Background: Increases in prescriptions of opioid medications for chronic pain have been accompanied by increases in opioid overdoses, abuse, and other harms and uncertainty about longterm effectiveness. Purpose: To evaluate evidence on the effectiveness and harms of long-term (>3 months) opioid therapy for chronic pain in adults. Data Sources: MEDLINE, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, PsycINFO, and CINAHL (January 2008 through August 2014); relevant studies from a prior review; reference lists; and ClinicalTrials.gov. Randomized trials and observational studies that involved adults with chronic pain who were prescribed longterm opioid therapy and that evaluated opioid therapy versus placebo, no opioid, or nonopioid therapy; different opioid dosing strategies; or risk mitigation strategies. Dual extraction and quality assessment. No study of opioid therapy versus no opioid therapy evaluated long-term (>1 year) outcomes related to pain, function, quality of life, opioid abuse, or addiction. Good-and fair-quality observational studies suggest that opioid therapy for chronic pain is associated with increased risk for overdose, opioid abuse, fractures, myocardial infarction, and markers of sexual dysfunction, although there are few studies for each of these outcomes; for some harms, higher doses are associated with increased risk. Evidence on the effectiveness and harms of different opioid dosing and risk mitigation strategies is limited. Limitations: Non-English-language articles were excluded, meta-analysis could not be done, and publication bias could not be assessed. No placebo-controlled trials met inclusion criteria, evidence was lacking for many comparisons and outcomes, and observational studies were limited in their ability to address potential confounding. Evidence is insufficient to determine the effectiveness of long-term opioid therapy for improving chronic pain and function. Evidence supports a dose-dependent risk for serious harms. Ann Intern Med. 2015;162:276-286. doi:10.7326/M14-2559 www.annals.org For author affiliations, see end of text. This article was published online first at www.annals.org on 13 January 2015. hronic 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 (3-5). This trend has been accompanied by greatly increased levels of prescription opioid overdose, abuse, addiction, and diversion (6 -15). 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 benefit-risk 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. 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 out- 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. 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. 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 dualmechanism medication with weak opioid μ-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, crosssectional studies, and case-control 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. 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 (25-27), 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. 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. 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. 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). No study of opioid therapy versus placebo, no opioid therapy, or nonopioid therapy evaluated long-term No randomized trial evaluated opioid abuse, addiction, or related outcomes with long-term opioid therapy versus placebo or no opioid therapy. In 1 fairquality 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 , available at www.annals.org) (30 -40), 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, 38 -40). 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, younger age, major depression, and use of psychotropic medications (31, 37). Definitions of opioid abuse, addiction, and related outcomes and methods used to identify these events varied (Appendix Table 1 ). All studies were conducted before the introduction of the diagnostic criteria for opioid use disorder in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) (41). One large, fair-quality retrospective cohort study (n = 9940) found that, compared with nonuse, recent opioid use was associated with an increased risk for any overdose events (adjusted hazard ratio [HR], 5.2 [CI, 2.1 to 12.5]) and serious overdose events (adjusted HR, 8.4 [CI, 2.5 to 28]) (Appendix Table 2 , available at www .annals.org) (42). The annual overdose rate was 256 per 100 000 person-years among patients who had recently received prescribed opioids versus 36 per 100 000 person-years among those who had not. Higher doses were associated with increased risk. A good-quality, population-based, nested casecontrol study (498 case patients) also found a dosedependent association with risk for overdose (43).  