Specific Migraine-Preventive Agents: Anticonvulsants

By | January 31, 2015

Anticonvulsant medication is increasingly recommended for migraine prevention, because it was proved to be effective by placebo-controlled, double-blind trials. With the exceptions of valproic acid, topiramate, and zonisamide, anticonvulsants may interfere substantially with the efficacy of oral contraceptives. Nine controlled trials of five different anticonvulsants were included in the AHCPR Technical Report.


The only placebo-controlled trial of carbamazepine suggested a significant benefit, but this trial was inadequately described in several important respects. Another trial, comparing carbamazepine with clonidine and pindolol, suggested that carbamazepine had a weaker effect on headache frequency than either comparator treatment, although differences from clonidine were not statistically significant. Carbamazepine (Tegretol), 600 to 1200 mg/day, may be effective in preventive migraine treatment ().


Gabapentin (600-1800 mg) was effective in episodic migraine and chronic migraine in a 12-week open-label study. Gabapentin was not effective in one placebo-controlled, double-blind study. In a more recent randomized, placebo-controlled, double-blind trial, gabapentin, at a dosage of 1800 to 2400 mg, was superior to placebo in reducing the frequency of migraine attacks. The responder rate was 36% for gabapentin and 14% for placebo (p = 0.W). The two treatment groups were comparable with respect to treatment-limiting AEs. Limited data were reported on AEs — the most common were dizziness or giddiness and drowsiness. Relatively high patient-withdrawal rates due to AEs were reported in some trials ().

Valproic Acid

Valproic acid is a simple eight carbon, two chain fatty acid with 80% bioavailability after oral administration. It is highly protein bound, with an elimination half-life between 8 and 17hours. Valproic acid possesses anticonvulsant activity in a wide variety of experimental epilepsy models. Valproate at high concentrations increases GABA levels in synaptosomes, perhaps by inhibiting its degradation; it enhances the postsynaptic response to GABA, and, at lower concentrations, it increases potassium conductance, producing neuronal hyperpolarization. Valproate turns off the firing of the 5-HT neurons of the dorsal raphe, which are implicated in controlling head pain. Disordered GABA metabolism during migraine has been reported. Imbalance in the plasma concentrations of GABA, an inhibitory aa, and glutamic acid, an excitatory aa, has also been observed.

The mechanism of action of valproate in migraine prevention may be related to facilitation of GABA-ergic neurotransmission. 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, one of which (2-en-valproic acid) accumulates in the brain, have an anticonvulsant effect and cause GABA accumulation in vivo. Other potential mechanisms of action include direct effects on neuronal membranes (it suppresses induced and spontaneous epileptiform activity), inhibition of kindling, and reduction of excitatory neurotransmission by the aa aspartate by blocking its release. Valproate also attenuates plasma extravasation in the Moskowitz model of NI by interacting with the GABAA receptor. The relevant receptor may be on the parasympathetic nerve fibers projecting from the sphenopalatine ganglia; in so doing, it attenuates nociceptive neurotransmission. In addition, valproate-induced increased central enhancement of GABAA activity may enhance central antinociception. Valproate also interacts with the central 5-HT System and reduces the firing rate of midbrain serotonergic neurons.

Five studies provided strong and consistent support for the efficacy of divalproex sodium (approved by the FDA) and sodium valproate. Two placebo-controlled trials of each of these agents showed them to be significantly better than placebo at reducing headache frequency. A single study compared divalproex sodium with propranolol and found differences favoring divalproex sodium; however, the statistical significance of these results could not be determined (open-label study with high dropout rates). A more recent study (not included in the AHCPR Technical Report) found divalproex sodium more effective compared with placebo, but not significantly different compared with propranolol, for prevention of migraine in patients without aura. An extended release form of divalproex sodium demonstrated comparable efficacy to the tablet formulation. The AE profile in the clinical trial, however, showed almost identical AE rates for the placebo and active treatment arms.

Clinical Trials. In 1988, prompted by his clinical observations of valproate’s benefits, Sorensen performed a prospective open trial of valproate. He studied 22 patients with severe migraine that was resistant to previous prophylactic treatment. Follow-up in 3 to 12 months revealed that 11 patients were migraine-free, six had a significant reduction in frequency, one had no change, and four had dropped out ().

