Abstract
We reviewed the electronic records of 74 migraine patients treated with topiramate for more than 6 weeks. Twenty-four patients had episodic migraine and 50 had chronic (transformed) migraine. Most (81%) started treatment at 25 mg per day and reached a dose of 100 mg twice a day (mean dose on the last follow-up visit was 208 mg). The mean headache frequency decreased from 20.6 days to 13.6 days per month (P < 0.0001) for all headaches (9.9-5.1 (P < 0.0001) and 25.7-17.7 (P < 0.001) for episodic migraine and chronic migraine, respectively). The percentage of patients whose headache frequency was reduced by ≥ 50% was 44.6% for all patients; 58.3 for episodic migraine and 38.0 for chronic migraine. For all patients mean headache severity (10-point scale) was reduced from 6.2 to 4.8 (P < 0.0001). Patients on monotherapy (20%) and polytherapy (80%) had similar reductions in headache frequency. Adverse events were usually mild to moderate and were seen in 58.1% (paresthesias in 25%, cognitive difficulties 14.9%). Mean weight loss was 3.1 ± 4 kg (3.8% of total body weight).
Introduction
Topiramate, originally synthesized as a hypoglycaemic agent but found to be devoid of hypoglycaemic activity, was subsequently developed as an anti-convulsant. It is currently approved for the adjunctive treatment of epilepsy. It is used as a mood stabilizer, anti-tremor agent, and in the treatment of neuropathic pain conditions, migraine (1–10) and cluster headache. It is a neuroprotective in animal stroke and epilepsy models (11).
Two small placebo-controlled trials of topiramate have demonstrated its efficacy in the treatment of migraine (7, 8). A number of open label studies have demonstrated efficacy in the treatment of migraine (12–19) and chronic daily headache (14–16, 20, 21). Large-scale multicentered, placebo-controlled trials are under way. Questions still remain about which headache patients might benefit most from topiramate and how to optimize its treatment effects. How should one best dose topiramate and what is the adverse event profile at a given dose for headache patients?
Methods
Patients with a diagnosis of episodic and chronic migraine (transformed migraine according to Silberstein criteria) (22) who were prescribed topiramate were identified from our electronic medical record system. Patients started on topiramate therapy on or after April 2000 and who remained on therapy for at least 6 continuous weeks with at least one subsequent visit prior to January 2001 were evaluated. Four patients who discontinued treatment before their first follow-up visit (after 6 weeks) were not included, but those who discontinued treatment after their first post 6-week follow-up were included in the analyses.
At each visit patients rated headache intensity (0–10 scale), frequency, and duration. Headache frequency, intensity, and duration were entered based upon a calendar review by a nurse or doctor when available, or based on patient recall when a calendar was not available. Some patients had two headache types. Patients were asked to determine the average duration of their more severe headaches. For study purposes, an average headache intensity on days with headache was determined. The Wilcoxon's signed rank test was used to compare pretreatment with end of study values.
Results
A review of the electronic medical record demonstrated that topiramate was prescribed to 463 patients. Ninety-three patients were excluded for a diagnosis other than episodic or chronic migraine (30 cluster headache, 28 post-traumatic headache, 15 new daily persistent headache, seven pseudotumour cerebri, and 13 other diagnoses); 257 patients were excluded because they were started on topiramate before April 2000, after October 2000, or on an unknown date; 35 patients who had no follow-up visit prior to analysis; and four patients who discontinued topiramate prior to follow-up were also excluded. Seventy-four patients met the inclusion criteria (Fig. 1). Their mean age was 43.2 years (range 16–71 years) (six men and 68 women; 62 patients were white, 10 African-American, and two Hispanic). The average age of migraine onset was 22.6 years (range 8–50 years).
Synopsis of patient selection.
Twenty-four patients had episodic migraine (six with and 18 without aura; two men and 22 women). Their mean age was 43.4 years (range 20–59 years) with a mean age of onset of 24.6 years. The mean headache frequency was 9.9 of 28 days; the mean headache severity was 6.0/10. Fifty patients had chronic migraine (four men and 46 women) with a mean age of 43.2 years (range 16–71 years) and a mean age of migraine onset of 21.7 years. The duration of chronic migraine was 6 years; the mean headache frequency was 25.7 out of 28 days, and the mean headache severity was 6.3/10.
Before starting topiramate, 80% of chronic migraine patients used an acute medication at least 3 days a week. The mean number of failed preventive drugs was 4.2 (range 0–13) and failed drug classes 3.4. Among all patients, 20% (15/74) were on monotherapy and 80% (59/74) on polytherapy. Seventy-seven percent (57/74) of patients had another medical diagnosis (Table 1). Fifty-six (78.4%) of the 72 patients had one or more psychiatric diagnosis (Table 1).
Coexisting conditions
Most of our patients (81%) started at a dose of 25 mg per day for 1 week which they increased by 25 mg per week until reaching 200 mg per day (100 mg bid) (the dose, at times, was further adjusted). Some patients (19%) were started on 15 mg per day for 1 week which they increased by 15 mg per week as tolerated until the next office visit. The mean daily dose was 208 mg (episodic migraine 190 mg, chronic migraine 217 mg). The mean duration of treatment prior to analysis was 149 days (range 52–271).
