Research Gaps on Use of Opioids for Chronic Noncancer Pain: Findings From a Review of the Evidence for an American Pain Society and American Academy of Pain Medicine Clinical Practice Guideline

Article Outline

• Abstract
• Materials and Methods
  • Data Sources and Searches
  • Evidence Selection
  • Data Extraction and Quality Assessment
  • Data Synthesis
• Results
  • Results of the Literature Search
  • Risk-Benefit Assessment
  • Informed Consent and Opioid Management Plans
  • Initiation and Titration of Chronic Opioid Therapy
  • Benefits and Harms of Chronic Opioid Therapy
  • Selection of Opioids and Dosing Methods
  • Methadone
  • Monitoring
  • High-Risk Patients
  • Dose Escalations and High-Dose Opioid Therapy
  • Opioid Rotation
  • Discontinuation of Opioid Therapy
  • Prevention and Treatment of Opioid-Related Adverse Effects
  • Use of Nonopioid Therapies
  • Driving and Work Safety
  • Breakthrough Pain
  • Opioid Use During Pregnancy
  • Opioid Prescribing Policies
• Discussion
• Acknowledgments
• Appendix 1. Search Strategies
  • Cochrane Database of Systematic Reviews, Through 3rd Quarter 2008
  • Cochrane Central Register of Controlled Trials and Ovid MEDLINE®, 1950 to July Week 3 2008 (Includes Systematic Reviews and Primary Studies)
    • General Search
    • Abuse
    • Driving
    • Drug Monitoring
    • Prognosis
    • Pseudoaddiction
    • Urine Testing
• Appendix 2. 
• Appendix 3. 
• Appendix 4. 
• Appendix 5. 
• Table 3. 
• Table 4. 
• References
• Copyright

Abstract 

Chronic noncancer pain is common and use of opioids is increasing. Previously published guidelines on use of opioids for chronic noncancer pain have been based primarily on expert consensus due to lack of strong evidence. We conducted searches on Ovid MEDLINE and the Cochrane databases through July 2008 to identify studies that addressed one or more of 37 Key Questions that a multidisciplinary expert panel identified as important to be answered to generate evidence-based recommendations on the use of opioids for chronic noncancer pain. A total of 14 systematic reviews, 38 randomized trials not included in a previously published systematic review, and 13 other studies met inclusion criteria. Almost all of the randomized trials of opioids for chronic noncancer pain were short-term efficacy studies. Critical research gaps on use of opioids for chronic noncancer pain include: lack of effectiveness studies on long-term benefits and harms of opioids (including drug abuse, addiction, and diversion); insufficient evidence to draw strong conclusions about optimal approaches to risk stratification, monitoring, or initiation and titration of opioid therapy; and lack of evidence on the utility of informed consent and opioid management plans, the utility of opioid rotation, the benefits and harms specific to methadone or higher doses of opioids, and treatment of patients with chronic noncancer pain at higher risk for drug abuse or misuse.

Perspective

Currently, clinical decisions regarding the use of opioids for chronic noncancer pain need to be made based on weak evidence. Research funding priorities need to be set to address these critical research needs if the care of patients with chronic noncancer pain is to improve.

Key words: Analgesics, opioid, pain, evidence-based medicine, risk assessment, drug monitoring, treatment outcomes, harms, research gaps, systematic review

Chronic noncancer pain (CNCP) is highly prevalent and can have significant negative effects on patients' functional capacity and quality of life.¹²⁵, ¹³⁶ Prescriptions for opioids have risen steadily in the United States,²¹, ¹⁰⁰ in part due to their increased use in patients with CNCP. However, the prescription of opioids for CNCP remains controversial. Although opioids can decrease pain and improve function in some patients with CNCP,⁵³, ⁷⁶ opioids are not always effective and are associated with important potential harms, including those related to drug misuse, abuse, and diversion.²³ In addition, uncertainty exists about long-term benefits and harms of opioids for CNCP.⁹⁹

Ideally, clinical decisions about the use of opioids for CNCP should be informed by high quality evidence. In reality, this principle is difficult to follow. Although a number of randomized trials are now available, they focus primarily on the evaluation of short-term benefits of opioids versus placebo in highly selected populations.⁵³, ⁷⁶ In addition, evidence on a number of other areas relevant to opioid prescribing, such as risk assessment before initiation of a trial of opioids, methods for initiating and titrating opioids, monitoring of patients on chronic opioid therapy, use of high-dose opioids, and treatment of high-risk patients, is sparse. In fact, although several recently published guidelines recommend judicious use of opioids in appropriately selected patients with CNCP who have not responded to other treatments and analgesic medications, most were developed using a consensus process, in part due to a lack of strong evidence to guide most recommendations.¹⁶, ⁵⁷, ⁷⁴, ⁷⁵, ¹²⁸, ¹³²

In 2006, the American Pain Society (APS) and the American Academy of Pain Medicine (AAPM) partnered to develop an evidence-based guideline on the use of opioids for CNCP. As part of this process, the APS/AAPM commissioned a systematic evidence review that addressed 37 Key Questions that a multidisciplinary expert panel believed to be critical to answer in order to develop evidence-based recommendations (Table 1).²⁸ The purpose of this article is to identify and summarize critical weaknesses (“research gaps”) in the literature on chronic opioid therapy for CNCP. We defined a research gap as an area in which the evidence base inadequately addressed a Key Question.

