Neurology
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A mechanism-based approach to treatment is alluring, but numerous practical problems impede its implementation. Although many new therapies have entered clinical trials, and randomized controlled trials have become larger and more sophisticated, pre-trial testing of underlying pain mechanisms is almost never performed for reasons of cost, risk to subjects, time required, and validation of the techniques used. Most registration clinical trials are performed in patients with post-herpetic neuralgia and painful diabetic neuropathy, but without more information on pain mechanisms, it remains uncertain how fully results in those two disorders can be generalized to patients with other types of chronic neuropathic pain. Examples of study designs and potential solutions are presented.
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This article reviews studies of the placebo response in antidepressant clinical trials, describes methods that have been attempted to decrease it, and discusses implications of the placebo response in depression for research on treatments for neuropathic pain. Literature reviews and research studies examining the placebo response in clinical trials of treatments for depression were reviewed. Existing data suggest that the placebo response in antidepressant clinical trials is substantial and that a high placebo response in a clinical trial is associated with a reduced likelihood of demonstrating the statistical superiority of antidepressant treatment vs. placebo. ⋯ In addition, there is little evidence that decreasing the placebo response rate makes it more likely that superiority of active vs. placebo treatment will be demonstrated. Analyses of neuropathic pain clinical trial databases should be conducted to examine factors associated with trial outcomes. Aspects of neuropathic pain clinical trials that require further consideration or investigation include the following: (a) exclusion of patients with mild pain severity; (b) exclusion of patients with short episode duration; (c) maximizing reliability, validity, and responsiveness of outcome measures; (d) minimizing extraneous contact with investigative staff and other sources of nonspecific therapeutic effects; (e) trial duration; (f) minimizing the number of treatment groups; (g) flexible vs. fixed dose designs; (h) strategies for identifying patients and accelerating enrollment; (i) identification of run-in periods that reduce the placebo response rate; and (j) registration of clinical trials and publication of negative studies.
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Clinical trials of opioid analgesics for chronic pain are recognized to frequently fail to distinguish the analgesic effect from placebo, despite known efficacy of the drug. This paper reviews the methodologic features of such trials that may be associated with risk of failure. A literature search yielded 23 randomized placebo-controlled studies of opioids with at least one week of continuous treatment; contacting pharmaceutical companies yielded six additional studies. ⋯ Study designs that lead to high dropout rates lack internal validity, unless dropout is the intended endpoint of the trial. Opioid analgesics should be studied in a manner that is clinically relevant, and that supports internal validity. More systematic attention is needed to clinical research methodology.