collection (2), and patient was transitioned to palliative care (1).

Provider Education

A primary goal of the POC was to educate PCPs on opioid safety, to ensure that each provider was able to use evidence-based medicine and identify potential high-risk situations during patient encounters. Provider education was delivered by physician and pharmacist pain specialists and took place from September 2013 to January 2015 at existing primary care meetings. Topics included UDS interpretation, opioid/BZD combination risks, the goals and requirements of the VA OSI, and legal requirements of the South Carolina Reporting and Identification Prescription Tracking System (SCRIPTS) PDMP.

Patient Education

Patient education was delivered through informational brochures either mailed or given out during clinic visits. The first brochure was mailed to patients and described the VA OSI goals and its potential impact on patients. A second handout described the risks associated with opioid/BZD combination therapy and encouraged patients to discuss these risks and alternate options with their providers. It was made available to primary care and mental health teams for distribution to patients.

Results

Interventions spanned 19 months, with an average of 1 intervention per month. The highest number of POC interventions in a single month was observed in October 2014, with 3 individual interventions from 3 separate categories.

Impact of POC Interventions on COT Monitoring

During the study period, patients meeting COT criteria who received an annual UDS increased from 47.8% to 75.5%, a 56.7% increase from baseline (Figure 1). During the same period, patients with an annual PDMP review note in their medical record also increased from 4.1% to 19.6%, a 324% increase from baseline (Figure 2). Although the study period began in FY 2012 third quarter, FY 2014 first quarter was the baseline for PDMP review note data collection because VA providers were not legally allowed to access the SCRIPTS database prior to FY 2014.

Impact of Interventions on High-Risk Opioid Prescribing

Patients who received an opioid prescription and a BZD derivative in the same fiscal quarter decreased 41.7% during the study period (Figure 3). A significant improvement was observed in each clinical variable at 6 months postintervention among high-dose COT patients who received an opioid safety review e-consult (Table 3). The median opioid dose per patient decreased 20% from baseline, from 300 mg MEDD to 240 mg MEDD. The number of patients with an annual UDS increased 31.7% from 41 to 54 patients. The number of patients with an annual PDMP review also increased 345%, from 11 patients to 49 patients. Finally, the number of patients with an active BZD order decreased > 75% from 17 patients at baseline to 4 patients at 6-month follow-up.

In the FY 2014 third quarter, prior to activation of the opioid safety review e-consult tool, 100 patients received high-dose COT. Follow-up at the conclusion of fourth quarter FY 2015 revealed 64 such patients, which represented a 36% decrease from baseline.

Discussion

During the study period, the POC used a variety of interventions from 4 distinct categories. Overall, these interventions successfully increased measures of appropriate COT monitoring (ie, UDS and PDMP utilization) and management of high-risk COT. Substantial improvements also were seen in the subgroup of patients receiving high-dose COT following creation and use of the opioid safety review e-consult tool.

Other VHA opioid management improvement initiatives were successful at reducing high-dose opioid prescribing through interventions similar to those described in this study. However, these initiatives did not address opioid monitoring practices or opioid/BZD combination therapy.^25,26 To the authors’ knowledge, no previous opioid management improvement initiatives have reported improvements in provider use of a state PDMP database.

There are a number of factors that also may have helped lead to the successful outcomes observed during the study period. First, the creation of an informatics tool allowed for sustained interventions over time. While targeted interventions and patient/provider education were certainly beneficial, the impact of these efforts wanes as time moves forward. Inevitably, a patient’s and a provider’s focus move to the next important issue, and new patients meet the criteria of the original targeted intervention.

Group Health Cooperative implemented an opioid risk reduction initiative that successfully increased UDS use over a 2-year postimplementation period.^21,26 While this initiative used a number of similar interventions to those implemented in this study (patient and provider education, targeted patient intervention), an informatics tool was not used. The annual UDS rate at the conclusion of the Group Health initiative was 50%, which contrasts with a final rate of 75.5% in this study. Although it is difficult to draw comparisons between the studies given differences in populations studied, periods of evaluation, and varying baseline annual UDS rates, the current study results demonstrate the potential effectiveness of informatics tools to help drive enduring changes in practice.

An additional factor that had a positive impact on outcomes the continued support and advocacy from RHJVAMC clinical and administrative leadership. A targeted review of all patients receiving concomitant BZDs and opioids would not be possible without mental health department leaders who believed in the value of the time consuming undertaking. Furthermore, an e-consult tool is effective only if actually submitted for patients and if a specialist’s recommendations are then followed by a PCP.

Finally, the interdisciplinary nature of the POC contributed to the success of each intervention described in this study. Patients receiving COT often have many complex physical, psychological, and social issues that must be considered in order to make a positive impact on patient care. To appropriately and effectively address these issues requires close collaboration between specialists from multiple disciplines.

Limitations

This study has several important limitations. First, its retrospective nature presents obvious documentation challenges. A second limitation is the brief period of evaluation following a number of POC interventions. For instance, 3 interventions took place in January 2015, leaving only 3 FY quarters of effectiveness data. Furthermore, increased awareness of the risks associated with opioid therapy in the VHA and the health care industry across the study period may have independently impacted the improvements observed in this study.

The lack of an assessment of both patient-centered and clinical outcomes is an additional limitation of this study. Rates of annual UDS and PDMP database reviews and the number of patients receiving high-risk COT are only surrogate metrics that may indicate appropriate prescribing and monitoring of these. Obtaining a UDS or PDMP review is meant to provide a practitioner with additional information to interpret when caring for a patient. These data are only meant to complement—not replace—skilled patient assessment by a provider. Although the authors observed no major patient or clinical adverse events during the study period, the possibility exists that a patient may have been negatively impacted by a population-level initiative to improve surrogate measures of appropriate drug use.

Future studies should assess changes in measures, such as pain scores, legitimate adverse events, and overdose occurrences in order to evaluate whether such opioid improvement initiatives truly benefit the patients who are ultimately affected by each intervention.

Conclusion

This study demonstrates the successful implementation of a VHA-based opioid management initiative to increase appropriate COT monitoring and appropriate management of high-risk patients. It is the authors’ hope that the findings may add to the growing body of literature describing successful opioid improvement initiatives and serve as a tool for other health systems that are confronted with these same issues.

The use of opioids to treat chronic noncancer pain (CNCP) has become increasingly common over the previous 2 decades. The Office of National Drug Control Policy (ONDCP) reported that from 1997 to 2007, there was a 4-fold increase in the mg per person per year sale of prescription opioids, from 74 mg to 369 mg.¹ The number of opioid prescriptions dispensed by pharmacies also has increased by 48% from 2000 to 2009.² Within the VA population, about half of the 1.44 million patients with a diagnosis of pain (excluding cancer pain) received opioids during 2011, and 57% of these patients received chronic opioid therapy (COT), which is at least 90 days of opioid use in a year.³

Despite this increased use of opioids, data regarding the efficacy of long-term opioid use for noncancer pain remain limited.^1,4-8 Instead, there is a growing body of evidence describing potential adverse effects (AEs) of long-term opioid use at even relatively modest doses, including sexual dysfunction, hyperalgesia, and altered brain structure.^9-11 Additionally, increases in the misuse and abuse of opioids as well as mortality associated with opioid toxicity have been observed.^12-14 Opioid pain relievers were involved in nearly 17,000 deaths in the U.S. in 2010, which represents a 3-fold increase since 1999. This number also represents 75% of all deaths that were attributed to prescription drug poisoning in 2010.¹³ Unfortunately, this alarming trend parallels the aforementioned increases in the utilization of prescription opioids for CNCP.

Given this accumulating data regarding the profound risks and limited benefit of COT, many organizations have advocated a reassessment of the upward trajectory of opioid utilization. In 2009, the American Pain Society (APS) in partnership with the American Academy of Pain Medicine (AAPM) released clinical guidelines for the use of COT in CNCP.⁶ In this guideline, the authors advocate a balanced approach to opioid use: Clinicians consider both the legitimate medical need for opioids in some patients with CNCP as well as the serious public health problem of abuse, addiction, and diversion.⁶ In 2011, the FDA, Drug Enforcement Agency (DEA), and ONDCP enacted the Prescription Drug Abuse Prevention Plan, which focused on 4 major areas: education, prescription monitoring, proper medication disposal, and law enforcement.⁴

In March 2016, the CDC released a new guideline for prescribing opioids for chronic pain that included 12 recommendations based on 3 key principles. First, nonopioids are preferred for chronic pain in all settings except for active cancer, palliative, and end-of-life care. Next, when opioids are used for chronic pain, they always should be prescribed at the lowest possible effective dose to reduce the risk of opioid use disorder and overdose. Finally, clinicians should exercise caution when prescribing opioids and monitor all patients closely for opioid-related risk.¹⁵

Recently, an August 2016 FDA review found that the combined use of opioids and benzodiazepines (BZDs) resulted in serious AEs, including respiratory depression and death. Based on these findings, the FDA requires that updated boxed warnings be added to the labeling of prescription opioid and BZDs.¹⁶

The VHA also has been at the forefront of this national movement to promote the appropriate use of opioids. In 2009, the VHA released a pain management directive that highlighted the risks of COT and required adoption of a stepped-care approach to opioid prescribing that focused on quality of life as the primary determinant of treatment quality.¹⁷ In 2010, the VHA released its guideline on opioid therapy for chronic pain, which also included tools for providers, such as a sample opioid therapy agreement, equivalent potency tables, and a urine drug screening guide.¹⁸ In 2014, the VHA released the Opioid Safety Initiative (OSI), which advocates for a team-based approach to reduce the use of opioids for veterans through a focus on alternate methods to alleviate pain.

At the Ralph H. Johnson VAMC (RHJVAMC) in Charleston, South Carolina, a multidisciplinary pain oversight committee (POC) was tasked with assisting in achieving the goals set forth in the VHA OSI. To reach these goals, the POC sought to develop and implement a population-based initiative targeting modifiable factors that are known to increase the risk of opioid-related toxicity and overdose. These factors included patient utilization of multiple prescribers or multiple pharmacies, high-dose COT (defined in the APS/AAPM guidelines as a morphine equivalent daily dose [MEDD] > 200 mg⁶), and use of concomitant central nervous system-active medications, chiefly BZDs.^19-23 The POC consisted of the RHJVAMC chiefs of mental health, primary care, and pharmacy; a physician specializing in pain and addiction medicine; a pharmacist specializing in pain and palliative care; quality management personnel; a patient advocate; and multiple physicians from the mental health and primary care departments.

Previous studies have described the successful implementation of opioid management initiatives in a variety of health care settings.^2,21,24-27 However, most of this work focused only on strategies to decrease prescribing of high-dose and long-acting opioid formulations. The study presented here sought to add to the existing body of knowledge through evaluation of an initiative aimed at increasing appropriate monitoring as a tool to decrease opioid-related patient risk. The primary aim of this study was to describe the types of interventions implemented by the POC during the study period. The secondary aim was to evaluate the effect of these interventions on the appropriate monitoring of COT as well as the appropriate management of high-risk COT > 200 mg MEDD.

