The Effectiveness and Risks of Long-Term Opioid Therapy for Chronic Pain: A Systematic Review for a National Institutes of Health Pathways to Prevention WorkshopFREE
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.
To evaluate evidence on the effectiveness and harms of long-term (>3 months) opioid therapy for chronic pain in adults.
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 long-term 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.
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.
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 (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 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.
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 (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.
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).
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.
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) (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) (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.
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.
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.
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.
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.
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 (48, 49).
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) (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, 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.
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 (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).
Risk Assessment Instruments
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). 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 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 (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.
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, 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 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 (50–52). 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, 61, 62, 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 (68–74) 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 (75–77). 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.
- 1. Classification of chronic pain. Descriptions of chronic pain syndromes and definitions of pain terms. Prepared by the International Association for the Study of Pain, Subcommittee on Taxonomy. Pain Suppl. 1986;3:S1-226. [PMID: 3461421] MedlineGoogle Scholar
Institute of Medicine. Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research. Washington, DC: National Academies Pr; 2011. Google Scholar
Sullivan MD, Edlund MJ, Fan MY, Devries A, Brennan Braden J, Martin BC. Trends in use of opioids for non-cancer pain conditions 2000–2005 in commercial and Medicaid insurance plans: the TROUP study. Pain. 2008;138:440-9. [PMID: 18547726] doi:10.1016/j.pain.2008.04.027 CrossrefMedlineGoogle Scholar
Boudreau D, VonKorff M, Rutter CM, Saunders K, Ray GT, Sullivan MD, et al. Trends in long-term opioid therapy for chronic non-cancer pain. Pharmacoepidemiol Drug Saf. 2009;18:1166-75. [PMID: 19718704] doi:10.1002/pds.1833 CrossrefMedlineGoogle Scholar
Olsen Y, Daumit GL, Ford DE. Opioid prescriptions by U.S. primary care physicians from 1992 to 2001. J Pain. 2006;7:225-35. [PMID: 16618466] CrossrefMedlineGoogle Scholar
Starrels JL, Becker WC, Weiner MG, Li X, Heo M, Turner BJ. Low use of opioid risk reduction strategies in primary care even for high risk patients with chronic pain. J Gen Intern Med. 2011;26:958-64. [PMID: 21347877] doi:10.1007/s11606-011-1648-2 CrossrefMedlineGoogle Scholar
Deyo RA, Smith DH, Johnson ES, Tillotson CJ, Donovan M, Yang X, et al. Prescription opioids for back pain and use of medications for erectile dysfunction. Spine (Phila Pa 1976). 2013;38:909-15. [PMID: 23459134] doi:10.1097/BRS.0b013e3182830482 CrossrefMedlineGoogle Scholar
