Michael C Rowbotham

California Pacific Medical Center Research Institute, San Francisco, California, United States

Are you Michael C Rowbotham?

Claim your profile

Publications (116)664.83 Total impact

  • Faustine L Dufka, Robert H Dworkin, Michael C Rowbotham
    [Show abstract] [Hide abstract]
    ABSTRACT: Transparency in research requires public access to unbiased information prior to trial initiation and openly available results upon study completion. The Repository of Registered Migraine Trials is a global snapshot of registered migraine clinical trials and scorecard of results availability via the peer-reviewed literature, registry databases, and gray literature. The 295 unique clinical trials identified employed 447 investigational agents, with 30% of 154 acute migraine trials and 11% of 141 migraine prophylaxis trials testing combinations of agents. The most frequently studied categories in acute migraine trials were triptans, nonsteroidal anti-inflammatory drugs, antiemetics, calcitonin gene-related peptide antagonists, and acetaminophen. Migraine prophylaxis trials frequently studied anticonvulsants, β-blockers, complementary/alternative therapies, antidepressants, and botulinum toxin. Overall, 237 trials were eligible for a results search. Of 163 trials completed at least 12 months earlier, 57% had peer-reviewed literature results, and registries/gray literature added another 13%. Using logistic regression analysis, studies with a sample size below the median of 141 subjects were significantly less likely to have results, but the dominant factor associated with availability of results was time since study completion. In unadjusted models, trials registered on ClinicalTrials.gov and trials with industry primary sponsorship were significantly more likely to have results. Recently completed trials rarely have publicly available results; 2 years after completion, the peer-reviewed literature contains results for fewer than 60% of completed migraine trials. To avoid bias, evidence-based therapy algorithms should consider factors affecting results availability. As negative trials are less likely to be published, special caution should be exercised before recommending a therapy with a high proportion of missing trial results.
    Neurology 09/2014; · 8.25 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: This article presents general considerations discussed at an IMMPACT consensus meeting regarding proof-of-concept (POC) clinical trials and major POC trial designs and their advantages and limitations when used to evaluate chronic pain treatments. Abstract Proof-of-concept (POC) clinical trials play an important role in developing novel treatments and determining whether existing treatments may be efficacious in broader populations of patients. The goal of most POC trials is to determine if a treatment is likely to be efficacious for a given indication and thus if it is worth investing the financial resources and participant exposure necessary for a confirmatory trial of that intervention. A challenge of designing POC trials is obtaining sufficient information to make this important go/no-go decision in a cost effective manner. An IMMPACT consensus meeting was convened to discuss design considerations for POC trials in analgesia with a focus on maximizing power with limited resources and participants. We present general design aspects to consider including patient population, active comparators and placebos, study power, pharmacokinetic-pharmacodynamic relationships, and minimization of missing data. Efficiency of single dose studies for treatments with rapid onset is discussed. The trade-off between parallel-group and cross-over designs with respect to overall sample sizes, trial duration, and applicability is summarized. The advantages and disadvantages of more recent trial designs including (1) N-of-1 designs, (2) enriched designs, (3) adaptive designs, and (4) sequential parallel comparison designs are summarized and recommendations for consideration are provided. More attention to identifying efficient yet powerful designs for POC clinical trials of chronic pain treatments may increase the percentage of truly efficacious pain treatments that are advanced to confirmatory trials while decreasing the percentage of ineffective treatments that continue to be evaluated rather than abandoned.
    Pain 05/2014; · 5.64 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The degree of variability in the patient baseline 7-day diary of pain ratings has been hypothesized to have a potential effect on the assay sensitivity of randomized clinical trials of pain therapies. To address this question, we obtained clinical trial data from the Food and Drug Administration (FDA) through the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership, and harmonized patient level data from 12 clinical trials (4 gabapentin and 8 pregabalin) in postherpetic neuralgia (PHN) and painful diabetic peripheral neuropathy (DPN). Models were developed using exploratory logistic regression to examine the interaction between available baseline factors and treatment (placebo vs. active-medication) in predicting patient response to therapy (i.e., >30% improvement). Our analysis demonstrated an increased likelihood of response in the placebo-treated group for patients with a higher standard deviation in the baseline 7-day diary without affecting the likelihood of a response in the active-medication treated group, confirming our hypothesis. In addition, there was a small but significant age-by-treatment interaction in the PHN model, and small weight-by-treatment interaction in the DPN model. The patient's sex, baseline pain level, and the study protocol only had an effect on the likelihood of response overall. Our results suggest the possibility that at least in some disease processes excluding patients with a highly variable baseline 7-day diary has the potential to improve the assay sensitivity of these analgesic clinical trials, although reductions of external validity must be considered when increasing the homogeneity of the investigated sample.
