by S Carson · 2008 · Cited by 2 — patients with osteoarthritis. 54. One was a short-term (6 weeks) study that found that controlled- release oxycodone (

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Drug Class Review Long -Acting Opioid Analgesics Final Update 6 Report July 2011 The purpose of Drug Effectiveness Review Project reports is to make available information regarding the comparative clinical effectiveness and harms of different drugs. Reports are not usage guidelines, nor should they be read as an endorsement of or recommendation for any particular drug, use, or approach. Oregon Health & Science University does not recommend or endorse any guideline or recommendation developed by users of these reports. Update 5: April 2008 Update 4: April 2006 Update 3: April 2005 Update 2: April 2004 Update 1: September 2003 Original Report: November 2002 Update 6 Authors Susan Carson, MPH Sujata Thakurta, MPA: HA Allison Low, BA Beth Smit h, DO Roger Chou, MD Drug Effectiveness Review Project Marian McDonagh, PharmD, Principal Investigator Oregon Evidence -based Practice Center Mark Helfand, MD, MPH, Director Oregon Health & Science University Copyright © 2011 by Oregon Health & Science U niversity Portland, Oregon 97239. All rights reserved.

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Th e medical literature relating to this topic is scanned periodically. ( See -institutes/evidence -based -policy -center/derp/documents/methods.cfm for description of scanning process). Prior versions of this report can be accessed at the DERP web site.

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STRUCTURED ABSTRACT Purpose We compared the effectiveness and harms of long -acting opioids and of long-acting opioids compared with short-acting opioids in adults with chronic noncancer pain. Data Sources To identify published studies, we searched MEDLINE , Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects , and reference lists of included studies. We also searched the US Food and Drug Administration Center for Drug Evaluation and Research website for additional unpublished data and solicited dossiers of information from pharmaceutical manufacturers. Review Methods Study selection, data abstraction, validity assessment, grading the strength of the evidence, and data synthesis were all carried out according to standard Drug Effectiveness Review Project review methods. Results and Conclusions Although we identified 10 head- to-head trials comparing 2 or more long-acting opioids, the evidence was insufficient t o determine if there are differences among long-acting opioids in effectiveness or harms. Eight trials found no statistical difference in pain relief or function between long-acting opioids. The 2 trials which found a significant difference were both open- label, rated poor quality, an d were inconsistent with higher- quality trials evaluating the same comparison that found no significant difference s. A shortcoming of the currently available evidence is that comparisons between specific long -acting opioids have been evaluated in only 1 to 3 trials each (most with small sample sizes), which may limit statistical power for detecting true differences. Studies that provided indirect data were too heterogeneous in terms of study design, patient populations, interven tions, assessed outcomes, and results to make accurate judgments regarding comparative efficacy or adverse event rates. Evidence was insufficient to determine if long -acting opioids as a class are more effective or associated with fewer harms than short- acting opioids. There was also insufficient evidence to draw conclusions about comparative effectiveness or safety in subgroups.

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TABLE OF CONTENTS INTRODUCTION .. 7 Purpose and Limitations of Systematic Reviews .. 7 Scope and Key Questions . 9 METHODS . 13 Literature Search . 13 Data Abstraction .. 13 Quality Assessment .. 13 Grading the Strength of Evidence .. 14 Data Synthesis . 14 RESULTS .. 15 Literature Search Results for Update 6 15 Overview of Included Trials 16 Key Question 1. What is the comparative effectiveness of different long -acting opioids in reducing pain and improving functional outcomes in adult patients being treated for chronic noncancer pain? . 17 Summary of findings . 17 Detailed assessment 18 Direct evidence .. 18 Indirect evidence .. 22 Key Question 2. What is the comparative effectiveness of long -acting opioids compared with short -acting opioids in reducing pain and improving functional outcomes when used for treatment of adults with chronic noncancer pain? 24 Summary of evidence .. 24 Detailed assessment 24 Direct evidence .. 24 Key Question 3. What are the comparative harms (including addiction and abuse) of different long -acting opioids in adult patients being treated for chronic noncancer pain? .. 26 Summary of evidence .. 26 Detailed assessment 27 Direct evidence .. 27 Indirect evidence .. 30 Randomized trials 30 Observational studies 31 Key Question 4. What are the comparative harms of long -acting opioids compared with short -acting opioids in adult patients being treated for chronic noncancer pain? . 33 Summary of evidence .. 33 Detailed assessment 33 Direct evidence .. 33 Key Questions 5 and 6. Are there subpopulations of patients (specifically by race, age, sex, socio -economic status type of pain, or comorbidities) with chronic noncancer pain for which one long -acting opioid is more effective or associated with fewer harms, or for which long -acting opioids are more effective or associated with fewer harms than short -acting opioids? 35 Summary 35 Detailed assessment 35 SUMMARY 36 Strength of Evidence . 36 Limitations .. 36 Applicability 36 CONCLUSION . 38 REFERENCES 39

