Systematic review of enriched enrolment, randomised withdrawal trial designs in chronic pain: a new framework for design and reporting.

Enriched enrolment, randomised withdrawal (EERW) pain trials select, before randomisation, patients who respond by demonstrating a predetermined degree of pain relief and acceptance of adverse events. There is uncertainty over the value of this design. We report a systematic review of EERW trials in chronic noncancer pain together with a critical appraisal of methods and potential biases in the methods used and recommendations for the design and reporting of future EERW trials. Electronic and other searches found 25 EERW trials published between 1995 and June 2014, involving 5669 patients in a randomised withdrawal phase comparing drug with placebo; 13 (median, 107 patients) had a randomised withdrawal phase of 6 weeks or less, and 12 (median, 334) lasted 12 to 26 weeks. Risks of bias included short duration, inadequate outcome definition, incomplete outcome data reporting, small size, and inadequate dose tapering on randomisation to placebo. Active treatment was usually better than placebo (22/25 trials). This review reduces the uncertainty around the value of EERW trials in pain. If properly designed, conducted, and reported, they are feasible and useful for making decisions about pain therapies. Shorter, small studies can be explanatory; longer, larger studies can inform practice. Current evidence is inadequate for valid comparisons in outcome between EERW and classical trials, although no gross differences were found. This systematic review provides a framework for assessing potential biases and the value of the EERW trials, and for the design of future studies by making recommendations for the conduct and reporting of EERW trials.

Research design considerations for confirmatory chronic pain clinical trials: IMMPACT recommendations.

There has been an increase in the number of chronic pain clinical trials in which the treatments being evaluated did not differ significantly from placebo in the primary efficacy analyses despite previous research suggesting that efficacy could be expected. These findings could reflect a true lack of efficacy or methodological and other aspects of these trials that compromise the demonstration of efficacy. There is substantial variability among chronic pain clinical trials with respect to important research design considerations, and identifying and addressing any methodological weaknesses would enhance the likelihood of demonstrating the analgesic effects of new interventions. An IMMPACT consensus meeting was therefore convened to identify the critical research design considerations for confirmatory chronic pain trials and to make recommendations for their conduct. We present recommendations for the major components of confirmatory chronic pain clinical trials, including participant selection, trial phases and duration, treatment groups and dosing regimens, and types of trials. Increased attention to and research on the methodological aspects of confirmatory chronic pain clinical trials has the potential to enhance their assay sensitivity and ultimately provide more meaningful evaluations of treatments for chronic pain.

A randomized, controlled, dose-ranging study investigating single doses of GW406381, naproxen sodium, or placebo in patients with acute pain after third molar tooth extraction.

OBJECTIVES: To evaluate the efficacy and tolerability of 4 doses of GW406381, a cyclooxygenase-2 inhibitor, compared with placebo in a standard model of acute inflammatory pain. METHODS: This randomized, double-blind, placebo-controlled, single-center study compared single doses of GW406381 (10 to 70 mg) or naproxen sodium 550 mg with placebo in patients after extraction of 2 or more partially bony impacted third molar teeth. A total of 300 patients were randomized (50 per group). The primary efficacy variable was the pain relief intensity difference score at each time point, which was calculated as the sum of the pain intensity difference and pain relief categorical scores at each time point. Each treatment was compared with placebo at each time point using an ordered hierarchical approach with closed testing procedures and last observation carried forward imputation methods. RESULTS: Pain relief intensity differences from placebo were statistically significant beginning at 1.5 hours postdosing for GW406381 70 and 50 mg and at 2-hour postdosing for GW406381 25 and 10 mg. The median time to onset of analgesia was 71 minutes for GW406381 50 mg, 72 minutes for GW406381 70 mg, and 36 minutes for naproxen. The median duration of analgesia was 5.9 hours for GW406381 50 mg, 7.9 hours for GW406391 70 mg, and 11.3 hours for naproxen. All treatments were well tolerated. DISCUSSION: GW406381 50 and 70 mg demonstrated clinically meaningful analgesia in this acute pain setting, although the onset of analgesia was greater than 1 hour.