Methods

This study involved a qualitative description of individual POC interventions as well as a retrospective data analysis that examined the clinical impact of these interventions during the study period from April 1, 2012 to September 30, 2015. This study was reviewed and approved by the Medical University of South Carolina Institutional Review Board and the RHJVAMC Research and Development Committee.

Setting

The RHJVAMC is a tertiary care teaching hospital with primary and specialized outpatient services that are provided at the main medical center in Charleston, South Carolina, and at 6 community-based outpatient clinics (CBOCs) located throughout southeastern South Carolina and parts of Georgia. Primary care is delivered by patient aligned care teams (PACTs) based on the patient-centered medical home model.²⁸ The PACT consists of a primary care provider (PCP) who is aided by dedicated nursing, pharmacy, and mental health care providers. In most cases, COT is prescribed and managed in the PACT setting. At the time of this initiative, a broad range of specialty services were available, including a multidisciplinary pain management team, orthopedics, and physical medicine and rehabilitation. In 2012, about 55,000 patients were enrolled and received care at RHJVAMC. The POC interventions were carried out at all clinic sites.

Patients

The study population included all patients prescribed COT at RHJVAMC during the study period. A patient was considered to be prescribed COT if at least 1 opioid-containing medication was dispensed to the patient in a selected fiscal quarter during the study period and the total cumulative supply of opioid-containing medications was ≥ 90 days for both the selected quarter and the prior quarter.

Furthermore, a high-risk COT subpopulation included any patient who satisfied either of the following criteria: (1) Receipt of outpatient prescription(s) for opioid-containing medication(s) (including tramadol) and a benzodiazepine derivative in the same fiscal quarter; patients were included in this subpopulation regardless of whether they met COT criteria; (2) Receipt of outpatient prescription(s) for opioid-containing medication(s) with at least 1 instance in which the MEDD was ≥ 200 mg in the designated quarter (Table 1). The MEDD was calculated for each fill in the fiscal quarter using the following equation:

If medication fills were within 3 days of each other, the prescriptions were considered to be taken together and the MEDD was summed. 

Intervention Descriptions

The primary aim of this study was to qualitatively describe each intervention implemented by the POC. The POC monthly meeting minutes were recorded and reviewed for the study period, and descriptive information regarding each intervention was extracted. Extracted information included implementation date(s), the responsible POC member, and a general description of each intervention. Interventions were then categorized as informatics tool, targeted patient intervention, provider education, or patient education.

Impact of Interventions on Monitoring

In order to characterize the impact of POC interventions on appropriate monitoring of COT, the electronic medical record (EMR) of each patient satisfying COT criteria was queried for the presence of an annual urine drug screen (UDS) result and a note in the chart signaling that a prescription drug monitoring program (PDMP) review had been performed. The authors defined appropriate UDS monitoring and PDMP review as the presence of a UDS result and a PDMP review note in the EMR in the year prior to the query date.

Prior to the start of the POC interventions, 4.1% of RJVAMC patients had an annual PDMP review and 47.8% had an annual UDS. Although more frequent UDS results and PDMP reviews are appropriate in most cases, yearly monitoring was considered by the POC to be a reasonable initial goal. The percentage of veterans receiving COT who had received appropriate monitoring for each measure was collected for each fiscal quarter during the study period. In addition, the difference between the initial and final fiscal quarter during the study period was calculated for each measure.

Impact of Interventions on High-Risk Opioid Prescribing

To assess the impact of POC interventions on appropriate management of high-dose COT, clinical variables were collected for patients who were prescribed high-dose COT and received targeted intervention in the form of a pain clinic e-consult. These variables were MEDD, presence of annual UDS, presence of annual PDMP review, and active BZD prescription. Each variable was assessed on the date of intervention (e-consult submission) and at 6 months postintervention. Changes in each clinical variable between baseline and at 6 months postintervention were then evaluated.

Data Sources

All patient data were obtained from the VHA Corporate Data Warehouse (CDW). The CDW contains extracts from VHA clinical and administrative systems that contain complete clinical data from October 1999 to the present. Population-level data were obtained from the Opioid Safety Initiative Master Dashboard National Report where available. Data not contained in this national dashboard were obtained through local data extractions from the CDW.

Informatics Tool

In September 2014, an e-consult tool was created to enable PCPs to efficiently consult the RHJVAMC pain clinic for advice on opioid-related issues in patients who require specialized attention. On activation of this EMR-based tool, the following patient data autopopulated in the consult: recent and active opioid prescription(s), UDS data from the previous 365 days, and PDMP review data from the previous 365 days. The consulting provider was then required to enter data on concomitant mental health disorders that were deemed pertinent to opioid safety as well as obstructive sleep apnea (OSA) status (OSA diagnosis and continuous positive airway pressure machine receipt and adherence).

The consulting provider was required to indicate whether the patient had an active BZD prescription. If yes, a text field allowed the provider to enter the specific agent(s) prescribed and dose(s). Data were required in all fields for the e-consult to be considered ready for pain clinic review. Common pain clinic recommendations included orders for additional laboratory tests to assess adherence and potential toxicity, drug tapers, and consideration for complementary and alternative medicine (CAM). If a drug taper was recommended (either opioid or BZD), specific taper schedules would be provided by a pharmacist specializing in pain management.

Targeted Patient Intervention

In April 2014, the POC and Mental Health service began a targeted review of all outpatients receiving combination opioid and BZD therapy. First, the POC distributed to each mental health provider a list of patients who were receiving combination opioid and BZD therapy. An opioid/BZD combination risk assessment tool (Table 2) was developed by the POC and made available to assist with these patient reviews. This tool prompted a provider to assess a patient’s stability on the current regimen as well as the presence of any absolute or relative contraindications to concomitant BZD and opioid use. Providers documented whether a discussion regarding the risks and benefits of opioids and BZDs had occurred with the patient. The tool encouraged providers to document a continued indication for combined BZD and opioid therapy use and whether the lowest effective BZD dose was being prescribed. A standardized BZD taper protocol also was developed by the POC to assist providers if a BZD taper was indicated. A total of 222 patients were reviewed over 7 months from April 2014 to October 2015.

Following completion of this targeted review in October 2015, the POC required that starting any patients on opioid and BZD combination therapy would require a specialist consult. For existing COT patients, a mental health consult would be required to initiate BZD therapy. For stable patients on BZD therapy, a pain clinic consult was required before initiating an opioid prescription. The Pharmacy service acted as a gatekeeper for these agents and refused to dispense either new agent until the proper consults had been submitted unless clinical necessity of an agent was apparent (ie, opioid prescription following invasive surgery).

The final targeted patient intervention occurred following deployment of the opioid safety review e-consult tool in September 2015. To review the highest risk COT patients, each PCP was given a list of their patients who were taking ≥ 200 mg MEDD. With support from the primary care service chief, PCPs were required to submit an e-consult for every patient who did not meet the e-consult exclusion criteria. In the fourth quarter of fiscal year (FY) 2014, and first quarter of FY 2015, 116 RHJVAMC patients received ≥ 200 mg MEDD with 49 meeting the exclusion criteria. Of the 67 patients eligible for pain clinic review, e-consults were placed for 58 patients over a 7-month period. The remaining 9 patients did not receive an e-consult because taper was initiated by the patient’s PCP without pain clinic assistance (6), aberrant patient behavior was identified during data collection (2), and patient was transitioned to palliative care (1).

Provider Education

A primary goal of the POC was to educate PCPs on opioid safety, to ensure that each provider was able to use evidence-based medicine and identify potential high-risk situations during patient encounters. Provider education was delivered by physician and pharmacist pain specialists and took place from September 2013 to January 2015 at existing primary care meetings. Topics included UDS interpretation, opioid/BZD combination risks, the goals and requirements of the VA OSI, and legal requirements of the South Carolina Reporting and Identification Prescription Tracking System (SCRIPTS) PDMP.

Patient Education

Patient education was delivered through informational brochures either mailed or given out during clinic visits. The first brochure was mailed to patients and described the VA OSI goals and its potential impact on patients. A second handout described the risks associated with opioid/BZD combination therapy and encouraged patients to discuss these risks and alternate options with their providers. It was made available to primary care and mental health teams for distribution to patients.

Results

Interventions spanned 19 months, with an average of 1 intervention per month. The highest number of POC interventions in a single month was observed in October 2014, with 3 individual interventions from 3 separate categories.

Impact of POC Interventions on COT Monitoring

During the study period, patients meeting COT criteria who received an annual UDS increased from 47.8% to 75.5%, a 56.7% increase from baseline (Figure 1). During the same period, patients with an annual PDMP review note in their medical record also increased from 4.1% to 19.6%, a 324% increase from baseline (Figure 2). Although the study period began in FY 2012 third quarter, FY 2014 first quarter was the baseline for PDMP review note data collection because VA providers were not legally allowed to access the SCRIPTS database prior to FY 2014.

Impact of Interventions on High-Risk Opioid Prescribing

Patients who received an opioid prescription and a BZD derivative in the same fiscal quarter decreased 41.7% during the study period (Figure 3). A significant improvement was observed in each clinical variable at 6 months postintervention among high-dose COT patients who received an opioid safety review e-consult (Table 3). The median opioid dose per patient decreased 20% from baseline, from 300 mg MEDD to 240 mg MEDD. The number of patients with an annual UDS increased 31.7% from 41 to 54 patients. The number of patients with an annual PDMP review also increased 345%, from 11 patients to 49 patients. Finally, the number of patients with an active BZD order decreased > 75% from 17 patients at baseline to 4 patients at 6-month follow-up.

In the FY 2014 third quarter, prior to activation of the opioid safety review e-consult tool, 100 patients received high-dose COT. Follow-up at the conclusion of fourth quarter FY 2015 revealed 64 such patients, which represented a 36% decrease from baseline.

Discussion

During the study period, the POC used a variety of interventions from 4 distinct categories. Overall, these interventions successfully increased measures of appropriate COT monitoring (ie, UDS and PDMP utilization) and management of high-risk COT. Substantial improvements also were seen in the subgroup of patients receiving high-dose COT following creation and use of the opioid safety review e-consult tool.

Other VHA opioid management improvement initiatives were successful at reducing high-dose opioid prescribing through interventions similar to those described in this study. However, these initiatives did not address opioid monitoring practices or opioid/BZD combination therapy.^25,26 To the authors’ knowledge, no previous opioid management improvement initiatives have reported improvements in provider use of a state PDMP database.

There are a number of factors that also may have helped lead to the successful outcomes observed during the study period. First, the creation of an informatics tool allowed for sustained interventions over time. While targeted interventions and patient/provider education were certainly beneficial, the impact of these efforts wanes as time moves forward. Inevitably, a patient’s and a provider’s focus move to the next important issue, and new patients meet the criteria of the original targeted intervention.

