Preventive Treatment Of Migra... Health Article

Because of the proven effectiveness of anticonvulsants and because of the belief that migraine is due to CNS hyperexcitability, headache experts increasingly recommend anticonvulsant medication for migraine prevention. With the exception of topiramate, valproic acid and zonisamide, anticonvulsants can interfere substantially with the efficacy of oral contraceptives [21,22]. They are discussed in order of efficacy in terms of migraine prevention.

Topiramate was originally synthesized as part of a research project to develop structural analogs of fructose-1,6-diphosphate that could inhibit the enzyme fructose 1,6-bisphosphatase, thereby blocking gluconeogenesis, but it has no hypoglycemic activity. Topiramate was originally marketed for the treatment of epilepsy [23] but is now approved by the Food and Drug Administration (FDA, http://www.fda.gov/) for migraine treatment. Topiramate is rapidly and almost completely absorbed, not extensively metabolized [24] and it readily enters the CNS [25,26]. It is not associated with significant reductions in estrogen exposure at doses <200 mg/day.

Topiramate can influence the activity of some types of voltage-activated Na ⁺ and Ca ²⁺ channels, GABA A receptors and the AMPA/kainate subtype of glutamate receptor [27,25]. It also inhibits some isozymes of carbonic anhydrase (CA) and exhibits selectivity for CA II and CA IV [28]. Topiramate blocks Na ⁺ channels in a voltage-sensitive, use-dependent manner [29]. It reduces the amplitude of tetrodotoxin-sensitive voltage-gated Na ⁺ currents in rat cerebellar granule cells, as measured by whole-cell current-clamp recordings [30]. Its effects on voltage-activated Na ⁺ and Ca ²⁺ channels, GABA A receptors and AMPA/kainate receptors are regulated by protein phosphorylation [31–34]. Subunits of each complex are phosphorylated by protein kinase (PK)A, PKC and possibly Ca ²⁺ /calmodulin-activated kinases. Topiramate might prevent PKA from phosphorylating these moieties, which would shift a population of channels towards the dephosphorylated state, thereby modulating channel and receptor activity [26].

Neuron activation within the trigeminocervical complex is likely to be the biological substrate for pain in migraine and cluster headache. Topiramate reduces superior-sagittal-sinus-evoked firing of neurons in the trigeminocervical complex in a dose-dependent fashion [35]. This inhibition is a plausible mechanism of its action in migraine prevention. Topiramate was effective in several open-label and pilot studies and in three large, multicenter, randomized, double-blind, placebo-controlled clinical trials. In addition, its chronic use has been associated with weight loss rather than weight gain.

Two large, pivotal, multicenter, randomized, double-blind, placebo-controlled clinical trials assessed the efficacy and safety of topiramate (50, 100 and 200 mg/day) in migraine prevention and found it to be effective at all doses [36,37]. A third trial compared two doses of topiramate (100 mg/day and 200 mg/day) with placebo or propranolol (160 mg/day) [38]. A dose of 100 mg/day of topiramate was superior to placebo in terms of migraine prevention. The results of the topiramate 100-mg/day and the propranolol groups were similar. The 100-mg/day dose of topiramate has the best effectiveness:AE ratio.

The most common AEs of topiramate are paresthesia, fatigue, decreased appetite, nausea, diarrhea, weight decrease, taste perversion, hypoesthesia and abdominal pain. Common CNS AEs are somnolence, insomnia, memory difficulties, language problems, concentration difficulties, mood problems and anxiety. Renal calculi can occur: their reported incidence is ∼1.5%, representing a twofold to fourfold increase compared with the estimated occurrence in the general population [39]. Acute myopia associated with secondary angle-closure glaucoma has been reported infrequently in patients receiving topiramate [40]. Oligohidrosis has also been reported in association with an elevation in body temperature.

Weight loss seems to be greatest in patients who are heavier at the onset of treatment and is seen most commonly in women [41]. The exact mechanism underlying weight loss is unclear. Rats given topiramate showed decreased levels of body fat, in addition to acutely reduced food intake and an increased metabolic rate. These animals also had decreased levels of total insulin, leptin and corticosterone [42]. Topiramate inhibits fat deposition, and the activity of lipoprotein lipase is reduced in adipose tissue in topiramate-treated rats [43].

Valproic acid is a simple eight-carbon, two-chain fatty acid with anticonvulsant activity in a wide range of experimental epilepsy models. The mechanism of action of valproate in migraine prevention might be related to the facilitation of GABA-mediated neurotransmission [44–48]. Valproate enhances GABA activity within the brain by inhibiting its degradation, stimulating its synthesis and release, and directly enhancing its postsynaptic effects. The valproate concentration required to inhibit GABA transaminase is greater than that which occurs during therapy. However, active metabolites (e.g. 2-en-valproic acid) accumulate in the brain, have an anticonvulsant effect and cause GABA accumulation in vivo [45]. Other potential mechanisms of action include direct effects on neuronal membranes (suppressing induced and spontaneous epileptiform activity), inhibition of kindling and reduction of excitatory neurotransmission by aspartate by blocking its release [47,48]. Valproate also attenuates NI by interacting with the GABA A receptor, which might be on the parasympathetic nerve fibers that project from the sphenopalatine ganglia; in so doing, it attenuates nociceptive neurotransmission [45]. Increased central enhancement of GABA A activity might enhance central antinociception [49]. Valproate also interacts with the central 5-HT system and reduces the firing rate of midbrain 5-HT-containing neurons [49].

Consistent evidence supports the efficacy of divalproex sodium (approved by the FDA) [17] , sodium valproate [17] and the extended-release formulation [50]. The effective dose for migraine of both divalproex sodium and sodium valproate is lower than that for epilepsy. The most frequent AEs are nausea, alopecia, tremor, asthenia, dyspepsia, somnolence and weight gain [51]. Hepatotoxicity and pancreatitis are the most serious AEs but irreversible hepatic dysfunction is extremely rare in adults [52]. Divalproex carries a high risk of congenital abnormality [46].

Gabapentin is used to treat certain forms of epilepsy, neuropathic pain and migraine. It binds with high affinity to two of the four known α 2 δ subunits (α 2 δ-1 and α 2 δ-2) of voltage-gated Ca ²⁺ channels. This produces inhibition of high-voltage-activated Ca ²⁺ currents, resulting in a reduction of synaptic transmission. This could be how gabapentin reduces fast glutamate-mediated and glycine-mediated synaptic transmission [53,54]. Gabapentin might be effective in migraine but the trial results are not conclusive [55–57]. The most common AEs are dizziness and drowsiness [17].

Lamotrigine blocks voltage-sensitive Na ⁺ channels, leading to the inhibition of neuronal glutamate release. Glutamate is essential for the propagation of CSD, which many believe to be the basis of the migraine aura [58]. Lamotrigine has been studied as part of a combination therapy for headache prevention in one relatively large, prospective, open-label trial of 65 patients, most of whom had chronic migraine [59]. There were 17 (48.6%) responders, at a mean dose of 55 mg/day. Those who had migraine with aura had a better response rate [12/18 (67%)], including four of eight whose headaches were chronic. Another open-label study assessed the impact of lamotrigine on aura itself and found that the drug significantly reduced both the frequency and duration of aura [59].

Lamotrigine was not effective in a double-blind, randomized, parallel-groups trial [60]. This trial was flawed because lamotrigine treatment was started at the full dose of 200 mg/day but, following a high incidence of skin rashes, a slow dose-escalation was introduced. Whereas studies indicate that lamotrigine is effective at preventing migraine with aura [61] , it is unclear whether it is effective in the absence of aura.