Table 1. Key Questions Used to Guide the Evidence Review

Risk-Benefit Assessment

1. In patients being considered for opioids for chronic noncancer pain, how accurate are patient features or characteristics for predicting:

a. Benefits of chronic opioid therapy?

b. Opioid-related harms?

c. Aberrant drug-related behaviors?

2. In patients being considered for opioids for chronic noncancer pain, how accurate are formal screening instruments for predicting benefits of opioid therapy, harms, or aberrant drug-related behaviors?

3. In patients being considered for opioids for chronic noncancer pain, how effective is risk assessment for:

a. Improving clinical outcomes?

b. Reducing risk of aberrant drug behaviors?

Benefits and Harms of Chronic Opioid Therapy (Including High-Risk Patients)

4. What are the benefits (including long-term benefits) of opioids for chronic noncancer pain?

5. What are the harms (including long-term harms) of opioids for chronic non-cancer pain? In patients at higher risk for abuse or addiction?

6. What are the benefits and harms of opioids for noncancer pain in patients with a history of substance abuse or addiction that are undergoing treatment for addiction?

7. What are the comparative benefits and harms of different opioids and different formulations of opioids for chronic noncancer pain?

8. Do the comparative benefits and harms of opioids vary in subpopulations defined by demographics (eg, age, gender, race), specific underlying pain conditions, or comorbidities (eg, liver disease, renal disease, respiratory disease, heart disease, HIV, drug misuse, cancer survivors)?

Prevention and Treatment of Opioid-Related Adverse Effects

9. How effective are different strategies for minimizing or treating opioid-related adverse events?

Driving and Work Safety

10. How does initial or chronic use of opioids impact driving or work safety?

Initiation and Titration of Chronic Opioid Therapy

11. What are the benefits and harms of different methods for initiating and titrating opioids for chronic noncancer pain?

Selection of Opioids and Dosing Methods

12. What are the benefits and harms of round-the-clock versus as needed dosing of opioids, or round-the-clock with as needed dosing versus as needed dosing alone for chronic noncancer pain?

13. What are the benefits and harms of regular intramuscular, subcutaneous, intranasal, buccal, or rectal versus oral or transdermal administration of opioids for chronic noncancer pain?

Breakthrough Pain

14. What are the comparative benefits of different strategies for treating acute exacerbations of pain or a new acute pain problem in patients on chronic opioids for chronic noncancer pain?

Opioid Rotation

15. What are the benefits and harms of opioid rotation versus continued treatment or dose escalation with the same opioid in patients with chronic noncancer pain?

16. What are the benefits and harms of different methods for switching patients on opioids for chronic noncancer pain from one opioid to another?

Dose Escalations and High-Dose Opioid Therapy

17. How accurate are patient characteristics or features for predicting lack of response to high doses of opioids for chronic noncancer pain?

18. How do dose-related responses for opioids change at different dose ranges or with long-term use?

19. What are the benefits and harms of high (>200 mg/d of morphine or equivalent) versus lower doses of opioids for chronic noncancer pain?

20. Are high doses of opioids associated with different or unique harms compared with lower doses?

Use of Nonopioid Therapies

21. How effective are patient education methods or clinician advice for improving outcomes associated with chronic opioid therapy?

22. How effective is coprescription with other pain-attenuating medications or combining opioids for improving pain control or decreasing adverse events associated with opioid analgesics?

23. What is the effect of concomitant use of drugs with CNS effects on adverse events associated with opioids for chronic noncancer pain?

24. What are the benefits associated with behavioral therapy, multidisciplinary rehabilitation, and/or functional restoration/work hardening in addition to or instead of opioids for chronic noncancer pain?

Informed Consent and Opioid Management Plans

25. How effective are opioid agreements/contracts for improving clinical benefits and reducing harms, including abuse, addiction, or other aberrant drug-related behaviors associated with opioids for chronic noncancer pain?

Methods for Monitoring Opioid Use and Detecting Aberrant Drug-Related Behaviors

26. In patients receiving opioids for chronic noncancer pain, how accurate are formal screening instruments for identifying aberrant drug-related behaviors?