Group Health Cooperative implemented an opioid risk reduction initiative that successfully increased UDS use over a 2-year postimplementation period.^21,26 While this initiative used a number of similar interventions to those implemented in this study (patient and provider education, targeted patient intervention), an informatics tool was not used. The annual UDS rate at the conclusion of the Group Health initiative was 50%, which contrasts with a final rate of 75.5% in this study. Although it is difficult to draw comparisons between the studies given differences in populations studied, periods of evaluation, and varying baseline annual UDS rates, the current study results demonstrate the potential effectiveness of informatics tools to help drive enduring changes in practice.

An additional factor that had a positive impact on outcomes the continued support and advocacy from RHJVAMC clinical and administrative leadership. A targeted review of all patients receiving concomitant BZDs and opioids would not be possible without mental health department leaders who believed in the value of the time consuming undertaking. Furthermore, an e-consult tool is effective only if actually submitted for patients and if a specialist’s recommendations are then followed by a PCP.

Finally, the interdisciplinary nature of the POC contributed to the success of each intervention described in this study. Patients receiving COT often have many complex physical, psychological, and social issues that must be considered in order to make a positive impact on patient care. To appropriately and effectively address these issues requires close collaboration between specialists from multiple disciplines.

Limitations

This study has several important limitations. First, its retrospective nature presents obvious documentation challenges. A second limitation is the brief period of evaluation following a number of POC interventions. For instance, 3 interventions took place in January 2015, leaving only 3 FY quarters of effectiveness data. Furthermore, increased awareness of the risks associated with opioid therapy in the VHA and the health care industry across the study period may have independently impacted the improvements observed in this study.

The lack of an assessment of both patient-centered and clinical outcomes is an additional limitation of this study. Rates of annual UDS and PDMP database reviews and the number of patients receiving high-risk COT are only surrogate metrics that may indicate appropriate prescribing and monitoring of these. Obtaining a UDS or PDMP review is meant to provide a practitioner with additional information to interpret when caring for a patient. These data are only meant to complement—not replace—skilled patient assessment by a provider. Although the authors observed no major patient or clinical adverse events during the study period, the possibility exists that a patient may have been negatively impacted by a population-level initiative to improve surrogate measures of appropriate drug use.

Future studies should assess changes in measures, such as pain scores, legitimate adverse events, and overdose occurrences in order to evaluate whether such opioid improvement initiatives truly benefit the patients who are ultimately affected by each intervention.

Conclusion

This study demonstrates the successful implementation of a VHA-based opioid management initiative to increase appropriate COT monitoring and appropriate management of high-risk patients. It is the authors’ hope that the findings may add to the growing body of literature describing successful opioid improvement initiatives and serve as a tool for other health systems that are confronted with these same issues.

The use of opioids to treat chronic noncancer pain (CNCP) has become increasingly common over the previous 2 decades. The Office of National Drug Control Policy (ONDCP) reported that from 1997 to 2007, there was a 4-fold increase in the mg per person per year sale of prescription opioids, from 74 mg to 369 mg.¹ The number of opioid prescriptions dispensed by pharmacies also has increased by 48% from 2000 to 2009.² Within the VA population, about half of the 1.44 million patients with a diagnosis of pain (excluding cancer pain) received opioids during 2011, and 57% of these patients received chronic opioid therapy (COT), which is at least 90 days of opioid use in a year.³

Despite this increased use of opioids, data regarding the efficacy of long-term opioid use for noncancer pain remain limited.^1,4-8 Instead, there is a growing body of evidence describing potential adverse effects (AEs) of long-term opioid use at even relatively modest doses, including sexual dysfunction, hyperalgesia, and altered brain structure.^9-11 Additionally, increases in the misuse and abuse of opioids as well as mortality associated with opioid toxicity have been observed.^12-14 Opioid pain relievers were involved in nearly 17,000 deaths in the U.S. in 2010, which represents a 3-fold increase since 1999. This number also represents 75% of all deaths that were attributed to prescription drug poisoning in 2010.¹³ Unfortunately, this alarming trend parallels the aforementioned increases in the utilization of prescription opioids for CNCP.

Given this accumulating data regarding the profound risks and limited benefit of COT, many organizations have advocated a reassessment of the upward trajectory of opioid utilization. In 2009, the American Pain Society (APS) in partnership with the American Academy of Pain Medicine (AAPM) released clinical guidelines for the use of COT in CNCP.⁶ In this guideline, the authors advocate a balanced approach to opioid use: Clinicians consider both the legitimate medical need for opioids in some patients with CNCP as well as the serious public health problem of abuse, addiction, and diversion.⁶ In 2011, the FDA, Drug Enforcement Agency (DEA), and ONDCP enacted the Prescription Drug Abuse Prevention Plan, which focused on 4 major areas: education, prescription monitoring, proper medication disposal, and law enforcement.⁴

In March 2016, the CDC released a new guideline for prescribing opioids for chronic pain that included 12 recommendations based on 3 key principles. First, nonopioids are preferred for chronic pain in all settings except for active cancer, palliative, and end-of-life care. Next, when opioids are used for chronic pain, they always should be prescribed at the lowest possible effective dose to reduce the risk of opioid use disorder and overdose. Finally, clinicians should exercise caution when prescribing opioids and monitor all patients closely for opioid-related risk.¹⁵

Recently, an August 2016 FDA review found that the combined use of opioids and benzodiazepines (BZDs) resulted in serious AEs, including respiratory depression and death. Based on these findings, the FDA requires that updated boxed warnings be added to the labeling of prescription opioid and BZDs.¹⁶

The VHA also has been at the forefront of this national movement to promote the appropriate use of opioids. In 2009, the VHA released a pain management directive that highlighted the risks of COT and required adoption of a stepped-care approach to opioid prescribing that focused on quality of life as the primary determinant of treatment quality.¹⁷ In 2010, the VHA released its guideline on opioid therapy for chronic pain, which also included tools for providers, such as a sample opioid therapy agreement, equivalent potency tables, and a urine drug screening guide.¹⁸ In 2014, the VHA released the Opioid Safety Initiative (OSI), which advocates for a team-based approach to reduce the use of opioids for veterans through a focus on alternate methods to alleviate pain.

At the Ralph H. Johnson VAMC (RHJVAMC) in Charleston, South Carolina, a multidisciplinary pain oversight committee (POC) was tasked with assisting in achieving the goals set forth in the VHA OSI. To reach these goals, the POC sought to develop and implement a population-based initiative targeting modifiable factors that are known to increase the risk of opioid-related toxicity and overdose. These factors included patient utilization of multiple prescribers or multiple pharmacies, high-dose COT (defined in the APS/AAPM guidelines as a morphine equivalent daily dose [MEDD] > 200 mg⁶), and use of concomitant central nervous system-active medications, chiefly BZDs.^19-23 The POC consisted of the RHJVAMC chiefs of mental health, primary care, and pharmacy; a physician specializing in pain and addiction medicine; a pharmacist specializing in pain and palliative care; quality management personnel; a patient advocate; and multiple physicians from the mental health and primary care departments.

Previous studies have described the successful implementation of opioid management initiatives in a variety of health care settings.^2,21,24-27 However, most of this work focused only on strategies to decrease prescribing of high-dose and long-acting opioid formulations. The study presented here sought to add to the existing body of knowledge through evaluation of an initiative aimed at increasing appropriate monitoring as a tool to decrease opioid-related patient risk. The primary aim of this study was to describe the types of interventions implemented by the POC during the study period. The secondary aim was to evaluate the effect of these interventions on the appropriate monitoring of COT as well as the appropriate management of high-risk COT > 200 mg MEDD.

Methods

This study involved a qualitative description of individual POC interventions as well as a retrospective data analysis that examined the clinical impact of these interventions during the study period from April 1, 2012 to September 30, 2015. This study was reviewed and approved by the Medical University of South Carolina Institutional Review Board and the RHJVAMC Research and Development Committee.

Setting

The RHJVAMC is a tertiary care teaching hospital with primary and specialized outpatient services that are provided at the main medical center in Charleston, South Carolina, and at 6 community-based outpatient clinics (CBOCs) located throughout southeastern South Carolina and parts of Georgia. Primary care is delivered by patient aligned care teams (PACTs) based on the patient-centered medical home model.²⁸ The PACT consists of a primary care provider (PCP) who is aided by dedicated nursing, pharmacy, and mental health care providers. In most cases, COT is prescribed and managed in the PACT setting. At the time of this initiative, a broad range of specialty services were available, including a multidisciplinary pain management team, orthopedics, and physical medicine and rehabilitation. In 2012, about 55,000 patients were enrolled and received care at RHJVAMC. The POC interventions were carried out at all clinic sites.

Patients

The study population included all patients prescribed COT at RHJVAMC during the study period. A patient was considered to be prescribed COT if at least 1 opioid-containing medication was dispensed to the patient in a selected fiscal quarter during the study period and the total cumulative supply of opioid-containing medications was ≥ 90 days for both the selected quarter and the prior quarter.

Furthermore, a high-risk COT subpopulation included any patient who satisfied either of the following criteria: (1) Receipt of outpatient prescription(s) for opioid-containing medication(s) (including tramadol) and a benzodiazepine derivative in the same fiscal quarter; patients were included in this subpopulation regardless of whether they met COT criteria; (2) Receipt of outpatient prescription(s) for opioid-containing medication(s) with at least 1 instance in which the MEDD was ≥ 200 mg in the designated quarter (Table 1). The MEDD was calculated for each fill in the fiscal quarter using the following equation:

If medication fills were within 3 days of each other, the prescriptions were considered to be taken together and the MEDD was summed. 

Intervention Descriptions

The primary aim of this study was to qualitatively describe each intervention implemented by the POC. The POC monthly meeting minutes were recorded and reviewed for the study period, and descriptive information regarding each intervention was extracted. Extracted information included implementation date(s), the responsible POC member, and a general description of each intervention. Interventions were then categorized as informatics tool, targeted patient intervention, provider education, or patient education.

Impact of Interventions on Monitoring

In order to characterize the impact of POC interventions on appropriate monitoring of COT, the electronic medical record (EMR) of each patient satisfying COT criteria was queried for the presence of an annual urine drug screen (UDS) result and a note in the chart signaling that a prescription drug monitoring program (PDMP) review had been performed. The authors defined appropriate UDS monitoring and PDMP review as the presence of a UDS result and a PDMP review note in the EMR in the year prior to the query date.

Prior to the start of the POC interventions, 4.1% of RJVAMC patients had an annual PDMP review and 47.8% had an annual UDS. Although more frequent UDS results and PDMP reviews are appropriate in most cases, yearly monitoring was considered by the POC to be a reasonable initial goal. The percentage of veterans receiving COT who had received appropriate monitoring for each measure was collected for each fiscal quarter during the study period. In addition, the difference between the initial and final fiscal quarter during the study period was calculated for each measure.

Impact of Interventions on High-Risk Opioid Prescribing

To assess the impact of POC interventions on appropriate management of high-dose COT, clinical variables were collected for patients who were prescribed high-dose COT and received targeted intervention in the form of a pain clinic e-consult. These variables were MEDD, presence of annual UDS, presence of annual PDMP review, and active BZD prescription. Each variable was assessed on the date of intervention (e-consult submission) and at 6 months postintervention. Changes in each clinical variable between baseline and at 6 months postintervention were then evaluated.