    Pain 05/2014; · 5.64 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Eliminating publication bias requires ensuring public awareness of studies and access to results. clinical trial registries provide basic trial information, but access to unbiased trial results is inadequate. nearly all studies of trial registration and results reporting have been limited to the clinicaltrials.gov registry. we analyzed trial registration, registry functionality, cross-registry harmonization, and results reporting on all fifteen primary registries in the who international clinical trials registry platform (ictrp) for post-herpetic neuralgia, painful diabetic neuropathy, and fibromyalgia. a total of 447 unique trials were identified, with 86 trials listed on more than one registry. a comprehensive search algorithm was used to find trial results in the peer-reviewed literature and the grey literature. creating a global database of registered trials and trial results proved surprisingly difficult for several reasons: 1) ictrp does not reliably identify trials listed on multiple registries; manual searches are necessary. 2) searching ictrp yields different results than searching individual registries. 3) outcome measure descriptions for multiply-registered trials vary between registries. 4) registry-publication pairings are often inaccurate or incomplete. 5) grey literature results are not permanent. overall, only 46% of all trials had results available. trials registered on clinicaltrials.gov were significantly more likely to have results (52% vs 18%, p<0.001), partly due to the ability to post results directly to the registry. in addition to the simple remedy of including trial registration numbers on all meeting abstracts and peer-reviewed papers, specific strategies are offered to facilitate identifying multiply-registered studies, and ensuring accurate pairing of results and publications.
    Pain 04/2014; · 5.64 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Studies on complications related to chronic nerve injury following sentinel lymph node biopsy (SLNB) and complete lymph node dissection (CLND) for melanoma are sparse. This review summarizes the existing literature on pain and neuropathic complications in melanoma patients undergoing SLNB with or without CLND. The Cochrane Central Register of Controlled Trials and the Embase and PubMed databases were searched. Full-text English language articles published before June 2013 were included. Prospective and retrospective studies assessing persistent (>1 month) sensory nerve injury, postoperative pain, neuropathic pain, and sensory disturbances following SLNB with or without CLND in melanoma patients were eligible. Nine studies (six prospective and three retrospective) including data for 3632 patients met our inclusion criteria. Outcome parameters were too heterogeneous to conduct a quantitative analysis, and few studies systematically evaluated pain and sensory abnormalities. Persistent postoperative pain was reported in 1-14% of patients following SLNB and in 6-34% following CLND and sensory abnormalities in 0.1-32 and 2-82%, respectively. In the one study that assessed the type of pain, neuropathic pain was suggested to explain persistent pain in 31-66% of patients with SLNB and 82-89% of patients with CLND. Sensory-nerve-related complications in melanoma patients seem to be less pronounced following SLNB compared with CLND. Prospective observational studies are necessary to identify predictors of persistent pain, to evaluate the prevalence and impact of pain and sensory abnormalities, and to develop strategies for prevention of long-term complications.
    Melanoma research 12/2013; · 2.06 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Assessing and mitigating the abuse liability (AL) of analgesics is an urgent clinical and societal problem. Analgesics have traditionally been assessed in randomized clinical trials (RCTs) designed to demonstrate analgesic efficacy relative to placebo or an active comparator. In these trials, rigorous, prospectively designed assessment for AL is generally not performed. The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) convened a consensus meeting to review the available evidence and discuss methods for improving the assessment of the AL of analgesics in clinical trials in patients with pain. Recommendations for improved assessment include: (1) performing trials that include individuals with diverse risks of abuse; (2) improving the assessment of AL in clinical trials (eg, training study personnel in the principles of abuse and addiction behaviors, designing the trial to assess AL outcomes as primary or secondary outcome measures depending on the trial objectives); (3) performing standardized assessment of outcomes, including targeted observations by study personnel and using structured adverse events query forms that ask all subjects specifically for certain symptoms (such as euphoria and craving); and (4) collecting detailed information about events of potential concern (eg, unexpected urine drug testing results, loss of study medication, and dropping out of the trial). The authors also propose a research agenda for improving the assessment of AL in future trials.
    Pain 11/2013; 154(11):2324-34. · 5.64 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The National Institutes of Health released the trial registry ClinicalTrials.gov in 2000 to increase public reporting and clinical trial transparency. This systematic review examined whether registered primary outcome specifications (POSs; i.e., definitions, timing, and analytic plans) in analgesic treatment trials correspond with published POSs. Trials with accompanying publications (n=87) were selected from the Repository of Registered Analgesic Clinical Trials (RReACT) database of all postherpetic neuralgia, diabetic peripheral neuropathy, and fibromyalgia clinical trials registered at ClinicalTrials.gov as of 12/1/2011. POSs never matched precisely; discrepancies occurred in 79% of the registry-publication pairs (21% failed to register or publish POs). These percentages did not differ significantly between industry and non-industry sponsored trials. Thirty percent of the trials contained unambiguous POS discrepancies (e.g., omitting a registered primary outcome [PO] from the publication, "demoting" a registered PO to a published secondary outcome), with a statistically significantly higher percentage of non-industry sponsored than industry-sponsored trials containing unambiguous POS discrepancies. POS discrepancies due to ambiguous reporting included vaguely worded PO registration, or failing to report the timing of PO assessment, statistical analysis used for the PO, or method to address missing PO data. At best, POS discrepancies may be attributable to insufficient registry requirements, carelessness (e.g., failing to report PO assessment timing), or difficulty uploading registry information. At worst, discrepancies could indicate investigator impropriety (e.g., registering imprecise POs ["pain"], then publishing whichever pain assessment produced statistically significant results). Improvements in PO registration, as well as journal policies requiring consistency between registered and published PO descriptions, are needed.
