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Dose-response trial of pregabalin adjunctive therapy in patients with partial seizures

From the University of Pennsylvania Medical Center Epilepsy Center (Dr. French), Philadelphia, and Pfizer Global Research and Development (Drs. Kugler, Knapp, and Garofalo, and J.L. Robbins), Ann Arbor Laboratories, Pfizer, Inc., MI.

Address correspondence and reprint requests to Dr. Jacqueline A. French, Department of Neurology, 3 West Gates, Hospital of the University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104; e-mail: frenchj{at}mail.med.upenn.edu

Background: Pregabalin is an ₂- ligand that has anxiolytic, analgesic, and anticonvulsant properties.

Objective: To establish the efficacy, safety, and tolerability of pregabalin administered twice-daily (BID) without dose titration as adjunctive treatment in patients with partial seizures and to confirm the dose-response relationship.

Methods: This 76-center, double-blind, randomized, placebo-controlled, parallel-group study consisted of an 8-week baseline and a 12-week double-blind phase. Patients with refractory partial seizures on one to three antiepileptic drugs were randomly assigned to one of five treatment groups (placebo or 50, 150, 300, and 600 mg/d pregabalin, all administered BID). Efficacy was assessed using seizure frequency reduction and responder rate (50% seizure reduction from baseline). Pharmacokinetic parameters were estimated.

Results: A total of 453 patients were included in the intent-to-treat analysis. The median baseline seizure rate was 10 per month. Seizure frequency reductions from baseline were 7% (placebo; n = 100), 12% (50 mg/d; n = 88), 34% (150 mg/d; n = 86), 44% (300 mg/d; n = 90), and 54% (600 mg/d; n = 89). Responder rates (50% seizure reduction) were 14% (placebo), 15% (50 mg/d), 31% (150 mg/d), 40% (300 mg/d), and 51% (600 mg/d). Discontinuation rates due to adverse events were 5% (placebo), 7% (50 mg/d), 1% (150 mg/d), 14% (300 mg/d), and 24% (600 mg/d). The 150-, 300-, and 600-mg/d pregabalin groups were associated with greater reductions in seizures (p 0.0001) and greater responder rates compared with the placebo group (p 0.006). There was a favorable dose-response trend for both seizure reductions (p 0.0001) and responder rate (p 0.001).

Conclusion: Adjunctive therapy with pregabalin 150, 300, and 600 mg/d, given in twice-daily doses without titration, is significantly effective and well tolerated in the treatment of patients with partial seizures as demonstrated in patients with refractory partial seizures.

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