A randomized, double-blind, placebo-controlled trial of a selective COX-2 inhibitor, GW406381, in patients with postherpetic neuralgia.

UNLABELLED: In this randomized, double-blind, placebo-controlled study, we evaluated the efficacy and safety of GW406381, an investigational selective cyclooxygenase (COX)-2 inhibitor with both peripheral and central actions, in 209 patients with postherpetic neuralgia (PHN). Patients were randomly assigned to GW406381 25 mg or 50 mg or placebo treatments for 3 weeks. The primary efficacy outcome measure was the change in average daily pain intensity score from baseline to the last week of treatment. Both doses of GW406381 produced greater reduction in pain score than placebo, but the treatment difference did not reach statistical significance. It was possible that the 3-week duration was too short, as there was a tendency for increasing separation from placebo over time that did not appear to reach maximum effect by the end of the study for either GW406381 treatment group. Overall, GW406381 was well tolerated in this elderly population. PERSPECTIVE: To our knowledge, this is the first report of a randomized, controlled clinical trial of a selective or nonselective COX inhibitor in neuropathic pain. The results of this study were inconclusive regarding the clinical relevance of the role of COX-2 in modulation of the symptoms of PHN.

Evaluation of GW406381 for treatment of osteoarthritis of the knee: two randomized, controlled studies.

CONTEXT: GW406381 is an investigational, highly selective cyclooxygenase-2 (COX-2) inhibitor that is effective in animal models of central sensitization and of inflammatory pain. OBJECTIVE: To examine dose response for efficacy and safety of GW406381 in adults with osteoarthritis (OA) of the knee. DESIGN: Two randomized, double-blind, placebo- and positive-control studies: Study A, a 6-week nonflare design; Study B, a 12-week flare design. PATIENTS: 649 patients entered Study A; 1331 patients entered Study B. STUDY A: GW406381 10, 20, 35, or 50 mg, celecoxib 200 mg, or placebo. Study B: GW406381 1, 5, 10, 25, or 50 mg, celecoxib 200 mg, or placebo. MAIN OUTCOME MEASURES: Study A, co-primary endpoints were change from baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscore and WOMAC question 1. Study B co-primary endpoints were change from baseline in WOMAC pain and function subscores and Patient Global Assessment of Arthritis Condition. A closed hierarchical test procedure was prespecified. RESULTS: Study A demonstrated that GW406381 50 mg was superior to placebo on WOMAC pain subscore (mean difference from placebo -6.9 mm; P= .012). No clear dose response was observed, and the results with celecoxib were no different from those of placebo. In Study B, no dose of GW406381 was superior to placebo on the co-primary endpoints. Celecoxib was superior to placebo on all co-primary endpoints. Dose-related blood pressure and renovascular effects were seen with GW406381. CONCLUSIONS: Overall, clinically meaningful efficacy in pain related to OA of the knee was not demonstrated for GW406381 despite its peripheral and central sites of action.

Analyzing multiple endpoints in clinical trials of pain treatments: IMMPACT recommendations. Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials.

The increasing complexity of randomized clinical trials and the practice of obtaining a wide variety of measurements from study participants have made the consideration of multiple endpoints a critically important issue in the design, analysis, and interpretation of clinical trials. Failure to consider important outcomes can limit the validity and utility of clinical trials; specifying multiple endpoints for the evaluation of treatment efficacy, however, can increase the rate of false positive conclusions about the efficacy of a treatment. We describe the use of multiple endpoints in the design, analysis, and interpretation of pain clinical trials, and review available strategies and methods for addressing multiplicity. To decrease the probability of a Type I error (i.e., the likelihood of obtaining statistically significant results by chance) in pain clinical trials, the use of gatekeeping procedures and other methods that correct for multiple analyses is recommended when a single primary endpoint does not adequately reflect the overall benefits of treatment. We emphasize the importance of specifying in advance the outcomes and clinical decision rule that will serve as the basis for determining that a treatment is efficacious and the methods that will be used to control the overall Type I error rate.

Interpreting the clinical importance of treatment outcomes in chronic pain clinical trials: IMMPACT recommendations.

