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

Roger Chou, MD; Judith A. Turner, PhD; Emily B. Devine, PharmD, PhD, MBA; Ryan N. Hansen, PharmD, PhD; Sean D. Sullivan, PhD; Ian Blazina, MPH; Tracy Dana, MLS; Christina Bougatsos, MPH; and Richard A. Deyo, MD, MPH
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This article was published online first at www.annals.org on 13 January 2015.


From Oregon Health & Science University, Portland, Oregon, and University of Washington, Seattle, Washington.

Disclaimer: The authors of this report are responsible for its content. Statements in the report should not be construed as endorsement by the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.

Acknowledgment: The authors thank Jeffrey Jarvik, MD, MPH, from the University of Washington; Suchitra Iyer, PhD, Agency for Healthcare Research and Quality task order officer; and the members of the National Institutes of Health Working Group.

Financial Support: This project was funded under contract HHSA290201200014I from the Agency for Healthcare Research and Quality of the U.S. Department of Health and Human Services.

Disclosures: Dr. Chou reports grants from the Agency for Healthcare Research and Quality during the conduct of the study and consultancies for the U.S. Department of Health and Human Services, the Physicians' Clinical Support System for Opioids (funded by the Substance Abuse and Mental Health Services Administration), the Mayday Foundation, the Collaborative Opioid Prescribing Education for REMS (funded by the University of Washington), and the University of Wisconsin outside the submitted work. Dr. Turner reports support from a contract to the University of Washington from the Agency for Healthcare Research and Quality during the conduct of the study. Dr. Hansen reports grants from the Agency for Healthcare Research and Quality during the conduct of the study and grants and personal fees from Mallinckrodt Pharmaceuticals and Pacira Pharmaceuticals outside the submitted work. Mr. Blazina reports support from the Agency for Healthcare Research and Quality for a larger report on which this manuscript is based. Ms. Dana reports grants from the Agency for Healthcare Research and Quality during the conduct of the study and outside the submitted work. Ms. Bougatsos reports support from the Agency for Healthcare Research and Quality for a larger report on which this manuscript is based. Dr. Deyo reports a contract from the Agency for Healthcare Research and Quality during the conduct of the study, personal fees from the Informed Medical Decisions Foundation and UpToDate outside the submitted work, and an endowment from Kaiser Permanente outside the submitted work. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M14-2559.

Requests for Single Reprints: Roger Chou, MD, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Mail Code BICC, Portland, OR 97239; e-mail, chour@ohsu.edu.

Current Author Addresses: Dr. Chou, Mr. Blazina, Ms. Dana, and Ms. Bougatsos: Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Mail Code BICC, Portland, OR 97239.

Dr. Turner: Department of Psychiatry and Behavioral Sciences, University of Washington, Box 356560, Seattle, WA 98195-6560.

Drs. Devine and Hansen: University of Washington, Box 357630, Seattle, WA 98195-7630.

Dr. Sullivan: University of Washington, 1959 NE Pacific Street, H-364, Box 357631, Seattle, WA 98195-7630.

Dr. Deyo: Oregon Health & Science University, Mail Code FM, 3181 SW Sam Jackson Park Road, Portland, OR 97239.

Author Contributions: Conception and design: R. Chou, J.A. Turner, R.N. Hansen, S.D. Sullivan.

Analysis and interpretation of the data: R. Chou, J.A. Turner, E.B. Devine, R.N. Hansen, S.D. Sullivan, I. Blazina, T. Dana, C. Bougatsos, R.A. Deyo.

Drafting of the article: R. Chou, J.A. Turner, E.B. Devine, R.N. Hansen, I. Blazina, T. Dana, C. Bougatsos.

Critical revision of the article for important intellectual content: R. Chou, J.A. Turner, E.B. Devine, R.N. Hansen, S.D. Sullivan, I. Blazina, T. Dana, R.A. Deyo.

Final approval of the article: R. Chou, J.A. Turner, E.B. Devine, R.N. Hansen, S.D. Sullivan, I. Blazina, T. Dana, R.A. Deyo.

Statistical expertise: R. Chou.

Obtaining of funding: R. Chou, J.A. Turner, S.D. Sullivan.

Administrative, technical, or logistic support: I. Blazina, T. Dana, C. Bougatsos.

Collection and assembly of data: R. Chou, J.A. Turner, E.B. Devine, R.N. Hansen, S.D. Sullivan, I. Blazina, T. Dana, C. Bougatsos.


Ann Intern Med. 2015;162(4):276-286. doi:10.7326/M14-2559
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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 long-term 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.