Data Sources

All patient data were obtained from the VHA Corporate Data Warehouse (CDW). The CDW contains extracts from VHA clinical and administrative systems that contain complete clinical data from October 1999 to the present. Population-level data were obtained from the Opioid Safety Initiative Master Dashboard National Report where available. Data not contained in this national dashboard were obtained through local data extractions from the CDW.

Informatics Tool

In September 2014, an e-consult tool was created to enable PCPs to efficiently consult the RHJVAMC pain clinic for advice on opioid-related issues in patients who require specialized attention. On activation of this EMR-based tool, the following patient data autopopulated in the consult: recent and active opioid prescription(s), UDS data from the previous 365 days, and PDMP review data from the previous 365 days. The consulting provider was then required to enter data on concomitant mental health disorders that were deemed pertinent to opioid safety as well as obstructive sleep apnea (OSA) status (OSA diagnosis and continuous positive airway pressure machine receipt and adherence).

The consulting provider was required to indicate whether the patient had an active BZD prescription. If yes, a text field allowed the provider to enter the specific agent(s) prescribed and dose(s). Data were required in all fields for the e-consult to be considered ready for pain clinic review. Common pain clinic recommendations included orders for additional laboratory tests to assess adherence and potential toxicity, drug tapers, and consideration for complementary and alternative medicine (CAM). If a drug taper was recommended (either opioid or BZD), specific taper schedules would be provided by a pharmacist specializing in pain management.

Targeted Patient Intervention

In April 2014, the POC and Mental Health service began a targeted review of all outpatients receiving combination opioid and BZD therapy. First, the POC distributed to each mental health provider a list of patients who were receiving combination opioid and BZD therapy. An opioid/BZD combination risk assessment tool (Table 2) was developed by the POC and made available to assist with these patient reviews. This tool prompted a provider to assess a patient’s stability on the current regimen as well as the presence of any absolute or relative contraindications to concomitant BZD and opioid use. Providers documented whether a discussion regarding the risks and benefits of opioids and BZDs had occurred with the patient. The tool encouraged providers to document a continued indication for combined BZD and opioid therapy use and whether the lowest effective BZD dose was being prescribed. A standardized BZD taper protocol also was developed by the POC to assist providers if a BZD taper was indicated. A total of 222 patients were reviewed over 7 months from April 2014 to October 2015.

Following completion of this targeted review in October 2015, the POC required that starting any patients on opioid and BZD combination therapy would require a specialist consult. For existing COT patients, a mental health consult would be required to initiate BZD therapy. For stable patients on BZD therapy, a pain clinic consult was required before initiating an opioid prescription. The Pharmacy service acted as a gatekeeper for these agents and refused to dispense either new agent until the proper consults had been submitted unless clinical necessity of an agent was apparent (ie, opioid prescription following invasive surgery).

The final targeted patient intervention occurred following deployment of the opioid safety review e-consult tool in September 2015. To review the highest risk COT patients, each PCP was given a list of their patients who were taking ≥ 200 mg MEDD. With support from the primary care service chief, PCPs were required to submit an e-consult for every patient who did not meet the e-consult exclusion criteria. In the fourth quarter of fiscal year (FY) 2014, and first quarter of FY 2015, 116 RHJVAMC patients received ≥ 200 mg MEDD with 49 meeting the exclusion criteria. Of the 67 patients eligible for pain clinic review, e-consults were placed for 58 patients over a 7-month period. The remaining 9 patients did not receive an e-consult because taper was initiated by the patient’s PCP without pain clinic assistance (6), aberrant patient behavior was identified during data collection (2), and patient was transitioned to palliative care (1).

Provider Education

A primary goal of the POC was to educate PCPs on opioid safety, to ensure that each provider was able to use evidence-based medicine and identify potential high-risk situations during patient encounters. Provider education was delivered by physician and pharmacist pain specialists and took place from September 2013 to January 2015 at existing primary care meetings. Topics included UDS interpretation, opioid/BZD combination risks, the goals and requirements of the VA OSI, and legal requirements of the South Carolina Reporting and Identification Prescription Tracking System (SCRIPTS) PDMP.

Patient Education

Patient education was delivered through informational brochures either mailed or given out during clinic visits. The first brochure was mailed to patients and described the VA OSI goals and its potential impact on patients. A second handout described the risks associated with opioid/BZD combination therapy and encouraged patients to discuss these risks and alternate options with their providers. It was made available to primary care and mental health teams for distribution to patients.

Results

Interventions spanned 19 months, with an average of 1 intervention per month. The highest number of POC interventions in a single month was observed in October 2014, with 3 individual interventions from 3 separate categories.

Impact of POC Interventions on COT Monitoring

During the study period, patients meeting COT criteria who received an annual UDS increased from 47.8% to 75.5%, a 56.7% increase from baseline (Figure 1). During the same period, patients with an annual PDMP review note in their medical record also increased from 4.1% to 19.6%, a 324% increase from baseline (Figure 2). Although the study period began in FY 2012 third quarter, FY 2014 first quarter was the baseline for PDMP review note data collection because VA providers were not legally allowed to access the SCRIPTS database prior to FY 2014.

Impact of Interventions on High-Risk Opioid Prescribing

Patients who received an opioid prescription and a BZD derivative in the same fiscal quarter decreased 41.7% during the study period (Figure 3). A significant improvement was observed in each clinical variable at 6 months postintervention among high-dose COT patients who received an opioid safety review e-consult (Table 3). The median opioid dose per patient decreased 20% from baseline, from 300 mg MEDD to 240 mg MEDD. The number of patients with an annual UDS increased 31.7% from 41 to 54 patients. The number of patients with an annual PDMP review also increased 345%, from 11 patients to 49 patients. Finally, the number of patients with an active BZD order decreased > 75% from 17 patients at baseline to 4 patients at 6-month follow-up.

In the FY 2014 third quarter, prior to activation of the opioid safety review e-consult tool, 100 patients received high-dose COT. Follow-up at the conclusion of fourth quarter FY 2015 revealed 64 such patients, which represented a 36% decrease from baseline.

Discussion

During the study period, the POC used a variety of interventions from 4 distinct categories. Overall, these interventions successfully increased measures of appropriate COT monitoring (ie, UDS and PDMP utilization) and management of high-risk COT. Substantial improvements also were seen in the subgroup of patients receiving high-dose COT following creation and use of the opioid safety review e-consult tool.

Other VHA opioid management improvement initiatives were successful at reducing high-dose opioid prescribing through interventions similar to those described in this study. However, these initiatives did not address opioid monitoring practices or opioid/BZD combination therapy.^25,26 To the authors’ knowledge, no previous opioid management improvement initiatives have reported improvements in provider use of a state PDMP database.

There are a number of factors that also may have helped lead to the successful outcomes observed during the study period. First, the creation of an informatics tool allowed for sustained interventions over time. While targeted interventions and patient/provider education were certainly beneficial, the impact of these efforts wanes as time moves forward. Inevitably, a patient’s and a provider’s focus move to the next important issue, and new patients meet the criteria of the original targeted intervention.

Group Health Cooperative implemented an opioid risk reduction initiative that successfully increased UDS use over a 2-year postimplementation period.^21,26 While this initiative used a number of similar interventions to those implemented in this study (patient and provider education, targeted patient intervention), an informatics tool was not used. The annual UDS rate at the conclusion of the Group Health initiative was 50%, which contrasts with a final rate of 75.5% in this study. Although it is difficult to draw comparisons between the studies given differences in populations studied, periods of evaluation, and varying baseline annual UDS rates, the current study results demonstrate the potential effectiveness of informatics tools to help drive enduring changes in practice.

An additional factor that had a positive impact on outcomes the continued support and advocacy from RHJVAMC clinical and administrative leadership. A targeted review of all patients receiving concomitant BZDs and opioids would not be possible without mental health department leaders who believed in the value of the time consuming undertaking. Furthermore, an e-consult tool is effective only if actually submitted for patients and if a specialist’s recommendations are then followed by a PCP.

Finally, the interdisciplinary nature of the POC contributed to the success of each intervention described in this study. Patients receiving COT often have many complex physical, psychological, and social issues that must be considered in order to make a positive impact on patient care. To appropriately and effectively address these issues requires close collaboration between specialists from multiple disciplines.

Limitations

This study has several important limitations. First, its retrospective nature presents obvious documentation challenges. A second limitation is the brief period of evaluation following a number of POC interventions. For instance, 3 interventions took place in January 2015, leaving only 3 FY quarters of effectiveness data. Furthermore, increased awareness of the risks associated with opioid therapy in the VHA and the health care industry across the study period may have independently impacted the improvements observed in this study.

The lack of an assessment of both patient-centered and clinical outcomes is an additional limitation of this study. Rates of annual UDS and PDMP database reviews and the number of patients receiving high-risk COT are only surrogate metrics that may indicate appropriate prescribing and monitoring of these. Obtaining a UDS or PDMP review is meant to provide a practitioner with additional information to interpret when caring for a patient. These data are only meant to complement—not replace—skilled patient assessment by a provider. Although the authors observed no major patient or clinical adverse events during the study period, the possibility exists that a patient may have been negatively impacted by a population-level initiative to improve surrogate measures of appropriate drug use.

Future studies should assess changes in measures, such as pain scores, legitimate adverse events, and overdose occurrences in order to evaluate whether such opioid improvement initiatives truly benefit the patients who are ultimately affected by each intervention.

Conclusion

This study demonstrates the successful implementation of a VHA-based opioid management initiative to increase appropriate COT monitoring and appropriate management of high-risk patients. It is the authors’ hope that the findings may add to the growing body of literature describing successful opioid improvement initiatives and serve as a tool for other health systems that are confronted with these same issues.

The Cherokee Nation has filed a lawsuit against 6 companies, accusing them of “turning a blind eye” to opioids being illegally prescribed to Cherokee adults and children. The lawsuit is the first of its kind filed in the U.S. “As we fight this epidemic in our hospitals, our schools, and our Cherokee homes, we will also use our legal system to make sure the companies, who put profits over people while our society is crippled by this epidemic, are held responsible for their actions,” said Cherokee Nation Principal Chief Bill John Baker.

According to DEA statistics, about 845 mg of opioids were distributed in the 14 counties of the Cherokee Nation in 2015—or between 360 and 720 opioid pills per every prescription. In The Washington Post, one of the lawyers for the Cherokee Nation said the “flood of opioids into Oklahoma has torn apart families and cost the Cherokees hundreds of millions of dollars.” Over the past 3 years, 2,684 opioid-related deaths have been reported in the state, according to Oklahoma Attorney General Mike Hunter.