27. In patients receiving opioids for chronic noncancer pain, what is the diagnostic accuracy of urine drug screening and different urine drug screening methods for:

a. Detecting illicit drug use?

b. Identifying the presence or absence of prescribed and non-prescribed opioids and estimating doses of opioids?

28. In patients receiving opioids for chronic noncancer pain, how effective is urine drug screening and different urine drug screen methods for reducing abuse, addiction, and other aberrant drug-related behaviors, or increasing adherence to taking opioids as prescribed?

29. In patients receiving opioids for chronic noncancer pain, how effective are other methods (pill counts, limited prescriptions, monitoring blood levels) for detecting or reducing abuse, addiction, other aberrant drug-related behaviors, or whether patients are taking opioids as prescribed?

30. Is reevaluation of patients on chronic opioid therapy at different intervals associated with different outcomes?

31. What are the benefits and harms associated with different methods for evaluating outcomes in patients receiving opioids for chronic noncancer pain?

32. In patients receiving opioids for chronic noncancer pain, what is the accuracy of tools for differentiating drug-related behaviors due to inadequate symptom relief from true aberrant drug-related behaviors?

33. In patients receiving opioids for chronic noncancer pain, what is the effect of diagnosing drug-related behaviors due to inadequate symptom relief on clinical outcomes?

Discontinuing Opioids

34. What patient features or characteristics predict improved outcomes with discontinuation of long-term opioids versus continued treatment?

35. What are the benefits and harms of different methods for discontinuing opioids?

Pregnancy

36. What are the benefits and harms of continuing opioids versus switching to alternative analgesics in women with chronic noncancer pain who become pregnant or are planning to become pregnant?

Opioid Prescribing Policies

37. What are the benefits and harms of opioid prescribing policies on clinical outcomes?

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Materials and Methods 

Data Sources and Searches 

We conducted searches (through July 2008) that combined terms for opioids and chronic pain on Ovid MEDLINE, the Cochrane Database of Systematic Reviews, and the Cochrane Central Register of Controlled Trials (Appendix 1 provides the detailed search strategies). Electronic searches were supplemented by reference lists and additional citations suggested by experts.

Evidence Selection 

We included studies that met all of the following criteria:

We excluded studies of patients with cancer pain or end-of-life conditions as clinical and ethical considerations may be different compared with patients with CNCP. We also excluded non-English language studies, uncontrolled observational studies (eg, case series, case reports, pre-post studies), retrospective studies of risk prediction instruments, studies only published as conference abstracts, and unpublished studies.

Data Extraction and Quality Assessment 

Two reviewers (R.C. and L.H.H.) independently rated the quality of each study. Discrepancies were resolved by discussion and a consensus process.

The quality of randomized trials, studies on diagnostic accuracy of risk assessment instruments, and systematic reviews was assessed using the criteria shown in Appendix 2, Appendix 3, and 4.⁵², ⁶², ⁷¹, ⁸⁰, ¹⁰³, ¹³⁴ For randomized trials and studies of risk prediction or diagnostic accuracy, studies were categorized as “higher-quality” if they met at least half of the predefined criteria.¹⁴, ¹⁵, ¹³⁴ For systematic reviews, studies were categorized as “higher-quality” if they received a score of 5 or higher (maximum score 7).⁵², ⁷⁰, ¹⁰³

Data Synthesis 

The overall strength of each body of evidence that addressed a particular Key Question (or part of a Key Question) was assessed using methods adapted from the U.S. Preventive Services Task Force.⁶² To assign an overall strength of evidence (good, fair, or poor), the number, quality, and size of the studies; consistency of results between studies; and directness of the evidence were considered. Minimum criteria for fair and good quality ratings are shown in Appendix 5. Consistent results from a number of higher-quality studies across a broad range of populations support a high degree of certainty that the results of the studies are true (the entire body of evidence would be considered “good-quality”). For a “fair-quality” body of evidence, results could be due to true effects or to biases present across some or all of the studies. For a “poor-quality” body of evidence, any conclusion is uncertain due to serious methodological shortcomings, sparse data, or inconsistent results.

This report focuses on research areas identified by the Key Questions that are addressed by only poor quality evidence (“research gaps”). It does not focus on areas addressed by fair or good evidence (eg, short-term efficacy of opioids).⁵³, ⁷⁶

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Results 

Results of the Literature Search 

The literature search yielded a total of 10,703 potentially relevant citations. Of these, we retrieved 186. After reviewing full-text articles, we judged 91 studies (including 15 systematic reviews and 38 randomized trials not included in previously published systematic reviews) to be relevant to one or more key questions and to meet inclusion criteria (Table 2). The most common reasons for study exclusion were evaluation of acute or postoperative pain; evaluation of cancer pain or pain associated with end of life; evaluation of parenteral opioids; evaluation of children; noncontrolled observational study design; and lack of original data (eg, review article or editorial).