Outcomes
The mean number of headache days was reduced from 20.6 prior to topiramate treatment to 13.6 at study endpoint evaluation (P<0.0001). For episodic migraine and chronic migraine these values were 9.9–5.1 (P<0.0001) and 25.7–17.7 (P<0.0001), respectively. Headache frequency was at least 50% reduced in 44.6% of all patients, 58.3% with episodic migraine, and 38.0% with chronic migraine. Mean headache severity was reduced from 6.2 to 4.8 (P<0.001). For episodic migraine and chronic migraine, respectively, these values were 6.0–4.9 (P<0.02) and 6.3–4.8 (P≤0.0001). Seventy-four percent of patients reported using less acute medications. Fifty-eight percent of episodic migraine patients reported shorter headache duration on topiramate and 45% of chronic migraine patients reported a shorter duration of their headache exacerbations (if continuous) or episodic headache (if not continuous).
Episodic or chronic migraine duration was not associated with a change in headache frequency. Patients on monotherapy and polytherapy had similar reductions in headache frequency. The patient's age, the titration schedule, the duration of treatment with topiramate, and the final topiramate dose did not correlate with the reduction in headache frequency for episodic migraine or chronic migraine.
Depressed patients (major depression, dysthymia, or depression NOS) had similar outcomes when compared with non-depressed patients. Patients with severe psychiatric disorders (e.g. major depression, bipolar disease, dissociative disorder) had similar reductions in headache frequency compared with those with less severe diagnoses (e.g. dysthymia, adjustment disorder) (P=NS for both comparisons).
Adverse events were reported in 58.1% of patients: paresthesias in 25%, cognitive difficulties in 14.9%, dizziness in 4%, and nausea in 4% (Table 2). Six patients (8.1%) discontinued topiramate; three due to adverse events and three due to ineffectiveness.
Adverse events
Mean weight loss was 3.1 ± 4 kg (3.8% of total body weight); 5.2 ± 4.3 kg on monotherapy, 2.6 ± 3.7 kg on polytherapy (Fig. 2). Age and headache diagnosis did not correlate with weight loss, but the duration of treatment and weight at baseline correlated positively with weight loss. Dose did not correlate with weight loss.
Weight loss for migraine patients on topiramate.
Discussion
Our findings are consistent with published placebo-controlled trials and observational studies. Edward (8), in a placebo-controlled trial of episodic migraine patients, found a 50% or greater reduction in headache frequency in 47% of patients. Potter (7), in a placebo-controlled trial of episodic migraine patients, reported a median percent reduction in monthly headaches of 33%. Von Seggern (12) mainly studied daily headache patients and reported a reduction in severe headaches of 30.2% and in all headaches of 17.8%. Beneficial effects of topiramate included not only a reduction in headache frequency, but also headache intensity, duration, and acute medication use. Previous studies of topiramate have only reported changes in headache frequency. Von Seggern showed a similar reduction in moderate to severe headaches among patients who had used nine or more preventives compared with those who used fewer than nine preventives prior to initiating topiramate. Similarly, we also found little difference between those who used less than four prior preventives and those who used four or more. This contrasts with the widely held belief that patients who have failed multiple preventives are unlikely to benefit from preventive treatment.
It is unlikely that our results are due to a placebo effect, since most of our patients had failed multiple prior preventive drugs often administered by us. The high efficacy rates in our study may be due to the ability to optimize dose and to individualize treatment. It represents a real life outcome study, and may be more representative of the outcomes that might be expected in a true clinical setting.
Topiramate worked well for patients with coexistent medical and psychiatric disorders. Previous reports suggest that depression predicts a poor response to treatment (23). This was not true in our present study. Topiramate appears to be effective even in depressed patients and those with other psychiatric diagnoses. These findings will need confirmation and future study.
In our study dose did not correlate with efficacy. This was not a controlled trial; when lower doses were ineffective, the dose was raised until the treatment was effective or adverse events occurred. Some patients could not increase their dose despite low efficacy because of adverse events. These factors would be expected to flatten out a dose–response curve.
The adverse events were relatively mild. Only two patients discontinued treatment after their first follow-up visit due to adverse events, and four patients discontinued before their first follow-up visit, possibly due to adverse events. The low adverse event rate may be due to the slow titration schedule of topiramate.
Similar to other trials in headache and non-headache populations, weight loss was a beneficial adverse event of treatment. The reported range of weight loss was consistent with previous studies (14, 24). Patients who weighed more at baseline and were on topiramate for a longer period of time lost more weight. Most headache preventive agents are associated with weight gain. Weight loss was less for patients on polytherapy, perhaps due to the propensity for weight gain associated with other preventive agents. Weight loss and reduction in headache frequency did not correlate with each other, suggesting different mechanisms for each.
Conclusion
Topiramate was effective in reducing headache frequency, severity, and duration in our episodic and chronic migraine patients. Topiramate was well tolerated and is associated with weight loss. In contrast to studies with other preventives, psychiatric co-morbidity and the number of previously failed preventive trials do not appear to effect treatment outcome.