UNLABELLED: A consensus meeting was convened by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) to provide recommendations for interpreting clinical importance of treatment outcomes in clinical trials of the efficacy and effectiveness of chronic pain treatments. A group of 40 participants from universities, governmental agencies, a patient self-help organization, and the pharmaceutical industry considered methodologic issues and research results relevant to determining the clinical importance of changes in the specific outcome measures previously recommended by IMMPACT for 4 core chronic pain outcome domains: (1) Pain intensity, assessed by a 0 to 10 numerical rating scale; (2) physical functioning, assessed by the Multidimensional Pain Inventory and Brief Pain Inventory interference scales; (3) emotional functioning, assessed by the Beck Depression Inventory and Profile of Mood States; and (4) participant ratings of overall improvement, assessed by the Patient Global Impression of Change scale. It is recommended that 2 or more different methods be used to evaluate the clinical importance of improvement or worsening for chronic pain clinical trial outcome measures. Provisional benchmarks for identifying clinically important changes in specific outcome measures that can be used for outcome studies of treatments for chronic pain are proposed. PERSPECTIVE: Systematically collecting and reporting the recommended information needed to evaluate the clinical importance of treatment outcomes of chronic pain clinical trials will allow additional validation of proposed benchmarks and provide more meaningful comparisons of chronic pain treatments.

Double-blind, placebo-controlled trial of lamotrigine in combination with other medications for neuropathic pain.

This randomized, double-blind, placebo-controlled study was undertaken to evaluate the efficacy and tolerability of lamotrigine added to gabapentin, a tricyclic antidepressant, or a nonopioid analgesic in patients whose neuropathic pain was inadequately controlled with these medications. Patients with neuropathic pain from diabetic peripheral neuropathy, postherpetic neuralgia, traumatic/surgical nerve injury, incomplete spinal cord injury, trigeminal neuralgia, multiple sclerosis, or HIV-associated peripheral neuropathy, who had a mean weekly pain score > or =4 on an 11-point numerical rating scale, were randomized to receive a flexible dose of lamotrigine 200, 300, or 400mg daily (n=111) or placebo (n=109) for up to 14 weeks (including eight weeks of dose escalation) in addition to their prestudy regimen of gabapentin, a tricyclic antidepressant, or a nonopioid analgesic. No statistically significant difference in the mean change in pain-intensity score from baseline to Week 14 (primary endpoint) was detected between lamotrigine and placebo (P=0.67). Differences between lamotrigine and placebo were not statistically significant for secondary efficacy assessments, including mean changes from baseline in the Short-Form McGill Pain Questionnaire, the Neuropathic Pain Scale, rescue medication use, and the percentages of patients rated as much improved or very much improved at the end of treatment on the Clinician Global Impression of Change scale and the Patient Global Impression of Change scale. Lamotrigine was generally well tolerated. Lamotrigine (up to 400 mg/day) added to gabapentin, a tricyclic antidepressant, or a nonopioid analgesic did not demonstrate efficacy as an adjunctive treatment of neuropathic pain but was generally safe and well tolerated.

Lamotrigine for treatment of pain associated with diabetic neuropathy: results of two randomized, double-blind, placebo-controlled studies.

To assess the efficacy and tolerability of lamotrigine in pain associated with diabetic neuropathy, two replicate randomized, double-blind, placebo-controlled studies were conducted. Patients (n=360 per study) with painful diabetic neuropathy were randomized to receive lamotrigine 200, 300, or 400 mg daily or placebo during the 19-week treatment phase, including a 7-week dose-escalation phase and a 12-week, fixed-dose maintenance phase. The mean reduction in pain-intensity score from baseline to week 19 (primary endpoint) was greater (p < or = 0.05) in patients receiving lamotrigine 400 mg than placebo in Study 2 (observed scores, -2.7 versus -1.6 on a 0- to 10-point scale). This finding was not replicated in Study 1. Lamotrigine 200 and 300 mg did not significantly differ from placebo at week 19 in either study. Lamotrigine 300 and 400 mg were only occasionally more effective than placebo for secondary efficacy endpoints. The 200-mg dose did not separate from placebo. In a post hoc analysis of pooled data including only patients who reached their target dose, lamotrigine 400 mg conferred greater (p0.05) mean reduction in pain-intensity score from baseline to week 19 than placebo (-2.5 for 300 mg and -2.7 for 400mg versus -2.0 for placebo). Adverse events were reported in 71-82% of lamotrigine-treated patients compared with 63-70% of placebo-treated patients. The most common adverse events with lamotrigine were headache and rash. Compared with placebo, lamotrigine (300 and 400 mg daily) was inconsistently effective for pain associated with diabetic neuropathy but was generally safe and well tolerated.