Table 2. Studies Meeting Inclusion Criteria for Each Key Question

Abbreviation: NA, not applicable.

Risk-Benefit Assessment 

Evidence on risk stratification instruments to predict occurrence of aberrant drug-related behaviors is primarily limited to 4 prospective studies.³, ¹⁷, ¹⁹, ¹⁴¹ The Opioid Risk Tool (ORT) and the Screener and Opioid Assessment of Patients with Pain (SOAPP) Version 1 and Revised SOAPP (SOAPP-R) instruments may be useful for predicting risk of future aberrant drug-related behaviors, but they require further study. Evidence is sparse for each instrument and characterized by presence of methodological shortcomings, such as high loss to follow-up, assessment of outcomes not blinded to results of the index test, and lack of external validation.²⁷ In addition, some instruments are associated with only modest likelihood ratios,¹⁷, ¹⁹ and interpretation of available studies is a challenge because the definitions and methods used to identify aberrant drug-related behaviors were not standardized and did not differentiate between relatively less and more serious behaviors.

In addition to assessing risk of aberrant drug-related behaviors, a comprehensive assessment prior to initiating a trial of opioid therapy should also include assessments of potential benefits (eg, analgesia, return of function) and opioid-related adverse effects (eg, opioid-induced bowel dysfunction, nausea/vomiting, cognitive effects, and pruritus). There is insufficient evidence from small observational studies,⁷, ³⁹, ⁶⁹ secondary analyses of clinical trials,⁴³, ⁷⁷ or indirect comparisons of placebo-controlled trials⁵³, ⁷⁶, ⁹⁴ to reliably identify factors that predict benefits or adverse effects. There is also insufficient evidence to identify predictors of “opioid responsiveness,” or the balance of benefits achievable with tolerable adverse effects.⁸¹, ⁹¹ No studies evaluated clinical outcomes associated with the use of different patient selection or risk stratification approaches.

Informed Consent and Opioid Management Plans 

No studies were found that evaluated whether an explicit or detailed informed consent process before initiating chronic opioid therapy for CNCP is associated with improved clinical outcomes, adherence to the treatment plan, or greater patient satisfaction, or how the consent process affects patients' choices regarding use of opioids. No studies evaluated the effects of patient education methods, including different methods for providing or documenting informed consent, before initiating a trial of opioids.

Controlled data on the effects of opioid management plans on patient outcomes are limited to a single small (n = 20), retrospective, observational study that found no association between signing an opioid contract and a “successful outcome” (not defined) in patients with a history of substance abuse.⁴² No studies were found that evaluated how differences in the content of opioid management plans or use of written versus oral management plans affected clinical outcomes, either in average- or high-risk patients.

Initiation and Titration of Chronic Opioid Therapy 

Two higher-quality trials found slower rates of dose titration of tramadol associated with fewer withdrawals due to adverse events compared to more rapid dose titration.¹⁰⁶, ¹¹⁵ However, tramadol is a relatively weak analgesic with both monoaminergic and opioidergic effects, and results of these trials may not be directly applicable to non-tramadol (particularly higher potency) opioids. There is insufficient evidence from two lower-quality trials to accurately judge benefits and harms of different methods for initiating and titrating non-tramadol opioids.⁷², ¹¹⁸

Benefits and Harms of Chronic Opioid Therapy 

Over 70 randomized trials evaluated benefits or harms of opioids for CNCP, but nearly all were short-term (16 weeks or shorter) efficacy studies. Systematic reviews on efficacy of opioids for CNCP are summarized in Tables 3 and 4.²⁵, ³⁰, ⁴⁰, ⁴¹, ⁴⁴, ⁵³, ⁶⁷, ⁷⁶, ⁸³, ⁹⁴, ⁹⁹, ¹¹⁹ In general, the trials excluded patients at higher risk for substance abuse or with significant medical or psychiatric comorbidities, and only 3 trials followed patients for more than 4 months.⁴, ⁷³, ¹¹⁷ Long-term observational evidence is also sparse and characterized by substantial heterogeneity.⁹⁹ Evidence on opioids specifically for low back pain, fibromyalgia, and daily headache is very limited or did not show a clear benefit.⁴⁰, ⁵³, ⁷⁶, ⁸³, ¹²⁰