A fair-quality cohort study (n = 2341 adults aged ≥60 years) found a higher fracture rate among current opioid users (6%) than among current nonusers (4%)  One fair-quality cohort study (n = 297 314) found that a cumulative opioid supply of at least 180 days over a 3.5-year period was associated with an increased risk for myocardial infarction versus no longterm opioid therapy (adjusted incidence rate ratio, 2.66 [CI, 2.30 to 3.08]) (Appendix Table 2 ) (45). Compared with a cumulative MED of 0 to 1350 mg over 90 days, the adjusted incidence rate ratio for myocardial infarction was 1.21 (CI, 1.02 to 1.45) for an MED of 1350 to less than 2700 mg and ranged from 1.42 to 1.89 for MEDs of at least 2700 mg. A good-quality case-control study (11 693 case patients) found that current opioid therapy versus nonuse was associated with increased odds of myocardial infarction (adjusted OR, 1.28 [CI, 1.19 to 1.37]) (46). No study evaluated associations between long-term opioid therapy and risk for arrhythmia or sudden death. One fair-quality cross-sectional study of men with back pain (n = 11 327) found that, compared with nonuse, long-term opioid use was associated with increased use of medications for erectile dysfunction or testosterone replacement (adjusted OR, 1.45 [CI, 1.12 to 1.87]) (Appendix Table 2 ) (7). Compared with MEDs of 0 to less than 20 mg/d, an MED of at least 120 mg/d was associated with increased risk (OR, 1.58 [CI, 1.03 to 2.43]), but there was no increased risk at MEDs of 20 to less than 120 mg/d. Sexual dysfunction was not measured directly; other study limitations included unknown duration of pain and inability to determine whether medication use preceded receipt of opioids. One good-quality case-control study (5300 case patients) found that MEDs of at least 20 mg/d were associated with increased odds of road trauma among drivers (Appendix Table 2 ) (47). Compared with MEDs of 1 to less than 20 mg/d, the adjusted ORs ranged from 1.21 to 1.42 for MEDs of at least 20 mg/d. No study evaluated risks for falls; infections; or psychological, cognitive, or gastrointestinal harms among patients with chronic pain who were receiving longterm opioid therapy versus placebo or no opioid therapy. Opioid Dosing Strategies Although 3 fair-quality, open-label trials (reported in 2 articles) compared sustained-versus immediaterelease opioids for titration of doses to stable pain control, results were inconsistent and difficult to interpret because of differences between treatment groups in dosing protocols (titrated vs. fixed dosing) and opioid doses (48, 49). Three randomized, head-to-head trials of various long-acting opioids found no differences in 1-year outcomes related to pain or function (Appendix Table 3 , available at www.annals.org) (50 -52). Two of the trials (50, 51) were rated fair-quality, and one (52) was rated poor-quality. Methodological limitations included high attrition and open-label design; the poor-quality trial also did not report statistical analyses comparing results between groups for most outcomes. Opioid doses were titrated to effect or were determined during a run-in period, and no trial was designed to assess risk for abuse or addiction. A fair-quality retrospective cohort study based on national pharmacy data from the Department of Veterans Affairs (VA) system compared all-cause mortality among patients with chronic pain who were prescribed methadone (n = 28 554) or long-acting morphine (n = 79 938) (53). In a propensity-stratified analysis, overall risk for death was lower with methadone than with morphine (adjusted HR, 0.56 [CI, 0.51 to 0.62]); a similar pattern was seen in all propensity quintiles except the highest. A fair-quality retrospective cohort study based on Oregon Medicaid data (n = 5684) found that, compared with sustained-release morphine, sustainedrelease oxycodone was associated with a lower risk for an emergency department visit or hospitalization involving an opioid-related adverse event (adjusted HR, 0.45 [CI, 0.26 to 0.77]) or death (adjusted HR, 0.71 [CI, 0.54 to 0.94]) (54). There were no statistically significant differences between methadone and long-acting morphine in risk for death or overdose symptoms. A limitation of this study was that overdose symptoms (alteration of consciousness, malaise, fatigue, lethargy, or respiratory failure) were nonspecific for opioid-related adverse events. One fair-quality randomized trial (n = 140) found no differences between more liberal dose escalation (doses increased according to preset dosing guidelines for inadequate pain relief) versus maintenance of current doses (doses increased only if medically necessary because of clear dosage tolerance or acute injury) after 12 months in pain, function, and use of nonopioid med- ications or physical therapy (55). There were also no differences in all-cause withdrawals or withdrawals due to opioid misuse. However, the difference in opioid doses prescribed at the end of the trial was relatively small (the mean MED was 52 mg/d with more liberal dosing vs. 40 mg/d with maintenance of current doses). No study compared the long-term effectiveness of short-versus long-acting opioids; short-plus longacting opioids versus long-acting opioids alone; scheduled, continuous dosing versus as-needed dosing; or opioid rotation versus maintenance of current therapy. Evidence was limited to small, poor-quality studies (56 -58) for the comparative effectiveness of tapering of opioid doses or discontinuation of therapy versus maintenance of therapy and for different strategies for tapering of doses. No study evaluated long-term benefits or harms associated with different strategies for treating acute exacerbations of