The lawsuit names McKesson Corporation, Cardinal Health, Inc., and AmerisourceBergen (which together control roughly 85% of prescription drug distribution in the U.S.) as well as CVS, Walgreens, and Walmart. The companies “enabled prescription opioids to fall into illicit distribution channels, failed to alert regulators of extreme volume, and incentivized sales of these drugs with financial bonuses,” said Cherokee Nation Attorney General Todd Hembree. He said the drug distributors and pharmacies knew or should have known that the amount of drugs they were sending and dispensing were suspicious. He charged that the corporations’ profit seeking has unleashed “a plague.”

“Tribal nations have survived disease, removal from our homelands, termination, and other adversities and still we prospered,” said Chief Baker. “However, I fear the opioid epidemic is emerging as the next great challenge of our modern era.”

The full petition is available at www.cherokeecourts.org.

The Cherokee Nation has filed a lawsuit against 6 companies, accusing them of “turning a blind eye” to opioids being illegally prescribed to Cherokee adults and children. The lawsuit is the first of its kind filed in the U.S. “As we fight this epidemic in our hospitals, our schools, and our Cherokee homes, we will also use our legal system to make sure the companies, who put profits over people while our society is crippled by this epidemic, are held responsible for their actions,” said Cherokee Nation Principal Chief Bill John Baker.

According to DEA statistics, about 845 mg of opioids were distributed in the 14 counties of the Cherokee Nation in 2015—or between 360 and 720 opioid pills per every prescription. In The Washington Post, one of the lawyers for the Cherokee Nation said the “flood of opioids into Oklahoma has torn apart families and cost the Cherokees hundreds of millions of dollars.” Over the past 3 years, 2,684 opioid-related deaths have been reported in the state, according to Oklahoma Attorney General Mike Hunter.

The lawsuit names McKesson Corporation, Cardinal Health, Inc., and AmerisourceBergen (which together control roughly 85% of prescription drug distribution in the U.S.) as well as CVS, Walgreens, and Walmart. The companies “enabled prescription opioids to fall into illicit distribution channels, failed to alert regulators of extreme volume, and incentivized sales of these drugs with financial bonuses,” said Cherokee Nation Attorney General Todd Hembree. He said the drug distributors and pharmacies knew or should have known that the amount of drugs they were sending and dispensing were suspicious. He charged that the corporations’ profit seeking has unleashed “a plague.”

“Tribal nations have survived disease, removal from our homelands, termination, and other adversities and still we prospered,” said Chief Baker. “However, I fear the opioid epidemic is emerging as the next great challenge of our modern era.”

The full petition is available at www.cherokeecourts.org.

The Cherokee Nation has filed a lawsuit against 6 companies, accusing them of “turning a blind eye” to opioids being illegally prescribed to Cherokee adults and children. The lawsuit is the first of its kind filed in the U.S. “As we fight this epidemic in our hospitals, our schools, and our Cherokee homes, we will also use our legal system to make sure the companies, who put profits over people while our society is crippled by this epidemic, are held responsible for their actions,” said Cherokee Nation Principal Chief Bill John Baker.

According to DEA statistics, about 845 mg of opioids were distributed in the 14 counties of the Cherokee Nation in 2015—or between 360 and 720 opioid pills per every prescription. In The Washington Post, one of the lawyers for the Cherokee Nation said the “flood of opioids into Oklahoma has torn apart families and cost the Cherokees hundreds of millions of dollars.” Over the past 3 years, 2,684 opioid-related deaths have been reported in the state, according to Oklahoma Attorney General Mike Hunter.

The lawsuit names McKesson Corporation, Cardinal Health, Inc., and AmerisourceBergen (which together control roughly 85% of prescription drug distribution in the U.S.) as well as CVS, Walgreens, and Walmart. The companies “enabled prescription opioids to fall into illicit distribution channels, failed to alert regulators of extreme volume, and incentivized sales of these drugs with financial bonuses,” said Cherokee Nation Attorney General Todd Hembree. He said the drug distributors and pharmacies knew or should have known that the amount of drugs they were sending and dispensing were suspicious. He charged that the corporations’ profit seeking has unleashed “a plague.”

“Tribal nations have survived disease, removal from our homelands, termination, and other adversities and still we prospered,” said Chief Baker. “However, I fear the opioid epidemic is emerging as the next great challenge of our modern era.”

The full petition is available at www.cherokeecourts.org.

Follicular lymphoma (FL), which accounts for about 20% to 30% of all non-Hodgkin lymphomas, is an incurable disease. Although people with FL are living longer, the median overall survival (OS) had been about 10 years—until recently. According to researchers from the Spanish Lymphoma Oncology Group, OS may be changing. In their long-term study of 1,074 patients with newly diagnosed FL, median OS was more than 20 years.

Related: Six Open Clinical Trials That Are Expanding Our Understanding of Immunotherapies

The difference, the researchers say, may be chemoimmunotherapy, specifically, the anti-CD20 monoclonal antibody rituximab. Patients were enrolled between 1980 and 2013 and followed for a median of 55 months. The researchers note that rituximab was added to the treatment options in 2003. When the researchers analyzed the patients who were still alive 10 years beyond the diagnosis, they found that 118 of 166 were free of evident clinical disease.

The prognostic factors the researchers enumerate are similar to those of other studies. The variables significantly associated with survival at 10 years were stage great than II, aged < 60 years, low Follicular Lymphoma International Prognostic Index, normal β2 microglobulin, no B symptoms on diagnosis, Performance Status 0 to 1, and treatment with anthracyclines and rituximab. But their data, the researchers add, support the conclusion that the initial combined treatment with rituximab and anthracyclines “could be considered key factors.” They note that randomized studies and meta-analyses have repeatedly made improvements in the survival of patients with FL.

Related: New Treatments Offer Hope in Diffuse Large B-Cell Lymphoma

“We believe that the weight of the introduction of [rituximab] in a young population, associated with chemotherapy,” the researchers say, “has given these high rates of survival in an unselected population.” They conclude, “in the [rituximab] era, the strategy of ‘wait and watch’ remains valid for patients with favorable prognostic factors and low-grade tumors.”

Source:
Provencio M, Sabín P, Gomez-Codina J, et al. PLoS One. 2017;12(5):e0177204.
doi: 10.1371/journal.pone.0177204

Follicular lymphoma (FL), which accounts for about 20% to 30% of all non-Hodgkin lymphomas, is an incurable disease. Although people with FL are living longer, the median overall survival (OS) had been about 10 years—until recently. According to researchers from the Spanish Lymphoma Oncology Group, OS may be changing. In their long-term study of 1,074 patients with newly diagnosed FL, median OS was more than 20 years.

Related: Six Open Clinical Trials That Are Expanding Our Understanding of Immunotherapies

The difference, the researchers say, may be chemoimmunotherapy, specifically, the anti-CD20 monoclonal antibody rituximab. Patients were enrolled between 1980 and 2013 and followed for a median of 55 months. The researchers note that rituximab was added to the treatment options in 2003. When the researchers analyzed the patients who were still alive 10 years beyond the diagnosis, they found that 118 of 166 were free of evident clinical disease.

The prognostic factors the researchers enumerate are similar to those of other studies. The variables significantly associated with survival at 10 years were stage great than II, aged < 60 years, low Follicular Lymphoma International Prognostic Index, normal β2 microglobulin, no B symptoms on diagnosis, Performance Status 0 to 1, and treatment with anthracyclines and rituximab. But their data, the researchers add, support the conclusion that the initial combined treatment with rituximab and anthracyclines “could be considered key factors.” They note that randomized studies and meta-analyses have repeatedly made improvements in the survival of patients with FL.

Related: New Treatments Offer Hope in Diffuse Large B-Cell Lymphoma

“We believe that the weight of the introduction of [rituximab] in a young population, associated with chemotherapy,” the researchers say, “has given these high rates of survival in an unselected population.” They conclude, “in the [rituximab] era, the strategy of ‘wait and watch’ remains valid for patients with favorable prognostic factors and low-grade tumors.”

Source:
Provencio M, Sabín P, Gomez-Codina J, et al. PLoS One. 2017;12(5):e0177204.
doi: 10.1371/journal.pone.0177204

Follicular lymphoma (FL), which accounts for about 20% to 30% of all non-Hodgkin lymphomas, is an incurable disease. Although people with FL are living longer, the median overall survival (OS) had been about 10 years—until recently. According to researchers from the Spanish Lymphoma Oncology Group, OS may be changing. In their long-term study of 1,074 patients with newly diagnosed FL, median OS was more than 20 years.

Related: Six Open Clinical Trials That Are Expanding Our Understanding of Immunotherapies

The difference, the researchers say, may be chemoimmunotherapy, specifically, the anti-CD20 monoclonal antibody rituximab. Patients were enrolled between 1980 and 2013 and followed for a median of 55 months. The researchers note that rituximab was added to the treatment options in 2003. When the researchers analyzed the patients who were still alive 10 years beyond the diagnosis, they found that 118 of 166 were free of evident clinical disease.

The prognostic factors the researchers enumerate are similar to those of other studies. The variables significantly associated with survival at 10 years were stage great than II, aged < 60 years, low Follicular Lymphoma International Prognostic Index, normal β2 microglobulin, no B symptoms on diagnosis, Performance Status 0 to 1, and treatment with anthracyclines and rituximab. But their data, the researchers add, support the conclusion that the initial combined treatment with rituximab and anthracyclines “could be considered key factors.” They note that randomized studies and meta-analyses have repeatedly made improvements in the survival of patients with FL.

Related: New Treatments Offer Hope in Diffuse Large B-Cell Lymphoma

“We believe that the weight of the introduction of [rituximab] in a young population, associated with chemotherapy,” the researchers say, “has given these high rates of survival in an unselected population.” They conclude, “in the [rituximab] era, the strategy of ‘wait and watch’ remains valid for patients with favorable prognostic factors and low-grade tumors.”

Source:
Provencio M, Sabín P, Gomez-Codina J, et al. PLoS One. 2017;12(5):e0177204.
doi: 10.1371/journal.pone.0177204

Federal Practitioner is inviting VA, DoD, and PHS health care providers and researchers to contribute to a special issue that will be published in November 2017 and will examine cardiovascular disease treatments, such as heart failure, atrial fibrillation, anticoagulation treatments, and other related conditions.

Interested authors should submit a brief 2 to 3 sentence abstract to [email protected] by July 7, 2017. Federal Practitioner welcomes case studies, literature reviews, original research, program profiles, guest editorials, and other evidence-based articles. The updated and complete submission guidelines, including details about the style and format, can be found here: 

http://www.mdedge.com/fedprac/page/submission-guidelines

Federal Practitioner uses Editorial Manager, a web-based manuscript submission and review system. All manuscripts must be submitted through this system.

All manuscripts submitted to Federal Practitioner for both special and regular issues will be subject to peer review. Peer reviews are conducted in a double-blind fashion, and the reviewers are asked to comment on the manuscript’s importance, accuracy, relevance, clarity, timeliness, balance, and reference citation. Final decisions on all submitted manuscripts are made by the Editor-in-Chief (or, in the event of a potential conflict of interest, a designated surrogate from the journal’s Editorial Advisory Association). 

