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Selph S, Carson S, Fu R, et al. Drug Class Review: Neuropathic Pain: Final Update 1 Report [Internet]. Portland (OR): Oregon Health & Science University; 2011 Jun.

Introduction

Neuropathic pain is defined by the International Association for the Study of Pain as “pain initiated or caused by a primary lesion or dysfunction in the nervous system.”1 Neuropathic pain can occur because of dysfunction or disease of the nervous system at the peripheral and/or central level.2 Neuropathic pain can be very severe and disabling, with significant functional, psychological, and social consequences. Regardless of the underlying cause of neuropathic pain, common treatment goals are to decrease pain and/or improve function.

Neuropathic pain is often classified by etiology or by the presumed site of neurologic involvement (central or peripheral). However, both peripheral and central nervous system lesions may contribute to most types of chronic neuropathic pain.3 More complex classification systems based on symptoms, signs, anatomical distribution, or hypotheses regarding etiologies have been proposed, but it is not clear if such classifications are accurate or reproducible. A mechanistic classification may be the preferred approach, but current knowledge of the pathophysiology of neuropathic pain is incomplete, and multiple mechanisms may be involved.4

Neuropathic pain is characterized by continuous or intermittent spontaneous pain, typically characterized by patients as burning, aching, or shooting. The pain may be provoked by normally innocuous stimuli (allodynia). Neuropathic pain is also commonly associated with hyperalgesia (increased pain intensity evoked by normally painful stimuli), paresthesia, and dysesthesia.4

Up to 3% of the general population reports neuropathic pain at some time. 5 The prevalence of different types of neuropathic pain varies widely.6 Neuropathic pain is most commonly associated with painful diabetic neuropathy, postherpetic neuralgia, or lumbar nerve root compression.6 Diabetic neuropathy occurs in approximately 10% of persons with diabetes.7 Prevalence of diabetic neuropathy increases with age, worsening glycemic control, and duration of diabetes. The most common form of diabetic peripheral neuropathy is a distal symmetric polyneuropathy.8 Post herpetic neuralgia is defined as pain persisting or recurring at the site of acute herpes zoster 3 or more months after the acute episode.9 It occurs in up to 25% of patients following an episode of shingles.10 Symptomatic spinal stenosis and lumbar disc herniation with nerve root compression occur in approximately 3% and 4% of patients with low back pain, respectively.11 Other causes of neuropathic pain include cancer-related pain, spinal cord injury, poststroke pain, HIV-associated neuropathy, and phantom limb pain. Uncommon but potentially debilitating neuropathic pain conditions include trigeminal neuralgia (incidence 4/100,000 population).12 In the United States, health care and disability-related costs associated with neuropathic pain are estimated at almost $40 billion annually.13

A number of medications (oral or topical) are available for treating neuropathic pain (Table 1). So me medications may act by decreasing nerve excitability and conduction in sensory axons. Others may have effects on neural damage-related synaptic changes (particularly for central pain). However, the mechanism of action for various drugs varies substantially and in some cases is not well understood. For example, antiepileptic drugs may target peripheral and/or central sensitization mechanisms involved in neuropathic pain, but the exact mechanisms of action are uncertain.12 Topical lidocaine, on the other hand, blocks sodium channels, which may stabilize nerve membranes.14

Table 1. Included drugs.

Table 1

Included drugs.

Choosing therapy for neuropathic pain is challenging because of the large number of medications available to treat this condition and potential differences between medications in effectiveness or harms. The objective of this report is to compare the effectiveness and safety of the drugs shown in Table 1. Simple analgesics such as acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), and opioids were not included in this review. However, NSAIDs and opioids for chronic pain, including neuropathic pain, are addressed in separate Drug Effectiveness Review Project15, 16 reviews available at http://www.ohsu.edu/drugeffectiveness/reports/final.cfm. Black box warnings for the interventions are listed in Appendix A.

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 B 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 Oregon Evidence-based Practice Center wrote preliminary key questions, identifying the populations, interventions, and outcomes of interest, and based on these, the eligibility criteria for studies. These were reviewed and revised by representatives of organizations participating in Drug Effectiveness Review Project. The participating organizations of 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 anticonvulsants, tricyclic antidepressants, serotonin–norepinephrine reuptake inhibitors (SNRIs), and the lidocaine patch for neuropathic pain?
  2. What are the comparative harms of anticonvulsants, tricyclic antidepressants, SNRIs, and the lidocaine patch for neuropathic pain?
  3. Are there differences in effectiveness or harms of anticonvulsants, tricyclic antidepressants, SNRIs, and the lidocaine patch based on demographics, socioeconomic status, comorbidities, or drug-drug interactions, when used to treat neuropathic pain?
Copyright © 2011 by Oregon Health & Science University.
Cover of Drug Class Review: Neuropathic Pain
Drug Class Review: Neuropathic Pain: Final Update 1 Report [Internet].
Selph S, Carson S, Fu R, et al.
Portland (OR): Oregon Health & Science University; 2011 Jun.

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