Efficacy, safety, and tolerability of pregabalin treatment for painful diabetic peripheral neuropathy: findings from seven randomized, controlled trials across a range of doses

OBJECTIVE—To evaluate the efficacy, safety, and tolerability of pregabalin across the effective dosing range, to determine differences in the efficacy of three times daily (TID) versus twice daily (BID) dosage schedules, and to use time-to-event analysis to determine the time to onset of a sustained therapeutic effect using data from seven trials of pregabalin in painful diabetic peripheral neuropathy (DPN).RESEARCH DESIGN AND METHODS—Data were pooled across seven double-blind, randomized, placebo-controlled trials using pregabalin to treat painful DPN with dosages of 150, 300, and 600 mg/day administered TID or BID. Only one trial included all three of these dosages, and TID dosing was used in four. All studies shared fundamental selection criteria, and treatment durations ranged from 5 to 13 weeks.RESULTS—Pooled analysis showed that pregabalin significantly reduced pain and pain-related sleep interference associated with DPN (150, 300, and 600 mg/day administered TID vs. placebo, all P ≤ 0.007). Only the 600 mg/day dosage showed efficacy when administered BID (P ≤ 0.001). Pain and sleep interference reductions associated with pregabalin appear to be positively correlated with dosage; the greatest effect was observed in patients treated with 600 mg/day. Kaplan-Meier analysis revealed that the median time to onset of a sustained (≥30% at end point) 1-point improvement was 4 days in patients treated with pregabalin at 600 mg/day, 5 days in patients treated with pregabalin at 300 mg/day, 13 days in patients treated with pregabalin at 150 mg/day, and 60 days in patients receiving placebo. The most common treatment-emergent adverse events were dizziness, somnolence, and peripheral edema.CONCLUSIONS—Treatment with pregabalin across its effective dosing range is associated with significant, dose-related improvement in pain in patients with DPN.The prevalence of diabetic neuropathy is as high as 50% in patients who have had diabetes for 25 years (1), and painful diabetic peripheral neuropathy (DPN) occurs in up to 26% of all people with diabetes (2). Symptoms range from mild dysesthesias to severe unremitting pain that can profoundly impact patients’ lives (3,4).Medications of several different classes are used to treat painful DPN with varying degrees of efficacy, safety, and tolerability. The antiepileptic agents gabapentin and pregabalin have attained widespread use in the treatment of painful DPN. These agents bind to the auxiliary α2-δ subunit of the voltage-sensitive calcium channel, thereby decreasing Ca²⁺ influx at nerve terminals and modulating neurotransmitter release (5).There are seven double-blind, randomized, placebo-controlled trials in painful DPN with pregabalin (6–12), five of which are published in full (7–11). The effective dosing range for treatment of neuropathic pain syndromes is 150 to 600 mg/day, administered either three times daily (TID) or twice daily (BID). Among the seven trials, dosages of 150, 300, and 600 mg/day were used, but only one trial included all three of these dosages. Thus, individually, the seven trials present an incomplete picture of the effective dosing range. In addition, TID dosing was used in the first four trials, whereas the three most recent trials of pregabalin in painful DPN used BID dosing.The objective of the current report is to use the pooled data from these seven trials to evaluate the efficacy, safety, and tolerability of pregabalin across the effective dosing range. We also use these data to determine differences in the efficacy of TID and BID dosing schedules. Finally, we use a time-to-event analysis of the pooled data to determine the time to onset of a sustained therapeutic effect across the range of doses.