- 8. Substance Abuse and Mental Health Services Administration. Treatment Episode Data Set (TEDS). 1999–2009. National Admissions to Substance Abuse Treatment Services. DASIS Series: S-56. HHS publication no. (SMA) 11-4646. Rockville, MD: Substance Abuse and Mental Health Services Administration; 2011. Accessed at http://wwwdasis.samhsa.gov/teds09/TEDS2k9NWeb.pdf on 12 December 2014. Google Scholar
- 9. Center for Behavioral Health Statistics and Quality. The DAWN Report: Highlights of the 2010 Drug Abuse Warning Network (DAWN) Findings on Drug-Related Emergency Department Visits. Rockville, MD: Substance Abuse and Mental Health Services Administration; 2012. Accessed at www.samhsa.gov/data/sites/default/files/DAWN096/DAWN096/SR096EDHighlights2010.pdf on 12 December 2014. Google Scholar
Starrels JL, Becker WC, Alford DP, Kapoor A, Williams AR, Turner BJ. Systematic review: treatment agreements and urine drug testing to reduce opioid misuse in patients with chronic pain. Ann Intern Med. 2010;152:712-20. [PMID: 20513829] doi:10.7326/0003-4819-152-11-201006010-00004 LinkGoogle Scholar
Warner M, Chen LH, Makuc DM, Anderson RN, Miniño AM. Drug poisoning deaths in the United States, 1980–2008. NCHS Data Brief. 2011:1-8. [PMID: 22617462] MedlineGoogle Scholar
Volkow ND, McLellan TA. Curtailing diversion and abuse of opioid analgesics without jeopardizing pain treatment. JAMA. 2011;305:1346-7. [PMID: 21467287] doi:10.1001/jama.2011.369 CrossrefMedlineGoogle Scholar
Saunders KW, Dunn KM, Merrill JO, Sullivan M, Weisner C, Braden JB, et al. Relationship of opioid use and dosage levels to fractures in older chronic pain patients. J Gen Intern Med. 2010;25:310-5. [PMID: 20049546] doi:10.1007/s11606-009-1218-z CrossrefMedlineGoogle Scholar
Rolita L, Spegman A, Tang X, Cronstein BN. Greater number of narcotic analgesic prescriptions for osteoarthritis is associated with falls and fractures in elderly adults. J Am Geriatr Soc. 2013;61:335-40. [PMID: 23452054] doi:10.1111/jgs.12148 CrossrefMedlineGoogle Scholar
- 15. Centers for Disease Control and Prevention. Prescription Drug Overdose in the United States: Fact Sheet. Atlanta, GA: Centers for Disease Control and Prevention; 2014. Accessed at www.cdc.gov/homeandrecreationalsafety/overdose/facts.html on 12 December 2014. Google Scholar
Furlan AD, Sandoval JA, Mailis-Gagnon A, Tunks E. Opioids for chronic noncancer pain: a meta-analysis of effectiveness and side effects. CMAJ. 2006;174:1589-94. [PMID: 16717269] CrossrefMedlineGoogle Scholar
Furlan A, Chaparro LE, Irvin E, Mailis-Gagnon A. A comparison between enriched and nonenriched enrollment randomized withdrawal trials of opioids for chronic noncancer pain. Pain Res Manag. 2011;16:337-51. [PMID: 22059206] CrossrefMedlineGoogle Scholar
Chou R, Fanciullo GJ, Fine PG, Adler JA, Ballantyne JC, Davies P, et al; American Pain Society-American Academy of Pain Medicine Opioids Guidelines Panel. Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain. J Pain. 2009;10:113-30. [PMID: 19187889] doi:10.1016/j.jpain.2008.10.008 CrossrefMedlineGoogle Scholar
- 19. American Pain Society, American Academy of Pain Medicine. Guideline for the Use of Chronic Opioid Therapy in Chronic Noncancer Pain: Evidence Review. Chicago: American Pain Society; 2009. Accessed at www.americanpainsociety.org/uploads/pdfs/Opioid_Final_Evidence_Report.pdf on 12 December 2014. Google Scholar
- 20. Chou R, Deyo R, Devine B, Hansen R, Sullivan S, Jarvik JG, et al. The Effectiveness and Risks of Long-Term Opioid Treatment of Chronic Pain. Evidence report/technology assessment no. 218. (Prepared by the Pacific Northwest Evidence-based Practice Center under contract no. 290-2012-00014-I). AHRQ publication no. 14-E005-EF. Rockville, MD: Agency for Healthcare Research and Quality; 2014. Accessed at www.effectivehealthcare.ahrq.gov/ehc/products/557/1971/chronic-pain-opioid-treatment-report-141007.pdf on 12 December 2014. Google Scholar