Federal Practitioner is inviting VA, DoD, and PHS health care providers and researchers to contribute to a special issue that will be published in November 2017 and will examine cardiovascular disease treatments, such as heart failure, atrial fibrillation, anticoagulation treatments, and other related conditions.

Interested authors should submit a brief 2 to 3 sentence abstract to [email protected] by July 7, 2017. Federal Practitioner welcomes case studies, literature reviews, original research, program profiles, guest editorials, and other evidence-based articles. The updated and complete submission guidelines, including details about the style and format, can be found here: 

http://www.mdedge.com/fedprac/page/submission-guidelines

Federal Practitioner uses Editorial Manager, a web-based manuscript submission and review system. All manuscripts must be submitted through this system.

All manuscripts submitted to Federal Practitioner for both special and regular issues will be subject to peer review. Peer reviews are conducted in a double-blind fashion, and the reviewers are asked to comment on the manuscript’s importance, accuracy, relevance, clarity, timeliness, balance, and reference citation. Final decisions on all submitted manuscripts are made by the Editor-in-Chief (or, in the event of a potential conflict of interest, a designated surrogate from the journal’s Editorial Advisory Association). 

Federal Practitioner is inviting VA, DoD, and PHS health care providers and researchers to contribute to a special issue that will be published in November 2017 and will examine cardiovascular disease treatments, such as heart failure, atrial fibrillation, anticoagulation treatments, and other related conditions.

Interested authors should submit a brief 2 to 3 sentence abstract to [email protected] by July 7, 2017. Federal Practitioner welcomes case studies, literature reviews, original research, program profiles, guest editorials, and other evidence-based articles. The updated and complete submission guidelines, including details about the style and format, can be found here: 

http://www.mdedge.com/fedprac/page/submission-guidelines

Federal Practitioner uses Editorial Manager, a web-based manuscript submission and review system. All manuscripts must be submitted through this system.

All manuscripts submitted to Federal Practitioner for both special and regular issues will be subject to peer review. Peer reviews are conducted in a double-blind fashion, and the reviewers are asked to comment on the manuscript’s importance, accuracy, relevance, clarity, timeliness, balance, and reference citation. Final decisions on all submitted manuscripts are made by the Editor-in-Chief (or, in the event of a potential conflict of interest, a designated surrogate from the journal’s Editorial Advisory Association). 

Photo © ASCO/David Eulitt 2017

CHICAGO—A new type of chimeric antigen receptor (CAR) T cell, one that is specific for the B-cell maturation antigen (BCMA), has produced durable remissions in patients with multiple myeloma (MM), according to research reported at the 2017 ASCO Annual Meeting (abstract LBA3001).

BCMA is a cell surface antigen universally expressed on malignant plasma cells. It plays a role in the progression of MM and is turning out to be a highly selective antigen to target in novel treatments for MM.

This trial of LCAR-B38M is one of the first clinical trials of CAR T cells to target BCMA.

“[W]hat makes our CAR T different from other CAR T all over the world is we are truly a bispecific CAR T modality,” Frank (Xiaohu) Fan, MD, PhD, explained in a media briefing, “especially our antigen-binding units compared to single domain antibodies.” Dr Fan is CSO of  Nanjing Legend Biotech in China, the developer of LCAR-B38M.

“We believe targeting BCMA alone should be enough to get a good efficacy,” he said.

To date the objective response rate is 100%.

The investigators treated 35 relapsed/refractory MM patients thus far with LCAR-B38M. Patients received the modified CAR T cells in 3 doses, on days 0, 2, and 6.

The investigators reported on 19 patients who they followed for more than 4 months, a criterion established by the International Myeloma Working Group for full efficacy evaluation.

Efficacy

Of the 19 patients, 14 (74%) achieved a stringent complete response (sCR), 4 (21%) a very good partial response (VGPR), and 1 (5%) a PR.

One patient who achieved a VGPR relapsed due to an extramedullary lesion.

Investigators observed no evidence of relapse among patients who achieved sCR.

Five patients have been followed for more than a year and all have maintained sCR.

Safety

Safety is a major issue with CAR T-cell therapies, with a frequent and major adverse event being cytokine release syndrome (CRS).

Of the 35 patients treated, 6 experienced no CRS, 17 had grade 1, 10 had grade 2, and 2 had grade 3 CRS. No patient experienced grade 4 CRS or any grade 5 event.

Because LCAR-B38M demonstrates “outstanding” efficacy with a “great” safety profile, the investigators believe this technology raises the hope of cure for MM patients.

A clinical trial of LCAR-B38M is planned in the United States.

Photo © ASCO/David Eulitt 2017

CHICAGO—A new type of chimeric antigen receptor (CAR) T cell, one that is specific for the B-cell maturation antigen (BCMA), has produced durable remissions in patients with multiple myeloma (MM), according to research reported at the 2017 ASCO Annual Meeting (abstract LBA3001).

BCMA is a cell surface antigen universally expressed on malignant plasma cells. It plays a role in the progression of MM and is turning out to be a highly selective antigen to target in novel treatments for MM.

This trial of LCAR-B38M is one of the first clinical trials of CAR T cells to target BCMA.

“[W]hat makes our CAR T different from other CAR T all over the world is we are truly a bispecific CAR T modality,” Frank (Xiaohu) Fan, MD, PhD, explained in a media briefing, “especially our antigen-binding units compared to single domain antibodies.” Dr Fan is CSO of  Nanjing Legend Biotech in China, the developer of LCAR-B38M.

“We believe targeting BCMA alone should be enough to get a good efficacy,” he said.

To date the objective response rate is 100%.

The investigators treated 35 relapsed/refractory MM patients thus far with LCAR-B38M. Patients received the modified CAR T cells in 3 doses, on days 0, 2, and 6.

The investigators reported on 19 patients who they followed for more than 4 months, a criterion established by the International Myeloma Working Group for full efficacy evaluation.

Efficacy

Of the 19 patients, 14 (74%) achieved a stringent complete response (sCR), 4 (21%) a very good partial response (VGPR), and 1 (5%) a PR.

One patient who achieved a VGPR relapsed due to an extramedullary lesion.

Investigators observed no evidence of relapse among patients who achieved sCR.

Five patients have been followed for more than a year and all have maintained sCR.

Safety

Safety is a major issue with CAR T-cell therapies, with a frequent and major adverse event being cytokine release syndrome (CRS).

Of the 35 patients treated, 6 experienced no CRS, 17 had grade 1, 10 had grade 2, and 2 had grade 3 CRS. No patient experienced grade 4 CRS or any grade 5 event.

Because LCAR-B38M demonstrates “outstanding” efficacy with a “great” safety profile, the investigators believe this technology raises the hope of cure for MM patients.

A clinical trial of LCAR-B38M is planned in the United States.

Photo © ASCO/David Eulitt 2017

CHICAGO—A new type of chimeric antigen receptor (CAR) T cell, one that is specific for the B-cell maturation antigen (BCMA), has produced durable remissions in patients with multiple myeloma (MM), according to research reported at the 2017 ASCO Annual Meeting (abstract LBA3001).

BCMA is a cell surface antigen universally expressed on malignant plasma cells. It plays a role in the progression of MM and is turning out to be a highly selective antigen to target in novel treatments for MM.

This trial of LCAR-B38M is one of the first clinical trials of CAR T cells to target BCMA.

“[W]hat makes our CAR T different from other CAR T all over the world is we are truly a bispecific CAR T modality,” Frank (Xiaohu) Fan, MD, PhD, explained in a media briefing, “especially our antigen-binding units compared to single domain antibodies.” Dr Fan is CSO of  Nanjing Legend Biotech in China, the developer of LCAR-B38M.

“We believe targeting BCMA alone should be enough to get a good efficacy,” he said.

To date the objective response rate is 100%.

The investigators treated 35 relapsed/refractory MM patients thus far with LCAR-B38M. Patients received the modified CAR T cells in 3 doses, on days 0, 2, and 6.

The investigators reported on 19 patients who they followed for more than 4 months, a criterion established by the International Myeloma Working Group for full efficacy evaluation.

Efficacy

Of the 19 patients, 14 (74%) achieved a stringent complete response (sCR), 4 (21%) a very good partial response (VGPR), and 1 (5%) a PR.

One patient who achieved a VGPR relapsed due to an extramedullary lesion.

Investigators observed no evidence of relapse among patients who achieved sCR.

Five patients have been followed for more than a year and all have maintained sCR.

Safety

Safety is a major issue with CAR T-cell therapies, with a frequent and major adverse event being cytokine release syndrome (CRS).

Of the 35 patients treated, 6 experienced no CRS, 17 had grade 1, 10 had grade 2, and 2 had grade 3 CRS. No patient experienced grade 4 CRS or any grade 5 event.

Because LCAR-B38M demonstrates “outstanding” efficacy with a “great” safety profile, the investigators believe this technology raises the hope of cure for MM patients.

A clinical trial of LCAR-B38M is planned in the United States.

Children’s Research Hospital

Malaria infection caused by Plasmodium falciparum, even after a one-time illness, can cause long-term bone loss, researchers report.

Parasite byproducts remain in the bone marrow and induce MyD88-dependent inflammatory responses in osteoclast and osteoblast precursors, resulting in bone resorption.

Researchers found that treatment with the vitamin D3 analog alfacalcidol can prevent bone loss related to malaria, at least in animals.

They suggest that bone therapies combined with anti-malarial drugs may prevent bone loss in infected individuals.

Cevayir Coban, MD, from Osaka University in Japan, and colleagues reported their findings in Science Immunology.

"Although chronic inflammatory conditions are known to facilitate bone disorders, our study—for the first time—shows that malaria can do the same thing,” Dr Coban said.

“One may think that the infection has been completely cured by anti-malarial treatment, and be feeling fully recovered,” she said. “However, sustained long-term accumulation of parasite by-products leave the bone in a state of chronic inflammation, leading to long-term bone loss. This is particularly worrisome in the young of age, where it may cause growth problems and osteoporotic, fragile bones."

To study the effect of Plasmodium infection on bone, the team used two mouse models, Plasmodium yoelii nonlethal (PyNL) and Plasmodium chabaudi chabaudi (Pcc).

PyNL infection invades reticulocytes and resembles Plasmodium vivax infection in humans. Pcc infection more closely resembles Plasmodium falciparum infection in humans. The investigators used Pcc infection to evaluate the effect of low-level chronic infection on bone homeostasis.

They infected 6-week-old adult mice with these parasite species and assessed changes in bone during the acute, convalescent, and chronic phases of infection.

Both parasites caused significantly reduced trabecular bone volume and increased trabecular bone spacing in infected mice. This continued for over 60 days after parasite clearance.

Michelle Lee, a PhD candidate and the first author of the study explains, "We found that Plasmodium products continuously accumulate in the bone marrow niche, which turns the bone noticeably black in color, and results in it being ‘eaten-up’ by bone resorbing cells known as osteoclasts, eventually disrupting bone homeostasis".