Evidence on harms associated with chronic opioid therapy is of poorer quality than evidence on benefits, as most trials were designed to primarily assess efficacy. A great deal of variability exists between trials in estimates of common adverse effects (eg, nausea, constipation, or somnolence), due in part to differences in methods for defining, assessing, or reporting adverse effects; differences in populations evaluated; and variable use of run-in periods.⁵³, ⁷⁶, ⁹⁴ Few trials were designed with sufficient statistical power to identify serious but rare adverse effects or with sufficient duration to evaluate long-term harms, even though many patients in clinical practice are prescribed chronic opioid therapy indefinitely. Evidence on risk of aberrant drug-related behaviors is also limited.⁶⁶, ⁸³ Trials excluded higher-risk patients and did not perform active surveillance for signs of abuse or addiction. In addition, all of the studies used poorly standardized definitions or inadequate methods to identify aberrant drug-related behaviors.⁹⁹

Several cross-sectional studies of patients with CNCP reported a dose-related association between chronic sustained-release oral opioid use and hypogonadism in men and decreased levels of dehydroepiandrosterone sulfate (DHEAS) in men and women.³⁵, ³⁶, ³⁷ Limitations of these studies include no adjustment for potential confounders and inability to establish causality because of their cross-sectional design. No evidence exists on endocrinologic effects of short-acting or intermittent opioids, and no randomized trials or controlled observational studies evaluated clinical outcomes associated with different approaches to monitoring or treating hypogonadism or DHEAS deficiency.

Observational studies showed an increased risk of fractures in older patients prescribed opioids but did not control well for potential confounders.¹²⁶ Several observational studies compared risks of adverse events between different opioids based on analyses of administrative databases, but are difficult to interpret because large baseline differences between groups prescribed different opioids were present, and the studies were limited in their ability to adjust or control for potential confounders.¹, ⁶³, ¹²⁴

Selection of Opioids and Dosing Methods 

Evidence that compared the benefits and harms of around-the-clock versus as needed dosing of opioids for CNCP is limited to one lower-quality trial that showed no clear differences.⁶⁰ A number of head-to-head trials have compared benefits or harms of different sustained-release opioids or compared sustained- versus immediate-release opioids, but the studies had methodological shortcomings, such as use of an open-label design, lack of intention-to-treat analysis, or high loss to follow-up.²⁶ The studies also excluded patients at higher risk for addiction or abuse, only evaluated around-the-clock dosing strategies, and were not designed to evaluate rates of aberrant drug-related behaviors.⁴, ²⁶, ⁶¹, ⁸⁴, ⁹⁷, ⁹⁸, ¹¹³, ¹¹⁴ Trials of patients with cancer pain suggest no advantages of intramuscular over oral administration of opioids and similar efficacy between oral and rectal routes of administration,⁸, ¹⁰, ¹¹, ³⁸, ⁹⁰ but no randomized trials or comparative observational studies were found that directly compared regular intramuscular, subcutaneous, intranasal, buccal, or rectal versus oral or transdermal administration of opioids in patients with CNCP.

Methadone 

Only one randomized trial evaluated methadone versus placebo for CNCP.⁹⁵ Its applicability to clinical practice is limited, as it randomized each patient to methadone or placebo every other day, with no treatment on alternate days. Evidence of serious harms (such as arrhythmias and deaths) associated with methadone for CNCP is limited to case series³⁴, ⁷⁹ case-control studies with small number of patients with chronic pain,²⁹ or descriptive epidemiologic studies.²², ²⁴, ¹⁰¹ These studies are difficult to interpret because they often did not distinguish between patients prescribed methadone for CNCP versus those who received methadone for maintenance treatment of heroin addiction or who obtained methadone without a prescription, did not compare risks associated with methadone versus other opioids, or did not account for increased rates of methadone usage.

Monitoring 

Evidence on methods for monitoring patients prescribed chronic opioid therapy is limited to studies of diagnostic accuracy of various instruments to identify aberrant drug-related behaviors in patients prescribed opioids.², ⁶, ¹⁸, ³¹, ⁶⁸, ⁸², ⁹², ¹³⁷, ¹⁴⁴ Although one higher-quality derivation study found that the Current Opioid Misuse Measure identified aberrant drug-related behaviors with modest accuracy,¹⁸ studies of other instruments either found low accuracy⁹², ¹³⁷ or are of limited value because they did not evaluate standard measures of diagnostic accuracy², ³¹, ⁶⁸ or because they had serious methodological shortcomings, such as use of a retrospective design,⁶, ⁸² assessment of outcomes not blinded to results of the index test,⁶, ⁸², ¹⁴⁴ poorly standardized definitions for aberrant drug-related behaviors, and use of an inadequate reference standard.¹⁴⁴ No reliable evidence was found on the diagnostic accuracy of urine toxicology testing, pill counts, or prescription drug monitoring programs, or on clinical outcomes associated with implementation of different monitoring approaches.