- 21. Agency for Healthcare Research and Quality. Methods Guide for Effectiveness and Comparative Effectiveness Reviews. Effective Health Care Program. AHRQ publication no. 10(13)-EHC063-EF. Rockville, MD: Agency for Healthcare Research and Quality; 2013. Accessed at www.effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?productid=318&pageaction=displayproduct on 12 December 2014. Google Scholar
- 22. Chou R, Deyo R, Devine B, Hansen R, Sullivan S, Jarvik J, et al. The effectiveness and risks of long-term opioid treatment of chronic pain. PROSPERO: International Prospective Register of Systematic Reviews. CRD42014007016. 2014. Accessed at www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42014007016 on 12 December 2014. Google Scholar
Furlan AD, Pennick V, Bombardier C, van Tulder M; Editorial Board, Cochrane Back Review Group. 2009 updated method guidelines for systematic reviews in the Cochrane Back Review Group. Spine (Phila Pa 1976). 2009;34:1929-41. [PMID: 19680101] doi:10.1097/BRS.0b013e3181b1c99f CrossrefMedlineGoogle Scholar
- 24. U.S. Preventive Services Task Force. Procedure Manual. AHRQ publication no. 08-05118-EF. Rockville, MD: U.S. Preventive Services Task Force; 2008. Accessed at www.uspreventiveservicestaskforce.org/uspstf08/methods/procmanual.htm on 12 December 2014. Google Scholar
- 25. Agency for Healthcare Research and Quality. Methods Guide for Medical Test Reviews. Effective Health Care Program. Rockville, MD: Agency for Healthcare Research and Quality; 2010. Accessed at http://effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?productid=558&pageaction=displayproduct on 12 December 2014 Google Scholar
Whiting PF, Rutjes AW, Westwood ME, Mallett S, Deeks JJ, Reitsma JB, et al; QUADAS-2 Group. QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies. Ann Intern Med. 2011;155:529-36. [PMID: 22007046] doi:10.7326/0003-4819-155-8-201110180-00009 LinkGoogle Scholar
McGinn TG, Guyatt GH, Wyer PC, Naylor CD, Stiell IG, Richardson WS. Users' guides to the medical literature: XXII: how to use articles about clinical decision rules. Evidence-Based Medicine Working Group. JAMA. 2000;284:79-84. [PMID: 10872017] CrossrefMedlineGoogle Scholar
- 28. Owens D, Lohr KN, Atkins D, Treadwell J, Reston J, Bass E, et al. Grading the strength of a body of evidence when assessing health care interventions for the Effective Health Care Program of the Agency for Healthcare Research and Quality: an update. In: Methods Guide for Effectiveness and Comparative Effectiveness Reviews. Rockville, MD: Agency for Healthcare Research and Quality; 2011. Accessed at http://effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?productid=1752&pageaction=displayproduct on 12 December 2014. Google Scholar
Edlund MJ, Martin BC, Russo JE, DeVries A, Braden JB, Sullivan MD. The role of opioid prescription in incident opioid abuse and dependence among individuals with chronic noncancer pain: the role of opioid prescription. Clin J Pain. 2014;30:557-64. [PMID: 24281273] doi:10.1097/AJP.0000000000000021 CrossrefMedlineGoogle Scholar
Banta-Green CJ, Merrill JO, Doyle SR, Boudreau DM, Calsyn DA. Opioid use behaviors, mental health and pain—development of a typology of chronic pain patients. Drug Alcohol Depend. 2009;104:34-42. [PMID: 19473786] doi:10.1016/j.drugalcdep.2009.03.021 CrossrefMedlineGoogle Scholar
Boscarino JA, Rukstalis M, Hoffman SN, Han JJ, Erlich PM, Gerhard GS, et al. Risk factors for drug dependence among out-patients on opioid therapy in a large US health-care system. Addiction. 2010;105:1776-82. [PMID: 20712819] doi:10.1111/j.1360-0443.2010.03052.x CrossrefMedlineGoogle Scholar
Compton PA, Wu SM, Schieffer B, Pham Q, Naliboff BD. Introduction of a self-report version of the Prescription Drug Use Questionnaire and relationship to medication agreement noncompliance. J Pain Symptom Manage. 2008;36:383-95. [PMID: 18508231] doi:10.1016/j.jpainsymman.2007.11.006 CrossrefMedlineGoogle Scholar