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FIGURES Figure 1. Results of literature search for Update 6 . 16 TABLES Table 1. Included drugs . 11 Table 2. Definitions of the grades of overall strength of evidence .. 14 Table 3 . Head -to -head trials of long -acting opioids 18 Table 4. Main results of trials of long -act ing opioid compared with short -acting opioid .. 25 Table 5. Specific adverse events in head -to -head trials of long -acting opioids 27 Table 6. Withdrawal rates in head -to -head trials of long -acting opioids for chronic noncancer pain 29 Table 7. Adverse events in trials of long -acting compared with short -acting opioids .. . 34 Table 8. Summary of evidence . 37 APPENDIX ES Appendix A. Glossary . 46 Appendix B. Boxed warnings of included drugs .. 55 Appendix C . Search strategies Update 6 . 65 Appendi x D . Excluded trials Update 6 .. 70 Appendix E. Strength of evidence 71 EVIDENCE TABLES

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We thank Leah Williams, our publications editor, for putting this report into its present form for you to read. Update 5 authors Roger Chou, MD Susan Carson, MPH Update 2, 3, and 4 author Roger Chou, MD Original Report and Update 1 authors Roger Chou, MD Elizabeth Clark, MD, MPH Carson S, Thakurta S, Low A, Smith B, Chou R. Drug class review: Long-acting opioid analgesics. Update 6 final report. Prepared by the Oregon Evidence- based Practice Center fo r the Drug Effectiveness Review Project. Oregon Health & Science University. Portland, OR. 2010. Available at: The Drug Effectiveness Review Project, composed of 12 organizations including 11 state Medicaid agencies, and the Canadian Agency for Drugs and Technology in Health comm issioned and funded for this report. These organizations selected the topic of the report and had input into its Key Questions. The content and conclusions of the report were entirely determined by the Evidence- based Practice Center researchers. The author s of this report have no financial interest in any company that makes or distributes the products reviewed in this report.

