Weight Variations in Patients Receiving Topiramate Migraine Prophylaxis in a Tertiary Care Setting

Abstract

Background

Migraine is a highly prevalent chronic neurologic disorder. Frequent headache attacks require prophylactic treatment, and side effects are limiting prescribing factors among traditional agents for migraine prophylaxis. Beta-blockers, antidepressants, calcium channel blockers, and anticonvulsants have been used since the 1960s, and their efficacy has been demonstrated in several controlled studies. However, weight gain commonly occurs with most of these drugs and makes adherence to treatment a troublesome issue for many patients. Topiramate is a new anticonvulsant with proven efficacy in migraine and other conditions, which reportedly confers weight loss in patients receiving doses up to 300 mg/day.

Objective

The aim of this study was to evaluate adherence, weight loss, tolerability, and response to topiramate in adult migraineurs receiving treatment in a tertiary care center.

Methods

During a 2,5-year period, all patients receiving topiramate for migraine were evaluated after 3 months of treatment. The parameters evaluated were adherence to treatment, frequency in reduction of attacks > 50%, the presence and amount of weight loss, and adverse events.

Results

Among 175 patients included, 134 (76.6%) adhered to the regimen, whereas 4% interrupted before the 3-month evaluation and 19.4% did not return for follow-up. Among the 134 patients evaluated, 82 (61.2%) revealed headache-frequency reduction > 50%; 105 (78.4%) patients experienced weight loss range 1-10 kg; average, 3.4 kg). The most frequent side effects were paresthesia (39.6%); emotional disturbances, including depression, irritability, and anxiety (17.9%); thinking impairment (12.7%); memory disturbances (12.7%); and altered taste (11.9%).

Conclusion

Despite methodologic limitations, we conclude that good adherence to topiramate in a "real-world" headache clinic occurred in most of the study participants. The majority of patients also experienced weight loss and reductions in headache frequency, with an acceptable side-effect profile.

Introduction

Migraine is a chronic neurologic disease characterized by intermittent attacks of headache and associated symptoms. Prevalence in the general population lies between 12% and 15%, and affects 18% to 20% of women, 6% of men, and up to 8% of children.[1,2] The intensity and frequency of attacks vary from patient to patient, leading to significant economic and social losses.[3] Patients with frequent, intense, and long-lasting headache attacks require preventive treatment, and agents used during the last 30 years have included beta-blockers, antidepressants, and calcium channel blockers. The mechanisms involved in the efficacy of these drugs remain unknown, and their use for this purpose was observed by chance through prescriptions for other pathologic conditions.[4]

The past decade has seen numerous advances in the treatment of migraine. The progressive understanding that cortical hyperexcitability is involved and that an imbalance exists between the inhibitory [mediated by gamma-aminobutyric acid (GABA)] and excitatory (mediated by glutamate) neuronal systems in migraine physiopathology has led to the identification of new drugs with prophylactic efficacy.[4,5] Nonetheless, many patients discontinue treatment because of the medication side effects.[6] The common use of beta-blockers; serotonin antagonists, such as methysergide and pizotifen; tricyclic antidepressants, such as amitriptyline, nortriptyline, imipramine, and doxepin; calcium channel antagonists, such as flunarizine; and other migraine prophylactic agents is hampered by adverse effects, including weight gain.[7]

Topiramate is a relatively new pharmacologic agent approved for use as an antiepileptic, but it has been suggested as a useful agent for preventing episodic migraine and chronic transformed migraine. In contrast to most other migraine prophylactic drugs, topiramate promotes weight loss.[8-11] This anticonvulsant has a singular chemical structure and was synthesized during a research project to discover substances analogous to fructose 1.6-diphosphate inhibitors of the glyconeogenic process. Its structural chain resembles a chemical radical in the acetazolamide molecule, which raised the possibility that topiramate possessed antiepileptic properties.[12] In addition, its multiple actions on calcium and sodium voltage channels, and on GABA-A and the kainate/AMPA receptor, also pointed toward its use for migraine prevention.[12] The first studies demonstrating the efficacy and tolerability of topiramate in the preventive treatment of migraine emerged in the late 1990s. Topiramate recently has been approved for migraine prevention, however, no formal studies have demonstrated its performance in a "real-world" practice, with regard to the patient adherence, weight-loss magnitude, and headache response.

Study Background and Methods

The aim of this study was to evaluate the efficacy, tolerability, and adherence to treatment with topiramate in patients with episodic and chronic migraine who were undergoing treatment at a private tertiary care center. In addition, we planned to observe changes in patients' weight during the study.

