Melissa Weimer

Systemic Pharmacologic Therapies for Low Back Pain: A Systematic Review for an American College of Physicians Clinical Practice Guideline.

Low back pain is one of the most frequently encountered conditions in clinical practice (1, 2). The most commonly prescribed medications for low back pain are nonsteroidal anti-inflammatory drugs (NSAIDs), skeletal muscle relaxants, antidepressants, and opioids (35); benzodiazepines, systemic corticosteroids, and antiseizure medications are also prescribed (3). Patients often use over-the-counter acetaminophen and NSAIDs. A 2007 guideline (6) and associated systematic review (7) from the American College of Physicians (ACP) and American Pain Society (APS) found evidence to support the use of acetaminophen and NSAIDs as first-line pharmacologic options for low back pain; secondary options were skeletal muscle relaxants, benzodiazepines, and antidepressants. New evidence and medications are now available. Here, we review the current evidence on benefits and harms of medications for low back pain. This article has been used by ACP to update a clinical practice guideline, also in this issue. Methods Detailed methods and data for our review, including the analytic framework, additional medications (topical capsaicin and lidocaine), nonpharmacologic therapies (addressed in a separate article) (8), search strategies, inclusion criteria, data extraction and quality-rating methods, and additional outcomes (for example, quality of life, global improvement, and patient satisfaction), are available in the full report (9). The protocol was developed by using a standardized process (10) with input from experts and the public and is registered in the PROSPERO database (11). This article addresses the key question, what are the comparative benefits and harms of different systemic pharmacologic therapies for acute or chronic nonradicular low back pain, radicular low back pain, or spinal stenosis? Data Sources and Searches A research librarian searched Ovid MEDLINE (January 2007 through April 2015), the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews (through April 2015). We used the prior ACP/APS review (12) to identify earlier studies. Updated searches were performed through November 2016. We also reviewed reference lists and searched ClinicalTrials.gov. Study Selection Two investigators independently reviewed abstracts and full-text articles against prespecified eligibility criteria. The population was adults with nonradicular or radicular low back pain of any duration (categorized as acute [<4 weeks], subacute [4 to 12 weeks], and chronic [12 weeks]). Excluded conditions were low back pain due to cancer, infection, inflammatory arthropathy, high-velocity trauma, or fracture; low back pain during pregnancy; and presence of severe or progressive neurologic deficits. We evaluated acetaminophen, NSAIDs, opioids, tramadol and tapentadol, antidepressants, skeletal muscle relaxants, benzodiazepines, corticosteroids, and antiseizure medications versus placebo, no treatment, or other therapies. We also evaluated the combination of 2 medications versus 1 medication alone. Outcomes were long-term (1 year) or short-term (6 months) pain or function, mood (for antidepressants), risk for surgery (for corticosteroids), and harms. Given the large number of medications addressed, we included systematic reviews of randomized trials (13, 14). For each medication, we selected the most recent, most relevant, and highest-quality comprehensive systematic review based on a validated assessment tool (14, 15). If more than 1 good-quality systematic review was available, we preferentially selected updates of those used in the ACP/APS review. We supplemented systematic reviews with additional trials. Although we did not include systematic reviews identified in update searches, we checked reference lists for additional studies. We excluded nonEnglish-language articles and abstract-only publications. Data Extraction and Quality Assessment One investigator extracted study data, and a second verified accuracy. For systematic reviews, we abstracted details about inclusion criteria, search strategy, databases searched, search dates, number and characteristics of included studies, quality assessment methods and ratings, synthesis methods, and results. For randomized trials, we abstracted details about the setting, sample size, eligibility criteria, population characteristics, treatment characteristics, results, and funding source. Two investigators independently assessed the quality of each study as good, fair, or poor using criteria developed by the U.S. Preventive Services Task Force (for randomized trials) (16) and AMSTAR (A Measurement Tool to Assess Systematic Reviews) (14). For primary studies included in systematic reviews, we used both the quality ratings and the overall grade (for example, good, fair, or poor, or high or low) as determined in the reviews. We classified the magnitude of effects as small/slight, moderate, or large/substantial