Pregabalin add-on treatment: A randomised, double-blind, placebo-controlled, dose-response study in adults with partial seizures
Arroyo S, Anhut H, Kugler AR, Lee CM, Knapp LE, Garofalo EA and Messmer S; Pregabalin 1008-011 International Study Group;
Commented by , 23 Feb 2004
Background
Pregabalin is a derivative of gabapentin, the anticonvulsant with the largest market share largely due to use in non-epilepsy indications, particularly neuropathic pain.
Pregabalin has not yet received marketing approval, but it is in late-stage clinical development for the treatment of epilepsy 0 && parent.frames.length) {
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Aim
To compare the efficacy and tolerability of pregabalin 150 mg/day, pregabalin 600 mg/day and placebo as adjunctive therapy in patients with refractory partial epilepsy.
Methods
The trial was conducted in 45 centres in Australia, Europe and South Africa, using a randomised, double-blind, parallel-group design.
Adults with uncontrolled partial seizures despite ongoing treatment with 1-3 anticonvulsants (excluding gabapentin) were randomised to adjunctive therapy with pregabalin 150 mg/day (n=99), 600 mg/day (n=92) or placebo (n=96), each given 3 times a day for 12 weeks. Dose titration in the 150 and 600 mg/day group was completed by days 4 and 8 respectively.
The primary efficacy endpoint was reduction in seizure frequency during 12-week treatment compared with pre-treatment 8-week baseline. Changes in seizure frequency were compared by analysis of variance on the intent-to-treat population.
Results
Baseline demographic and illness characteristics were well matched across groups. Median baseline seizure frequency was 11 seizures/28 days.
Mean % seizure reduction in the 150 and 600 mg/day groups was 20.6% and 47.8% respectively compared with a 1.8% increase in the placebo group (p<0.001 for both active treatments vs. placebo).
Proportion of responders (patients with at least 50% seizure reduction vs. baseline) was 43.5% at 600 mg/day, 14.1% at 150 mg/day and 6.2% on placebo. For this endpoint, only the highestdose group differed significantly from placebo.
Withdrawal rates due to adverse events were 6% on placebo, and 10% and 18% at 150 and 600 mg/day respectively. The most common adverse events, somnolence and dizziness, were dose-related and affected a about one quarter of patients in the highest dose group.
Comment
Pregabalin is a ligand of the alpha2-delta subunit of voltage-gated calcium channels. By binding to this site, pregabalin inhibits calcium influx and, consequently, the release of neurotrasmitters, including glutamate, from nerve terminals 0 && parent.frames.length) {
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Efficacy outcome was consistent with that seen in two earlier trials 0 && parent.frames.length) {
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Tolerability was relatively favorable. Future long-term studies should look carefully at changes in body weight: over 12 weeks, 14% of patients given 600 mg/day gained weight (vs. 2% on placebo).
Because pregabalin and gabapentin share identical modes of action, it is peculiar that the authors do not comment on their comparative efficacy. Response rates on pregabalin 600 mg/day have been consistently much greater than those found with gabapentin at the highest doses tested. This may be explained by the fact that pregabalin shows complete bioavailability within the therapeutic dose range. By contrast, the efficacy of gabapentin is hampered by a decrease in bioavailability with increasing dose, due to a saturable absorption process.
At 150 to 600 mg/day, pregabalin is likely to prove a valuable agent for the management of partial seizures. Like gabapentin, pregabalin is not expected to be useful in the treatment of generalized epilepsies.
References
- Selak I. Pregabalin. Curr Opin Invest Drugs 2001;2:828-834
- Dworkin RH, Corbin AE, Young JP et al. Pregabalin for the treatment of postherpetic neuralgia: A randomized, placebo-controlled trial. Neurology 2003;60:1631-1274-1283
- Pande AC, Crockatt JG, Feltner DE et al. Pregabalin in generalized anxiety disorder: A placebo-controlled trial. Am J Psychiatry 2003;60:1274-1283
- Fink K, Dooley DJ, Meder WP et al. Inhibition of Neuronal Ca2+ influx by gabapentin and pregabalin in the human neocortex. Neuropharmacology 2002;42:226-236
- French JA, Kugler AR, Robbins JL et al. Dose-response trial of pregabalin adjunctive therapy in patients with partial seizures. Neurology 2003; 60:1631-1637
- Beydoun AA, Uhtman BM, Ramsay RE et al. Pregabalin add-on trial: double-blind multicentre study in patients with partial epilepsy. Epilepsia 2000; 41 (suppl 7):253-254
- Cramer JA, Fisher R, Ben-Menachem E et al. New antiepileptic drugs: Comparison of key clinical trials. Epilepsia 1999;40:590-600
- Perucca E. Clinical pharmacology and therapeutic use of the new antiepileptic drugs. Fundam Clin Pharmacol. 2001;15:405-417