The research team also investigated the impact of malaria infection on bone growth at a young age by infecting 3-week-old mice with PyNL. These mice had significantly shorter femurs and lower trabecular bone volume compared with uninfected litter mates 3 weeks after infection, when the mice were 6 weeks old.

A key finding of the study, investigators report, is that although Plasmodium infection resolves systemically, a state of chronic inflammation evolves in the bone marrow that may be associated with continued accumulation of Plasmodium byproducts—proteins, hemozoin, and nucleic acids—in the bone marrow. These byproducts are capable of modulating immune responses.

The team also evaluated whether vitamin D supplementation would alleviate bone loss caused by Plasmodium. They treated mice with alfacalcidol, which is used to treat osteoporosis. Treatment with lower doses of oral alfacalcidol was sufficient to prevent malaria-induced bone loss, while higher doses enhanced bone growth despite infection.

This work was supported by the Grants-in-Aid for Scientific Research, the Japan Agency for Medical Research and Development, the Uehara Memorial and Yamada Science, the Grant-in-Aid for Young Scientists, and a Japanese Government Scholarship (Ministry of Education, Culture, Sports, Science and Technology). 

Children’s Research Hospital

Malaria infection caused by Plasmodium falciparum, even after a one-time illness, can cause long-term bone loss, researchers report.

Parasite byproducts remain in the bone marrow and induce MyD88-dependent inflammatory responses in osteoclast and osteoblast precursors, resulting in bone resorption.

Researchers found that treatment with the vitamin D3 analog alfacalcidol can prevent bone loss related to malaria, at least in animals.

They suggest that bone therapies combined with anti-malarial drugs may prevent bone loss in infected individuals.

Cevayir Coban, MD, from Osaka University in Japan, and colleagues reported their findings in Science Immunology.

"Although chronic inflammatory conditions are known to facilitate bone disorders, our study—for the first time—shows that malaria can do the same thing,” Dr Coban said.

“One may think that the infection has been completely cured by anti-malarial treatment, and be feeling fully recovered,” she said. “However, sustained long-term accumulation of parasite by-products leave the bone in a state of chronic inflammation, leading to long-term bone loss. This is particularly worrisome in the young of age, where it may cause growth problems and osteoporotic, fragile bones."

To study the effect of Plasmodium infection on bone, the team used two mouse models, Plasmodium yoelii nonlethal (PyNL) and Plasmodium chabaudi chabaudi (Pcc).

PyNL infection invades reticulocytes and resembles Plasmodium vivax infection in humans. Pcc infection more closely resembles Plasmodium falciparum infection in humans. The investigators used Pcc infection to evaluate the effect of low-level chronic infection on bone homeostasis.

They infected 6-week-old adult mice with these parasite species and assessed changes in bone during the acute, convalescent, and chronic phases of infection.

Both parasites caused significantly reduced trabecular bone volume and increased trabecular bone spacing in infected mice. This continued for over 60 days after parasite clearance.

Michelle Lee, a PhD candidate and the first author of the study explains, "We found that Plasmodium products continuously accumulate in the bone marrow niche, which turns the bone noticeably black in color, and results in it being ‘eaten-up’ by bone resorbing cells known as osteoclasts, eventually disrupting bone homeostasis".

The research team also investigated the impact of malaria infection on bone growth at a young age by infecting 3-week-old mice with PyNL. These mice had significantly shorter femurs and lower trabecular bone volume compared with uninfected litter mates 3 weeks after infection, when the mice were 6 weeks old.

A key finding of the study, investigators report, is that although Plasmodium infection resolves systemically, a state of chronic inflammation evolves in the bone marrow that may be associated with continued accumulation of Plasmodium byproducts—proteins, hemozoin, and nucleic acids—in the bone marrow. These byproducts are capable of modulating immune responses.

The team also evaluated whether vitamin D supplementation would alleviate bone loss caused by Plasmodium. They treated mice with alfacalcidol, which is used to treat osteoporosis. Treatment with lower doses of oral alfacalcidol was sufficient to prevent malaria-induced bone loss, while higher doses enhanced bone growth despite infection.

This work was supported by the Grants-in-Aid for Scientific Research, the Japan Agency for Medical Research and Development, the Uehara Memorial and Yamada Science, the Grant-in-Aid for Young Scientists, and a Japanese Government Scholarship (Ministry of Education, Culture, Sports, Science and Technology). 

Children’s Research Hospital

Malaria infection caused by Plasmodium falciparum, even after a one-time illness, can cause long-term bone loss, researchers report.

Parasite byproducts remain in the bone marrow and induce MyD88-dependent inflammatory responses in osteoclast and osteoblast precursors, resulting in bone resorption.

Researchers found that treatment with the vitamin D3 analog alfacalcidol can prevent bone loss related to malaria, at least in animals.

They suggest that bone therapies combined with anti-malarial drugs may prevent bone loss in infected individuals.

Cevayir Coban, MD, from Osaka University in Japan, and colleagues reported their findings in Science Immunology.

"Although chronic inflammatory conditions are known to facilitate bone disorders, our study—for the first time—shows that malaria can do the same thing,” Dr Coban said.

“One may think that the infection has been completely cured by anti-malarial treatment, and be feeling fully recovered,” she said. “However, sustained long-term accumulation of parasite by-products leave the bone in a state of chronic inflammation, leading to long-term bone loss. This is particularly worrisome in the young of age, where it may cause growth problems and osteoporotic, fragile bones."

To study the effect of Plasmodium infection on bone, the team used two mouse models, Plasmodium yoelii nonlethal (PyNL) and Plasmodium chabaudi chabaudi (Pcc).

PyNL infection invades reticulocytes and resembles Plasmodium vivax infection in humans. Pcc infection more closely resembles Plasmodium falciparum infection in humans. The investigators used Pcc infection to evaluate the effect of low-level chronic infection on bone homeostasis.

They infected 6-week-old adult mice with these parasite species and assessed changes in bone during the acute, convalescent, and chronic phases of infection.

Both parasites caused significantly reduced trabecular bone volume and increased trabecular bone spacing in infected mice. This continued for over 60 days after parasite clearance.

Michelle Lee, a PhD candidate and the first author of the study explains, "We found that Plasmodium products continuously accumulate in the bone marrow niche, which turns the bone noticeably black in color, and results in it being ‘eaten-up’ by bone resorbing cells known as osteoclasts, eventually disrupting bone homeostasis".

The research team also investigated the impact of malaria infection on bone growth at a young age by infecting 3-week-old mice with PyNL. These mice had significantly shorter femurs and lower trabecular bone volume compared with uninfected litter mates 3 weeks after infection, when the mice were 6 weeks old.

A key finding of the study, investigators report, is that although Plasmodium infection resolves systemically, a state of chronic inflammation evolves in the bone marrow that may be associated with continued accumulation of Plasmodium byproducts—proteins, hemozoin, and nucleic acids—in the bone marrow. These byproducts are capable of modulating immune responses.

The team also evaluated whether vitamin D supplementation would alleviate bone loss caused by Plasmodium. They treated mice with alfacalcidol, which is used to treat osteoporosis. Treatment with lower doses of oral alfacalcidol was sufficient to prevent malaria-induced bone loss, while higher doses enhanced bone growth despite infection.

This work was supported by the Grants-in-Aid for Scientific Research, the Japan Agency for Medical Research and Development, the Uehara Memorial and Yamada Science, the Grant-in-Aid for Young Scientists, and a Japanese Government Scholarship (Ministry of Education, Culture, Sports, Science and Technology). 

A 32-year-old woman comes to your office for help with her recurrent migraines, which she’s had since her early 20s. She is otherwise healthy and active. She is frustrated by the frequency of her migraines and the resulting debilitation. She has tried prophylactic medications in the past but stopped taking them because of the adverse effects. What do you recommend for treatment?

Daily preventive medication can be helpful for patients whose chronic migraines have a significant impact on their lives. Many have a goal of reducing headache frequency, severity, and/or disability, while avoiding acute medication escalation.² An estimated 38% of patients with migraine are appropriate candidates for prophylactic therapy, but only 3% to 13% are taking preventive medications.³

Evidence-based guidelines from the American Academy of Neurology and the American Headache Society state that antiepileptic drugs (divalproex sodium, sodium valproate, topiramate) and many ß-blockers (metoprolol, propranolol, timolol) are effective and should be recommended for migraine prevention.² Medications such as antidepressants (amitriptyline, venlafaxine) and other ß-blockers (atenolol, nadolol) are probably effective and can be considered.² However, adverse effects—including somnolence—are listed as “frequent” with amitriptyline and “occasional to frequent” with topiramate.⁴

Researchers have investigated melatonin before. But a 2010 double-blind, crossover RCT of 46 patients with two to seven migraine attacks per month found no significant difference in reduction of headache frequency between extended-release melatonin (2 mg taken 1 h before bed) and placebo over an eight-week period.⁵

STUDY SUMMARY

More than 50% reduction in headache frequency

This RCT, conducted in Brazil, compared the effectiveness of melatonin to amitriptyline and placebo for migraine prevention in 196 adults (ages 18 to 65) with chronic migraine.¹ Eligible patients had a history of at least three migraine attacks or four migraine headache days per month. Patients were randomized to take identical-appearing melatonin (3 mg), amitriptyline (25 mg), or placebo nightly. The investigators appear to have concealed allocation adequately and used double-blinding.

The primary outcome was the number of headache days per month, compared to baseline. Secondary endpoints included reduction in migraine intensity, duration, number of analgesics used, and percentage of patients with more than 50% reduction in migraine headache days.

Compared to placebo, headache days per month were reduced in both the melatonin group (6.2 d vs 4.6 d, respectively; mean difference [MD], –1.6) and the amitriptyline group (6.2 d vs 5 d, respectively; MD, –1.2) at 12 weeks, based on intention-to-treat analysis. Mean headache intensity (0-10 pain scale) was also lower at 12 weeks in the melatonin group (4.8 vs 3.6; MD, –1.2) and in the amitriptyline group (4.8 vs 3.5; MD, –1.3), compared to placebo.

Headache duration (hours/month) at 12 weeks was reduced in both groups (MD, –4.4 h for amitriptyline and –4.8 h for melatonin), as was the number of analgesics used (MD for amitriptyline and for melatonin, –1) when compared to placebo. There was no significant difference between the melatonin and amitriptyline groups for these outcomes.

Patients taking melatonin were more likely to have more than 50% improvement in headache frequency compared to those taking amitriptyline (54% vs 39%; number needed to treat [NNT], 7). Melatonin worked much better than placebo (54% vs 20%; NNT, 3).

Adverse events were reported more often in the amitriptyline group than in the melatonin group (46 vs 16), with daytime sleepiness being the most frequent complaint (41% of patients in the amitriptyline group vs 18% of the melatonin group; number needed to harm [NNH], 5). There was no significant difference in adverse events between melatonin and placebo (16 vs 17). Melatonin resulted in weight loss (mean, –0.14 kg), whereas those taking amitriptyline gained weight (+0.97 kg).

