Showing papers by "Michael C. Rowbotham published in 2012"

Considerations for improving assay sensitivity in chronic pain clinical trials: IMMPACT recommendations.

Abstract: A number of pharmacologic treatments examined in recent randomized clinical trials (RCTs) have failed to show statistically significant superiority to placebo in conditions in which their efficacy had previously been demonstrated. Assuming the validity of previous evidence of efficacy and the comparability of the patients and outcome measures in these studies, such results may be a consequence of limitations in the ability of these RCTs to demonstrate the benefits of efficacious analgesic treatments vs placebo ("assay sensitivity"). Efforts to improve the assay sensitivity of analgesic trials could reduce the rate of falsely negative trials of efficacious medications and improve the efficiency of analgesic drug development. Therefore, an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials consensus meeting was convened in which the assay sensitivity of chronic pain trials was reviewed and discussed. On the basis of this meeting and subsequent discussions, the authors recommend consideration of a number of patient, study design, study site, and outcome measurement factors that have the potential to affect the assay sensitivity of RCTs of chronic pain treatments. Increased attention to and research on methodological aspects of clinical trials and their relationships with assay sensitivity have the potential to provide the foundation for an evidence-based approach to the design of analgesic clinical trials and expedite the identification of analgesic treatments with improved efficacy and safety.

Randomized control trial of topical clonidine for treatment of painful diabetic neuropathy.

Abstract: A length-dependent neuropathy with pain in the feet is a common complication of diabetes (painful diabetic neuropathy). It was hypothesized that pain may arise from sensitized-hyperactive cutaneous nociceptors, and that this abnormal signaling may be reduced by topical administration of the α(2)-adrenergic agonist, clonidine, to the painful area. This was a randomized, double-blind, placebo-controlled, parallel-group, multicenter trial. Nociceptor function was measured by determining the painfulness of 0.1% topical capsaicin applied to the pretibial area of each subject for 30minutes during screening. Subjects were then randomized to receive 0.1% topical clonidine gel (n=89) or placebo gel (n=90) applied 3 times a day to their feet for 12weeks. The difference in foot pain at week 12 in relation to baseline, rated on a 0-10 numerical pain rating scale (NPRS), was compared between groups. Baseline NPRS was imputed for missing data for subjects who terminated the study early. The subjects treated with clonidine showed a trend toward decreased foot pain compared to the placebo-treated group (the primary endpoint; P=0.07). In subjects who felt any level of pain to capsaicin, clonidine was superior to placebo (P<0.05). In subjects with a capsaicin pain rating ⩾2 (0-10, NPRS), the mean decrease in foot pain was 2.6 for active compared to 1.4 for placebo (P=0.01). Topical clonidine gel significantly reduces the level of foot pain in painful diabetic neuropathy subjects with functional (and possibly sensitized) nociceptors in the affected skin as revealed by testing with topical capsaicin. Screening for cutaneous nociceptor function may help distinguish candidates for topical therapy for neuropathic pain.

Core outcome measures for opioid abuse liability laboratory assessment studies in humans: IMMPACT recommendations.

Abstract: A critical component in development of opioid analgesics is assessment of their abuse liability (AL). Standardization of approaches and measures used in assessing AL have the potential to facilitate comparisons across studies, research laboratories, and drugs. The goal of this report is to provide consensus recommendations regarding core outcome measures for assessing the abuse potential of opioid medications in humans in a controlled laboratory setting. Although many of the recommended measures are appropriate for assessing the AL of medications from other drug classes, the focus here is on opioid medications because they present unique risks from both physiological (e.g., respiratory depression, physical dependence) and public health (e.g., individuals in pain) perspectives. A brief historical perspective on AL testing is provided, and those measures that can be considered primary and secondary outcomes and possible additional outcomes in AL assessment are then discussed. These outcome measures include the following: subjective effects (some of which comprise the primary outcome measures, including drug liking; physiological responses; drug self-administration behavior; and cognitive and psychomotor performance. Before presenting recommendations for standardized approaches and measures to be used in AL assessments, the appropriateness of using these measures in clinical trials with patients in pain is discussed.

Adherence to CONSORT harms-reporting recommendations in publications of recent analgesic clinical trials: an ACTTION systematic review.

Abstract: Recommendations for harms (ie, adverse events) reporting in randomized clinical trial publications were presented in a 2004 extension of the Consolidated Standards of Reporting Trials (CONSORT) statement. Our objectives were to assess harms reporting in 3 major pain journals (European Journal of Pain, Journal of Pain, and PAIN®) to determine whether harms reporting improved following publication of the 2004 CONSORT recommendations, and to examine study factors associated with adequacy of harms reporting. A total of 101 randomized, double-blind, noninvasive pharmacologic trials were identified in the 2000-2003 (epoch 1) and 2008-2011 (epoch 2) issues of these journals. Out of 10 reporting recommendations, the mean number fulfilled was 6.08 (SD2.65). Although more harms recommendations were fulfilled in epoch 2 (m(2)=6.49, SD2.66) than in epoch 1 (m(1)=5.39, SD2.52; P=0.04), only the recommendation to report harms per arm was satisfied by >90% of trials in epoch 2, whereas <60% reported withdrawals due to harms. Several trial characteristics (study design, participant type, pain type, frequency of treatment administration, treatment administration method, sponsor, and number of randomized participants) were significantly associated with harms reporting. However, when trial characteristics and epoch were entered into a multiple regression analysis, only trials studying pain patients, those using oral treatments, and industry-sponsored trials were associated with better harms reporting. Despite some improvement in harms reporting, greater improvement is needed to provide informative, consistent reporting of adverse events and safety in analgesic clinical trials.

A snapshot and scorecard for analgesic clinical trials for chronic pain: the RReACT database.

Abstract: It was not long ago that public access to information about drug trials, especially for off-label uses, was almost nonexistent [21,23]. During those ‘‘dark ages,’’ patients with chronic pain and their phy­ sicians had difficulty learning about research studies seeking par­ ticipants. The 1997 FDA Modernization Act resulted in the creation of the ClinicalTrials.gov registry website, maintained by the National Library of Medicine on behalf of the National Insti­ tutes of Health (http://www.ClinicalTrials.gov/) [2,15,25]. In 2005, the International Committee of Medical Journal Editors re­ quired clinical trials to be registered in a public trials registry in or­ der to be considered for publication in an International Committee of Medical Journal Editors journal, though unregistered studies may still be published in journals not requiring preregistration [1,14]. The 2007 Food and Drug Administration (FDA) Amend­ ments Act requires that all FDA phase II-IV biologic drug and device trials be registered on ClinicalTrials.gov [3,15,25]. Access to results of completed trials is equally important, with persistent concerns about publication bias and the lag time between study completion and publication in the peer-reviewed literature [25]. The FDA Amendments Act partially addresses this concern by requiring posting of summarized results on ClinicalTrials.gov within 1 year of study completion [19], but recent studies found that only 22% of applicable trials met their ClinicalTrials.gov report­ ing deadline, and only 8%-10% of all completed trials reported re­ sults on the registry [7,8,12]. Visualizing the entire analgesic clinical trial landscape is chal­ lenging. We present the Repository of Registered Analgesic Clinical Trials (RReACT) database, which provides a snapshot of registered analgesic clinical trials and a scorecard for public availability of re­ sults. The project is part of the Analgesic Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) initiative, a public-private partnership between the FDA, the National Insti­ tutes of Health, industry, and academia. The RReACT database is freely accessible via the ACTTION website (http://www.act­ tion.org/).