based on the definitions in the ACP/APS review (Table 1) (6, 17). We also reported risk estimates based on the proportion of patients achieving successful pain or function outcomes (for example, >30% or >50% improvement). Table 1. Definitions for Magnitude of Effects, Based on Mean Between-Group Differences Data Synthesis and Analysis We synthesized data qualitatively for each medication, stratified according to the duration of symptoms (acute, subacute, or chronic) and presence or absence of radicular symptoms. We reported meta-analysis results from systematic reviews. When statistical heterogeneity was present, we examined the degree of inconsistency and evaluated subgroup and sensitivity analyses. We did not conduct an updated meta-analysis; rather, we qualitatively examined whether results of new studies were consistent with pooled or qualitative findings from prior systematic reviews. Qualitative assessments were based on whether the findings from the new studies were in the same direction as the prior systematic reviews and whether the magnitude of effects was similar; when prior meta-analyses were available, we analyzed whether the estimates and CIs from new studies were encompassed in the CIs from pooled estimates. We assessed the strength of evidence (SOE) for each body of evidence as high, moderate, low, or insufficient based on aggregate study quality, precision, consistency, and directness (18). Role of the Funding Source The Agency for Healthcare Research and Quality (AHRQ) of the U.S. Department of Health and Human Services funded this review. AHRQ staff assisted in developing the scope and key questions. The AHRQ had no role in study selection, quality assessment, or synthesis. Results Literature Search The search and selection of articles are summarized in the Figure. Database searches found 2847 potentially relevant articles. After dual review of abstracts and titles, we selected 746 articles for full-text dual review; 46 publications met inclusion criteria. Quality ratings are summarized in Supplement Tables 1 and 2. Supplement. Data Supplement. Figure. Summary of evidence search and selection. ACP = American College of Physicians; AHRQ = Agency for Healthcare Research and Quality; APS = American Pain Society; NSAID = nonsteroidal anti-inflammatory drug; RCT = randomized, controlled trial; SR = systematic review. * Cochrane databases include the Cochrane Central Register of Controlled Trials and the Cochrane Database of Systematic Reviews. Other sources include prior reports, reference lists of relevant articles, and systematic reviews. Publications may be included or excluded for multiple reasons. Acetaminophen Ten trials evaluated acetaminophen; 9 of these (sample sizes, 39 to 456) were included in the ACP/APS review (19). We identified 1 additional large (n= 1643), good-quality, placebo-controlled trial (20). Six trials compared acetaminophen with NSAIDs and were included in a systematic review of NSAIDs (Supplement Table 3) (21, 22). Along with the new trial, 3 others (2325) were rated good- or high-quality. For acute low back pain, 1 new trial found no differences between 4 weeks or less of scheduled or as-needed acetaminophen (about 4 g/d) and placebo in pain (differences, 0.20 point on a 0- to 10-point scale), function (differences, 0.60 point on the 0- to 24-point RolandMorris Disability Questionnaire [RDQ]), or risk for serious adverse events (about 1% in each group) after 12 weeks (Supplement Table 4) (20). One trial of acetaminophen versus no treatment included in the ACP/APS review (26) also found no differences. We found no difference between acetaminophen and NSAIDs in pain intensity (standardized mean difference [SMD], 0.21 [95% CI, 0.02 to 0.43]) at 3 weeks or less based on 3 low-quality trials, although estimates favored NSAIDs (22). Acetaminophen had a lower risk for adverse events than NSAIDs (relative risk [RR], 0.57 [CI, 0.36 to 0.89]). Evidence was insufficient to determine the effects of acetaminophen versus various nonpharmacologic therapies (24, 27, 28) or amitriptyline (25); each comparison was evaluated in 1 trial with methodological shortcomings. No study evaluated acetaminophen for chronic or radicular low back pain. NSAIDs Seventy trials evaluated NSAIDs; 57 were in the ACP/APS review. Sixty-five trials (total n= 11237; sample sizes, 20 to 690), 28 of which were high-quality, were included in a systematic review (Supplement Table 3) (22). We identified 5 additional trials (n= 54 to 525) (Supplement Table 5) (2933). One trial was rated good-quality (31), and 4 were rated fair-quality (29, 30). For acute back pain, 1 systematic review (22) found that NSAIDs were associated with greater mean improvements in pain intensity than placebo (4 trials: weighted mean difference, 8.39 points on a 0- to 100-point scale [CI, 12.68 to 4.10 points]; chi-square test, 3.47 points; P> 0.10) (3437). One additional trial (n= 171) reported consistent findings (29). Three trials in this review found no differences between an NSAID and placeb