Study Selection: Randomized trials and observational studies that involved adults with chronic pain who were prescribed long-term opioid therapy and that evaluated opioid therapy versus placebo, no opioid, or nonopioid therapy; different opioid dosing strategies; or risk mitigation strategies.

Data Extraction: Dual extraction and quality assessment.

Data Synthesis: 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.

Conclusion: 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.

Primary Funding Source: Agency for Healthcare Research and Quality.


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 (12). 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 (1617). 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 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 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, cross-sectional 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.

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.

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).

Grahic Jump Location
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).

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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% (3031, 34). In pain clinic settings, prevalence of misuse ranged from 8% to 16% and prevalence of addiction ranged from 2% to 14% (3233, 3536, 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, younger age, major depression, and use of psychotropic medications (31, 37).

Table Jump PlaceholderAppendix Table 1. Uncontrolled Studies of Long-Term Opioid Use and Abuse, Misuse, and Related Outcomes 

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).

Overdose

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) (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. Compared with an MED of 1 to 19 mg/d, the adjusted HRs for overdose ranged from 1.44 (CI, 0.57 to 3.62) for an MED of 20 to 49 mg/d to 8.87 (CI, 3.99 to 19.72) for an MED of at least 100 mg/d. A similar pattern was observed for serious overdose.

Table Jump PlaceholderAppendix Table 2. Studies of Harms 

A good-quality, population-based, nested case–control study (498 case patients) also found a dose-dependent association with risk for overdose (43). Compared with an MED of 1 to 19 mg/d, the adjusted ORs ranged from 1.32 (CI, 0.94 to 1.84) for an MED of 20 to 49 mg/d to 2.88 (CI, 1.79 to 4.63) for an MED of at least 200 mg/d.

Fractures

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%) after a mean follow-up of 33 months, but the difference was not statistically significant (adjusted HR, 1.28 [CI, 0.99 to 1.64]) (Appendix Table 2) (13). A test for dose response was also of borderline statistical significance.

One good-quality case–control study (21 739 case patients) found current opioid use to be associated with increased risk for hip, humerus, or wrist fracture versus nonuse (adjusted OR, 1.27 [CI, 1.21 to 1.33]) (44). The risk was highest with 1 prescription (OR, 2.70 [CI, 2.34 to 3.13]) and decreased with higher numbers of prescriptions, with no increased risk with more than 20 cumulative prescriptions.

Cardiovascular Events

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 long-term 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.

Endocrinological Harms

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.

Motor Vehicle Accidents

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.

Other Harms

No study evaluated risks for falls; infections; or psychological, cognitive, or gastrointestinal harms among patients with chronic pain who were receiving long-term opioid therapy versus placebo or no opioid therapy.

Opioid Dosing Strategies
Initiation of Opioid Therapy and Titration of Doses

Although 3 fair-quality, open-label trials (reported in 2 articles) compared sustained- versus immediate-release 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 (4849).

Comparative Effectiveness and Harms of Long-Acting Opioids

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) (5052). Two of the trials (5051) 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.

Table Jump PlaceholderAppendix Table 3. Head-to-Head Trials and Observational Studies of Different Long-Acting Opioids 

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, sustained-release 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.

Dose Escalation

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 medications 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).

Other Opioid Dosing Strategies

No study compared the long-term effectiveness of short- versus long-acting opioids; short- plus long-acting 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 (5658) 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).

Risk Assessment Instruments

Four studies (5962) 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). Three studies (6062) (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 poor-quality 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 poor-quality studies (6061) 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.

Table Jump PlaceholderAppendix Table 4. Studies of Risk Assessment Instruments 
Table Jump PlaceholderAppendix Table 5. Predictive Value of Risk Assessment Instruments 
Risk Mitigation Strategies

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, 4243, 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 long-acting opioids, scheduled and continuous versus as-needed dosing, use of opioid rotation, and methods for tapering doses or discontinuing long-term therapy was insufficient to reach reliable conclusions.

As detailed in the full report (20), evidence on different methods for treating acute exacerbations of chronic pain was limited to trials that evaluated immediate pain relief with buccal or intranasal fentanyl, with no data on long-term outcomes. In 2007, the U.S. Food and Drug Administration released a public health advisory because of case reports of deaths and other life-threatening adverse effects in patients prescribed buccal fentanyl (65).