High-Risk Patients 

Nearly all randomized trials of opioids for CNCP excluded patients at higher risk for abuse or addiction.⁵³, ⁷⁶ No controlled study evaluated different methods for selecting high-risk patients for a trial of opioid therapy or different strategies for initiating and titrating opioids and monitoring these patients.¹⁴³

Dose Escalations and High-Dose Opioid Therapy 

Evidence on benefits and harms of high-dose opioids is very sparse. In randomized trials of opioids,⁵³, ⁷⁶ the highest daily dose permitted was 240 mg/d of morphine,¹¹¹ and the highest average dose was 120 mg/d.⁶⁹ Evidence from observational studies on benefits and harms of high-dose opioid therapy is also sparse. No trial or controlled observational study evaluated outcomes associated with dose escalation above 200 mg/d of morphine (or equivalent) versus maintaining the current dose, switching to an alternative opioid, or discontinuing therapy in patients with inadequate symptom relief on lower doses. Evidence that high-dose opioids are associated with unique toxicities (such as arrhythmia, endocrinologic abnormalities, or hyperalgesia) is limited to small cross-sectional studies or case series that were not designed to evaluate causality or did not control for potential confounders.⁵, ³⁴, ³⁵, ³⁶, ³⁷, ⁷⁹

Opioid Rotation 

Evidence on effects of opioid rotation (switching from one opioid to a different opioid) in patients with CNCP is limited to 2 small prospective before-after studies⁵⁰, ⁵¹ and 3 retrospective studies⁶⁴, ¹¹⁰, ¹³⁰ with inconsistent results. No studies compared different methods of opioid rotation.

Discontinuation of Opioid Therapy 

No randomized trials or controlled observational studies evaluated patient features or characteristics associated with improved outcomes with discontinuation of long-term opioid therapy versus continued treatment. There is insufficient evidence from 1 small (n = 10), higher-quality trial³³ to evaluate benefits and harms of continued opioid therapy versus abrupt cessation, and insufficient evidence from 2 lower-quality nonrandomized trials¹¹², ¹²⁷ to evaluate benefits and harms of other methods for discontinuing opioids.

Prevention and Treatment of Opioid-Related Adverse Effects 

Three published randomized trials evaluated the oral opioid antagonists alvimopan¹⁰⁴, ¹⁴⁰ or low-dose naltrexone¹³⁹ for opioid-induced bowel dysfunction in patients with CNCP. The findings from the naltrexone trial are difficult to interpret because of high loss to follow-up and differential dosing frequencies, and alvimopan has not been approved by the U.S. Food and Drug Administration for use in patients with chronic pain, in part due to an increased rate of myocardial infarctions observed in an unpublished trial.⁵⁸ Other trials of opioid antagonists did not meet inclusion criteria because they enrolled healthy volunteers, persons undergoing surgery, or terminally ill patients.¹², ⁸⁸ For example, trials of subcutaneous methylnaltrexone showed improvement in opioid-induced bowel dysfunction compared with placebo without opioid withdrawal and mild adverse effects, but only enrolled patients at end-of-life due to cancer or other advanced disease.¹⁰⁹, ¹²⁹ Essentially all other evidence on prevention and treatment of opioid-related adverse effects in patients with CNCP is anecdotal.⁸⁷

Use of Nonopioid Therapies 

No randomized trials directly evaluated the efficacy of behavioral therapy, multidisciplinary rehabilitation, or functional restoration versus or in addition to chronic opioid therapy in patients with CNCP. Two randomized trials of multidisciplinary rehabilitation and functional restoration evaluated opioid use as a secondary outcome and reported inconclusive results.³², ¹⁰⁵ Other evidence on the use of nonopioid therapies is almost entirely limited to trials of patients with chronic pain in general (not necessarily patients prescribed opioids).⁴⁸, ⁵⁹, ⁶⁵, ⁷⁸, ⁸⁵, ⁹⁶, ¹⁰², ¹²¹, ¹³⁵ No study evaluated methods for identifying patients with CNCP more likely to benefit from nonopioid versus opioid therapy.

Driving and Work Safety 

Evidence on driving and work safety is limited to epidemiologic studies and studies that evaluated the performance of patients on chronic opioid therapy on standardized driving tests.²⁰, ⁴⁵, ⁴⁶, ⁵⁴, ⁵⁵, ⁸⁹, ¹¹⁶ Limitations of the evidence include a reliance on cross-study comparisons to interpret epidemiologic studies (eg, comparing rates of opioid use in persons involved in motor vehicle accidents compared to estimates of opioid use in the general population), use of simulated and other controlled driving tests that may not completely reflect real-world driving conditions, and probable selection bias, as patients experiencing somnolence, impaired cognition, or other central nervous system opioid-related adverse effects are probably less likely to drive or to participate in studies that evaluate driving ability. No study evaluated the effects of opioid therapy on work safety.