chronic pain; effects on immediate pain relief are detailed in the full report (20). Four studies (59 -62) evaluated the accuracy of risk assessment instruments, administered before the initiation of opioid therapy, for predicting opioid abuse or misuse (Appendix Tables 4 and 5, available at www .annals.org). Three studies (60 -62) (2 fair-quality and 1 poor-quality) reported inconsistent results for the 10-item Opioid Risk Tool. Based on a cutoff score of greater than 4 (on a scale of 0 to 25), sensitivity ranged from 0.20 to 0.99; two of these studies reported specificities of 0.88 and 0.16. Two studies (59, 61) evaluated the accuracy of version 1 of the 14-item Screener and Opioid Assessment for Patients with Pain instrument. One fair-quality study (59) reported a sensitivity of 0.68 (CI, 0.52 to 0.81) and specificity of 0.38 (CI, 0.29 to 0.49) based on a cutoff score of at least 8 (on a scale of 0 to 56), resulting in weak positive and negative likelihood ratios (1.11 and 0.83, respectively). One poorquality study (61) reported a sensitivity of 0.73, based on a cutoff score of at least 6 (specificity not reported). The accuracy of other risk assessment instruments was evaluated in 1 poor-quality study each. Methodological shortcomings included unclear blinding of outcome assessors to findings of the screening instrument and use of definitions for aberrant drug-related behaviors that were not well-standardized or described. The poorquality studies (60, 61) also did not apply the risk assessment instruments to all patients or included only patients with abuse or misuse. No study evaluated the effectiveness of risk prediction instruments for improving outcomes related to overdose, addiction, abuse, or misuse. No study evaluated the effectiveness of risk mitigation strategies for improving outcomes related to overdose, addiction, abuse, or misuse. The evidence in this review is summarized in the Table. We identified no studies of long-term opioid therapy for chronic pain versus no opioid therapy or nonopioid therapies that evaluated effects on pain, function, or quality of life at 1 year or longer. Most placebo-controlled, randomized trials were shorter than 6 weeks, and almost all were shorter than 16 weeks (17). We did not include uncontrolled studies for these outcomes; reliable conclusions cannot be drawn from such studies because of the lack of a nonopioid comparison group and heterogeneity of the results (63). More evidence is available on harms of opioid therapy. Controlled observational studies published after our prior review (19) suggest that, compared with no opioid use, opioid therapy for chronic pain is associated with increased risk for overdose (42), opioid abuse and dependence (29), fractures (13), myocardial infarction (46), and use of medications to treat sexual dysfunction (7). For fractures, 1 study found that the risk was highest shortly after the start of opioid therapy (44). For some harms, studies suggest that higher opioid doses are associated with increased risk (7, 13, 29, 42, 43, 45) . As with all observational studies, findings are susceptible to residual confounding. Although we restricted inclusion to studies that attempted to control for potential confounders, most studies were based on information available in administrative databases, which are typically limited in their ability to address potentially important confounders. In uncontrolled studies, rates of abuse and related outcomes varied substantially, even after the studies were stratified by setting (primary care or pain clinic). Studies differed in how addiction, abuse, misuse, and dependence were defined and in the methods used to identify these outcomes. Our review found higher rates of abuse and related outcomes than a previous systematic review that included studies that did not report predefined methods for ascertaining opioid addiction (63). All studies were done before the recent DSM-5 definition of opioid use disorder was published (41). Evidence on the effectiveness of different opioid dosing strategies is limited. A trial of a more liberal dose-escalation strategy versus maintenance of current doses found no differences in outcomes, but doses were similar at the end of the trial (55). One study from Washington reported a decrease in the number of opioid-associated overdose deaths after implementation of a guideline that included an MED threshold of 120 mg/d for reassessment and consultation (64), but this study did not meet our inclusion criteria because it was a before-after study in which changes in the number of overdose deaths could have resulted from factors other than use of the dose threshold. Evidence on benefits and harms of methods for initiating opioid therapy and titrating doses, use of short-versus longacting opioids, scheduled and continuous versus asneeded dosing, use of opioid rotation, and methods Effectiveness and Risks of Long-Term Opioid Therapy for Chronic Pain
Authors in REF , evaluated evidences on the effectiveness and harms of long-term Opioid therapy for chronic pain in adults.
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
Annals of Internal Medicine
Annals of Internal Medicine
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