Efficacy of pregabalin in post-traumatic peripheral neuropathic pain: a randomized, double-blind, placebo-controlled phase 3 trial

Abstract

The growing need for symptomatic treatment of post-traumatic neuropathic pain (PTNP) continues to be unmet. Studies evaluating the efficacy of pregabalin for reducing neuropathic pain following trauma and surgery yielded positive results over ≤ 8-week treatment. To assess the efficacy and tolerability of pregabalin over 3 months in patients with PTNP, a randomized, double-blind, placebo-controlled, parallel-group trial evaluated patients with PTNP at 101 centers in 11 countries-the longest, largest such trial. Adults diagnosed with PTNP were randomly assigned (1:1) to 15 weeks of pregabalin (flexibly dosed 150-600 mg/day) or matching placebo. Primary efficacy analysis was by mixed-model repeated measures comparing change from baseline to week 15 in weekly mean pain scores between active and placebo groups. Evaluable patients included 274 in the pregabalin group and 265 in the placebo group. Trauma was surgical in 49.6% of patients, non-surgical in the remainder. The primary efficacy analysis showed no statistically significant difference between pregabalin and placebo groups in the change from baseline to week 15 [mean difference, - 0.22 points (95% confidence interval, 0.54-0.10); p = 0.1823]. However, comparisons for key secondary outcome measures yielded p values < 0.05 favoring pregabalin. Consistent with the known safety profile of pregabalin, the most common adverse events were dizziness and somnolence (14.6 and 9.9% of patients, respectively) with pregabalin (vs 4.2 and 3.4% with placebo). These findings demonstrate the feasibility of conducting a large, phase 3 registration trial in the heterogeneous PTNP study population.ClinicalTrials.gov NCT01701362.

Keywords: Neuropathic pain; Post-surgical neuropathic pain; Post-traumatic neuropathic pain; Pregabalin.

Conflict of interest statement

Ethical standards

The protocol complied with the Declaration of Helsinki (1964), and was reviewed and approved by the institutional review board at each participating center.

Informed consent

All participants provided written, informed consent.

Conflicts of interest

JM has participated in advisory boards (Pfizer, Editas Medicine, Flexion Therapeutics, Teva, Quark, Pacira, Inspirion Delivery Sciences, Quartet, Pacira Egalet, Biogen, Nektar, Endo, Immune Pharma, Chromocell, Collegium, Purdue, Novartis, Sanofi, Convergence, Aptinyx, Daiichi Sankyo, Allergan, Plasmasurgical, and Grunenthal), received research funding (Depomed, Pfizer), and served on Data Safety Monitoring Boards (Allergan, Novartis). M Resnick, R Yang, J Scavone, E Whalen, G Gregorian, B Parsons, and L Knapp are employees of Pfizer Inc. S Greenberg was an employee of Pfizer at the time of the study and development of the manuscript. N Katz is employed by Analgesic Solutions, which provided a central eligibility verification service to identify patients with PTNP.

Data sharing statement

Upon request, and subject to certain criteria, conditions and exceptions (see https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information), Pfizer will provide access to individual de-identified participant data from Pfizer-sponsored global interventional clinical studies conducted for medicines, vaccines and medical devices (1) for indications that have been approved in the US and/or EU or (2) in programs that have been terminated (i.e., development for all indications has been discontinued). Pfizer will also consider requests for the protocol, data dictionary, and statistical analysis plan. Data may be requested from Pfizer trials 24 months after study completion. The de-identified participant data will be made available to researchers whose proposals meet the research criteria and other conditions, and for which an exception does not apply, via a secure portal. To gain access, data requestors must enter into a data access agreement with Pfizer.

Figures

Fig. 1

Trial profile. Subjects may have met more than one criterion for exclusion. Of 584 not meeting eligibility criteria, 190 did not meet requirements for neuropathic pain assessment; 71 did not meet the required duration of PTNP; 69 did not meet pain diary criteria prior to randomization; 65 were unwilling/unable to comply with study procedures; 44 had exclusionary pain conditions; 43 did not have the implicated peripheral nerve identified; 34 had other exclusionary NeP conditions; 34 had creatinine clearance ≤ 60 mL/min; and 22 were taking prohibited medications

Fig. 2

Change from baseline in weekly mean pain score (daily pain NRS; ITT population). *Unadjusted p < 0.05 from MMRM analysis. Changes in weekly mean pain score ± standard error were estimated from mixed-model repeated measures (MMRM) model. Weekly mean pain numerical rating scale (NRS) scores are derived from the daily pain NRS and calculated as the mean of the available scores in the 7 days. Generally, week “n” mean pain score is defined as the mean of the 7 daily diary pain ratings from day 2 + 7*(n–1) to day 1 + 7*n. At least four entries within the last 7 days are required to calculate a mean score. NRS ranged from 0 (“no pain”) to 10 (“worst possible pain”), with higher scores indicating increased pain. ITT intention to treat