C. J. Nikles

N-of-1 randomized trials to assess the efficacy of gabapentin for chronic neuropathic pain

OBJECTIVE The objective of this study was to compare the efficacy of gabapentin with placebo for neuropathic pain at the individual and population levels. DESIGN This study used an n-of-1 trial methodology with three double-blind, randomized, crossover comparisons of gabapentin with placebo. SETTING This study was carried out at specialist outpatient clinics at two Australian hospitals. Patients. The patients are adults with chronic neuropathic pain. INTERVENTIONS Following a dose-finding period, participants underwent three comparisons of 2-week periods on gabapentin (600-1,800 mg per day) and placebo. The dose-finding period was commenced by 112 patients, of whom 39 had no response so they did not enroll, leaving 73 trial participants. Of these, 48 completed and 7 partially completed their trials, and 18 withdrew. OUTCOME MEASURES The five outcome measures were the visual analog scale (0-10) of pain, sleep interference and functional limitation; frequency of adverse events and medication preference. The aggregate response was determined by weighting the response to each measure equally. RESULTS Of the 55 participants who completed at least one cycle, the aggregate response to gabapentin was better than placebo in 16 (29%), of whom 15 continued gabapentin posttrial. No difference was shown in 38 (69%), and 1 (2%) showed a better response to placebo. Fifteen of these 39 continued gabapentin posttrial. Meta-analysis of the mean scores showed lower mean (standard deviation) scores for gabapentin by 0.8 (0.2) for pain, 0.6 (0.2) for sleep interference, and 0.6 (0.2) for functional limitation. CONCLUSIONS The response rate and mean reduction in symptoms with gabapentin were small. Gabapentin prescribing posttrial was significantly influenced by the trial results.

N-of-1 trials can be aggregated to generate group mean treatment effects: a systematic review and meta-analysis

OBJECTIVES To evaluate how data from n-of-1 trials may be used in systematic reviews and meta-analyses by examining the effects of amphetamine and methylphenidate for attention-deficit hyperactivity disorder (ADHD). STUDY DESIGN AND SETTING Electronic search of MEDLINE, EMBASE, and PsychINFO for English language articles published from 1950 to 2013. N-of-1 trials of pediatric participants with ADHD that assessed either amphetamine or methylphenidate vs. placebo were included. The primary outcome was improvement of core symptoms of ADHD, which was assessed by multiple rating scales. Studies with obtainable individual participant data were included in the meta-analysis. Weighted mean differences were computed using a random-effects model. RESULTS Nine studies were included in the amphetamine-placebo comparison and 10 in the methylphenidate-placebo comparison. Meta-analyses were consistently in favor of amphetamine in 10 of 11 ADHD symptom domains and methylphenidate in 7 of 12 symptom domains. A high degree of heterogeneity across participant treatment response was observed. CONCLUSIONS Meta-analysis of n-of-1 trials suggests that amphetamine and methylphenidate are effective treatments for pediatric ADHD. Synthesizing n-of-1 trials enables assessment of individual responses to treatment as well as aggregate summaries across individuals and studies. It offers a promising general approach with applications across diverse treatments and disorders.

Pilot Study To Determine the Optimal Dose of Methylphenidate for an n-of-1 Trial for Fatigue in Patients with Cancer

PURPOSE In advanced cancer, the prevalence of fatigue is high and can be related to treatment or disease. Methylphenidate hydrochloride (MPH) is a central nervous system stimulant that has been used to palliate fatigue. There is no standard dose for MPH when used for this indication; recommended doses range from 5–20 + mg/d. METHOD To identify a dose to test formally in a subsequent n-of-1 trial of fatigue, we recruited patients with advanced cancer and a fatigue score of 4 or more on a 10-point scale. Following a 3-day baseline assessment, each patient titrated MPH at doses ranging from 5 mg/d to 15 mg twice daily at 3-day intervals. In a daily diary, patients recorded measures of fatigue, depression, toxicity, and symptom control. RESULTS Ten patients provided consent, 9 completed 8 days and 5 received maximum dose at day 15. Three patients were unwilling to increase the dose to maximum levels as they were satisfied with the response at a lower dose. Across all patients, there was a pattern of rapidly improving fatigue and depression scores to day 9 (5 mg twice daily), with minimal improvement thereafter. CONCLUSION The results indicate a dose of 5 mg twice daily for the definitive study. There was little correlation between performance status and maximum tolerated dose. No patient withdrew because of toxicity.