Interpreting patient treatment response in analgesic clinical trials: Implications for genotyping, phenotyping, and personalized pain treatment

Departments of Anesthesiology and Neurology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. Electronic address: .
Pain (Impact Factor: 5.21). 09/2013; 155(3). DOI: 10.1016/j.pain.2013.09.019
Source: PubMed
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    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 whether a treatment is likely to be efficacious for a given indication and thus whether it is worth investing the financial resources and participant exposure necessary for a confirmatory trial of that intervention. A challenge in 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 crossover designs with respect to overall sample sizes, trial duration, and applicability is summarized. The advantages and disadvantages of more recent trial designs, including N-of-1 designs, enriched designs, adaptive designs, and 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.
    No preview · Article · May 2014 · Pain
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    ABSTRACT: 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 non-cancer 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 to placebo; 13 (median 107 patients) had a randomised withdrawal phase of six weeks or less, and 12 (median 334) lasted 12-26 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, though 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.
    Full-text · Article · Jan 2015 · Pain
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    ABSTRACT: Background Previous analysis of a single data set in acute pain following third molar extraction demonstrated a strong relationship between the speed of reduction of pain intensity and overall pain relief, as well as need for additional analgesia.Methods Individual patient data analysis of a single randomized, double-blind trial of placebo, paracetamol 1000 mg, ibuprofen sodium 400 mg and ibuprofen-poloxamer 400 mg following third molar extraction. Visual analogue scale pain intensity (VASPI) and other measurements were made at baseline, every 5-45 min, and at 60, 90, 120, 180, 240, 300 and 360 min.ResultsMost patients produced consistent VASPI results over time. For placebo and paracetamol, few patients achieved low VASPI scores and maintained them. For both ibuprofen formulations, VASPI scores fell rapidly during the first hour and were then typically maintained until later re-medication. Analysis of all patients showed that rapid VASPI reduction in the first hour was strongly correlated with good overall pain relief (high total pain relief over 0-6 h), and with lesser need for additional analgesia within 6 h. Results for this analysis were in very good agreement with a previous analysis, validating the relationship between fast initial pain intensity reduction and overall good pain relief in this setting.Conclusions In acute pain following third molar extraction, faster acting analgesic formulations provide earlier onset of pain relief, better overall pain relief and a less frequent need for additional analgesia, indicating longer lasting pain relief.
    Full-text · Article · Feb 2015 · European journal of pain (London, England)