Limited evidence indicates no clear differences in effectiveness of different long-acting opioids when patients are permitted to have doses titrated for adequate pain control (5052). However, no randomized trial was designed to assess relative harms, such as overdose, abuse, or addiction. Methadone is disproportionately represented in case series and epidemiologic studies of opioid-associated deaths; this is believed to be related to its long and variable half-life and potential for electrocardiographic QTc interval prolongation (66). However, the highest-quality observational study, which controlled for confounders by using a propensity-adjusted analysis, found methadone to be associated with lower risk for death compared with sustained-release morphine in a VA setting (53). These results suggest that methadone may not be associated with increased risk for death in some settings. More research is needed to understand the factors that contribute to safer prescribing in different clinical settings.

Evidence on the accuracy and effectiveness of risk assessment instruments for predicting opioid abuse or misuse in patients before initiation of long-term opioid therapy was sparse and was characterized by methodological limitations and inconsistent findings, which precluded reliable conclusions (59, 6162, 67). No study evaluated the effectiveness of risk mitigation strategies, such as the use of urine drug screening, prescription drug monitoring program data, or abuse-deterrent formulations, in reducing harms. Although a previous review found that opioid management plans and urine drug screening were associated with decreased risk for misuse behaviors (10), its conclusions were based on 4 studies that did not meet the inclusion criteria for our review because the effects of these strategies could not be separated from those of concurrent opioid prescribing interventions and because the studies used a historical control group or a before–after design.

Our review has limitations. We excluded non–English-language articles and studies published only as abstracts. We did not attempt meta-analysis and could not use graphical or statistical methods to assess for publication bias because of the paucity of evidence, but we identified no unpublished randomized trials that met our inclusion criteria. Studies that evaluated outcomes after less than 1 year might provide evidence that is relevant to long-term prescribing. However, we found no placebo-controlled trials that lasted at least 6 months. Some potentially relevant studies (6874) were excluded because it was not possible to determine whether patients had chronic pain or received long-term opioid therapy.

Despite these limitations, the lack of scientific evidence on effectiveness and harms of long-term opioid therapy for chronic pain is clear and is in striking contrast to its widespread use for this condition and the large increase in prescription opioid–related overdoses. Although it has been asserted that long-term opioid therapy may be more appropriate for certain types of pain problems or for patients assessed as being at lower risk for overdose or misuse, there was insufficient evidence (as detailed in the full report) to determine how benefits and harms vary in patient subgroups defined by demographic, pain, or other clinical characteristics (20). Studies generally restricted inclusion to persons with noncancer pain or were excluded because it was not possible to determine whether patients with cancer were at the end of life.

Well-designed studies are urgently needed to address the key questions of this review. Randomized trials evaluating benefits and harms of long-term opioid therapy are challenging to conduct, but more flexible, large pragmatic studies or well-designed controlled observational studies, with assessment of and control for potential confounders, could advance scientific knowledge in this area. Studies that include patients who are potentially at higher risk for adverse outcomes are needed because such patients are commonly prescribed long-term opioid therapy (7577). Additional research is needed to develop and validate accurate risk prediction instruments and to determine how using them and other risk mitigation strategies affects patient outcomes. More research is needed on the comparative benefits and harms of different opioids, formulations, and dosing protocols and on comparative benefits and harms of long-term opioid therapy in patient subgroups characterized by type of pain problem and other potentially important characteristics. Greater standardization of methods for defining and identifying abuse-related outcomes is also needed (78).

In summary, reliable conclusions about the effectiveness of long-term opioid therapy for chronic pain are not possible due to the paucity of research to date. Accumulating evidence supports the increased risk for serious harms associated with long-term opioid therapy, including overdose, opioid abuse, fractures, myocardial infarction, and markers of sexual dysfunction; for some harms, the risk seems to be dose-dependent. Research is needed to understand long-term patient outcomes, the risks for opioid abuse and related problems, and the effects of different opioid prescription methods and risk mitigation strategies.

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Deyo RA, Smith DH, Johnson ES, Donovan M, Tillotson CJ, Yang X, et al. Opioids for back pain patients: primary care prescribing patterns and use of services. J Am Board Fam Med. 2011; 24:717-27.
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Mailis-Gagnon A, Lakha SF, Ou T, Louffat A, Yegneswaran B, Umana M, et al. Chronic noncancer pain: characteristics of patients prescribed opioids by community physicians and referred to a tertiary pain clinic. Can Fam Physician. 2011; 57:e97-105.
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Figures

Grahic Jump Location
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).