In 1992, Hering and Kuritzky evaluated sodium valproate’s efficacy in migraine treatment in a double-blind, randomized, crossover study. Thirty-two patients were divided into two groups and given either 400 mg of sodium valproate twice a day or placebo for eight weeks. Sodium valproate was effective in preventing migraine or reducing the frequency, severity, and duration of attacks in 86.2% of 29 patients, whose attacks were reduced from 15.6 to 8.8 a month.

Jensen et al., in 1994, studied 43 patients with migraine without aura in a triple-blind, placebo- and dose-controlled, crossover study of slow-release sodium valproate. After a four-week medication-free run-in period, the patients were randomized to sodium valproate (n =W) or placebo (n =W). Thirty-four patients completed the trial. Fifty percent of the patients had a reduction in migraine frequency to 50% or less for the valproate group compared with 18% for placebo. During the last four weeks of valproate treatment, 65% responded. The most commun AEs (33%o valproate and 16% placebo) were intensified nausea and dyspepsia, tiredness, increased appetite, and weight gain, and were usually mild or moderate. Fifty-eight percent of the patients had no AEs.

In 1995, in a multicenter, double-blind, randomized, placebo-controlled investigation, Mathew et al. compared the effectiveness and safety of divalproex sodium and placebo in migraine prophylaxis. A four-week, single-blind, placebo-baseline phase was followed by a 12-week treatment phase (four-week dose adjustment, eight-week maintenance). One hundred seven patients were randomized to divalproex sodium or placebo (2:1 ratio), with 70 receiving divalproex sodium and 37 receiving placebo. Forty-eight percent of the divalproex sodium-treated patients and 14%o of the placebo-treated patients showed a 50% or greater reduction in migraine headache frequency from baseline (p < 0.001). No significant treatment-group differences were observed in average peak severity or duration of individual migraine headaches. Treatment was stopped in 13% of the divalproex sodium-treated patients and 5% percent of the placebo-treated patients, because of intolerance (p, not significant).

Klapper et al. evaluated the efficacy and safety of divalproex sodium as prophylactic monotherapy in a multicenter, double-blind, randomized, placebo-controlled study. Patients with two or more migraine attacks during the baseline phase were randomized to a daily divalproex sodium dose of 500, 1000, or 1500 mg, or placebo. The primary efficacy variable was four-week headache frequency during the experimental phase. During the experimental phase, the mean reduction in the combined daily divalproex sodium groups was 1.8 migraines per four weeks compared with a mean reduction of 0.5 attacks per four weeks in the placebo group. Overall, 43% of divalproex sodium-treated patients achieved 50% or more reduction in their migraine attack rates, compared with 21% of placebo-treated patients. A statistically significant (p < 0.W) dose-response effect across the dose range placebo, 500, 1000, and 1500 mg, was observed for both overall reduction in attack frequency and a 50% or more reduction in attack frequency. With the exception of nausea, AEs were similar in ail groups (divalproex sodium 24%, placebo 7%, p = 0.W) and most AEs were mild or moderate in severity.

In an open-label study, Silberstein and Collins evaluated the long-term safety of divalproex sodium in patients who had completed one of two previous double -blind, placebo-controlled studies. The results, including data from the double-blind study, represented 198 patient-years of divalproex exposure. The average dose was 974mg/day. Reasons for premature discontinuation (67%) included administrative problems (31%), drug intolerance (21%), and treatment ineffectiveness (15%). The most frequently reported AEs were nausea (42%), infection (39%), alopecia (31%), tremor (28%), asthenia (25%), dyspepsia (25%), and somnolence (25%). Divalproex was found to be safe and initial improvements were maintained for periods more than 1080 days. No unexpected AEs or safety concerns unique to the use of divalproex in the prophylactic treatment of migraine were found.

Freitag et al. evaluated the efficacy and safety of extended-release divalproex sodium compared with placebo in prophylactic monotherapy treatment. Treatment was initiated by administering a dose of 500 g once daily for one week, and the dose was then increased to 1000 mg once daily, with an option, if intolerance occurred, to permanently decrease the dose to 500 mg during the second week. The mean reductions in the four-week migraine headache rate were 1.2 (from a baseline mean of 4.4) in the extended-release divalproex sodium group and 0.6 (from a baseline mean of 4.2) in the placebo group (p = 0.006); reductions with extended-release divalproex sodium were significantly greater than with placebo in ail three four-week segments of the treatment period. The proportion of subjects achieving at least 50% reduction in experimental phase migraine headache rate was higher in the extended-release divalproex sodium group (36/119; 30%) than in the placebo group (28/115; 24%), but the difference was not significant (p = 0.251).