Cowan DT, Wilson-Barnett J, Griffiths P, Allan LG. A survey of chronic noncancer pain patients prescribed opioid analgesics. Pain Med. 2003;4:340-51. [PMID: 14750910] CrossrefMedlineGoogle Scholar
Fleming MF, Balousek SL, Klessig CL, Mundt MP, Brown DD. Substance use disorders in a primary care sample receiving daily opioid therapy. J Pain. 2007;8:573-82. [PMID: 17499555] CrossrefMedlineGoogle Scholar
Højsted J, Nielsen PR, Guldstrand SK, Frich L, Sjøgren P. Classification and identification of opioid addiction in chronic pain patients. Eur J Pain. 2010;14:1014-20. [PMID: 20494598] doi:10.1016/j.ejpain.2010.04.006 CrossrefMedlineGoogle Scholar
Portenoy RK, Farrar JT, Backonja MM, Cleeland CS, Yang K, Friedman M, et al. Long-term use of controlled-release oxycodone for noncancer pain: results of a 3-year registry study. Clin J Pain. 2007;23:287-99. [PMID: 17449988] CrossrefMedlineGoogle Scholar
Reid MC, Engles-Horton LL, Weber MB, Kerns RD, Rogers EL, O'Connor PG. Use of opioid medications for chronic noncancer pain syndromes in primary care. J Gen Intern Med. 2002;17:173-9. [PMID: 11929502] CrossrefMedlineGoogle Scholar
Saffier K, Colombo C, Brown D, Mundt MP, Fleming MF. Addiction Severity Index in a chronic pain sample receiving opioid therapy. J Subst Abuse Treat. 2007;33:303-11. [PMID: 17376639] CrossrefMedlineGoogle Scholar
Schneider JP, Kirsh KL. Defining clinical issues around tolerance, hyperalgesia, and addiction: a quantitative and qualitative outcome study of long-term opioid dosing in a chronic pain practice. J Opioid Manag. 2010;6:385-95. [PMID: 21268999] CrossrefMedlineGoogle Scholar
Wasan AD, Butler SF, Budman SH, Fernandez K, Weiss RD, Greenfield SF, et al. Does report of craving opioid medication predict aberrant drug behavior among chronic pain patients? Clin J Pain. 2009;25:193-8. [PMID: 19333168] doi:10.1097/AJP.0b013e318193a6c4 CrossrefMedlineGoogle Scholar
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Arlington, VA: American Psychiatric Association; 2013. Google Scholar
Dunn KM, Saunders KW, Rutter CM, Banta-Green CJ, Merrill JO, Sullivan MD, et al. Opioid prescriptions for chronic pain and overdose: a cohort study. Ann Intern Med. 2010;152:85-92. [PMID: 20083827] doi:10.7326/0003-4819-152-2-201001190-00006 LinkGoogle Scholar
Gomes T, Mamdani MM, Dhalla IA, Paterson JM, Juurlink DN. Opioid dose and drug-related mortality in patients with nonmalignant pain. Arch Intern Med. 2011;171:686-91. [PMID: 21482846] doi:10.1001/archinternmed.2011.117 CrossrefMedlineGoogle Scholar
Li L, Setoguchi S, Cabral H, Jick S. Opioid use for noncancer pain and risk of fracture in adults: a nested case-control study using the general practice research database. Am J Epidemiol. 2013;178:559-69. [PMID: 23639937] doi:10.1093/aje/kwt013 CrossrefMedlineGoogle Scholar
Carman WJ, Su S, Cook SF, Wurzelmann JI, McAfee A. Coronary heart disease outcomes among chronic opioid and cyclooxygenase-2 users compared with a general population cohort. Pharmacoepidemiol Drug Saf. 2011;20:754-62. [PMID: 21567652] doi:10.1002/pds.2131 CrossrefMedlineGoogle Scholar
Li L, Setoguchi S, Cabral H, Jick S. Opioid use for noncancer pain and risk of myocardial infarction amongst adults. J Intern Med. 2013;273:511-26. [PMID: 23331508] doi:10.1111/joim.12035 CrossrefMedlineGoogle Scholar
Gomes T, Redelmeier DA, Juurlink DN, Dhalla IA, Camacho X, Mamdani MM. Opioid dose and risk of road trauma in Canada: a population-based study. JAMA Intern Med. 2013;173:196-201. [PMID: 23318919] doi:10.1001/2013.jamainternmed.733 CrossrefMedlineGoogle Scholar
Salzman RT, Roberts MS, Wild J, Fabian C, Reder RF, Goldenheim PD. Can a controlled-release oral dose form of oxycodone be used as readily as an immediate-release form for the purpose of titrating to stable pain control? J Pain Symptom Manage. 1999;18:271-9. [PMID: 10534967] CrossrefMedlineGoogle Scholar