Lack of effect of two oral sodium channel antagonists, lamotrigine and 4030W92, on intradermal capsaicin-induced hyperalgesia model.

Preclinical studies have emphasized that persistent small afferent input will induce a state of central facilitation, which can be regulated by systemically administered sodium channel blockers. We have extended these preclinical studies to the human volunteers by examining the effects of lamotrigine and 4030W92, two structurally related voltage-sensitive sodium channel antagonists, on acute sensory thresholds and facilitated processing induced by intradermal capsaicin. Fifteen healthy subjects received 4030W92, lamotrigine, and placebo in a randomized order using double-blinded crossover design methodology in three sessions each separated by a 7-day washout period. In each session, baseline neurosensory testing was performed on the volar aspect of the subject's left forearm. Subjects were then dosed with either lamotrigine (300 mg), 4030W92 (100 mg), or placebo, followed 2 h later by capsaicin (100 microg) injected intradermally on the volar aspect of the left forearm. Pain scores, blood pressure, heart rate, and respiratory rate were measured at the time of injection and every 5 min for 15 min. Fifteen minutes after the capsaicin injection, the hyperalgesic area was determined by von Frey hair, stroking, and heat; the flare response was outlined; and neurosensory testing again was performed halfway between the edge of the hyperalgesic area and the capsaicin injection site. While capsaicin significantly decreased the hot pain and VF pain thresholds, oral lamotrigine and 4030W92 failed to alter this response to capsaicin, relative to placebo treatment. Similarly, oral lamotrigine or 4030W92 did not alter the pain scores reported from mechanical pain stimuli at any time postcapsaicin. This study showed a lack of effect of two structurally similar sodium channel antagonists on a human experimental pain model using intradermal capsaicin, which is consistent with other studies on the effects of sodium channel antagonists of capsaicin-induced pain and hyperalgesia. This lack of effect stands in contrast to reported effects of sodium channel antagonists on preclinical models of cutaneous hyperalgesia or effects of lamotrigine on clinical neuropathic pain.

Core outcome domains for chronic pain clinical trials: IMMPACT recommendations.

OBJECTIVE: To provide recommendations for the core outcome domains that should be considered by investigators conducting clinical trials of the efficacy and effectiveness of treatments for chronic pain. Development of a core set of outcome domains would facilitate comparison and pooling of data, encourage more complete reporting of outcomes, simplify the preparation and review of research proposals and manuscripts, and allow clinicians to make informed decisions regarding the risks and benefits of treatment. METHODS: Under the auspices of the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT), 27 specialists from academia, governmental agencies, and the pharmaceutical industry participated in a consensus meeting and identified core outcome domains that should be considered in clinical trials of treatments for chronic pain. CONCLUSIONS: There was a consensus that chronic pain clinical trials should assess outcomes representing six core domains: (1) pain, (2) physical functioning, (3) emotional functioning, (4) participant ratings of improvement and satisfaction with treatment, (5) symptoms and adverse events, (6) participant disposition (e.g. adherence to the treatment regimen and reasons for premature withdrawal from the trial). Although consideration should be given to the assessment of each of these domains, there may be exceptions to the general recommendation to include all of these domains in chronic pain trials. When this occurs, the rationale for not including domains should be provided. It is not the intention of these recommendations that assessment of the core domains should be considered a requirement for approval of product applications by regulatory agencies or that a treatment must demonstrate statistically significant effects for all of the relevant core domains to establish evidence of its efficacy.