Breakthrough Pain 

Evidence on the use of short-acting opioids for treatment of breakthrough pain in patients on chronic opioid therapy for CNCP is restricted to two trials that evaluated transmucosal fentanyl for breakthrough pain.¹⁰⁷, ¹²³ The usefulness of these trials is limited by their short duration of follow-up and by comparisons to placebo rather than to other opioids or nonopioid interventions for managing breakthrough pain.¹⁰⁷, ¹²³

Opioid Use During Pregnancy 

Almost all of the literature on pregnancy and opioids has focused on women in methadone maintenance treatment, or women who used opioids for analgesia during labor, rather than pregnant women receiving chronic opioid therapy for CNCP. No randomized trials or controlled observational studies evaluated the effects of different strategies for managing CNCP with opioids (including tapering or discontinuation of opioids) during pregnancy.

Opioid Prescribing Policies 

Although several studies found that the implementation of prescription monitoring programs for Schedule II opioids was associated with a decrease in prescription rates for Schedule II opioids,¹²², ¹³⁸ it is not possible to determine from these studies whether the changes were due to decreased inappropriate or unnecessary Schedule II opioid use, or if these changes resulted in subsequent under treatment of pain or had negative effects on other clinical outcomes. No study evaluated patient outcomes associated with implementation of a prescription monitoring program, formulary restrictions, or other policies related to opioid prescribing. Claims of positive effects of prescription monitoring programs on reducing diversion are primarily based on anecdotal reports of impressions of efficacy from policy makers and law enforcement officials.¹³³ No studies evaluated how clinicians' knowledge of policy affects healthcare practice, patient care, or patient outcomes.

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Discussion 

Prescribing opioids for CNCP is far from straightforward. In addition to assessing patients and determining when a trial of opioids may be appropriate, clinicians must make choices regarding how to initiate, adjust, monitor, and in some cases discontinue chronic opioid therapy. Conventionally, it has been considered that clinical decisions such as these should be informed by well-conducted randomized controlled trials, controlled observational studies, or studies evaluating diagnostic test accuracy. However, for virtually every research question that an interdisciplinary expert panel assembled by the APS/AAPM thought was important to be asked to generate recommendations on use of chronic opioid therapy in patients CNCP, the findings from this systematic review identified important research gaps.

Available randomized trials of opioids are best described as efficacy⁵⁶ studies conducted in ideal settings and with selected populations, usually with short-term follow-up.⁵³, ⁷⁶ Effectiveness trials and well-conducted prospective cohort studies (eg, registry studies¹⁰⁸) that assess long-term outcomes in less selected populations are needed to evaluate important benefits and harms (including those related to opioid misuse or abuse) relevant to clinical practice and to better understand why some patients continue chronic opioid therapy and others do not. More research is also needed to clarify optimal opioid dosing strategies. For example, although proposed advantages of using a long-acting opioid with around-the-clock dosing over as-needed and/or short-acting opioids include more consistent control of pain, improved adherence, and lower risk of addiction or abuse, no adequately conducted studies have demonstrated these possible benefits.¹⁶, ⁵⁷, ⁷⁴, ⁷⁵, ¹²⁸, ¹³² Research is needed on the optimal approaches to initiate and titrate opioids and to treat breakthrough pain, on the utility of opioid rotation, and to determine if and how benefits or harms associated with methadone or other specific opioids differ.

Evidence on methods for performing risk assessment before starting opioids and for monitoring patients once on chronic opioid therapy is limited to a handful of diagnostic accuracy and prognosis studies that focused on prediction³, ¹⁷, ¹⁹, ¹⁴¹ or identification², ⁶, ¹⁸, ³¹, ⁶⁸, ⁸², ⁹², ¹³⁷, ¹⁴⁴ of variably defined aberrant drug-related behaviors. All of these studies had at least some methodological shortcomings, including use of nonstandardized definitions for aberrant drug-related behaviors with uncertain clinical significance. No reliable evidence exists on the diagnostic accuracy of urine drug testing or on how use of screening instruments, urine drug testing, prescription monitoring programs, pill counts, or other risk assessment or monitoring approaches affects clinical decision-making or patient outcomes. Studies are needed to validate the diagnostic accuracy of risk assessment and monitoring instruments in a variety of settings using standardized definitions for clinically relevant aberrant-drug related behaviors and to determine whether using such instruments improves clinical outcomes. To help clinicians perform more balanced and comprehensive benefit-to-harm evaluations, future studies should develop and validate instruments that assess potential benefits and opioid-related adverse effects in conjunction with aberrant drug-related behaviors.¹³

Very little evidence exists on benefits and harms of higher doses of opioids, despite controversy regarding the appropriate role of higher dose therapy in persons who do not respond to lower doses.⁹, ⁴⁹ Studies are needed to quantify the risks associated with higher doses of opioids, to evaluate whether higher doses are associated with different or unique harms (such as endocrinologic dysfunction³⁵, ³⁶, ³⁷ or hyperalgesia⁵) compared with lower doses, and to determine if there are patient characteristics that predict lack of response to higher doses of opioids. If a causal association between the use of higher doses of opioids and specific harms is found, additional research is needed to evaluate potential predictors of these harms, to determine their clinical impact, and to identify methods for minimizing their incidence and effects.