    Pain 08/2013; · 5.64 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: OBJECTIVE: Our objective was to identify patient, study, and site factors associated with assay sensitivity in placebo-controlled neuropathic pain trials. METHODS: We examined the associations between study characteristics and standardized effect size (SES) in a database of 200 publicly available randomized clinical trials of pharmacologic treatments for neuropathic pain. RESULTS: There was considerable heterogeneity in the SESs among the examined trials. Univariate meta-regression analyses indicated that larger SESs were significantly associated with trials that had 1) greater minimum baseline pain inclusion criteria, 2) greater mean subject age, 3) a larger percentage of Caucasian subjects, and 4) a smaller total number of subjects. In a multiple meta-regression analysis, the associations between SES and minimum baseline pain inclusion criterion and age remained significant. CONCLUSIONS: Our analyses have examined potentially modifiable correlates of study SES and shown that a minimum pain inclusion criterion of 40 or above on a 0 to 100 scale is associated with a larger SES. These data provide a foundation for investigating strategies to improve assay sensitivity and thereby decrease the likelihood of falsely negative outcomes in clinical trials of efficacious treatments for neuropathic pain.
    Neurology 05/2013; · 8.25 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Postherpetic neuralgia (PHN) is a common complication after herpes zoster (HZ). Subjects who completed a longitudinal observational 6-month study (4 visits) of the natural history of HZ were recontacted for 2 additional follow-up visits that included pain and sensory symptom assessment, quantitative sensory testing, capsaicin response test, and 3-mm punch skin biopsies in HZ-affected, mirror-image, and control skin sites. Forty-three subjects (14 with PHN at 6months) of the original 94 subjects in the cohort were comprehensively assessed at a median 3.9years after HZ onset (visit 5), and 10 subjects underwent a final assessment at a median 7.7years after HZ onset (visit 6). At 3.9years, none of the 29 subjects who had been pain free at 6months had a recurrence of pain. Only 2 of the 14 subjects with PHN at 6months still had pain at 3.9years. One subject with PHN at 6months was free of symptoms at 3.9years but had very mild pain at 7.7years. Sensory function continued on a path toward normalization, but was still abnormal in many subjects, especially those who met criteria for PHN at 6months. Even at 7.7years, reinnervation of HZ-affected skin was not apparent.
    Pain 04/2013; · 5.64 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The development of valid and informative treatment risk-benefit profiles requires consistent and thorough information about adverse event (AE) assessment and participants' AEs during randomized controlled trials (RCTs). Despite a 2004 extension of the Consolidated Standards of Reporting Trials (CONSORT) statement recommending the specific AE information that investigators should report, there is little evidence that analgesic RCTs adequately adhere to these recommendations. This systematic review builds on prior recommendations by describing a comprehensive checklist for AE reporting developed to capture clinically important AE information. Using this checklist, we coded AE assessment methods and reporting in all 80 double-blind RCTs of noninvasive pharmacologic treatments published in the European Journal of Pain, Journal of Pain, and PAIN® from 2006 to 2011. Across all trials, reports of AEs were frequently incomplete, inconsistent across trials, and, in some cases, missing. For example, >40% of trials failed to report any information on serious adverse events. Trials of participants with acute or chronic pain conditions and industry-sponsored trials typically provided more and better-quality AE data than trials involving pain-free volunteers or trials that were not industry sponsored. The results of this review suggest that improved AE reporting is needed in analgesic RCTs. We developed an ACTTION (Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks) AE reporting checklist that is intended to assist investigators in thoroughly and consistently capturing and reporting these critically important data in publications.
    Pain 03/2013; · 5.64 Impact Factor
  • Pain 03/2013; · 5.64 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Informed consent is the cornerstone of human research subject protection. Many subjects sign consent documents without understanding the study purpose, procedures, risks, benefits, and their rights. Proof of comprehension is not required and rarely obtained. Understanding might improve by using an interactive system with multiple options for hearing, viewing and reading about the study and the consent form at the subject's own pace with testing and immediate feedback. This prospective randomized study compared the IRB-approved paper ICF for an actual clinical research study with an interactive presentation of the same study and its associated consent form using an iPad device in two populations: clinical research professionals, and patients drawn from a variety of outpatient practice settings. Of the 90 participants, 69 completed the online test and survey questions the day after the session (maximum 36 hours post-session). Among research professionals (n = 14), there was a trend (p = .07) in the direction of iPad subjects testing better on the online test (mean correct = 77%) compared with paper subjects (mean correct = 57%). Among patients (n = 55), iPad subjects had significantly higher test scores than standard paper consent subjects (mean correct = 75% vs 58%, p < .001). For all subjects, the total time spent reviewing the paper consent was 13.2 minutes, significantly less than the average of 22.7 minutes total on the three components to be reviewed using the iPad (introductory video, consent form, interactive quiz). Overall satisfaction and overall enjoyment slightly favored the interactive iPad presentation. This study demonstrates that combining an introductory video, standard consent language, and an interactive quiz on a tablet-based system improves comprehension of research study procedures and risks.