Patients and Methods

This was an open-label, longitudinal, prospective study in which all patients prescribed topiramate during a 2.5-year period were assessed after receiving it for 3 months against certain, previously established parameters. The study population included all patients who were diagnosed with migraine, according to International Headache Society criteria,[13] or chronic migraine (transformed), according to criteria proposed by Silberstein and colleagues,[14] and were prescribed topiramate headache prophylaxis between July 2000 and February 2003. The study was carried out at a specialized, private headache center, and all patients gave written informed consent to release information of their diagnoses and treatment outcomes with topiramate and any other headache medications.

The choice of topiramate as prophylaxis was based on the personal experience of the first author who has used topiramate frequently with his patients, when there were no contraindications and other medications had failed.

The study population included adults who were 18-70 years of age, who were not regularly using other medications (except drugs for treating chloride-peptic diseases, such as ranitidine and omeprazole) and who had no history of urethral lithiasis, and were not overusing symptomatic medications for headache.[15] Patients taking nortriptyline at doses up to 30 mg/day, who had not changed their dose during the previous 2-month period, were not excluded.

All patients began using topiramate according to the following regimen:

• 12.5 mg in the morning and at night during the first 10 days;

• 25 mg in the morning and at night during the following 14 days;

• 37.5 mg in the morning and at night during the following 14 days; and

• 50 mg twice daily until follow-up at 3 months.

Topiramate 25-mg tablets were used in whole or part, up to doses of 100 mg/day. On reaching this dose, patients then used 50-mg tablets twice daily. All subjects were required to contact the physician overseeing their treatment 45 days from beginning the study regimen to report any adverse affects. The rationale behind using an anticonvulsant drug for migraine headache was thoroughly discussed with all patients, who were also instructed to drink at least 3 L of water per day to reduce the risk of kidney stones. Patients were also instructed to keep headache diaries and notes on each adverse effect that they experienced.

We assessed the following parameters after 3 months of treatment:

• Adherence to the treatment;

• Achievement of a 50% or greater reduction in headaches per month;

• The presence of weight loss (in kg);

• The presence of alterations in taste (in +/4);

• The presence of thought impairment (in +/4);

• The presence of disturbances in memory (in +/4);

• The presence of paresthesias in fingers and/or toes (in +/4); and

• The presence of any other changes.

Results

A total of 175 patients (155 women, mean age 39.6 years; 20 men, mean age 41.7 years) were enrolled in the study. The headache diagnoses included chronic migraine in 89 (50.8%) and episodic migraine in 86 (49.2%) patients. Nineteen patients who had been taking nortriptyline at stable doses up to 30 mg daily for at least 8 weeks before the study period were allowed to use this agent concomitantly during the study.

After 3 months, 134 (76.6%) patients had adhered to the protocol; 34 (19.4%) patients did not return for follow-up; and 7 (4%) interrupted treatment during the 3-month period. Of the 134 patients who completed the 3-month regimen, 121 (90.3%) were women and 13 (9.7%) were men; 124 (92.5%) were taking topiramate 100 mg/day; 4 (3%) were taking 75 mg/day; 4 (3%) were taking 125 mg/day; and 2 (1.5%) were taking 150 mg/day. Among these 134 patients, 82 (61.2%) experienced a reduction in attack frequency of 50% or more, and 52 (38.8%) experienced reductions of less than 50% or reported no reduction in frequency of attacks. In all, 105 (78.4%) patients lost weight (from 1 to 10 kg; mean weight loss, 3.44 kg [(Table 1)]), whereas 29 (21.6%) patients did not.

Table 1.

Adherence to Treatment and Reduction in Headache Frequency

Patient Groups	n (%)
Patients who returned	134 (76.6%)
Patients who did not return	34 (19.4%)
Patients who interrupted before end	7 (4%)
	n = 134
Patients who had > 50% reduction	82 (61.2%)
Patients who did not have > 50% reduction	52 (38.8%)

Side effects included paresthesias in the fingers and/or toes (53 patients, 39.6%); thinking impairment (17 patients; 12.7%); taste alterations (16 patients, 11.9%); emotional disturbances, including depression, anxiety, and irritability (24 patients, 17.9%), and disturbances in memory (17 patients, 12.7%). The mean intensity of these effects is shown in (Table 2). The patients were also instructed to report each and every adverse effect throughout the use of the medication. Less frequent side effects included drowsiness (4 patients, 3%); diarrhea (3 patients, 2.2%); tachycardia (4 patients, 3%); insomnia (4 patients, 3%); asthenia (4 patients, 3%); and epigastric distress, constipation, shivering, decreased libido, dizziness, hair loss, urethral lithiasis, and drying of the eyes, each in 1 patient (1.3%) ((Table 2)).

Table 2.