A number of other areas related to use of opioids for CNCP are also associated with important research gaps. For example, there is a lack of evidence on benefits and harms of opioid management plans and different methods for providing informed consent.⁴⁷ There is also insufficient evidence to reliably inform clinical decisions regarding driving and work-related risks in patients prescribed chronic opioid therapy, and essentially no evidence regarding benefits and harms of chronic opioid therapy for CNCP during pregnancy, or on how policies related to opioid prescribing affect clinical outcomes. Controlled observational studies that are designed to minimize bias, address potential confounders, and evaluate patient-centered outcomes could help fill a number of these research gaps, particularly when randomized controlled trials are not ethical or feasible (eg, chronic opioid therapy during pregnancy, driving safety, opioid-prescribing policies).

A potential limitation of our study is that non-English language studies, unpublished studies, uncontrolled observational studies of opioid interventions, and nonprospective studies of risk prediction were excluded. However, language restrictions do not necessarily lead to biased findings,⁹³ and we are not aware of non-English language or unpublished studies likely to change any of our main conclusions. In addition, the quality of unpublished studies is often difficult to assess due to incomplete reporting, and results can change between initial presentation and final journal publication.¹³¹ Observational studies were excluded if they lacked adequate safeguards against bias, did not include control subjects, or did not adequately demonstrate causality.

The presence of large and persistent evidence gaps on the use of chronic opioid therapy for CNCP represents a serious deficit in knowledge given the high prevalence of CNCP, increasing use of chronic opioid therapy for this indication, the need for complex and ongoing decision-making by clinicians to balance potential benefits against potentially serious harms, and the formulation of policies and regulations in the absence of evidence. Our study provides guidance for setting future research priorities. Until evidence gaps are adequately addressed, many clinical and policy decisions related to the use of chronic opioid therapy for CNCP will need to be made without strong supportive evidence. At a minimum, this deficit will result in continued uncertainty regarding best practices, and at worst these deficiencies could contribute to unnecessary harms.

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Acknowledgments 

The authors thank Laurie Hoyt Huffman for reviewing literature and data abstraction and Jayne Schablaske, Michelle Pappas, and Tracy Dana for administrative support with the manuscript.

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Appendix 1. Search Strategies 

Cochrane Database of Systematic Reviews, Through 3rd Quarter 2008 

Cochrane Central Register of Controlled Trials and Ovid MEDLINE^®, 1950 to July Week 3 2008 (Includes Systematic Reviews and Primary Studies) 

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Appendix 2. 

Criteria for Grading Quality of Randomized Controlled TrialsCriteria List for Methodological Quality Assessment^∗

This list includes only the internal validity criteria (n = 11) that refer to characteristics of the study that might be related to selection bias (criteria A and B), performance bias (criteria D, E, G, and H), attrition bias (criteria I and K and detection bias (criteria F and J). The internal validity criteria should be used to define methodologic quality in the meta-analysis.

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Appendix 3. 

Criteria for Grading Quality of Studies Reporting Diagnostic Accuracy of Risk Stratification and Monitoring Instruments

References: Harris et al,⁶² Lijmer et al,⁸⁰ Whiting et al¹⁴² McGinn et al.⁸⁶

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Appendix 4. 

Criteria for Grading Quality of Systematic Reviews

^∗ Operationalization of Oxman criteria,¹⁰³ adapted from Furlan et al. ⁵²

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Appendix 5. 

Methods for Grading the Overall Strength of a Body of Evidence

Adapted from methods developed by the U.S. Preventive Services Task Force.⁶²

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Table 3. 

Included Systematic Reviews on Efficacy of Opioids for Chronic Noncancer Pain

Abbreviations: RCT, randomized controlled trial; CI, confidence interval; SMD, standardized mean difference; RR, relative risk; TDF, transdermal fentanyl; SRM, sustained-release morphine; CP, cancer pain; CNCP, chronic noncancer pain.

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Table 4. 

Quality^∗ Ratings of Systematic Reviews on Efficacy of Opioids for Chronic Noncancer Pain

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