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Sy stematic reviews weigh the quality of the evidence, allowing a greater contribution from studies that meet high methodological standards and, thereby, reducing the likelihood of biased results. In general, for questions about the relative benefit of a drug, the results of well- executed randomized controlled trials are considered better evidence than results of cohort, case – control, and cross -sectional studies. In turn, these studies provide bette r evidence than uncontrolled trials and case series. For questions about tolerability and harms, observational study designs may provide important information that is not available from controlled trials. Within the hierarchy of observational studies, well-conducted cohort designs are preferred for assessing a common outcome. Case -control studies are preferred only when the outcome measure is rare and the study is well conducted. Systematic reviews pay particular attention to whether results of can be generalized to broader applications. Efficacy studies provide the best information about how a drug performs in a controlled setting. These studies attempt to tightly control potential confounding factors and bias; however, for this reason the results of efficacy studies may not be applicable to many, and sometimes to most, patients seen in everyday practice. Most efficacy studies use strict eligibility criteria that may exclude patients based on their age, sex, adherence to treatment, or sever ity of illness. For many drug classes, including the antipsychotics, unstable or severely impaired patients are often excluded from trials. In addition, efficacy studies frequently exclude patients who have comorbid disease, meaning disease other than the one under study. Efficacy studies may also use dosing regimens and follow-up protocols that are impractical in typical practice settings. These studies often restrict options that are of value in actual practice, such as combination therapies and switching to other drugs. Efficacy studies also often examine the short-term effects of drugs that in practice are used for much longer periods. Finally, efficacy studies tend to assess effects by using objective measures that do not capture all of the benefits and harms of a drug or do not reflect the outcomes that are most important to patients and their families. Systematic reviews highlight studies that reflect actual clinical in unselected patients and community practice settings. Effectiveness st udies conducted in primary care or office -based settings use less stringent eligibility criteria, more often assess health outcomes, and have longer follow -up periods than most efficacy studies. The results of effectiveness studies are more applicable to the fiaveragefl patient than results from the highly selected populations in efficacy studies. Examples of effectiveness outcomes include quality of life, frequency or duration of hospitalizations, social function, and the ability to work. These outcomes are more important to patients, family, and care providers than surrogate or intermediate measures, such as scores based on psychometric scales. Efficacy and effectiveness studies overlap. For example, a study might use very narrow inclusion criteria like an efficacy study, but, like an effectiveness study, might examine flexible dosing regimens, have a long follow-up period, and measure quality of life and functional outcomes. For this report we sought evidence about outcomes that are important to patients and would normally be considered appropriate for an effectiveness study. However, many of the studies that reported these outcomes were short -term and used strict inclusion criteria to select eligible patients. For these reasons, it was neither possible nor desirable to exclude evidence based on these characteristics. Labeling a study as either an efficacy or an effectiveness study, although convenient, is of limited value; it is more useful to consider whether the patient population, interventions, time fram e, and outcomes are relevant to one™s practice or to a particular patient.

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St udies anywhere on the continuum from efficacy to effectiveness can be useful in comparing the clinical value of different drugs. Effectiveness studies are more applicable to practice, but efficacy studies are a useful scientific standard for determining whether characteristics of different drugs are related to their effects on disease. Systematic reviews thoroughly cover the efficacy data in order to ensure that decision makers can assess the scope, quality, and relevance of the available data. This thoroughness is not intended to obscure the fact that efficacy data, no matter how large the quantity, may have limited applicability to practice. Clinicians can judge the relevance of s tudy results to their practice and should note where there are gaps in the available scientific information. Unfortunately, for many drugs there exist few or no effectiveness studies and many efficacy studies. Yet clinicians must decide on treatment for pa tients who would not have been included in controlled trials and for whom the effectiveness and tolerability of the different drugs are uncertain. Systematic reviews indicate whether or not there exists evidence that drugs differ in their effects in variou s subgroups of patients, but they do not attempt to set a standard for how results of controlled trials should be applied to patients who would not have been eligible for them. With or without an evidence report, these decisions must be informed by clinica l judgment. In the context of development of recommendations for clinical practice, systematic reviews are useful because they define the strengths and limits of the evidence, clarifying whether assertions about the value of an intervention are based on s trong evidence from clinical studies. By themselves, they do not say what to do. Judgment, reasoning, and applying one™s values under conditions of uncertainty must also play a role in decision making. Users of an evidence report must also keep in mind tha t does not mean ; that is, if the evidence supporting an assertion is insufficient, it does not mean the assertion is untrue. The quality of the evidence on effectiveness is a key component, but not the only component, in making decisions about clinical policy. Additional criteria include acceptability to physicians and patients, potential for unrecognized harm, applicability of the evidence to practice, and consideration of equity and justice. Scope and Key Questions The key questions and scope of the review were originally developed and refined by the Oregon Evidence- based Practice Center with input from a statewide panel of experts (pharmacists, primary care clinicians, pain care specialists, and representatives of the public) . Sub sequently, the key questions were reviewed and revised by representatives of organizations participating in the Drug Eff ectiveness Review Project . The participating organizations of the Drug Effectiveness Review Project are responsible for ensuring that th e scope of the review reflects the populations, drugs, and outcome measures of interest to both clinicians and patients. The participating organizations approved the following key questions to guide this review: 1. What is the comparative effectiveness of di fferent long-acting opioids in reducing pain and improving functional outcomes in adult patients being treated for chronic non cancer pain?