Methadone Overdose and Cardiac Arrhythmia Potential: Findings From a Review of the Evidence for an American Pain Society and College on Problems of Drug Dependence Clinical Practice Guideline

UNLABELLED The number of deaths associated with methadone use increased dramatically in parallel with marked increases in its use, particularly for treatment of chronic pain. To develop a clinical guideline on methadone prescribing to reduce potential harms, the American Pain Society commissioned a review of various aspects related to methadone safety. This article summarizes evidence related to unintentional overdose due to methadone and harms related to cardiac arrhythmia potential. We searched Ovid MEDLINE, the Cochrane Library, and PsycINFO databases through January 2014 for studies assessing harms associated with methadone use; we judged 70 studies to be relevant and to meet inclusion criteria. The majority of studies on overdose and cardiac arrhythmia risk are observational and provide weak evidence on which to base clinical guidelines. In patients prescribed methadone for treatment of opioid dependence, data suggest that mortality benefits related to reduction in illicit drug use outweigh harms. Despite epidemiologic data showing marked increases in the numbers of methadone-related deaths that have been primarily attributed to increased use of methadone for chronic pain, evidence on methadone and mortality risk in this population has been somewhat contradictory. There is some evidence that recent initiation of methadone, psychiatric admissions, and concomitant use of benzodiazepines are associated with a higher risk for overdose. Evidence on cardiac risks is primarily limited to case reports of torsades de pointes, primarily in patients on high doses of methadone, and to studies showing an association between methadone use and prolongation of QTc intervals. Research is needed to understand the effectiveness of dosing methods, electrocardiogram monitoring, and other risk mitigation strategies in patients prescribed methadone. PERSPECTIVE This systematic review synthesizes the evidence related to methadone use and risk for overdose and cardiac arrhythmia. Findings regarding the association between methadone use and QTc interval prolongation and risk factors for methadone-associated overdose suggest potential targets for risk mitigation strategies, though research is needed to determine the effectiveness of such strategies at reducing adverse outcomes.

The Source of Methadone in Overdose Deaths in Western Virginia in 2004

Objectives:Methadone-related overdose deaths increased in the United States by 468% from 1999 to 2005. Current studies associate the nonmedical use of methadone with methadone-related deaths. This study describes medical examiner cases in rural Virginia in 2004 with methadone identified by toxicology and compares cases according to source of methadone. Methods:In 2004, all intentional and unintentional poisoning deaths from the Office of The Chief Medical Examiner, Western District of Virginia, were reviewed to identify cases in which methadone was a direct or contributing cause of death. The Virginia Prescription Monitoring Program was reviewed for prescription opioids in the name of these identified decedents. Decedent participation in local opioid treatment programs (OTP) was also assessed. Results:The source of methadone in the 61 methadone-related overdose deaths was mostly nonprescribed (67%), although 28% of decedents were prescribed methadone for analgesia. Only 5% of decedents were actively enrolled in an OTP. The majority of deaths were attributed to polysubstance overdose. Conclusions:The majority of methadone overdose deaths in this study were related to illicit methadone use, rather than prescribed or OTP uses. Interventions to decrease methadone-related deaths should focus on reduction of nonprescription use of methadone.