WHAT’S NEW

Effective alternative with minimal adverse effects

Melatonin is an accessible and affordable option for prevention of migraine. The 3-mg dosing reduces headache frequency—measured by both the number of migraine headache days per month and the percentage of patients with a more than 50% reduction in headache events—as well as headache intensity, with minimal adverse effects.

CAVEATS

Product consistency, missing study data

This trial used 3-mg dosing, so it is not clear if other doses are also effective. In addition, melatonin’s OTC status means there could be a lack of consistency in quality/actual doses between brands.

Furthermore, in this trial, neither the amitriptyline nor the melatonin dose was titrated according to patient response or adverse effects, as it might be in clinical practice. As a result, we are not sure of the actual lowest effective dose or if greater effect (with continued minimal adverse effects) could be achieved with higher doses.

Lastly, 69% to 75% of patients in the treatment groups completed the 16-week trial, and the researchers reported using three different analytic techniques to estimate missing data. (For example, the primary endpoint analysis included data for 90.8% of randomized patients [178 of 196], and the authors treated all missing data as nonheadache days.) It is unclear how the missing data would affect the outcome—although in this type of analysis, it would tend toward a null effect.

CHALLENGES TO IMPLEMENTATION

Challenges are negligible

There are really no challenges to implementing this practice changer; melatonin is readily available and is affordable.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2017. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice (2017;66[5]:320-322).

A 32-year-old woman comes to your office for help with her recurrent migraines, which she’s had since her early 20s. She is otherwise healthy and active. She is frustrated by the frequency of her migraines and the resulting debilitation. She has tried prophylactic medications in the past but stopped taking them because of the adverse effects. What do you recommend for treatment?

Daily preventive medication can be helpful for patients whose chronic migraines have a significant impact on their lives. Many have a goal of reducing headache frequency, severity, and/or disability, while avoiding acute medication escalation.² An estimated 38% of patients with migraine are appropriate candidates for prophylactic therapy, but only 3% to 13% are taking preventive medications.³

Evidence-based guidelines from the American Academy of Neurology and the American Headache Society state that antiepileptic drugs (divalproex sodium, sodium valproate, topiramate) and many ß-blockers (metoprolol, propranolol, timolol) are effective and should be recommended for migraine prevention.² Medications such as antidepressants (amitriptyline, venlafaxine) and other ß-blockers (atenolol, nadolol) are probably effective and can be considered.² However, adverse effects—including somnolence—are listed as “frequent” with amitriptyline and “occasional to frequent” with topiramate.⁴

Researchers have investigated melatonin before. But a 2010 double-blind, crossover RCT of 46 patients with two to seven migraine attacks per month found no significant difference in reduction of headache frequency between extended-release melatonin (2 mg taken 1 h before bed) and placebo over an eight-week period.⁵

STUDY SUMMARY

More than 50% reduction in headache frequency

This RCT, conducted in Brazil, compared the effectiveness of melatonin to amitriptyline and placebo for migraine prevention in 196 adults (ages 18 to 65) with chronic migraine.¹ Eligible patients had a history of at least three migraine attacks or four migraine headache days per month. Patients were randomized to take identical-appearing melatonin (3 mg), amitriptyline (25 mg), or placebo nightly. The investigators appear to have concealed allocation adequately and used double-blinding.

The primary outcome was the number of headache days per month, compared to baseline. Secondary endpoints included reduction in migraine intensity, duration, number of analgesics used, and percentage of patients with more than 50% reduction in migraine headache days.

Compared to placebo, headache days per month were reduced in both the melatonin group (6.2 d vs 4.6 d, respectively; mean difference [MD], –1.6) and the amitriptyline group (6.2 d vs 5 d, respectively; MD, –1.2) at 12 weeks, based on intention-to-treat analysis. Mean headache intensity (0-10 pain scale) was also lower at 12 weeks in the melatonin group (4.8 vs 3.6; MD, –1.2) and in the amitriptyline group (4.8 vs 3.5; MD, –1.3), compared to placebo.

Headache duration (hours/month) at 12 weeks was reduced in both groups (MD, –4.4 h for amitriptyline and –4.8 h for melatonin), as was the number of analgesics used (MD for amitriptyline and for melatonin, –1) when compared to placebo. There was no significant difference between the melatonin and amitriptyline groups for these outcomes.

Patients taking melatonin were more likely to have more than 50% improvement in headache frequency compared to those taking amitriptyline (54% vs 39%; number needed to treat [NNT], 7). Melatonin worked much better than placebo (54% vs 20%; NNT, 3).

Adverse events were reported more often in the amitriptyline group than in the melatonin group (46 vs 16), with daytime sleepiness being the most frequent complaint (41% of patients in the amitriptyline group vs 18% of the melatonin group; number needed to harm [NNH], 5). There was no significant difference in adverse events between melatonin and placebo (16 vs 17). Melatonin resulted in weight loss (mean, –0.14 kg), whereas those taking amitriptyline gained weight (+0.97 kg).

WHAT’S NEW

Effective alternative with minimal adverse effects

Melatonin is an accessible and affordable option for prevention of migraine. The 3-mg dosing reduces headache frequency—measured by both the number of migraine headache days per month and the percentage of patients with a more than 50% reduction in headache events—as well as headache intensity, with minimal adverse effects.

CAVEATS

Product consistency, missing study data

This trial used 3-mg dosing, so it is not clear if other doses are also effective. In addition, melatonin’s OTC status means there could be a lack of consistency in quality/actual doses between brands.

Furthermore, in this trial, neither the amitriptyline nor the melatonin dose was titrated according to patient response or adverse effects, as it might be in clinical practice. As a result, we are not sure of the actual lowest effective dose or if greater effect (with continued minimal adverse effects) could be achieved with higher doses.

Lastly, 69% to 75% of patients in the treatment groups completed the 16-week trial, and the researchers reported using three different analytic techniques to estimate missing data. (For example, the primary endpoint analysis included data for 90.8% of randomized patients [178 of 196], and the authors treated all missing data as nonheadache days.) It is unclear how the missing data would affect the outcome—although in this type of analysis, it would tend toward a null effect.

CHALLENGES TO IMPLEMENTATION

Challenges are negligible

There are really no challenges to implementing this practice changer; melatonin is readily available and is affordable.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2017. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice (2017;66[5]:320-322).

A 32-year-old woman comes to your office for help with her recurrent migraines, which she’s had since her early 20s. She is otherwise healthy and active. She is frustrated by the frequency of her migraines and the resulting debilitation. She has tried prophylactic medications in the past but stopped taking them because of the adverse effects. What do you recommend for treatment?

Daily preventive medication can be helpful for patients whose chronic migraines have a significant impact on their lives. Many have a goal of reducing headache frequency, severity, and/or disability, while avoiding acute medication escalation.² An estimated 38% of patients with migraine are appropriate candidates for prophylactic therapy, but only 3% to 13% are taking preventive medications.³

Evidence-based guidelines from the American Academy of Neurology and the American Headache Society state that antiepileptic drugs (divalproex sodium, sodium valproate, topiramate) and many ß-blockers (metoprolol, propranolol, timolol) are effective and should be recommended for migraine prevention.² Medications such as antidepressants (amitriptyline, venlafaxine) and other ß-blockers (atenolol, nadolol) are probably effective and can be considered.² However, adverse effects—including somnolence—are listed as “frequent” with amitriptyline and “occasional to frequent” with topiramate.⁴

Researchers have investigated melatonin before. But a 2010 double-blind, crossover RCT of 46 patients with two to seven migraine attacks per month found no significant difference in reduction of headache frequency between extended-release melatonin (2 mg taken 1 h before bed) and placebo over an eight-week period.⁵

STUDY SUMMARY

More than 50% reduction in headache frequency

This RCT, conducted in Brazil, compared the effectiveness of melatonin to amitriptyline and placebo for migraine prevention in 196 adults (ages 18 to 65) with chronic migraine.¹ Eligible patients had a history of at least three migraine attacks or four migraine headache days per month. Patients were randomized to take identical-appearing melatonin (3 mg), amitriptyline (25 mg), or placebo nightly. The investigators appear to have concealed allocation adequately and used double-blinding.

The primary outcome was the number of headache days per month, compared to baseline. Secondary endpoints included reduction in migraine intensity, duration, number of analgesics used, and percentage of patients with more than 50% reduction in migraine headache days.

Compared to placebo, headache days per month were reduced in both the melatonin group (6.2 d vs 4.6 d, respectively; mean difference [MD], –1.6) and the amitriptyline group (6.2 d vs 5 d, respectively; MD, –1.2) at 12 weeks, based on intention-to-treat analysis. Mean headache intensity (0-10 pain scale) was also lower at 12 weeks in the melatonin group (4.8 vs 3.6; MD, –1.2) and in the amitriptyline group (4.8 vs 3.5; MD, –1.3), compared to placebo.

Headache duration (hours/month) at 12 weeks was reduced in both groups (MD, –4.4 h for amitriptyline and –4.8 h for melatonin), as was the number of analgesics used (MD for amitriptyline and for melatonin, –1) when compared to placebo. There was no significant difference between the melatonin and amitriptyline groups for these outcomes.

Patients taking melatonin were more likely to have more than 50% improvement in headache frequency compared to those taking amitriptyline (54% vs 39%; number needed to treat [NNT], 7). Melatonin worked much better than placebo (54% vs 20%; NNT, 3).

Adverse events were reported more often in the amitriptyline group than in the melatonin group (46 vs 16), with daytime sleepiness being the most frequent complaint (41% of patients in the amitriptyline group vs 18% of the melatonin group; number needed to harm [NNH], 5). There was no significant difference in adverse events between melatonin and placebo (16 vs 17). Melatonin resulted in weight loss (mean, –0.14 kg), whereas those taking amitriptyline gained weight (+0.97 kg).

WHAT’S NEW

Effective alternative with minimal adverse effects

Melatonin is an accessible and affordable option for prevention of migraine. The 3-mg dosing reduces headache frequency—measured by both the number of migraine headache days per month and the percentage of patients with a more than 50% reduction in headache events—as well as headache intensity, with minimal adverse effects.

CAVEATS

Product consistency, missing study data

This trial used 3-mg dosing, so it is not clear if other doses are also effective. In addition, melatonin’s OTC status means there could be a lack of consistency in quality/actual doses between brands.

Furthermore, in this trial, neither the amitriptyline nor the melatonin dose was titrated according to patient response or adverse effects, as it might be in clinical practice. As a result, we are not sure of the actual lowest effective dose or if greater effect (with continued minimal adverse effects) could be achieved with higher doses.

Lastly, 69% to 75% of patients in the treatment groups completed the 16-week trial, and the researchers reported using three different analytic techniques to estimate missing data. (For example, the primary endpoint analysis included data for 90.8% of randomized patients [178 of 196], and the authors treated all missing data as nonheadache days.) It is unclear how the missing data would affect the outcome—although in this type of analysis, it would tend toward a null effect.

CHALLENGES TO IMPLEMENTATION

Challenges are negligible

There are really no challenges to implementing this practice changer; melatonin is readily available and is affordable.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2017. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice (2017;66[5]:320-322).