Patient Outcomes in Dose Reduction or Discontinuation of Long-Term Opioid Therapy

Approximately 10 million U.S. adults are prescribed long-term opioid therapy (LTOT) for chronic pain despite inadequate evidence of long-term benefit and growing evidence of harms (1, 2). No published studies have compared LTOT (>1 year) versus placebo, no opioid, or nonopioid therapies (2). In recent decades, a dramatic increase in the prescription of opioid medications has been accompanied by increases in opioid overdose (3); more than 33000 opioid overdose deaths occurred in 2015 (4). Higher prescribed opioid dose is associated with overdose risk (57) as well as incidence of opioid use disorder, depression, fracture, motor vehicle accident, and suicide (812). Dose reduction or discontinuation, or opioid tapering, may decrease these risks, and expert guidelines recommend tapering when risks outweigh benefits (13, 14). Opioid tapering can be challenging for both patients and clinicians. In routine practice, discontinuation of LTOT is uncommon, ranging from 8% to 35% in prior cohort studies (15, 16). In a survey of patients receiving high-dose opioid medications for chronic pain, nearly half reported wanting to cut down or stop, yet 80% were receiving high-dose opioids 1 year later (17). Among patients who had a nonfatal overdose while being prescribed LTOT, 91% continued use of opioid medications after the overdose (18). There is little evidence to guide clinicians in the process of opioid tapering, especially in primary care settings, where most opioid therapy is prescribed (19, 20). In addition, little is known about the risks and benefits of opioid tapering. Potential risks include withdrawal symptoms, increased pain, and loss to follow-up (20). However, some patients report improvements in function and quality of life after tapering (21). The effects of opioid tapering on patient outcomes have not been systematically reviewed. To address these gaps, we systematically reviewed the evidence on the effectiveness of strategies to reduce or discontinue LTOT prescribed for chronic pain and the effect of dose reduction or discontinuation of LTOT on important patient outcomes. Methods A multidisciplinary team of investigators with expertise in pain and opioid management developed 2 key questions to address the study objectives. These key questions assessed 1) the effectiveness of strategies to reduce or discontinue LTOT, and 2) the effect of dose reduction or discontinuation of LTOT on prespecified patient outcomes of pain severity, pain-related function, quality of life, opioid withdrawal symptoms, substance use, or adverse events. We followed the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines (22), and the protocol is registered in the PROSPERO database (CRD42015020347). Data Sources and Searches We searched MEDLINE, EMBASE, PsycINFO, CINAHL, and the Cochrane Library from inception through 19 April 2017. We consulted with a research librarian to design a search strategy based on our key questions. We developed a MEDLINE search strategy, which was also applied to other databases, using multiple subject headings (where available) and text words for key concepts of opioids, tapering, and pain. No language or year limits were applied. Within this broader search, we identified potentially relevant systematic reviews and meta-analyses published since 2005. The full electronic search strategy for MEDLINE is presented in Appendix Table 1. We examined reference lists from all included studies and from relevant systematic reviews and published expert guidelines. We also sought input from expert contacts. Records retrieved from each search strategy were organized using the EndNote bibliographic management application (Clarivate Analytics). Appendix Table 1. Ovid MEDLINE Search Strategy Study Selection Two investigators (J.W.F. and H.R.D.) independently reviewed abstracts identified by the search strategy and, when necessary, the full text to determine inclusion. Discrepancies were resolved by consensus. We included studies that involved adults (aged 18 years) who were prescribed LTOT for chronic pain (defined as pain lasting >3 months) and that addressed at least 1 key question. Studies that did not report pain duration were included if the average duration of opioid therapy was more than 3 months. We did not require interventions to involve explicit goals or mandatory conditions of opioid dose reduction. Eligible study designs included randomized trials, cohort studies, casecontrol studies, and case series. We excluded case reports and cross-sectional studies, as well as studies that did not describe the clinical intervention or report patient-level data. We also excluded studies that were not published in English; involved nonhuman participants; addressed only acute, surgical, postoperative, obstetric, or cancer pain; involved only palliative or hospice care; evaluated only illicit or nonmedical use of opioid medications; or addressed only reduction