Nausea, vomiting, and gastrointestinal distress are the most common AEs of valproate therapy. These are generally self-limited and are slightly less common with divalproex sodium than with sodium valproate. When therapy is continued, the incidence of gastrointestinal symptoms decreases, particularly after six months. In three of four placebo-controlled trials, the overall percentage of patients reporting AEs with divalproex sodium or sodium valproate was not higher than with placebo. The fourth trial found significantly higher rates of nausea, asthenia, somnolence, vomiting, tremor, and alopecia with divalproex sodium. On rare occasions, valproate administration is associated with severe AEs such as hepatitis and pancreatitis. The frequency of these AEs varies with the number of concomitant medications used, the patient’s age and generai state of health, and the presence of genetic and metabolic disorders. Valproate is potentially teratogenic and should not be used by pregnant women or women considering pregnancy. Valproate has little effect on cognitive functions and rarely causes sedation. The frequency of these adverse reactions varies with the number of concomitant medications used, the patient’s age, the presence of genetic and metabolic disorders, and the patient’s generai state of health. These idiosyncratic reactions are unpredictable.

The risk of valproate hepatotoxicity is highest in children under the age of two years, especially those treated with multiple antiepileptic drugs, those with metabolic disorders, and those with severe epilepsy accompanied by mental retar-dation and organie brain disease. The relative risk of hepatotoxicity from valproate is low in migraineurs. Hyperandrogenism, resulting from elevated testosterone levels, ovarian cysts, and obesity, is of particular concern in young women with epilepsy who use valproate. It is uncertain if valproate can cause these symptoms in young women with migraine or mania.

Because of valproate’s potential idiosyncratic interactions with barbiturates (severe sedation and coma), migraine patients who are on valproate should not be given barbiturate-containing combination analgesies for symptomatic headache relief. If these drugs are used, they should be given with caution and at a low dose. Absolute contraindications to valproate are pregnancy and a history of pancreatitis or a hepatic disorder such as chronic hepatitis or cirrhosis of the liver. Other important contraindications are hematologie disorders, including thrombocytopenia, pancytopenia, and bleeding disorders.

Valproic acid is available as 250 mg capsules and as a syrup (250 mg/5mL). Divalproex sodium is a stable coordination complex comprising sodium valproate and valproic acid in a 1:1 molar ratio. An enteric-coated form of divalproex sodium is available as 125, 250, and 500 mg capsules and a sprinkle formulation. Start with 250 to 500 mg/day in divided doses and slowly increase the dose. Monitor serum levels if there is a question of toxicity or compliance. (The usual therapeutic level is from 50 to 100 mg/mL.) The maximum recommended dose is 60 mg/kg/day. An extended release form of divalproex sodium demonstrated comparable efficacy to the tablet formulation. The AE profile in the clinical trial showed almost identical adverse effect rates for the placebo and active treatment arms.


Topiramate is a structurally unique anticonvulsant that was discovered serendipitously. It was originally synthesized as part of a research project to discover structural analogs of fructose-1,6-diphosphate capable of inhibiting the enzyme fructose-1,6-bisphosphatase, thereby blocking gluconeogenesis, but it has no hypoglycemie activity. Topiramate is a derivative of the naturally occurring monosaccharide D-fructose and contains a sulfamate functionality. The structural resemblance of its (9-sulfamate moiety to the sulfonamide moiety in acetazolamide prompted an evaluation of possible anticonvulsant effects. Topiramate was originally marketed for the treatment of epilepsy; it is now FDA approved for migraine.

Topiramate is rapidly and almost completely absorbed. It is not extensively metabolized and is eliminated predominantly unchanged in the urine.

The average elimination half-life is approximately 21 hours. Topiramate readily enters the CNS parenchyma; in rats, the concentration in whole brain was approximately one-third of that in blood plasma one hour after oral dosing. The bioavailability of topiramate from the tablet formulation is about 80%, and is not affected by food.

