Abstract
Zonisamide is a new antiepileptic drug with multiple mechanisms of action and a favourable pharmacokinetic profile. Preliminary data suggest that zonisamide may be effective in migraine prophylaxis. We evaluated the efficacy and tolerability of zonisamide for migraine prophylaxis in refractory patients. We reviewed the charts of adult patients with International Headache Society-defined episodic migraine (EM) or with transformed migraine (TM) according to the Silberstein- Lipton criteria, who had been treated with zonisamide at our out-patient clinic for at least 60 days. Demographic data, zonisamide dosage and duration of treatment were collected and analysed. Headache frequency, attack duration, headache severity and headache-related disability before and after treatment initiation with zonisamide were compared. Thirty-three patients were included in the study (average age 43.9 ± 8.4 years; 23 (70%) with TM and 10 (30%) with EM). The patients had failed an average of 6.2 migraine prophylactic drugs prior to zonisamide. The average zonisamide daily dose was 337.9 ± 146.3 mg and the average duration of treatment was 186.4 ± 174.0 days. The average number of days with headache per month was reduced in the entire study population from 20.7 ± 9.5 before zonisamide treatment to 18.0 ± 11.3 after its initiation (P = 0.06) [in TM from 24.7 ± 7.3 to 21.0 ± 10.7 (P = 0.06); in EM from 11.6 ± 7.6 to 11.0 ± 9.7 (P = NS)]. No significant changes in other headache parameters were found. Fourteen patients (42.4%) reported adverse events (AEs), the most common of which was fatigue. Most patients (12/14, 85.7%) rated AEs as mild or moderate. In this group of refractory migraine patients, zonisamide therapy did not result in a statistically significant beneficial effect on headache or on associated symptoms.
Keywords
Introduction
Zonisamide, a new antiepileptic drug, has been approved in the USA as adjunctive therapy for the treatment of partial seizures in adults (1, 2). Chemically a sulphonamide analogue, zonisamide is thought to have several mechanisms of action, including a rate-dependent blockade of voltage-gated sodium channels and reduction of ion flow through T-type calcium channels (3–5). It is also a weak carbonic anhydrase inhibitor. Zonisamide has a favourable pharmacokinetic profile which includes high oral bioavailability and a long half-life (63 h), permitting a once- or twice-daily dosing regimen (6).
There are only a limited number of current migraine preventive medications that have proven efficacy. Their use is often limited because of adverse events (AEs) in a significant number of patients (7). Because of its pharmacological properties, zonisamide is potentially an effective drug for migraine prevention and preliminary data suggest that it may be effective for this indication (8–10). The long half-life of the drug makes it a good candidate for migraine patients that have poor compliance to preventive therapy that involves multiple daily dosing.
The aim of this study was to evaluate the efficacy and tolerability of zonisamide for migraine prophylaxis in refractory patients attending a tertiary headache centre.
Methods
The study was approved by the Jefferson University Hospital Institutional Review Board. We reviewed the charts of adult patients (≥18 years old) who had a diagnosis of episodic migraine (EM) with or without aura, as defined by the International Headache Society (IHS), or of transformed migraine (TM) according to the Silberstein–Lipton criteria (11, 12). Included patients had been treated with zonisamide at the Jefferson Headache Center from January 2001 to June 2003 for a minimum of 60 days. Demographic data, including weight, zonisamide dosage and duration of treatment, were collected and analysed. The history of patients’ previous migraine treatments and their outcome was analysed. The following disease-related parameters were evaluated: number of headache days per month, average headache severity (measured using an 11-point verbal scale), average headache attack duration and headache-associated disability, as measured by the number of missed days from school/work per month. Data on these parameters before initiation of zonisamide treatment and at the last office visit after treatment initiation were abstracted and compared. The type, severity, and prevalence of AEs were abstracted.
Statistical analysis
We used the paired t-test to compare the value of each parameter before initiation of zonisamide treatment with the corresponding value at the last follow-up after treatment initiation. The level of significance was set at P < 0.05.
Results
Thirty-three patients (27 women and six men) were included in the study. Their average age was 43.9 ± 8.4 years (range 20–61 years). Twenty-three (70%) had TM and 10 (30%) had EM. The average duration of disease was 23.8 ± 12.1 years (range 2–51 years). Twenty-four patients (72%) had psychiatric comorbidity, including depression (n = 15), anxiety (n = 4), adjustment disorder (n = 4) and bipolar disorder (n = 2). The patients had failed an average of 6.2 migraine prophylactic drugs prior to zonisamide. The headache-preventive medication class most commonly used prior to zonisamide therapy was anticonvulsants (30 patients, 91%), followed by antidepressants (22 patients, 66%), herbal medications, vitamins and minerals (18 patients, 54%) and antipsychotic drugs (16 patients, 48%) (Table 1). Seventeen patients were on zonisamide alone and 16 were on polytherapy (i.e. on zonisamide and at least one other migraine preventive drug). The patients used a variety of acute pain medications during the study evaluation period, including triptans, non-steroidal anti-inflammatory drugs, neuroleptics and, rarely, opioids. In accordance with our clinical practice, the use of these medications was limited to no more than 3 days/week in total and no more than 2 days/week for triptans and opioids.