    PLoS ONE 01/2013; 8(3):e58603. · 3.73 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Human experimental pain models leading to development of secondary hyperalgesia are used to estimate efficacy of analgesics and antihyperalgesics. The ability to develop an area of secondary hyperalgesia varies substantially between subjects, but little is known about the agreement following repeated measurements. The aim of this study was to determine if the areas of secondary hyperalgesia were consistently robust to be useful for phenotyping subjects, based on their pattern of sensitization by the heat pain models. We performed post-hoc analyses of 10 completed healthy volunteer studies (n = 342 [409 repeated measurements]). Three different models were used to induce secondary hyperalgesia to monofilament stimulation: the heat/capsaicin sensitization (H/C), the brief thermal sensitization (BTS), and the burn injury (BI) models. Three studies included both the H/C and BTS models. Within-subject compared to between-subject variability was low, and there was substantial strength of agreement between repeated induction-sessions in most studies. The intraclass correlation coefficient (ICC) improved little with repeated testing beyond two sessions. There was good agreement in categorizing subjects into 'small area' (1(st) quartile [<25%]) and 'large area' (4(th) quartile [>75%]) responders: 56-76% of subjects consistently fell into same 'small-area' or 'large-area' category on two consecutive study days. There was moderate to substantial agreement between the areas of secondary hyperalgesia induced on the same day using the H/C (forearm) and BTS (thigh) models. Secondary hyperalgesia induced by experimental heat pain models seem a consistent measure of sensitization in pharmacodynamic and physiological research. The analysis indicates that healthy volunteers can be phenotyped based on their pattern of sensitization by the heat [and heat plus capsaicin] pain models.
    PLoS ONE 01/2013; 8(5):e62733. · 3.73 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Development of secondary hyperalgesia following a cutaneous injury is a centrally mediated, robust phenomenon. The pathophysiological role of endogenous opioid signalling to the development of hyperalgesia is unclear. Recent animal studies, carried out after the resolution of inflammatory pain, have demonstrated reinstatement of tactile hypersensitivity following administration of μ-opioid-receptor-antagonists. In the present study in humans, we analyzed the effect of naloxone when given after the resolution of secondary hyperalgesia following a first-degree burn injury. Twenty-two healthy volunteers were included in this placebo-controlled, randomized, double-blind, cross-over study. Following baseline assessment of thermal and mechanical thresholds, a first-degree burn injury (BI; 47°C, 7 minutes, thermode area 12.5 cm(2)) was induced on the lower leg. Secondary hyperalgesia areas around the BI-area, and separately produced by brief thermal sensitization on the contralateral thigh (BTS; 45°C, 3 minutes, area 12.5 cm(2)), were assessed using a polyamide monofilament at pre-BI and 1, 2, and 3 hours post-BI. At 72 hrs, BI and BTS secondary hyperalgesia areas were assessed prior to start of a 30 minutes intravenous infusion of naloxone (total dose 21 microg/kg) or placebo. Fifteen minutes after start of the infusion, BI and BTS secondary hyperalgesia areas were reassessed, along with mechanical and thermal thresholds. Secondary hyperalgesia areas were demonstrable in all volunteers 1-3 hrs post-BI, but were not demonstrable at 72 hrs post-burn in 73-86% of the subjects. Neither magnitude of secondary hyperalgesia areas nor the mechanical and thermal thresholds were associated with naloxone-treated compared to placebo-treated subjects. Naloxone (21 microg/kg) did not reinstate secondary hyperalgesia when administered 72 hours after a first-degree burn injury and did not increase BTS-generated hyperalgesia. The negative results may be due to the low dose of naloxone or insufficient tissue injury to generate latent sensitization.
    PLoS ONE 01/2013; 8(5):e64608. · 3.73 Impact Factor
  • [Show abstract] [Hide abstract]
    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.
    Pain 12/2012; 153(12):2315–2324. · 5.64 Impact Factor
  • [Show abstract] [Hide abstract]
    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.
    Pain 09/2012; · 5.64 Impact Factor
  • Source
    Kaitlin Greene, Robert H Dworkin, Michael C Rowbotham
    Pain 07/2012; 153(9):1794-7. · 5.64 Impact Factor
  • [Show abstract] [Hide abstract]
    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.
    Pain 06/2012; 153(9):1815-23. · 5.64 Impact Factor
  • [Show abstract] [Hide abstract]
    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.
    Pain 04/2012; 153(6):1148-58. · 5.64 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Preclinical and clinical studies suggest that neuronal nicotinic receptor (NNR) agonists may be a novel and effective therapy for numerous painful conditions. Analgesic efficacy and safety of the highly selective α(4)β(2) NNR agonist ABT-894 was evaluated in 2 separate randomized, double-blind, multicenter, placebo-controlled clinical trials in patients with diabetic peripheral neuropathic pain (DPNP). Study 1 (280 patients randomized) tested 1, 2, and 4 mg ABT-894 twice daily compared with placebo and 60 mg duloxetine once per day over 8 weeks of treatment. Study 2 (124 patients randomized) tested 6 mg ABT-894 twice daily vs placebo for 8 weeks. The primary efficacy outcome measure in both studies was the weekly mean of the 24-hour average pain score recorded in each patient's diary. In both trials, none of the ABT-894 dose groups showed efficacy compared with placebo, whereas duloxetine achieved a statistically significant improvement over placebo in Study 1. All dose levels of ABT-894 were well tolerated, and no significant safety issues were identified. These results are in contrast to the outcome of a previously reported study of DPNP using the less selective α(4)β(2) NNR agonist ABT-594, which demonstrated efficacy compared with placebo, albeit with significant tolerability limitations. The failure of the highly selective α(4)β(2) NNR agonist ABT-894 indicates that it may not be possible to define a therapeutic index for this mechanism or that selectively targeting α(4)β(2) NNRs may not be a viable approach to treating neuropathic pain.
    Pain 02/2012; 153(4):862-8. · 5.64 Impact Factor