Jamison RN, Raymond SA, Slawsby EA, Nedeljkovic SS, Katz NP. Opioid therapy for chronic noncancer back pain. A randomized prospective study. Spine (Phila Pa 1976). 1998;23:2591-600. [PMID: 9854758] CrossrefMedlineGoogle Scholar
Allan L, Richarz U, Simpson K, Slappendel R. Transdermal fentanyl versus sustained release oral morphine in strong-opioid naïve patients with chronic low back pain. Spine (Phila Pa 1976). 2005;30:2484-90. [PMID: 16284584] CrossrefMedlineGoogle Scholar
Wild JE, Grond S, Kuperwasser B, Gilbert J, McCann B, Lange B, et al. Long-term safety and tolerability of tapentadol extended release for the management of chronic low back pain or osteoarthritis pain. Pain Pract. 2010;10:416-27. [PMID: 20602712] doi:10.1111/j.1533-2500.2010.00397.x CrossrefMedlineGoogle Scholar
Mitra F, Chowdhury S, Shelley M, Williams G. A feasibility study of transdermal buprenorphine versus transdermal fentanyl in the long-term management of persistent non-cancer pain. Pain Med. 2013;14:75-83. [PMID: 23320402] doi:10.1111/pme.12011 CrossrefMedlineGoogle Scholar
Krebs EE, Becker WC, Zerzan J, Bair MJ, McCoy K, Hui S. Comparative mortality among Department of Veterans Affairs patients prescribed methadone or long-acting morphine for chronic pain. Pain. 2011;152:1789-95. [PMID: 21524850] doi:10.1016/j.pain.2011.03.023 CrossrefMedlineGoogle Scholar
Hartung DM, Middleton L, Haxby DG, Koder M, Ketchum KL, Chou R. Rates of adverse events of long-acting opioids in a state Medicaid program. Ann Pharmacother. 2007;41:921-8. [PMID: 17504834] CrossrefMedlineGoogle Scholar
Naliboff BD, Wu SM, Schieffer B, Bolus R, Pham Q, Baria A, et al. A randomized trial of 2 prescription strategies for opioid treatment of chronic nonmalignant pain. J Pain. 2011;12:288-96. [PMID: 21111684] doi:10.1016/j.jpain.2010.09.003 CrossrefMedlineGoogle Scholar
Cowan DT, Wilson-Barnett J, Griffiths P, Vaughan DJ, Gondhia A, Allan LG. A randomized, double-blind, placebo-controlled, cross-over pilot study to assess the effects of long-term opioid drug consumption and subsequent abstinence in chronic noncancer pain patients receiving controlled-release morphine. Pain Med. 2005;6:113-21. [PMID: 15773875] CrossrefMedlineGoogle Scholar
Ralphs JA, Williams AC, Richardson PH, Pither CE, Nicholas MK. Opiate reduction in chronic pain patients: a comparison of patient-controlled reduction and staff controlled cocktail methods. Pain. 1994;56:279-88. [PMID: 8022621] CrossrefMedlineGoogle Scholar
Tennant FS, Rawson RA. Outpatient treatment of prescription opioid dependence: comparison of two methods. Arch Intern Med. 1982;142:1845-7. [PMID: 6181749] CrossrefMedlineGoogle Scholar
Akbik H, Butler SF, Budman SH, Fernandez K, Katz NP, Jamison RN. Validation and clinical application of the Screener and Opioid Assessment for Patients with Pain (SOAPP). J Pain Symptom Manage. 2006;32:287-93. [PMID: 16939853] CrossrefMedlineGoogle Scholar
Jones T, Moore T, Levy JL, Daffron S, Browder JH, Allen L, et al. A comparison of various risk screening methods in predicting discharge from opioid treatment. Clin J Pain. 2012;28:93-100. [PMID: 21750461] doi:10.1097/AJP.0b013e318225da9e CrossrefMedlineGoogle Scholar
Moore TM, Jones T, Browder JH, Daffron S, Passik SD. A comparison of common screening methods for predicting aberrant drug-related behavior among patients receiving opioids for chronic pain management. Pain Med. 2009;10:1426-33. [PMID: 20021601] doi:10.1111/j.1526-4637.2009.00743.x CrossrefMedlineGoogle Scholar
Webster LR, Webster RM. Predicting aberrant behaviors in opioid-treated patients: preliminary validation of the Opioid Risk Tool. Pain Med. 2005;6:432-42. [PMID: 16336480] CrossrefMedlineGoogle Scholar
Noble M, Treadwell JR, Tregear SJ, Coates VH, Wiffen PJ, Akafomo C, et al. Long-term opioid management for chronic noncancer pain. Cochrane Database Syst Rev. 2010:CD006605. [PMID: 20091598] doi:10.1002/14651858.CD006605.pub2 CrossrefMedlineGoogle Scholar
