Gabapentin

Gabapentin (GBP) is a antiepileptic drug (AED) indicated as adjunct therapy for treatment of partial seizures, with and without secondary generalizati on, in patients 12 and older with epilepsy. GBP (1-(aminomethyl) cyclohexan eacetic acid) is structurally related to gamma-aminobutyric acid (GABA), wh ich readily crosses the blood-brain barrier. Radiolabeled GBP binds through out the central nervous system in anatomic areas important in treatment of seizures. Its precise mechanism of action is unknown. An open-label, dose-r anging study of doses up to 1,800 mg produced greater than or equal to 50% seizure reductions [re spender rate (RR)] in 29% of patients with partial s eizures. Three double-blind, placebo-controlled, parallel add-on trials at doses of 300-1,800 mg have produced RR of up to 28%, with a placebo RR of 8 -10%. An active controlled, parallel group comparison of 600 mg to 2,400 mg in monotherapy conversion design showed no significant difference among th e 600 mg, 1,200 mg, and 2,400 mg groups compared to a placebo group. An inp atient, active-controlled comparison of 300 mg and 3,600 mg in a parallel-d esign monotherapy trial showed that time to exit from the study was signifi cantly longer for the 3,600-mg group and the completion rate significantly higher (53% vs. 17%) for patients receiving 3,600 mg/day vs. 300 mg/day of GBP. Successful double-blind, placebo-controlled trials in refractory child hood partial seizures and benign childhood epilepsy with centrotemporal spi kes have been recently concluded. Absence was not successfully treated in o ne small double-blind trial. Open-label reports emphasize adjustments of patients to higher doses than t hose indicated in the package labeling. An open-label trial of GBP therapy in patients with partial seizures (n = 2,216) produced progressively greate r seizure freedom rates as patients were titrated from greater than or equa l to 900 mg daily to greater than or equal to 1,800 mg daily (15.1% vs. 33. 4%), with a similar effect on RR (18.1% vs. 44.9%). An add-on, open-label s tudy treating partial seizures (n = 141) reported an RR of 71%, with 46% se izure-free in the last 8 weeks of treatment and doses up to 2,400 mg daily. A comparison trial of three doses of GBP to 600 mg of carbamazepine showed similar retention rates for 1,800 mg of GBP and 600 mg of CBZ. Another stu dy reported 48% of patients experiencing 50% reduction, nine of whom had do ses greater than 2,400 mg. Treatment in children has reported a 34.4% RR in 32 children with refractory partial seizures. A French open-label adjuncti ve trial documented a 33.9% RR; 13.4% were seizure-free during the evaluati on period. Adverse experiences most commonly noted included somnolence, diz ziness, and ataxia. Weight gain was sometimes reported with higher doses of GBP, and pediatric reports cite prominent behavioral changes, including hy peractivity, irritability, and agitation. GBP appears best used at doses at and potentially above those suggested in its package labeling. Although ef ficacy occurs at lower levels, increased GBP doses are associated with addi tional efficacy. Reports suggest that initiation at 2,400 mg or 3,600 mg ma y not be associated with increased adverse experiences. Titration to 900 or 1,200 mg on the first day of GBP therapy appear to be well tolerated.