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Abstract & Commentary
Synopsis: The newer AEDs possess the potential advantages of better tolerability and fewer drug-drug interactions compared with standard treatments such as tricyclic antidepressants or established AEDs. However, with the exception of data supporting the efficacy of gabapentin in PHS and PDN, there is currently insufficient evidence to determine whether the newer AEDs have equal or superior efficacy relative to proven pharmacotherapies.
Source: Pappagallo M. Clin Ther. 2003;25:2506-2538.
Shared pathophysiologic mechanisms for migraine, neuropathic pain, and epilepsy underscore the notion that antiepileptic drugs (AED) should be standard treatment for the former. Five new AEDs and their use in these nonepileptic painful disorders are summarized. Each shares one or more of several mechanisms of action, including sodium or calcium channel blockade, inhibition of glutamate transmission or nitric oxide formation, enhanced GABAergic or serotonergic transmission, or free-radical scavenging.
Gabapentin, in controlled clinical trials, has been demonstrably efficacious for post-herpetic neuralgia, painful diabetic neuropathy, and migraine prophylaxis. Preliminary reports in the noncontrolled setting suggest it may also be beneficial in trigeminal neuralgia and for dysesthetic limb pain and painful spasms in multiple sclerosis.
Lamotrigine was beneficial, in controlled trials, for painful HIV neuropathy, painful diabetic neuropathy, and central post-stroke pain. Results in the latter were not dramatic, and 10% (3/30) withdrew due to adverse effects, but other studies showed that tolerability was comparable to gabapentin. Open-label use of lamotrigine, in combination with other agents for migraine prophylaxis, resulted in approximately a 50% improvement, 66% in those with aura, and case reports indicate it may be useful in SUNCT—short-lasting, unilateral, neuralgiform headache with conjunctival injection and tearing.
Oxcarbazepine has no controlled trials to its credit. Open-label use has reportedly been beneficial in carbamazepine-refractory trigeminal neuralgia and gabapentin-refractory painful radiculopathy. Tolerability was comparable to carbamazepine in the former and not problematic in the latter. Its use in migraine prophylaxis has yet to be examined.
Topiramate was efficacious in the controlled setting in painful diabetic neuropathy, with 36% reporting a > 50% decrease in pain as measured by a visual analog score, compared to 21% with placebo (P = .005). Intercostal neuralgia and trigeminal neuralgia are other reported instances where it may be useful, although a recent controlled, crossover study in 3 patients with tic showed no benefit. Large, well-performed, controlled studies have demonstrated statistically significant benefit in migraine prophylaxis.
Zonisamide, in open-label study, has shown promise for refractory cervical or lumbar radiculopathy and, in retrospective review, in painful diabetic neuropathy (n =30), fibromyalgia (n = 19), and pelvic pain (n = 7). Only 7% overall (n = 10) discontinued medication due to side effects. Migraine prophylaxis, in open-label study, showed an approximately 40% improvement and an even more striking 50% improvement in chronic daily headache.
Dizziness and somnolence are seen with all the newer AEDs but are dose related, and tolerance generally develops over time. Other adverse effects include fatigue, cognitive dysfunction, diplopia, nausea/vomiting, weight loss, and rash. Generally, these improve once steady-state levels are reached and do not lead to discontinuation of medication. Lamotrigine has the highest incidence of rash at 10%, less so when it is begun at a low dose and increased slowly. Although serious in only 3%, immediate medication withdrawal is necessary in all instances of rash. Overall, oxcarbazepine has the highest rate of reported adverse effects among the newer AEDs, but rash is rare, hepatic and hematologic toxicity is not a serious concern, and it is better tolerated as monotherapy. Topiramat has the highest rate of cognitive side effects (10%), again less so if started low and slow. Weight loss is an often-desired side effect, averaging 5.9 kg at 1 year and 10.9 kg in patients obese at baseline. As a sulfonamide, zonisamide has an inherent risk of rash and hematologic toxicity, but in practice this has not been a significant problem (rash incidence, 2%). It has also been used uneventfully in sulfa-allergic patients. Drug interactions are generally not a problem with 2 notable exceptions. Oral contraceptives should not be used with topiramate or oxcarbazepine due to their induction of the cytochrome P enzyme family, and lamotrigine dosage should be lowered when combined with valproic acid due to decreased clearance induced on the former by the latter.
Comment by Michael Rubin, MD
Lamotrigine’s initial dose and subsequent titration may be increased more rapidly in the absence of concurrent valproate use. If no valproate is on board, lamotrigine may be initiated at 50 mg/d (25 b.i.d.) and then increased by 25-50 mg/d on a weekly basis. When lamotrigine is added to valproate for migraine prophylaxis, the dosages are reasonable.
Regarding the concurrent use of oral contraceptives with topiramate or oxcarbazepine, there is some evidence to suggest that the cytochrome P isoenzyme involved is not induced until one reaches a topiramate blood level > 200/d and an oxcarbazepine blood level > 1200/d. Furthermore, no relative or absolute contraindication to contraceptive use exists for topiramate or oxcarbazepine because the induced cytochrome P increases estrogen metabolism, not progesterone. Breakthrough bleeding can be a problem, however, and an oral contraceptive with more estrogen might be warranted. Consult your gynecologist.
Lastly, topiramate and zonisamide inhibit carbonic anhydrase and thus, should be avoided when using other carbonic anhydrase inhibitors as the combination may increase the risk of clinically significant hyperchloremic metabolic acidosis leading to osteomalacia or nephrolithiasis.
Dr. Rubin is Professor of Clinical Neurology, New York Presbyterian Hospital-Cornell Campus, New York, NY.