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2. What is the comparative effectiveness of long -acting opioids compared with short- acting opioids in reducing pain and improving functional outcomes when used for treatment of adults with chronic non cancer pain? 3. What are the comparative harms (including addiction and abuse) of different long- acting opioids in adult patients being treated for chronic non cancer pain? 4. What are the comparative harms of long-acting opioids compared with short -acting opioids in adult patients being treated for chronic non cancer pain? 5. Are there subpopulations of patients (specifically by race, age, sex, socioeconomic status type of pain, o r comorbidities) with chronic noncancer pain for which one long- acting opioid is more effective or associated with fewer harms? 6. Are there subpopulations of patients (specifically by race, age, sex, socio economic status, type of pain, or comorbidities) wi th chronic noncancer pain for which long-acting opioids are more effective or associated with fewer harms than short -acting opioids? Several aspects of the key questions deserve comment: The population included in th is review wa s adult ( 18 years old or greater) patients with chronic noncancer pain. We defined chronic noncancer pain as continuous or recurring pain for at least 6 months . Cancer patients and patients with HIV were excluded from this review. We included oral or transdermal long-acting opioids. Alth ough dosing frequency varies for an individual formulation of morphine, we refer to dosing twice daily in a trial as fis ustained -releasefl and once daily as fiextended -releasefl. fiLong -actingfl was defined as opioids administered 3 times daily or less frequently. Included drugs are shown below in Table 1. Black box warnings of the included drugs are provided in Appendix B. Although extended- release tapentadol is available in Canada and Europe, the participating organizations of Drug Effectiveness Review Project elected to exclude it from this review because it is not yet available in the United States. Extended- release Tramadol was also excluded because its m echanism of action is different from the other included long-acting opioids. It is believed that tramadol works -opioid receptors and weak inhibition of reuptake of norepinephrine and serotonin.

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Table 1. Included drugs Drug Trade name(s) Forms Recommended usual dosing frequency (times per day) Buprenorphine ButransŽ ER transdermal film Every 7 days Codeine Codeine Contin a ER oral tablet 2 Dihydrocodeine DHC Continus ®b Oral tablet 2 Fentanyl Duragesic ® ER transdermal film Every 72 hours Hydromorphone Exalgo ® ER oral tablet 1 Levorphanol c Generic Oral tablet 3-4 Methadone Dolophine ® Oral tablet 2-3 Morphine Avinza ® Kadian ® MS Contin ® Oramorph SR ® ER oral capsule ER oral capsule ER oral tablet ER oral tablet 1 1-2 1-3 2-3 Morphine sulfate and naltrexone hydrochlori de EmbedaŽ ER oral capsule 1-2 Oxycodone OxyContin ® ER oral tablet 2 Oxymorphone Opana ER ®c ER oral tablet 2 Abbreviations: ER, extended release; SR, sustained release. a Only available in Canada . b Only available in Europe . c Not available in Canada . The main efficacy measures were pain intensity, pain relief, and function. There is no single accepted standard regarding how to measure these outcomes. Most studies measure pain intensity using either visual analog or categorical pain scale s. Visu al analog scales consist of a line on a piece of paper labeled 0 at one end, indicating no pain, and a maximum number (commonly 100) at the other, indicating excruciating pain. Patients designate their current pain level on the line. An advantage of visual analog scales is that they provide a continuous range o f values for relative severity. A disadvantage is that the meaning of a pain score for any individual patient depends on the patient™s subjective experience of pain. This poses a challenge in objectiv ely comparin g scores between patients , and even differen t scores from the same patient. Categorical pain scales, on the other hand, consist of several pain category options from which a patient must choose (for example, no pain, mild pain , moderate pain, o r severe pain ). A disadvantage of categorical scales is that patients must chose between categories that may not accurately describe their pain. The best approach may be to utilize both methods. 8 Pain control (improvement in pain) and pain relief (resolution of pain) are als o measured using visual analog and categorical scales. Studies usually evaluate function using the Medical Outcomes Study Short Form-36 (SF- 36), Short Form-12 (SF-12), or other multi -question assessments . These questionnaires measure how well an individual functions physically, socially, cognitively, and psychologically. Another approach to measuring function is to focus on how well the medication helps commonly faced problems in daily living by patients with chronic pain, such as getting enough sleep or staying focused on the job. Some studies also report effects on mood and the preference for a medication over another.

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