An Investigation of Factors Contributing to Higher Levels of Placebo Response in Clinical Trials in Neuropathic Pain: A Systematic Review and Meta-Analysis

Background In new drug development in neuropathic pain (NeP), randomized, double-blind, placebo-controlled trials (PCTs) with long treatment durations in a parallel-group design are recommended for confirmatory trials. Objective This study was conducted to identify potential factors contributing to elevated placebo response in parallel-group PCTs for oral drugs with at least a 4-week treatment duration. Methods A literature search was conducted through MEDLINE and EMBASE, and was supplemented with data from ClinicalTrials.gov and US/Japanese regulatory approval review information. Using the 30 or 50 % responder rate (RR), logistic regression analyses were performed to investigate the relationship between the degree of placebo response and several potential influencing factors. Result The search identified 71 trials (n = 6,126). The estimated 50 % RRs (95 % confidence intervals) in the placebo group were as follows: peripheral neuropathic pain (P-NeP) 23 % (21, 26 %); central neuropathic pain (C-NeP) 14 % (10, 19 %); postherpetic neuralgia (PHN) 19 % (15, 24 %); painful diabetic peripheral neuropathy (pDPN) 26 % (23, 29 %); posttraumatic peripheral neuropathic pain (PT) 15 % (10, 20 %). From the logistic regression analyses, it was found that there was a significant association between placebo response (50 % RR and 30 % RR) and NeP classification (P < 0.05). Associations between placebo response and several factors were seen in univariate logistic regression analyses of 50 % RR. Multivariate analyses showed that age and baseline pain intensity in PHN, and treatment duration, trial design (fixed-dose/flexible-dose) and baseline pain intensity in pDPN, were associated with placebo response, suggesting that a reduced placebo response correlated with increasing age and baseline pain intensity, and a higher placebo response correlated with a longer treatment period and flexible dosing regimen. A similar pattern observed in the analysis of 50 % RR was suggested in the analysis of 30 % RR, with the exception of treatment duration. In addition, investigations of trials with at least a 12-week treatment duration in pDPN found associations with the number of patients per site, patient enrolment rate, proportion of male patients and baseline pain intensity, suggesting that a higher placebo response correlated with an increasing number of patients per site, and a reduced placebo response correlated with increasing patient enrolment rate and proportion of male patients and baseline pain intensity. Conclusion The results of this study suggest that NeP condition, trial design, and demographic and baseline characteristics may contribute to elevated placebo response in clinical trials in patients with NeP. In addition, the magnitude of placebo response and the effect of treatment duration are greater in pDPN than in PHN. These facts should be considered when planning and conducting confirmatory trials in NeP.