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Carson S, Thakurta S, Low A, et al. Drug Class Review: Long-Acting Opioid Analgesics: Final Update 6 Report [Internet]. Portland (OR): Oregon Health & Science University; 2011 Jul.

  • This publication is provided for historical reference only and the information may be out of date.

This publication is provided for historical reference only and the information may be out of date.

Cover of Drug Class Review: Long-Acting Opioid Analgesics

Drug Class Review: Long-Acting Opioid Analgesics: Final Update 6 Report [Internet].

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Literature Search

Searches to identify articles relevant to each key question were performed of the Cochrane Central Register of Controlled Trials® (4th Quarter, 2010), Cochrane Database of Systematic Reviews® (2005 to January 2011), Database of Abstracts of Reviews of Effects (1st Quarter 2011), MEDLINE® (1966-January Week 4, 2011), EMBASE (1980–2001), and reference lists of included studies and review articles. In electronic searches, we combined terms for pain with terms for opioid analgesics and narcotics and relevant research designs (see Appendix C for complete search strategies). In addition, we requested dossiers of published and unpublished information from the relevant pharmaceutical companies for this review. All received dossiers were screened for studies or data not found through other searches. All citations were imported into an electronic database (Endnote® X2, Thomson Reuters).

Data Abstraction

We abstracted information on population characteristics, interventions, subject enrollment, and results for efficacy, effectiveness, and harms outcomes for trials, observational studies, and systematic reviews. Equianalgesic doses of opioid medications were estimated using published tables.19 We recorded intent-to-treat results if they were available and the trial did not report high overall loss to follow-up. In trials with crossover, because of the potential for differential withdrawal prior to crossover and drug carryover effects biasing subsequent results, outcomes for the first intervention were recorded if available. A second reviewer checked all data.

Validity Assessment

We assessed the internal validity (quality) of trials based on the predefined criteria (see These criteria are based on the US Preventive Services Task Force and the National Health Service Centre for Reviews and Dissemination (United Kingdom) criteria.12, 13 We rated the internal validity of each trial based on the methods used for randomization, allocation concealment, and blinding; the similarity of compared groups at baseline; maintenance of comparable groups; adequate reporting of dropouts, attrition, crossover, adherence, and contamination; loss to follow-up; and the use of intent-to-treat analysis. Trials that had a fatal flaw were rated poor quality; trials that met all criteria were rated good quality; the remainder were rated fair quality. As the fair-quality category is broad, studies with this rating vary in their strengths and weaknesses: The results of some fair-quality studies are likely to be valid, while others are only possibly valid. A poor -quality trial is not valid; the results are at least as likely to reflect flaws in the study design as a true difference between the compared drugs. A fatal flaw is reflected by failure to meet combinations of items of the quality assessment checklist. A particular randomized trial might receive 2 different ratings, 1 for effectiveness and another for adverse events.

The criteria used to rate observational studies of adverse events reflect aspects of the study design that are particularly important for assessing adverse event rates. We rated observational studies as good quality for adverse event assessment if they adequately met 6 or more of the 7 predefined criteria, fair quality if they met 3 to 5 criteria, and poor quality if they met 2 or fewer criteria.

Included systematic reviews were also rated for quality. We rated the internal validity based a clear statement of the questions(s); reporting of inclusion criteria; methods used for identifying literature (the search strategy), validity assessment, and synthesis of evidence; and details provided about included studies. Again, these studies were categorized as good when all criteria were met.

Two reviewers independently assigned quality ratings. Overall quality rating and quality rating scores were compared between reviewers. Differences were resolved by consensus.

Grading the Strength of Evidence

We graded strength of evidence based on the guidance established for the Evidence-based Practice Center Program of the Agency for Healthcare Research and Quality.20 Developed to grade the overall strength of a body of evidence, this approach incorporates 4 key domains: risk of bias (includes study design and aggregate quality), consistency, directness, and precision of the evidence. It also considers other optional domains that may be relevant for some scenarios, such as a dose-response association, plausible confounding that would decrease the observed effect, strength of association (magnitude of effect), and publication bias.

Table 2 describes the grades of evidence that can be assigned. Grades reflect the strength of the body of evidence to answer key questions on the comparative effectiveness, efficacy, and harms of different long-acting opioids and long-acting opioids compared with short-acting opioids. Grades do not refer to the general efficacy or effectiveness of pharmaceuticals. Two reviewers independently assessed each domain for each outcome and differences were resolved by consensus.

Table 2. Definitions of the grades of overall strength of evidence.

Table 2

Definitions of the grades of overall strength of evidence.

Strength of evidence was graded for each key outcome measure and was limited to head-to-head comparisons except where a case could be made for assessing the strength of indirect evidence.

Data Synthesis

We constructed evidence tables showing the study characteristics, quality ratings, and results for all included studies. We reviewed studies using a hierarchy of evidence approach, where the best evidence is the focus of our synthesis for each question, population, intervention, and outcome addressed. Studies that evaluated 1 long-acting opioid against another or a long-acting opioid compared with a short-acting opioid provided direct evidence of comparative effectiveness and adverse event rates. Where possible, these data are the primary focus. Direct comparisons were preferred over indirect comparisons; similarly, effectiveness and long-term safety outcomes were preferred to efficacy and short-term tolerability outcomes.

In theory, trials that compare long-acting opioids with other drug classes or with placebos can also provide evidence about effectiveness. This is known as an indirect comparison and can be difficult to interpret for a number of reasons, primarily heterogeneity of trial populations, interventions, and outcomes assessment. Data from indirect comparisons are used to support direct comparisons, where they exist, and are used as the primary comparison where no direct comparisons exist. Indirect comparisons should be interpreted with caution.

Quantitative analyses were conducted using meta-analyses of outcomes reported by a sufficient number of studies that were homogeneous enough that combining their results could be justified. In order to determine whether meta-analysis could be meaningfully performed, we considered the quality of the studies and the heterogeneity among studies in design, patient population, interventions, and outcomes. When meta-analysis could not be performed, the data were summarized qualitatively.

Public Comment

This report was posted to the Drug Effectiveness Review Project website for public comment. We received comments from 3 pharmaceutical companies, 1 representing professional or advocacy organization.

Copyright © 2011 by Oregon Health & Science University.
Bookshelf ID: NBK62336


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