In a pharmacokinetic interaction study with a concomitantly administered combination oral contraceptive product containing 1 mg norethindrone (NET) plus 35 mcg ethinyl estradiol (EE), topiramate at doses of 50 to 200 mg/day was not associated with statistically significant changes in mean exposure [area under the curve (AUC)] to either component of the oral contraceptive. Topiramate is therefore not associated with significant reductions in estrogen exposure at doses below 200 mg/day. At doses above 200 mg/day, there may be a dose-related reduction in exposure to the estrogen component of oral contraceptives.

The anticonvulsant activity of most antiepileptic drugs is thought to be due to a state-dependent blockade of voltage-dependent Na+ or Ca2+ channels or an ability to enhance the activity of GABA at GABAA receptors. Topiramate can influence the activity of some types of voltage-activated Na+ and Ca2+ channels, GABAA receptors, and the a-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid (AMPA)/kainate subtype of glutamate receptors. Topiramate also inhibits some isozymes of carbonic anhydrase (CA) and exhibits selectivity for CA II and CA IV. Topiramate blocks Na+ channels in a voltage-sensitive, use-dependent manner. Topiramate can reduce the amplitude of tetrodotoxin-sensitive voltage-gated Na+ currents in rat cerebellar granule cells, as measured by whole-cell current-clamp recordings.

The effects of topiramate on voltage-activated Na+ channels, voltage-activated calcium channels, GABAA receptors, and AMPA/kainate receptors are ail regulated by protein phosphorylation. One or more subunit of each complex is phosphorylated by protein kinase A, protein kinase C, and possibly CA2+/CaM-activated kinases. The consensus peptide sequence at the protein kinase A-mediated phosphorylation site exhibits homology, i.e., the GluR6 subunit of the AMPA/ kainate receptor contains an RRQS, the (3 subunit of the GABAA receptor contains RRAS, and some subtypes of the primary subunit of Na+ and Ca2+ channels contain RRNS and RRPT, respectively (R, arginine; Q, glutamine; S, serine; T, threonine; A, alanine; and N, asparagine). Immediately upon binding to the site, topiramate could exert either a positive or a negative allosteric modulatory effect; secondarily, topiramate would prevent protein kinase A from accessing the serine hydroxyl site, thereby preventing phosphorylation, which, over time, would shift a population of channels toward the dephosphorylated state. Thus, topiramate may bind to the membrane channel complexes at phosphorylation sites in the inner loop and thereby allosterically modulate ionic conductance through the channels.

Storer and Goadsby studied the effect of topiramate on trigeminocervical activation in the anesthetized cat. Activation of neurons within the trig-minocervical complex is likely to be the biological substrate for pain in migraine and cluster headache. The superior sagittal sinus (SSS) was isolated and electrically stimulated. Units linked to SSS stimulation were recorded in the most caudal part of the trigeminal nucleus. Topiramate reduced SSS-evoked firing of neurons in the trigeminocervical complex in a dose-dependent fashion. Its inhibition is a plausible mechanism of the action of migraine or cluster headache preventive medicines.

Clinical Profile

Pilot Studies. Topiramate has been shown to be effective in a number of open-label and pilot studies. In addition, its chronic use has been associated with weight loss, not weight gain (a common reason to discontinue preventive medication).

In a preliminary safety and efncacy study, 213 patients were randomized (2:1) to topiramate or placebo and were titrated to either 200 mg/day or maximum tolerated dose over an eight-week period, followed by a 12-week maintenance period. For each protocol, the monthly migraine rate, migraine days, and percent reduction in migraine frequency for the intent-to-treat (ITT) population (n = 211) were assessed by an analysis of covariance (ANCOVA) with baseline migraine rate as covariate and last observation carried forward. A disproportionately high number of topiramate patients dropped out during the first four weeks of the study. ANCOVA was insensitive for detection of drug-placebo differences in the ITT population, but was sensitive to demonstrate superiority of topiramate versus placebo for patients completing the trial (n= 155, p = 0.03). However, a repeated measured analysis using the ITT population demonstrated statistically significant reductions in monthly migraine rate (p = 0.04) and migraine days (p = 0.04), and percent reduction in migraine episodes (p = 0.02) for topiramate patients versus placebo patients. A weighted regression analysis also demonstrated a statistically significant reduction in migraine rate for topiramate patients versus placebo patients (p = 0.05).