Sex Differences in the Medical Care of VA Patients with Chronic Non-Cancer Pain

OBJECTIVE Despite a growing number of women seeking medical care in the veterans affairs (VA) system, little is known about the characteristics of their chronic pain or the pain care they receive. This study sought to determine if sex differences are present in the medical care veterans received for chronic pain. DESIGN Retrospective cohort study using VA administrative data. SUBJECTS The subjects were 17,583 veteran patients with moderate to severe chronic non-cancer pain treated in the Pacific Northwest during 2008. METHODS Multivariate logistic regression assessed for sex differences in primary care utilization, prescription of chronic opioid therapy, visits to emergency departments for a pain-related diagnosis, and physical therapy referral. RESULTS Compared with male veterans, female veterans were more often diagnosed with two or more pain conditions, and had more of the following pain-related diagnoses: fibromyalgia, low back pain, inflammatory bowel disease, migraine headache, neck or joint pain, and arthritis. After adjustment for demographic characteristics, pain diagnoses, mental health diagnoses, substance use disorders, and medical comorbidity, women had lower odds of being prescribed chronic opioid therapy (adjusted OR [AOR] 0.67, 95% CI 0.58-0.78), greater odds of visiting an emergency department for a pain-related complaint (AOR 1.40, 95% CI 1.18-1.65), and greater odds of receiving physical therapy (AOR 1.19, 95% CI 1.05-1.33). Primary care utilization was not significantly different between sexes. CONCLUSIONS Sex differences are present in the care female veterans receive for chronic pain. Further research is necessary to understand the etiology of the observed differences and their associations with clinical outcomes.

Research Gaps on Methadone Harms and Comparative Harms: Findings From a Review of the Evidence for an American Pain Society and College on Problems of Drug Dependence Clinical Practice Guideline

UNLABELLED Methadone-associated overdose deaths have dramatically increased. In order to inform an evidence-based clinical practice guideline to improve safety of methadone prescribing, the American Pain Society commissioned a systematic review on various aspects related to methadone safety. We searched Ovid MEDLINE, Cochrane Library, and PsycINFO databases through July 2012 to identify studies that addressed 1 or more of 17 Key Questions related to methadone safety; an update search was performed in 2014 for new studies related to methadone-related overdose and risks related to cardiac arrhythmias. A total of 168 studies met inclusion criteria for the review. The purpose of this article is to highlight critical research gaps in the literature related to methadone safety. These include lack of evidence on risk factors associated with methadone-overdose deaths and adverse events, limited evidence to evaluate the comparative mortality of methadone versus other opioids, insufficient evidence to fully understand the harms associated with methadone use during pregnancy, and insufficient evidence to determine effects of risk mitigation strategies such as electrocardiogram monitoring, strategies for managing patients with prolonged QTc intervals on screening, urine drug testing, alternative dosing regimens for initiation and titration of therapy, and timing of follow-up. Therefore, most guideline recommendations are based on weak evidence. More research is needed to guide safe methadone prescribing practices and decrease the adverse events associated with methadone. PERSPECTIVE This article summarizes critical research gaps in the literature related to methadone safety, based on a systematic review commissioned by the American Pain Society. Critical research gaps were identified in a number of areas, highlighting the need for additional research to guide safer prescribing and risk mitigation strategies.