Publication Stats

5k Citations
664.83 Total Impact Points

Top Journals


  • 2010–2014
    • California Pacific Medical Center Research Institute
      San Francisco, California, United States
  • 2013
    • University of Rochester
      Rochester, New York, United States
  • 1983–2012
    • University of California, San Francisco
      • • Department of Neurology
      • • Division of Hospital Medicine
      San Francisco, California, United States
  • 2011
    • IT University of Copenhagen
      København, Capital Region, Denmark
  • 1987–2011
    • CSU Mentor
      • • Department of Neurology
      • • Department of Medicine
      Long Beach, California, United States
  • 2009
    • Oxford University Hospitals NHS Trust
      Oxford, England, United Kingdom
  • 2008
    • Oregon Health and Science University
      • Comprehensive Pain Center
      Los Angeles, CA, United States
    • University of San Francisco
      San Francisco, California, United States
  • 2001
    • Rigshospitalet
      • Department of Anaesthesiology
      Copenhagen, Capital Region, Denmark
  • 2000–2001
    • Herlev Hospital
      • Department of Anaesthesiology
      Herlev, Capital Region, Denmark
    • Beth Israel Medical Center
      • Department of Pain Medicine and Palliative Care
      New York City, New York, United States
  • 1999
    • Rabin Medical Center
      Tell Afif, Tel Aviv, Israel
    • Christian-Albrechts-Universität zu Kiel
      • UKSH Klinik für Neurologie
      Kiel, Schleswig-Holstein, Germany
  • 1995
    • Erasmus MC
      • Daniel den Hoed Centre
      Rotterdam, South Holland, Netherlands