Pivotai Phase III trials — Efficacy. Silberstein et al., in the first pivotal placebo-controlled clinical trial of 487 patients, assessed the efficacy and safety of topiramate (50, 100, and 200 mg/day) in migraine prevention in a 26-week, multicenter, randomized, double-blind, placebo-controlled study (MIGRW). The primary efficacy measure was the change in mean monthly migraine frequency between baseline and the double-blind phase. Eligible subjects entered a washout period of up to 14 days, which was followed by a prospective baseline period of 28 days. Patients who completed the baseline period and met the entry criteria were randomized to one of four treatment groups: 50 mg/day topiramate, 100 mg/day topiramate, 200 mg/day topiramate, or placebo. Patients randomized to topiramate started at a dose of 25 mg/day; the daily dose was increased by 25 mg weekly (for a total of eight weeks) until patients reached either their assigned dose or maximum tolerated dose, whichever was lower. Patients then continued on that dose for 18 weeks. In the group treated with topiramate 100 mg/day, there was a mean reduction of 2.1 monthly migraine episodes (5.4-3.3), compared with 0.8 for placebo. The responder rate (patients with 50% or more reduction in monthly migraine frequency) was 52% with topiramate 200 mg/day (p < 0.001), 54% with topiramate 100 mg (p < 0.001), 36% with topiramate 50 mg/day (p = 0.039), compared with 23% with placebo ().

Topiramate treatment was also associated with reduced consumption of acute-treatment medications. The onset of efficacy was observed within the first month of treatment. The 200 mg dose was not significantly more effective than the 100 mg dose. The most common AEs were paresthesias, fatigue, nausea, anorexia, and abnormal taste. Body weight was reduced by an average of 3.8% in the 100 and 200 mg groups.

Brandes et al. assessed the efficacy and safety of topiramate (50, 100, and 200 mg/day) in the prevention of migraine headaches in the second 26-week, multi-center, randomized, double-blind, placebo-controlled study (MIGRW). The primary and secondary efficacy measures were identical to MIGR-001. A total of 483 patients were randomized to the four treatment groups (placebo, 120; topiramate 50 mg/day, 120; topiramate 100 mg/day, 122; and topiramate 200 mg/day, 121). The ITT population consisted of 468 patients. The mean monthly number of migraine periods decreased significantly for those patients on 100 mg/day of topiramate (from 5.8 to 3.5, p = 0.008) or 200 mg/day of topiramate (from 5.1 to 2.9, p = 0.001) versus placebo (from 5.6 to 4.W). Significant reductions were evident as early as the first month of treatment. A significantly greater proportion of patients exhibited at least a 50% reduction in mean monthly migraines in the groups treated with 50 mg/day of topiramate (39%, p = 0.W), 100 mg/day of topiramate (49%, p = 0.001), and 200 mg/day of topiramate (47%, p =0.001). Patients treated with 200 mg/day of topiramate lost an average of 4.8% of body weight from baseline through the double-blind phase. In this second pivotai study, topiramate was associated with significant improvement in migraine at doses of 100 or 200 mg/day in each efficacy measure assessed. The onset of efficacy was observed as early as the first month of treatment.

Diener et al. compared two doses of topiramate (100 or 200 mg/day) to placebo or propranolol (160 mg/day) in a randomized, double-blind, parallel-group, multicenter trial of 575 subjects conducted in 68 centers in 13 countries. Topiramate 100 mg/day was superior to placebo as measured by average monthly migraine period rate, average monthly migraine days, rate of rescue medication use, and percentage of patients with a 50% or greater decrease in average monthly migraine period rate (responder rate 37%). The topiramate 100 mg/day and propranolol groups were similar in change from baseline to the core double-blind phase in average monthly migraine period rate and other secondary efficacy variables. Topiramate 200 mg/day failed in the primary end point compared to placebo but had a significantly higher responder rate (35% vs. placebo 22%). Topiramate 100 mg/day (responder rate 37%) was better tolerated than topiramate 200 mg/day, and was comparable to propranolol (responder rate 43%). These findings provide clear evidence that topiramate is effective in migraine prophylaxis. The 100 mg dose offers the best relationship between efficacy and tolerability. A major shortcoming of this trial is the high dropout rate of patients in the topiramate 200 mg group due to adverse effects. This high dropout rate resulted in the nonsuperiority of topiramate 200 mg over placebo ().