Franklin GM, Mai J, Turner J, Sullivan M, Wickizer T, Fulton-Kehoe D. Bending the prescription opioid dosing and mortality curves: impact of the Washington State opioid dosing guideline. Am J Ind Med. 2012;55:325-31. [PMID: 22213274] doi:10.1002/ajim.21998 CrossrefMedlineGoogle Scholar
U.S. Food and Drug Administration. Public Health Advisory: Important Information for the Safe Use of Fentora (fentanyl buccal tablets). Silver Spring, MD: U.S. Food and Drug Administration; 2013. Google Scholar
Chou R, Cruciani RA, Fiellin DA, Compton P, Farrar JT, Haigney MC, et al. Methadone safety: a clinical practice guideline from the American Pain Society and College on Problems of Drug Dependence, in collaboration with the Heart Rhythm Society. J Pain. 2014;15:321-37. [PMID: 24685458] doi:10.1016/j.jpain.2014.01.494 CrossrefMedlineGoogle Scholar
Jones T, Moore T. Preliminary data on a new opioid risk assessment measure: the Brief Risk Interview. J Opioid Manag. 2013;9:19-27. [PMID: 23709300] doi:10.5055/jom.2013.0143 CrossrefMedlineGoogle Scholar
Bohnert AS, Valenstein M, Bair MJ, Ganoczy D, McCarthy JF, Ilgen MA, et al. Association between opioid prescribing patterns and opioid overdose-related deaths. JAMA. 2011;305:1315-21. [PMID: 21467284] doi:10.1001/jama.2011.370 CrossrefMedlineGoogle Scholar
Paulozzi LJ, Kilbourne EM, Shah NG, Nolte KB, Desai HA, Landen MG, et al. A history of being prescribed controlled substances and risk of drug overdose death. Pain Med. 2012;13:87-95. [PMID: 22026451] doi:10.1111/j.1526-4637.2011.01260.x CrossrefMedlineGoogle Scholar
Byas-Smith MG, Chapman SL, Reed B, Cotsonis G. The effect of opioids on driving and psychomotor performance in patients with chronic pain. Clin J Pain. 2005;21:345-52. [PMID: 15951653] CrossrefMedlineGoogle Scholar
Gaertner J, Frank M, Bosse B, Sabatowski R, Elsner F, Giesecke T, et al. [Oral controlled-release oxycodone for the treatment of chronic pain. Data from 4196 patients]. Schmerz. 2006;20:61-8. [PMID: 15926076] CrossrefMedlineGoogle Scholar
Galski T, Williams JB, Ehle HT. Effects of opioids on driving ability. J Pain Symptom Manage. 2000;19:200-8. [PMID: 10760625] CrossrefMedlineGoogle Scholar
Sabatowski R, Schwalen S, Rettig K, Herberg KW, Kasper SM, Radbruch L. Driving ability under long-term treatment with transdermal fentanyl. J Pain Symptom Manage. 2003;25:38-47. [PMID: 12565187] CrossrefMedlineGoogle Scholar
Menefee LA, Frank ED, Crerand C, Jalali S, Park J, Sanschagrin K, et al. The effects of transdermal fentanyl on driving, cognitive performance, and balance in patients with chronic nonmalignant pain conditions. Pain Med. 2004;5:42-9. [PMID: 14996236] CrossrefMedlineGoogle Scholar
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. [PMID: 22086815] doi:10.3122/jabfm.2011.06.100232 CrossrefMedlineGoogle Scholar
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. [PMID: 21402957] MedlineGoogle Scholar
Seal KH, Shi Y, Cohen G, Cohen BE, Maguen S, Krebs EE, et al. Association of mental health disorders with prescription opioids and high-risk opioid use in US veterans of Iraq and Afghanistan. JAMA. 2012;307:940-7. [PMID: 22396516] doi:10.1001/jama.2012.234 CrossrefMedlineGoogle Scholar
O'Connor AB, Turk DC, Dworkin RH, Katz NP, Colucci R, Haythornthwaite JA, et al. Abuse liability measures for use in analgesic clinical trials in patients with pain: IMMPACT recommendations. Pain. 2013;154:2324-34. [PMID: 24148704] doi:10.1016/j.pain.2013.06.035 CrossrefMedlineGoogle Scholar
Author, Article, and Disclosure Information
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.
Corresponding Author: Roger Chou, MD, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Mail Code BICC, Portland, OR 97239; e-mail, chour@ohsu.
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.
This article was published online first at www.annals.org on 13 January 2015.