While most patients with epilepsy have good seizure control with a single antiepileptic drug (AED), up to 30% develop refractory epilepsy requiring combinations of AEDs.1 Topiramate represents one of four AEDs released in the 1990s indicated as adjunctive therapy in the treatment of refractory partial seizures, with or without secondary generalization. The three other AEDs are gabapentin, lamotrigine and vigabatrin. All four AEDs are on formulary at VHHSC and restricted to neurology service. Lamotrigine is also approved as monotherapy for generalized seizures after withdrawal of concomitant AEDs; the other 3 agents are currently under study for this indication. Table 1 compares the mechanism of action of AEDs.
Table 1. Mechanism of Action of AEDs
|AED||Mechanism of Action|
|phenytoin, carbamazepine, sodium valproate, lamotrigine, topiramate||Blocks sodium channels|
|sodium valproate, vigabatrin, gabapentin||Increases GABAa levels|
|phenobarbital, clobazam, topiramate||Enhances GABAa receptors|
aGABA = gamma-amino butyric acid
Studies have shown adjunctive therapy with topiramate reduces seizure frequency by at least one-half in 35-52% of adult patients with resistant partial epilepsy compared to 0-19% of placebo recipients.2,3 There have been no head-to-head trials comparing the new AEDs to each another. Marson et al performed a meta-analysis of 28 randomised, placebo-controlled trials of supplementary AEDs in patients with refractory partial epilepsy to compare the efficacy (i.e. ability to reduce seizure frequency by at least 50%) of the newer agents.1 The authors found all four AEDs were significantly better than placebo at preventing seizures, but none were significantly different from the other, though the confidence intervals were wide. Odds ratios for subjects with at least 50% response relative to placebo were: topiramate 4.22 (95% confidence interval 2.80-6.35), vigabatrin 3.68 (95% CI 2.45-5.51), lamotrigine 2.32 (95% CI 1.47-3.68) and gabapentin 2.29 (95% CI 1.53-3.43). The authors suggested that topiramate and vigabatrin may be the best choices in patients with refractory epilepsy due to their apparent higher efficacy. Gabapentin and lamotrigine may be the best options in patients with a history of drug intolerance but adequate seizure control.
Other factors to consider when choosing between the newer AEDs include mechanism of action, route of elimination, drug interactions, adverse effect profile, dosage frequency and cost.
Table 2. Comparison of newer AEDs
|Drug||Topiramate (Topamax)||Gabapentin (Neurontin)||Lamotrigine (Lamictal)||Vigabatrin (Sabril)|
|Route of Elimination||Renal||Renal||Hepatic||Renal|
|AED Interactions||Yesa||-||Yesb||not significant|
|Major Adverse Effects||cognitive disturbance; psychiatric symptoms||-||potentially life-threatening skin rashes (1:1000)||visual field constriction (rare); psychiatric symptoms|
|Dose||200-600mg/day divided in 2 doses||900-3600 mg/day divided in 2-3 doses||200-400mg/day given in1-2 doses||2-3g/day as a single dose|
Marson AG, Kadir ZA, Chadwick DW. New antiepileptic drugs: a systematic review of their efficacy and tolerability. Br Med J 1996;313:1169-74.
Langtry HD, Gillis JC, David R. Topiramate. Drugs 1997;54:752-71.
Privitera MD. Topiramate: a new antiepileptic drug. Ann Pharmacother 1997;31:1164-73.