The Effectiveness and Risks of Long-Term Opioid Therapy for Chronic Pain: A Systematic Review for a National Institutes of Health Pathways to Prevention Workshop

Chronic pain, often defined as pain lasting longer than 3 months or past the normal time for tissue healing, is common and is a major cause of decreased quality of life and disability (1, 2). Prescriptions of opioid medications for chronic pain have increased dramatically (35). This trend has been accompanied by greatly increased levels of prescription opioid overdose, abuse, addiction, and diversion (615). Compared with placebo, opioid therapy has been found to be associated with alleviation of pain in the short term (16, 17). However, most opioid trials do not extend beyond 6 weeks and are of limited relevance to long-term opioid use. Furthermore, clinical decision making for long-term opioid therapy is complex and requires individualized benefitrisk assessments; opioid selection and dose initiation and titration strategies; integration of risk assessment and mitigation strategies; and consideration of alternative, nonopioid therapies (18). The purpose of this review was to evaluate the evidence on the effectiveness and harms of opioid therapy for chronic pain. We updated a prior review (19) and expanded on it by focusing on long-term benefits and harms of opioid therapy, risk for overdose and injuries, dosing strategies, and risk assessment and mitigation. Methods Detailed methods and data for this review, including the detailed key questions, analytic framework, search strategies, inclusion criteria, and study data extraction and quality rating methods, are available in the full report (20). The protocol was developed by using a standardized process (21) with input from experts and the public and is registered in the PROSPERO database (CRD42014007016) (22). This review focuses on adults with chronic pain and addresses the following key questions: What is the effectiveness of long-term opioid therapy versus placebo, no opioid therapy, or nonopioid therapy for long-term (>1 year) outcomes related to pain, function, and quality of life? What are the risks of opioids versus placebo or no opioids on opioid abuse, addiction, and related outcomes; overdose; and other harms, including falls, fractures, motor vehicle accidents, endocrinological harms, and cardiovascular events? What is the comparative effectiveness of opioid dosing strategies on pain; function; quality of life; and risk for overdose, addiction, abuse, or misuse? What is the accuracy of risk assessment before initiation of opioid therapy for predicting risk for opioid overdose, addiction, abuse, or misuse? What is the effectiveness of risk mitigation strategies on outcomes related to overdose, addiction, abuse, or misuse? Opioid dosing strategies refers to opioid selection, dose initiation and titration, scheduled and continuous versus as-needed dosing, dose escalation versus maintenance, opioid rotation versus continuation of current therapy, methods for discontinuation of opioid therapy, tapering of doses versus continuation of therapy, and different tapering method. Risk mitigation strategies include patient education; opioid therapy plans; urine drug screening; and use of prescription drug monitoring program data, monitoring instruments, more frequent monitoring intervals, pill counts, and abuse-deterrent formulations. Data Sources and Searches A research librarian searched MEDLINE, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, PsycINFO, and CINAHL for English-language articles published from January 2008 through August 2014. We also included relevant studies from a prior review (19), reviewed reference lists, and searched ClinicalTrials.gov. Study Selection Two investigators independently reviewed abstracts and full-text articles against prespecified eligibility criteria. We included studies of adults (aged 18 years) with chronic pain (>3 months) who were prescribed long-term opioid therapy (defined as opioid use on most days for >3 months). We included studies of long-term opioid therapy versus placebo, no therapy, another drug, or nondrug therapy; studies of different opioid dosing strategies; and studies of risk mitigation strategies that evaluated the outcomes described in the key questions. We focused on outcomes reported after at least 1 year of opioid therapy. For overdose and injuries (such as fractures, falls, and motor vehicle accidents), we included studies with any duration of opioid prescription for chronic pain because such outcomes can occur early during therapy. We also included studies of any duration on dose initiation and titration and opioid therapy discontinuation. Studies of parenteral opioids and tramadol (a dual-mechanism medication with weak opioid -receptor affinity) were excluded. We included studies that did not report pain duration if the average duration of opioid therapy was more than 3 months and studies that did not report the duration of therapy if patients were prescribed long-acting