Pregabalin for the management of partial epilepsy

Abstract

Pregabalin is one of the latest antiepileptic drugs introduced for the treatment of partial epilepsy. Its efficacy and safety as adjunctive therapy in refractory partial epilepsy have been established in four double-blind placebo-controlled trials (n = 1396) and 4 long-term open-label studies (n = 1480). In 3 fixed-dose trials, the proportion of patients with a >/=50% reduction in seizure frequency across the effective dose-range (150-600 mg/day) ranged between 14% and 51%, with a clear dose-response relationship. Suppression of seizure activity could be demonstrated as early as day 2. The most frequently reported CNS-related adverse events included dizziness, somnolence, ataxia and fatigue, were usually mild or moderate, and tended to be dose related. In long-term studies, weight gain was reported as an adverse event by 24% of patients. When pregabalin dose was individualized to according to response within the 150 to 600 mg/day dose range, tolerability was considerably improved compared with use of a high-dose, fixed-dose regimen (600 mg/day) without titration. In long-term studies up to 4 years, no evidence of loss efficacy was identified. During the last year on pregabalin, 3.7% of patients were seizure-free. Pregabalin appears to be a useful addition to the therapeutic armamentariun for the management of refractory partial epilepsy.

Keywords: adjunctive therapy; antiepileptic drugs; clinical trials; efficacy; partial seizures; pregabalin; tolerability.

Figure 1

Trial design used in a pregabalin randomized flexible-dose (150–600 mg/day) versus fixed-dose (600 mg/day) double-blind adjunctive-therapy trial in patients with refractory partial-onset seizures, with or without secondary generalization. Adapted from Elger et al 2005.

Figure 2

Seizure reduction in short-term fixed-dose pregabalin adjunctive therapy studies. Dose response relationship for seizure reduction (shown as response ratio [RRatio] on right y axis and percent change from baseline as calculated from RRatio on left y-axis) is shown for each of the three short-term fixed-dose pregabalin studies (French et al 2000; Arroyo et al 2004; Beydoun et al 2005). P values shown represent a significant difference from placebo in the same study. Adapted from Brodie et al 2004.

Figure 3

Responder rates (proportion of patients with ≥50% reduction in seizure frequency compared with baseline) in each of four randomized adjunctive-therapy double-blind trials of pregabalin in patients with refractory partial-onset seizures, with or without secondary generalization. The first three trials (French et al 2003; Arroyo et al 2004; Beydoun et al 2005) included fixed-dose pregabalin treatment groups whilst the fourth trial (Elger et al 2005) included both flexible-dose (150–600 mg/day) and fixed-dose (600 mg/day) groups. *Significantly different from placebo in the same study. Abbreviations: PGB, pregabalin; PBO, placebo.

Figure 4

Kaplan-Meier analysis of time to discontinuation due to adverse events with flexible (150–600 mg/day) versus fixed (600 mg/day) pregabalin dosing. Patients in the fixed-dose group discontinued from the study due to adverse events earlier than those in the flexible-dose group. Adapted from Elger et al 2005.