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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.

Introduction

Chronic pain, typically defined as pain for at least 3 to 6 months, is a common cause of major disability. An estimated 1 in 5 adult Americans, or 30 million people, experience chronic pain.1 Chronic noncancer pain afflicts a significant subset of patients, causing personal suffering, reduced productivity, and substantial health care costs.2 Opioids have been endorsed by the American Academy of Pain Medicine, the American Pain Society,3 and the Canadian Pain Society,4 among others, as appropriate treatment for refractory chronic noncancer pain in the general population and in older patients,5 when used judiciously and according to guidelines similar to those followed with cancer patients.

Opioids are natural derivatives of morphine.6 As a class, these medications act on common receptors. They are the most potent medications available for treatment of most types of severe pain. They are also associated with a variety of adverse events, including abuse and addiction. Opioids are available in short- and long-acting preparations. Because chronic pain may not resolve with time, use of opioid analgesics for these conditions is commonly long term. Despite the widespread use of long-acting opioids, there is little data regarding the comparative benefits and harms associated with specific long -acting opioids for chronic noncancer pain.7

The purpose of this report is to determine whether there is evidence that 1 or more long-acting opioid is superior to others in terms of benefits and harms and whether long-acting opioids as a class are superior to short-acting opioids when used for treatment of chronic noncancer pain.

Purpose and Limitations of Systematic Reviews

Systematic reviews, also called evidence reviews, are the foundation of evidence-based practice. They focus on the strength and limits of evidence from studies about the effectiveness of a clinical intervention. Systematic reviews begin with careful formulation of research questions. The goal is to select questions that are important to patients and clinicians then to examine how well the scientific literature answers those questions. Terms commonly used in systematic reviews, such as statistical terms, are provided in Appendix A and are defined as they apply to reports produced by the Drug Effectiveness Review Project.

Systematic reviews emphasize the patient’s perspective in the choice of outcome measures used to answer research questions. Studies that measure health outcomes (events or conditions that the patient can feel, such as fractures, functional status, and quality of life) are preferred over studies of intermediate outcomes (such as change in bone density). Reviews also emphasize measures that are easily interpreted in a clinical context. Specifically, measures of absolute risk or the probability of disease are preferred to measures such as relative risk. The difference in absolute risk between interventions depends on the number of events in each group, such that the difference (absolute risk reduction) is smaller when there are fewer events. In contrast, the difference in relative risk is fairly constant between groups with different baseline risk for the event, such that the difference (relative risk reduction) is similar across these groups. Relative risk reduction is often more impressive than absolute risk reduction. Another useful measure is the number needed to treat (or harm). The number needed to treat is the number of patients who would need be treated with an intervention for 1 additional patient to benefit (experience a positive outcome or avoid a negative outcome). The absolute risk reduction is used to calculate the number needed to treat.

Systematic 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 better 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 efficacy studies 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 severity 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 effectiveness in unselected patients and community practice settings. Effectiveness studies 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 “average” 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 frame, and outcomes are relevant to one’s practice or to a particular patient.

Studies 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 study 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 patients 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 various 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 clinical 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 strong 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 that not proven does not mean proven not; 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). Subsequently, the key questions were reviewed and revised by representatives of organizations participating in the Drug Effectiveness Review Project. The participating organizations of the Drug Effectiveness Review Project are responsible for ensuring that the 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 different long-acting opioids in reducing pain and improving functional outcomes in adult patients being treated for chronic noncancer pain?
  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?
  3. What are the comparative harms (including addiction and abuse) of different long-acting opioids in adult patients being treated for chronic noncancer pain?
  4. What are the comparative harms of long-acting opioids compared with short-acting opioids in adult patients being treated for chronic noncancer pain?
  5. Are there subpopulations of patients (specifically by race, age, sex, socioeconomic status type of pain, or 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, socioeconomic status, type of pain, or comorbidities) with 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:

Population. The population included in this review was 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.

Drugs. We included oral or transdermal long-acting opioids. Although dosing frequency varies for an individual formulation of morphine, we refer to dosing twice daily in a trial as “sustained-release” and once daily as “extended -release”. “Long-acting” 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 mechanism of action is different from the other included long-acting opioids. It is believed that tramadol works through binding of parent and M1 metabolite to μ-opioid receptors and weak inhibition of reuptake of norepinephrine and serotonin.

Table 1. Included drugs.

Table 1

Included drugs.

Outcomes. 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 scales. Visual 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 of 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 objectively comparing scores between patients, and even different 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, or 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 also 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.

The following adverse events were specifically reviewed: abuse, addiction, nausea, vomiting, constipation, dizziness, somnolence, and confusion. These were felt to be the most common and troubling adverse events in clinical practice. We recorded rates of these adverse events as well as rates of discontinuation due to specific adverse events when reported. In some studies, only “serious” adverse events or adverse events “thought related to treatment medication” were reported. Many studies did not define these terms.

We specifically examined whether opioids differ in the risk of abuse and addiction. Although standardized definitions for abuse and addiction have been proposed, they are not used consistently in studies investigating this outcome.9, 10 We recorded any information about abuse and addiction, including rates of death and hospitalization, when available.

Because of inconsistent reporting of outcomes, trial withdrawal rates may be a more reliable measure in studies of opioids. This outcome may be a surrogate measure for either clinical efficacy or adverse events. One trial that examined reason for withdrawal found that withdrawals were primarily due to adverse events in patients on long-acting oxycodone, but in patients on placebo, withdrawals were due to inadequate pain control.11 High withdrawal rates therefore probably indicate some combination of poor tolerability and ineffectiveness. An important subset is withdrawal due to any adverse event (those who discontinue specifically because of adverse events).

Study types. We included controlled clinical trials to evaluate efficacy. The validity of controlled trials depends on how they are designed. Randomized, properly blinded clinical trials are considered the highest level of evidence for assessing efficacy.12–14 Clinical trials that are not randomized or blinded and those that have other methodological flaws are less reliable, but are also discussed in our report.

Trials that compare a long -acting opioid with another long-acting opioid (“head-to-head” trials) or a long-acting opioid with a short-acting opioid provide direct evidence of comparative benefits and harms. Trials that compare a long-acting opioid with placebo may provide indirect data about comparative benefits and harms. However, reliable comparisons from such trials may not be possible if they evaluate significantly different populations, interventions, or outcomes, or if the trials have important methodological flaws.

To evaluate adverse event rates, we included clinical trials and observational cohort studies designed to assess adverse events between different long-acting opioids. Clinical trials are often not designed to, or use inadequate methods to, assess adverse events and may select patients at lower risk for adverse events (in order to minimize dropout rates and maximize potential benefits). Well-designed observational studies designed to assess adverse events may include broader populations more applicable to real-world practice, carry out observations over a longer time period, use higher-quality techniques for assessing adverse events, or examine larger sample sizes.

One issue that complicates the interpretation of studies of opioids for chronic pain is “incomplete cross-tolerance.” In medical jargon, a patient who finds that a particular opioid is less effective over time is said to have become “tolerant” to that drug. “Incomplete cross-tolerance” means that a patient’s “tolerance” for an opioid may not carry over to other opioids. If incomplete cross-tolerance occurs, individuals who have been taking a specific opioid may do better if they switch to a different opioid—not because the new one is a better drug, but simply because it is not the one they have been taking. In observational studies of both cancer and noncancer patients, there is some evidence that incomplete cross-tolerance occurs.15–18

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

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