of interventional pain techniques. Data Extraction and Quality Assessment We developed an instrument for data extraction based on prior systematic reviews conducted by the investigators. Three investigators piloted the data extraction instrument using a randomly chosen study, and the results were returned to the pool for formal review. These investigators discussed difficulties with the extraction instrument and reached consensus on minor modifications. Using the finalized instrument, 2 investigators independently extracted data on design, patient sample, setting, interventions, measures, and results from each study. When dose information was not provided by the study, we used a standard algorithm for calculating morphine-equivalent doses (MEDs) of opioid medications (23). Two reviewers independently assessed study quality (risk of bias in individual studies) using criteria developed by the U.S. Preventive Services Task Force (USPSTF), which facilitate rating of study quality as good, fair, or poor (Appendix Table 2). The investigators were blinded to each other's ratings, and discrepancies were resolved by consensus or by a third reviewer, if necessary. We did not exclude studies on the basis of quality. Appendix Table 2. USPSTF Quality Rating Criteria for RCTs and Cohort Studies Data Synthesis We assessed the overall quality of the evidence using a method developed by the GRADE (Grading of Recommendations Assessment, Development and Evaluation) Working Group (24). GRADE provides explicit criteria that address study design, risk of bias, imprecision, inconsistency, indirectness, and magnitude of effect to rate the quality of evidence across studies. This method rates the quality of the evidence from high (very confident that the true effect lies close to that of the estimate of effect) to very low (very little confidence in the effect estimate) (Appendix Table 3). All authors iteratively discussed GRADE assessments to achieve consensus. We present systematic review results organized by key question. We did not attempt meta-analyses because of heterogeneity across studies and methodological limitations of the studies. Appendix Table 3. GRADE Criteria for Assessing Quality of Evidence* Role of the Funding Source The Veterans Health Administration's Substance Use Disorder Quality Enhancement Research Initiative funded the study through its Locally Initiated Projects program (QLP 59-046). The funding sources had no role in the design and conduct of the study; collection, management, analysis, or interpretation of the data; or preparation, review, or approval of the manuscript. Results Database searches identified 3522 abstracts, from which 74 studies met criteria for full-text review. Seventeen additional articles were identified from reference lists and expert contacts. Of these 91 studies, 68 articles representing 67 studies met inclusion criteria (2592) (Appendix Figure). These studies included 11 randomized controlled trials, 8 controlled observational studies, and 48 uncontrolled observational studies. Studies presented data on 12546 patients (range, 5 to 1457 patients); 10 studies conducted at a single center (32, 33, 36, 4448, 70, 80) and 2 studies each at 3 centers (37, 49, 50, 52, 63, 64) may have included data on individual participants in more than 1 study. We categorized studies into 8 mutually exclusive intervention types: interdisciplinary pain programs, buprenorphine-assisted dose reduction, behavioral interventions, detoxification, ketamine-assisted dose reduction, acupuncture, other outpatient programs, and other interventional programs (Table 1). Interventions occurred in outpatient settings, inpatient settings, or both in 42, 15, and 10 studies, respectively; 5 studies were conducted in primary care settings. Among 48 studies reporting baseline opioid dose for participants receiving LTOT, the mean daily dose ranged from 29 to 556 mg MED. Study interventions had an objective of opioid discontinuation or dose reduction in 43 and 12 studies, respectively; 12 studies reported on this outcome in secondary or exploratory analyses. Table 1. Effectiveness of Strategies to Reduce or Discontinue LTOT (n= 67 studies) Appendix Figure. Study flow diagram. All included studies assessed the effectiveness of strategies to reduce or discontinue LTOT (key question 1). Study quality as assessed by the USPSTF criteria was good for 3 studies, fair for 13 studies, and poor for 51 studies. The GRADE quality of evidence to address the effectiveness of strategies to reduce or discontinue LTOT was very low (Table 2; Appendix Table 4). In the remainder of this section, we highlight results from good- and fair-quality studies. Descriptions of all included studies are available in Appendix Table 5. Table 2. Summary of Findings and Quality-of-Evidence Assessment Appendix Table 4. Derivation of GRADE Score* Appendix Table 5. Characteristics of Studies Evaluating the Effectiveness of Strategies to Reduce or Discontinue LTOT for Chronic Pain Thirty-on