Planning and designing the Improving Addiction Care Team (IMPACT) for hospitalized adults with substance use disorder

&NA; People with substance use disorders (SUD) have high rates of hospitalization and readmission, long lengths of stay, and skyrocketing healthcare costs. Yet, models for improving care are extremely limited. We performed a needs assessment and then convened academic and community partners, including a hospital, community SUD organizations, and Medicaid accountable care organizations, to design a care model for medically complex hospitalized patients with SUD. Needs assessment showed that 58% to 67% of participants who reported active substance use said they were interested in cutting back or quitting. Many reported interest in medication for addiction treatment (MAT). Participants had high rates of costly readmissions and longer than expected length of stay. Community stakeholders identified long wait times and lack of resources for medically complex patients as key barriers. We developed the Improving Addiction Care Team (IMPACT), which includes an inpatient addiction medicine consultation service, rapid‐access pathways to posthospital SUD treatment, and a medically enhanced residential care model that integrates antibiotic infusion and residential addiction care. We developed a business case and secured funding from Medicaid and hospital payers. IMPACT provides one pathway for hospitals, payers, and communities to collaboratively address the SUD epidemic.

Correlates of prescription opioid therapy in Veterans with chronic pain and history of substance use disorder

Patients with a history of substance use disorder (SUD) are more likely to be prescribed opioid medications for chronic pain than patients without an SUD history; however, little is known about prescription opioid therapy in populations composed exclusively of patients with SUD. This study examined correlates of prescription opioid therapy in 214 Veterans with chronic noncancer pain and an SUD history. Participants completed psychosocial questionnaires and participated in a structured mental health diagnostic interview, and medical diagnoses and opioid pharmacy data were abstracted from their Department of Veterans Affairs electronic medical records. Participants were categorized into three groups based on opioid prescriptions in the past 90 d: no opioid therapy (n = 134), short-term (<90 d) opioid therapy (n = 31), or long-term (>/= 90 d) opioid therapy (n = 49). Relative to participants prescribed no or short-term opioid therapy, participants who were prescribed long-term opioid therapy had a greater number of pain diagnoses; reported higher levels of pain severity, interference, and catastrophizing; and endorsed lower chronic pain self-efficacy. In a multivariate model, number of pain diagnoses and pain interference were associated with a greater likelihood of being prescribed long-term opioid therapy after controlling for demographic and clinical characteristics. Findings highlight the poor pain-related functioning in patients with SUD histories who are prescribed long-term opioid therapy.

Lessons learned from the implementation of a medically enhanced residential treatment (MERT) model integrating intravenous antibiotics and residential addiction treatment

Abstract BACKGROUND: Hospitalizations for severe infections associated with substance use disorder (SUD) are increasing. People with SUD often remain hospitalized for many weeks instead of completing intravenous antibiotics at home; often, they are denied skilled nursing facility admission. Residential SUD treatment facilities are not equipped to administer intravenous antibiotics. We developed a medically enhanced residential treatment (MERT) model integrating residential SUD treatment and long-term IV antibiotics as part of a broader hospital-based addiction medicine service. MERT had low recruitment and retention, and ended after six months. The goal of this study was to describe the feasibility and acceptability of MERT, to understand implementation factors, and explore lessons learned. METHODS: We conducted a mixed-methods evaluation. We included all potentially eligible MERT patients, defined by those needing ≥2 weeks of intravenous antibiotics discharged from February 1 to August 1, 2016. We used chart review to identify diagnoses, antibiotic treatment location, and number of recommended and actual IV antibiotic-days completed. We audio-recorded and transcribed key informant interviews with patients and staff. We conducted an ethnographic analysis of interview transcripts and implementation field notes. RESULTS: Of the 45 patients needing long-term intravenous antibiotics, 18 were ineligible and 20 declined MERT. 7 enrolled in MERT and three completed their recommended intravenous antibiotic course. MERT recruitment barriers included patient ambivalence towards residential treatment, wanting to prioritize physical health needs, and fears of untreated pain in residential. MERT retention barriers included high demands of residential treatment, restrictive practices due to PICC lines, and perceptions by staff and other residents that MERT patients “stood out” as “different.” Despite the challenges, key informants felt MERT was a positive construct. CONCLUSIONS: Though MERT had many possible advantages; it proved more challenging to implement than anticipated. Our lessons may be applicable to future models integrating post-hospital intravenous antibiotics and SUD care.