opioids, which are not recommended for short-term use. We also included studies of patients with cancer pain who were not at the end of life. Studies of acute pain, addiction treatment, and pregnant or breastfeeding women were excluded. We included randomized trials and observational studies (cohort studies with concurrent controls, cross-sectional studies, and casecontrol studies) that controlled for potential confounders. We also included observational studies without a nonopioid control group that involved patients with chronic pain who were prescribed opioid therapy for at least 1 year and assessed abuse, misuse, or addiction as a primary outcome by using predefined methods. Finally, we included studies on the accuracy of risk prediction instruments administered before initiation of opioid therapy for predicting misuse, abuse, or addiction. Data Extraction and Quality Assessment One investigator extracted details about the study design, patient sample, setting, opioid therapy characteristics, and results. Another investigator verified the extracted data for accuracy. Two investigators independently assessed risk of bias for each study (including studies in the prior review) as good, fair, or poor by using predefined criteria for randomized trials (23), observational studies (24), and risk prediction instruments (2527), in conjunction with the approach recommended in the Agency for Healthcare Research and Quality (AHRQ) methods guides (21, 25). Discrepancies were resolved through a consensus process. Data Synthesis and Analysis We assessed the overall strength of each body of evidence as high, moderate, low, or insufficient by using the approach described in the AHRQ Methods Guide for Effectiveness and Comparative Effectiveness Reviews (28), based on aggregate study quality, precision, consistency, and directness. We did not attempt meta-analyses because of the small number of studies; variability in study designs, patient samples, and interventions; and methodological shortcomings of the studies. Role of the Funding Source The AHRQ funded the review, and a working group convened by the National Institutes of Health assisted in developing the review's scope and key questions. Both had no role in study selection, quality assessment, or synthesis. The investigators are solely responsible for the content. Results The literature search and selection is summarized in the Figure. Database searches resulted in 4209 potentially relevant articles. After dual review of abstracts and titles, 39 studies (in 40 publications) were included. Five of these studies, which assessed immediate effects of opioids used to treat acute pain exacerbations, were omitted here but are discussed in the full report (20). Figure. Summary of evidence search and selection. * Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews. Includes reference lists of relevant articles and systematic reviews. Some studies have multiple publications, and some are included for >1 key question. Includes 5 studies on acute exacerbations of pain, which are discussed in the full report (20). Long-Term Effectiveness No study of opioid therapy versus placebo, no opioid therapy, or nonopioid therapy evaluated long-term (>1 year) outcomes related to pain, function, or quality of life. Harms Opioid Abuse, Addiction, and Related Outcomes No randomized trial evaluated opioid abuse, addiction, or related outcomes with long-term opioid therapy versus placebo or no opioid therapy. In 1 fair-quality study that used claims data from a large commercial health plan, long-term opioid therapy (>90 days' supply of opioids within 12 months of a new chronic pain diagnosis) versus no opioid prescription was associated with increased risk for a diagnosis of opioid abuse or dependence (29). Rates of opioid abuse or dependence ranged from 0.7% with low-dose therapy (morphine-equivalent dose [MED] of 1 to 36 mg/d) to 6.1% with high-dose therapy (MED 120 mg/d) compared with 0.004% with no opioids; adjusted odds ratios (ORs) ranged from 14.9 (95% CI, 10.4 to 21.5) for low-dose therapy to 122.5 (CI, 72.8 to 206.0) for high-dose therapy. In 10 fair-quality uncontrolled studies (Appendix Table 1) (3040), estimates of opioid abuse, addiction, and related outcomes varied substantially, even after stratification by setting. No study reported blinding of outcome assessors to patient characteristics, and some studies also did not assess predefined outcomes in all patients. In primary care settings, prevalence of opioid abuse ranged from 0.6% to 8% and prevalence of dependence ranged from 3% to 26% (30, 31, 34). In pain clinic settings, prevalence of misuse ranged from 8% to 16% and prevalence of addiction ranged from 2% to 14% (32, 33, 35, 36, 3840). Prevalence of aberrant drug-related behaviors (such as aberrant urine drug test results, medication agreement violations, or other behaviors indicative of misuse) ranged from 6% to 37%. Factors associated with increased risk for misuse included history of substance use disorder