Headache preventive medications used unsuccessfully by patients prior to zonisamide treatment
Zonisamide treatment was started at a dose of 100 mg/day and, in the majority of patients (18/33, 55%), was titrated up by 100 mg/day every week to an initial target dose of 300 mg/day. In 12 (36%) patients, the rate of zonisamide titration was slower and in three (9%) it was more rapid. In 16 (48%) patients, the zonisamide dose was increased above 300 mg/day, up to a maximum of 600 mg/day, in an attempt to achieve headache control, while nine (27%) patients remained on < 300 mg/day because of decreased tolerance. The average zonisamide daily dose was 337.9 ± 146.3 mg (range 100–600 mg). The average total duration of treatment was 186.4 ± 174.0 days (range 61–780 days) and the average duration of treatment on the maximal maintenance dose of zonisamide was 159 ± 210 days.
The average number of days with headache per month was reduced from 20.7 ± 9.5 before the initiation of zonisamide treatment to 18.0 ± 11.3 after treatment initiation (P = 0.06) (Fig. 1). The corresponding median values were 24 and 18 days. Data stratification showed that the number of days with headache per month was reduced from 24.7 ± 7.3 before initiation of zonisamide treatment to 21.0 ± 10.7 after treatment initiation in patients with TM (P = 0.06). The corresponding values for patients with EM were 11.6 ± 7.6 and 11.0 ± 9.7 days (P = NS) (Fig. 1). No significant changes in headache severity, headache duration or the number of missed days from school or work occurred after zonisamide treatment was initiated.
Average number of headache days per month before and after treatment with zonisamide. TM, Transformed migraine; EM, episodic migraine.
Fourteen patients (42.4%) reported AEs, the most common of which was fatigue (4 patients, 12%). Other AEs included irritability, anxiety, concentration difficulties, dizziness, gastrointestinal upset, foot oedema and renal calculi. Most patients (12/14, 85.7%) rated AEs as mild or moderate. There was no significant change in weight with zonisamide therapy (the average weight before treatment initiation was 80.0 ± 25.5 kg vs. 80.9 ± 25.9 kg at the last office visit after treatment initiation).
Discussion
In this retrospective study of refractory migraine patients, zonisamide treatment was associated with a small, statistically non-significant decrease in the number of headache days per month. There was no significant effect of zonisamide on any of the other headache parameters. Interestingly, the mild beneficial effect of zonisamide was seen in TM, but not in EM patients.
Other studies have suggested that zonisamide may be effective in migraine prevention. Drake et al. conducted an open label study to examine the effect of zonisamide on headache in 34 refractory migraine patients (8). Zonisamide treatment was initiated at a dose of 100 mg/day and titrated up to 400 mg/day as tolerated. Significant improvement in headache frequency, severity and duration was evident 1 month after initiation of zonisamide therapy, which continued throughout the 3-month study period. Zonisamide was well tolerated. Smith conducted an open label study to evaluate the efficacy of zonisamide, given at a dose of 100–200 mg/day, on 16 patients with refractory chronic daily headache (9). Three months after initiation of zonisamide treatment, both average headache frequency and average headache duration decreased (by 34% and 24%, respectively). Zonisamide also decreased headache-related disability in this study and was well tolerated. Krusz examined the effect of zonisamide on 33 patients who had refractory migraine with or without tension-type headache (10). The zonisamide dose range was 100–600 mg/day. Of the 23 patients who had been evaluated, 14 had a decrease in headache frequency of 25–65%. Our population of patients may have been more refractory than these. This might be due to differences in various demographic and disease-related factors, including age, disease duration, attack frequency and severity and comorbidity.
Our study showed no statistically significant beneficial effect of zonisamide on headache or on any of the other evaluated parameters. It should be noted that our study population consisted of refractory patients who had failed multiple migraine-preventive drugs prior to zonisamide therapy. They also had a high prevalence of depression and anxiety, rendering their management more challenging.
The limitations of this study include a small sample size, a retrospective, open label, non-controlled design, and variability among patients in zonisamide dosing regimen. Additionally, study patients were taking various doses of other preventive and acute pain medications at the time of study, potentially confounding the results.
Controlled studies are needed to evaluate the role of zonisamide in migraine prevention.
Footnotes
Acknowledgements
This study was supported by Eisai Inc.