Efficacy, Safety, and Tolerability of Pregabalin Treatment for Painful Diabetic Peripheral Neuropathy

Abstract

EDITH DURSO-DECRUZ, PHD 2 BIROL EMIR, PHD 2 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 doubleblind, 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 painrelated sleep interference associated with DPN (150, 300, and 600 mg/day administered TID vs. placebo, all P Յ 0.007). Only the 600 mg/day dosage showed efficacy when administered BID (P Յ 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 (Ն30% 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. Diabetes Care 31:1448-1454, 2008T he 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 ␣2-␦ subunit of the voltage-sensitive calcium channel, thereby decreasing Ca 2ϩ 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 ...

A randomized trial of pregabalin in patients with neuropathic pain due to spinal cord injury

“…Treatment-emergent peripheral edema was reported in 13.4% of pregabalin-treated patients in this study, which is similar to the incidence reported in the previous trial of pregabalin for SCI (10%) 14 and comparable with that reported for diabetic peripheral neuropathy (6%-16%) 22,23 and postherpetic neuralgia (approximately 12%). 22 Therefore, patients with SCI do not seem more susceptible to developing peripheral edema in response to pregabalin than patients with other neuropathic pain conditions.…”

“…Indeed, somnolence occurred more frequently in the placebo arm (13%) in this study than what is reported for other placebo-controlled trials of pregabalin (2%-6%). 13,22,23 Overall, somnolence observed in this study was mostly mild in intensity (8 moderate and 1 severe case in pregabalin-treated patients) and discontinuations due to somnolence occurred in only 1.8% of patients receiving pregabalin.…”

“…However, somnolence occurred more frequently in this study (33%) and in the previous SCI study (41%) 14 than in trials of pregabalin for the treatment of diabetic peripheral neuropathy or postherpetic neuralgia (12%-16%). 22,23 This increased frequency of somnolence could be attributable to the use of concomitant medications, specifically benzodiazepines, which add to the CNS side effects of pregabalin. Additionally, somnolence in patients with SCI may result from sleep disturbance related to spasticity, incontinence, and mood disorders that are often observed in this population.…”

Diabetic Neuropathy: A Position Statement by the American Diabetes Association

“…However, not all trials with pregabalin have been positive (15,86,95,96), especially when treating advanced refractory patients (93). Pregabalin, in contrast to gabapentin (see below), has a linear, dose-proportional absorption in the therapeutic dose range (150-600 mg/day) (88). In addition, pregabalin has a more rapid onset of action and more limited dosage range that requires minimal titration.…”

Clinical practice guidelines for management of neuropathic pain: Expert panel recommendations for South Africa

“…Recommendations from recent international and regional guidelines were reviewed in addition to discussion of recent systematic reviews, meta-analyses, and peer-reviewed randomised, double-blind, placebo-controlled studies; [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] a number of Cochrane reviews were also referred to. [31][32][33][34][35][36][37][38][39][40] The validity, clinical relevance, and applicability of the evidence for peripheral and central NeuP in South Africa were discussed.…”