Grahic Jump Location

Tables

Table Jump PlaceholderAppendix Table 1. Uncontrolled Studies of Long-Term Opioid Use and Abuse, Misuse, and Related Outcomes 
Table Jump PlaceholderAppendix Table 2. Studies of Harms 
Table Jump PlaceholderAppendix Table 3. Head-to-Head Trials and Observational Studies of Different Long-Acting Opioids 
Table Jump PlaceholderAppendix Table 4. Studies of Risk Assessment Instruments 
Table Jump PlaceholderAppendix Table 5. Predictive Value of Risk Assessment Instruments 

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Long-Term Opioid Therapy for Chronic Pain: But What Drives Prescribing?
Posted on February 5, 2015
Michael Lubrano, MD, MPH; Jonathan P. Wanderer, MD, MPhil; Jesse M. Ehrenfeld, MD, MPH
Dr Lubrano, Dept. of Medicine, NYU School of Medicine; Dr Wanderer, Dept. of Anesthesiology, Vanderbilt University
Conflict of Interest: None Declared
There is no doubt that opioid prescribing has increased over the past several decades. As detailed in Chou and colleague’s recent review (1), improving risk mitigation strategies for negative outcomes from long term opioid use is likely warranted. The authors highlight an absence of adequate, scientific evidence for long-term opioid therapy and note that this paucity of data is in “striking contrast” to the widespread use of opiates. While the Chou et. al. describe the consequences of current opioid prescribing patterns, they do not address what is driving this practice.

In the late 1990s, The Joint Commission (TJC) made well-intended recommendations that pain be better recognized (2). The American Pain Society subsequently developed a Pain Care Bill of Rights and promoted pain as a “fifth vital sign.” Other organizations followed suit, including the Veterans Administration which published a “Pain as the 5th Vital Sign Toolkit” in 2000, further justifying the use of opiates for non-malignant pain. The opiate-boom began.

With this modern culture of opiate prescribing, we have seen an incongruity between physician treatment goals and the perceptions that patients have regarding the management of their pain (3). These situations inevitably result in patient-provider conflict. Face-to-face requests for opiates by patients often contradict a number of practice guidelines suggesting non-pharmacologic or non-opioid alternatives for pain. Most patients do not have formal medical training and are largely unaware of what constitutes “quality” medical care, or of adverse medication effects.

In the world of pain management, patient satisfaction surveys may lead to unintended consequences. Government programs now look to patient satisfaction as a surrogate for healthcare quality. For example, Medicare reimbursements partially rely on this metric as part of the CMS Hospital Inpatient Value-Based Purchasing program (4). Not only are physician salaries subject to adjustment based on these data but promotion delays or termination may occur as a result. Overworked physicians with very little time are therefore heavily incentivized to meet their patient’s expectations by prescribing opiates (5). Pain is a vital sign, after all.

While Chou and colleagues make a number of salient suggestions for reducing harms of long-term opioid therapy, we may never be fully successful in curbing these risks without addressing the causes of opiate prescribing. Concerns regarding patient demand, patient satisfaction, and quality measures serve to further complicate this, and deserve attention as our government moves to alter reimbursement without consideration for clinical reality.

References;
1. Chou R, Turner JA, Devine EB, Hansen RN, Sullivan SD, Blazina I, Dana T, Bougatsos C, Deyo RA.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. Ann Intern Med. 2015 Jan 13. [Epub ahead of print]
2. Joint Commission on Accreditation of Healthcare Organizations. Pain assessment and management: an organizational approach. Oakbrook Terrace, IL: Joint Commission on Accreditation of Healthcare Organizations, 2000.
3. Frantsve LME, Kerns RD. Patient-provider interactions in the management of chronic pain: current findings within the context of shared medical decision making. Pain Med. 2007; 8(1):25–35.
4. Hospital Inpatient Value-Based Purchasing Program [Centers for Medicare & Medicaid Services web site]. Available at:http://www.gpo.gov/fdsys/pkg/FR-2011-05-06/pdf/2011-10568.pdf
5. Zgierska A, Miller M, Rabago D. Patient satisfaction, prescription drug abuse, and potential unintended consequences. JAMA. 2012 Apr 4;307(13):1377-8.
Narcotic Prescribing, Benefits and Risks
Posted on March 8, 2015
J Walden Retan MD
The Pain Clinic, Cooper Green/Mercy Health Services, Birmingham, AL
Conflict of Interest: None Declared
Prescriptions of narcotic medications for chronic pain have increased dramatically over the past three decades. The trend has been accompanied by greatly increased levels of prescription narcotic overdose, abuse, addiction and diversion.

The trend is commonly blamed on irresponsible prescribing. As an unintended consequence of the blame, many younger physicians refuse to prescribe narcotics for people with chronic pain. Not for anyone. Not for any pain. The result is that pain is the only treatable condition I can think of that many physicians deliberately will not treat.