Safety and Tolerability. Data for safety and tolerability in migraine is based on the experience of 1135 patients in multicenter, double-blind studies, who received total daily doses of 50, 100, or 200 mg of topiramate. The most common AE was paresthesia, which occurred in 35% of subjects in the topiramate 50 mg group, 51%o in the topiramate 100 mg group, and 49% in the topiramate 200 mg group compared with 6% in the placebo group. Paresthesias were rated as mild-to-moderate in the majority of patients, and were treatment limiting in only 8% of these subjects; when bothersome, they can be controlled with potassium supplementation. The other most common AEs were fatigue, decreased appetite, nausea, diarrhea, weight decrease, taste perversion, hypoesthesia, and abdominal pain. The most common CNS AEs were somnolence, insomnia, difficulty with memory, language problems, difficulty with concentration, mood problems, and anxiety.

The percentages of subjects who discontinued due to AEs were 17%, 25%, and 29%o in the TPM 50, 100, and 200 mg groups, respectively, and 10% in the placebo group. Most dropouts were due to side effects that occurred early in the trial. There were no clinically important changes in clinical laboratory tests of liver function, renal function, or hematologie parameters, or abnormalities in vital sign measurements or neurologie examinations. In the study that included both topiramate and propranolol, the overall incidence of treatment-emergent and treatment-limiting AEs for topiramate 100 was comparable to propranolol 160 mg/day.

Neurobehavioral AEs occurred at rates comparable to those seen for studies of other conditions, such as monotherapy in epilepsy, utilizing topiramate as a single antiepileptic treatment. The most common of these AEs were dizziness, slowed thinking, somnolence, ataxia, fatigue, confusion, and impaired concentration. Most of these AEs were seen during the first two months of the initial titration period, and had resolved in 60% to 90% of patients with continued use of topiramate. Two studies have prospectively evaluated neuropsychometric changes with adjunctive topiramate treatment in patients with epilepsy. These studies support clinical observations that AEs occur most prominently during titration, with most changes not persisting after maintenance treatment. In clinical practice, the incidence of CNS AEs can be reduced with a low starting dose and a slower dose-escalation rate.

Renal calculi can occur with the use of topiramate. The reported incidence is about 1.5%, representing a two to fourfold increase over the estimated occurrence in the generai population. Most patients faced with this problem do not need surgery and go on to continue treatment with topiramate once they pass the stone. Patients who take topiramate for epilepsy have weight loss that occurs early in the treatment and is maximal by 15 to 18 months. The weight loss appears to be greatest in patients who are heavier at the onset and is most commonly seen in female patients. The mechanism is unclear. Rats treated with stopiramate showed decreased body fat as well as acutely reduced food intake and an increased metabolic rate. These animais also had decreased levels of total insulin, leptin, and corticosterone. Other investigators suggest that topiramate inhibits fat deposition. The activity of lipoprotein lipase is reduced in adipose tissue in topiramate-treated rats.

In the migraine trials, body weight was reduced by an average of 2.3% in the 50 mg group, 3.2% in the 100 mg group, and 3.8% in the 200 mg group. Patients on propranolol gained 2.3% of their baseline body weight.

A syndrome consisting of acute myopia associated with secondary angle closure glaucoma has been reported infrequently in patients receiving topiramate. There were no cases of this condition reported in the clinical studies. Symptoms include acute onset of decreased visual acuity and/or ocular pain. Ophthalmologic findings can include myopia, anterior chamber shallowing, ocular hyperemia, and increased intraocular pressure. Mydriasis may or may not be present. This syndrome may be associated with supraciliary effusion resulting in anterior displacement of the lens and iris, with secondary angle closure glaucoma. Symptoms typically occur within one month of initiating topiramate therapy. In contrast to primary narrow-angle glaucoma, which is rare in patients under 40 years of age, secondary angle-closure glaucoma associated with topiramate has been reported in pediatrie patients as well as adults. The primary treatment to reverse symptoms is discontinuation of topiramate as rapidly as possible, according to the judgment of the treating physician. Other measures, in conjunction with discontinuation, may be helpful.