"The Effectiveness and Risks of Long-Term Opioid Therapy for Chronic Pain" (Ann Intern Med 2015;162:276-286) perpetuates the negative image of narcotic prescriptions for chronic pain. In a review of 4209 English-language articles, the authors could find no study of the long-term outcomes related to pain, function, or quality of life. Not one. The article is then given over entirely to a discussion of risks. But risk, alone, is never the basis for a physician's or a patient's decision. It is always the balance of risk versus benefit. Omission of discussion of benefit from an article on the effectiveness and risks of therapy is, at a minimum…curious.

There are other curious problems with the article. It speaks of overdose deaths as if all deaths were the same. There’s no mention of the tragic deaths of children who sample parent’s medicines with lethal results. It doesn’t recognize that some overdose deaths are suicides. Chronic pain can cause patients to lose jobs, self-sufficiency, family, all their belongings and hope. Suicides in patients with chronic pain are not surprising.

There’s no mention of diverted narcotics, prescribed for pain, becoming gateway drugs for heroin.

The article speaks of heightened ED drug use in narcotic-treated patients as a possible indicator of opoid-induced sexual dysfunction. Another hypothesis is that pain impairs sexual appetite. Treatment of that pain can allow sexual activity to rebound, uncovering the ED problem.

The article speaks of increased risk of myocardial infarction in narcotic-treated people. Is it the narcotic? Or the changes in activity and diet, forced by pain, that increases the risk?

And so on.

In the end, the article might have closed by pointing out the similarities between narcotics and alcohol. The great majority of people who use alcohol, and of people who are prescribed narcotics, use them responsibly. A minority don’t. The minority attracts all the attention.

Many older physicians…and I…still prescribe narcotics for our patients who have significant chronic pain, despite acknowledged risks. We believe it’s the right thing to do.
In response
Posted on April 4, 2015
Roger Chou
Department of Medical Informatics and Clinical Epidemiology, Oregon Health & Science University
Conflict of Interest: Research funding from the Agency for Healthcare Research and Quality to conduct the review that is the subject of the correspondence
We agree with Dr. Lubrano and colleagues that effectively managing the risks of long-term prescribing opioids will not just be based on evidence regarding benefits and harms (the subject of our systematic review), but also will require that clinicians and policymakers understand and address policy and factors related to the physician-patient interaction that may drive less appropriate prescribing practices.1

As Dr. Retan notes, we identified no studies meeting pre-defined inclusion criteria on the effectiveness of long-term opioid therapy for chronic pain. He does not describe any studies that we overlooked. Therefore, it is unclear what evidence he believes should have been included to discuss long-term benefits. For mortality and overdose-related events, it was generally not possible for studies to exclude cases due to intentional suicide attempts, though the authors controlled for psychological diagnoses and psychiatric medication use.2, 3 For these and other harms, we described limitations of the evidence, including the inability to completely address potential confounders and (in the case of endocrine-related adverse events) the reliance on a surrogate outcome (use of medications for erectile dysfunction and testosterone replacement).4 We describe the associations as reported in the studies and did not speculate about the underlying causes of myocardial infarction or other harms.

High levels of scrutiny for opioid prescribing are warranted based on the substantial increases in opioid-related deaths and prescription opioid abuse.5 It does not seem appropriate, as Dr. Retan states, to equate alcohol use, a substance used recreationally, with long-term opioid therapy, a drug prescribed for medical purposes. Curiously, while downplaying the harms of opioids, Dr. Retan at the same time notes additional harms related to diversion and sampling of opioids by family members and friends and critiques our review for not addressing them. To clarify, our review focused on benefits and harms in persons prescribed opioids. However, we are unaware of any study that has attempted to estimate the harms related to diversion and sampling of opioids from persons prescribed versus not prescribed opioids, or evaluated dose-dependent effects on such outcomes.

1. Reuben DB, Alvanzo AA, Ashikaga T, et al. National Institute of Health Pathways to Prevention Workshop: The rold of opioids in the treatment of chronic pain. Ann Intern Med 2015;162:295-300.
2. Dunn KM, Saunders DW, Rutter CM et al. Opioid prescriptions for chronic pain and overdose: a cohort study. Ann Intern Med 2010;152:85-92.
3. Gomes T, Mamdani MM, Dhalla IA et al. Opioid dose and drug-related mortality in patients with nonmalignant pain. Arch Intern Med 2011;17:686-91.
4. Deyo RA, Smith DH, Johnson E, et al. Prescription opioids for back pain and use of medications for erectile dysfunction. Spine 2013;38:909-15.
5. Okie S. A flood of opioids, a rising tide of deaths. N Engl J Med 2010;363:1981-5
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