Oligohidrosis (decreased sweating), infrequently resulting in hospitalization, has been reported in association with an elevation in body temperature. Some of the cases were reported after exposure to elevated environmental temperatures. Most of the reports have been in children.

Conclusion. The MIGR-001, MIGR-002, and MIGR-003 trials represent the largest controlled clinical trials of topiramate in migraine prevention to date, and together represent the largest controlled trials of a migraine preventive. Topiramate was associated with improvements in each of the efficacy measures presented. Treatment with topiramate 100 or 200 mg/day was associated with significant reductions in migraine frequency, migraine days, and number of migraine attacks per month. Treatment with topiramate was also associated with reduced use of acute medications. Topiramate is effective for migraine prophylaxis. The 100 mg dose seems to have the best efficacy/tolerability ratio. Cognitive side effects are of less concern with doses of 100 mg or less.

Topiramate administration should be started with a dose of 15 to 25 mg at bed-time and the dose should be increased by 15 to 25 mg/week. The dose should not be increased if bothersome AEs develop, one must wait until they resolve (they usually do). If they do not resolve, the dosage of the drug should be decreased to the last tolerable dose, then increased by a lower dose more slowly. The aim should be to reach a dose of 50 to 100 mg/day given twice a day. It is our experience that patients who tolerate the lower doses with only partial improvement often have increased benefit with higher doses. The dose can be increased to 600 mg/day or higher.


Lamotrigine blocks voltage-sensitive sodium channels, leading to inhibition of neuronal glutamate release of glutamate. Glutamate is essential in the propagation of CSD, which many believe is the basis of the migraine aura. Lamotrigine has been studied as combination therapy for headache prevention in one relatively large, prospective, open-label trial of 65 patients, most of whom had chronic migraine. Only 35 patients were compilant with treatment to warrant inclusion in the analysis, with 12 dropping out because of AEs. The primary end point was reduction in frequency of severe headaches. There were 17 (48.6%) responders, at amean dose of 55 mg/day. Those who had migraine with aura had a better response rate (12/18 or 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.

Chen et al. reported two patients with migraine with persistent aura-like visual phenomena for months to years. After two weeks of lamotrigine treatment, both had resolution of the visual symptoms.

Steiner et al. compared the safety and efficacy of lamotrigine and placebo in migraine prophylaxis in a double-blind, randomized, parallel-groups trial. A total of 110 patients entered; after a one-month placebo run-in period, placebo responders and noncompliers were excluded, leaving 77 to be treated with lamotrigine (n =37) or placebo (n =40) for up to three months. Initially, lamotrigine therapy was begun at the full dose of 200 mg/day, but, following a high incidence of skin rashes, a slow dose-escalation was introduced: 25 mg/day for two weeks, 50 mg/day for two weeks, and then 200 mg/day. Attack rates were reduced from baseline means of 3.6 per month on lamotrigine and 4.4 on placebo, to 3.2 and 3.0, respectively, during the last month of treatment. Improvements were greater on placebo, and these changes, not statistically significant, indicate that lamotrigine was ineffective for migraine prophylaxis. There were more AEs on lamotrigine than on placebo, most commonly rash. With slow dose-escalation, their frequency was reduced and the rate of withdrawal for AEs was similar in both treatment groups.


Two retrospective, open-label studies of zonisamide in the preventive treatment of episodic migraine have been reported. In the study conducted by Drake et al., 34 patients with refractory migraine with or without aura were treated adjunctively with zonisamide at doses as high as 400 mg/day. Headache data were obtained from patient headache diaries and telephone reports. A 40% reduction in headache severity, a 50% reduction in headache duration, and a 25% decrease in headache frequency were found at three months compared to baseline values. Four patients (12%) discontinued the drug because of AEs and nine stopped the medicine because they believed it was not working. Krusz reported improvement in 14/33 (42%o) of patients, with four dropouts due to AEs. Zonisamide was also examined as monotherapy in a small, prospective, open-label study of nine patients with episodic migraine with or without aura. The drug was titrated to a mean dose of 244 mg/day, and investigator efficacy ratings were made for ail patients who remained on a stable dose of the drug for six weeks. It was effective or very effective in 6 of 9 (67%) patients.