Side Effects Reported

	n (%)	Intensity
Weight loss	105 (78.4%)	1-10-3.44 kg (Mean)
Paresthesia	53 (39.6%)	+/4: 8.9%
		++/4: 24.6%
		+++/4: 3.7%
		++++/4: 2.2%
Thinking impairments	17 (12.7%)	+/4: 4.5%
		++/4: 7.5%
		+++/4: 0.7%
Alterations in taste	16 (11.9%)	+/4: 6%
		++/4: 5.2%
		+++/4: 0.7%
Emotional disturbances*	24 (17.9%)	+/4: 4.5%
		++/4: 6.7%
		+++/4: 4.5%
		++++/4: 3%
Memory disturbances	17 (12.7%)	+/4: 3%
		++/4: 7.5%
		+++/4: 2.2%
Other side effects**	Drowsiness, diarrhea, tachycardia, insomnia, asthenia, epigastralgia, constipation, shivering, decrease in libido, dizziness, hair loss, urethral lithiasis, and drying of the eyes	4 (3%), 3 (2.2%), 4 (3%), 4 (3%), 4 (3%),1 (1.3%)

*Includes depression, anxiety, and irritability

**Includes drowsiness, diarrhea, tachycardia, insomnia, asthenia, epigastralgia, constipation, shivering, decrease in libido, dizziness, hair loss, urethral lithiasis, and drying of eyes

Discussion

This was an open-label, uncontrolled study designed to observe the response of patients prescribed topiramate for migraine headache at a tertiary center. In addition, the patients were included in the study solely because they used topiramate as a normal treatment approach for their headaches.

Several points must be considered when interpreting this study. First, our methodology does not allow for comparisons with other options used in the preventive treatment of migraine. Second, participants comprised a "dependent" patient population who had sought care at a private center specializing in headache treatment, which, in Brazil, is the last resort of patients for whom treatment in the public system, health plan clinics, and other professionals has failed. Conclusions regarding all other patients with migraine cannot be inferred from the results in this sample of patients. However, we believe that the present study is relevant for those practicing in neurology clinics who use topiramate as part of their therapeutic resource for such patients. Topiramate has recently received a formal indication for migraine prevention or treatment but did not have such indication when the study was conducted.

Topiramate was initially studied for migraine prophylaxis in an open-label study of 37 patients who were refractory to previous treatment.[8] Those investigators used doses of 25-100 mg daily, albeit at lower mean doses than the present study. They observed patients for 3-9 months and reported a greater than 40% reduction in headache frequency for 60% of their sample. Only 8% of this sample dropped out or interrupted treatment, whereas 23.5% of our sample did not complete the study. Krucz and Scott[9] used doses up to 325 mg/day and observed a greater reduction in frequency (72%) for 18 (64.2%) of 29 patients. However, 35.7% of this sample dropped out or interrupted the treatment.

Comparisons With Previous Studies

In 2000, Edwards and colleagues[10] conducted the first controlled study of topiramate for migraine. This study assessed 30 patients who were randomized to receive topiramate (30 patients) or placebo (30 patients) following a 4-week run-in period. The patients in the topiramate group titrated the doses during a 6-week period up to a maximum of 200 mg/day. Four patients also continued to take other migraine prophylactic medications. The investigators observed that 46.7% of patients in the active drug group experienced greater than 50% reductions in headache frequency as compared with 6.7% of patients in the placebo group. These numbers were lower than those observed in our study despite a lower dose of drug. With regard to adherence, 7 (23.4%) patients in Edwards and colleagues'[10] study stopped topiramate, a lower proportion than in our study roughly equal to our results.

Potter and associates[11] studied randomized 40 patients with migraine to receive topiramate (n = 19) or placebo (n = 21). Adherence in the combined groups was 87.5% (35 patients), with an average daily dose of 125 mg. Twelve of the 19 patients receiving topiramate were using other preventive drugs concomitantly. The mean basal frequency and the average frequency were assessed after 20 weeks. The group using topiramate achieved a significant reduction in headaches (5.14-3.31, P = .0015), and more patients in this group than the placebo group had a reduction in frequency over 50%. However, published results did not include the percentage of patients in each of the groups that had this reduction. The average reduction in headache frequency after 20 weeks was 33% among patients in the topiramate group; 2 patients withdrew because of adverse effects.

Storey and colleagues[16] randomized 40 patients to receive topiramate (n = 19) or placebo (n = 21), with average daily topiramate doses of 125 mg. The dose-adjustment period lasted 8 weeks, with 8 weeks for the actual study. Patients gradually titrated their doses up to 200 mg daily or to a maximum tolerated dose. Only 2 patients interrupted the medication regimen. Weight loss occurred in 53% of the patients, substantially less than in our study. The precise amounts of weight loss were not included in their report. Compared with our results, a lower percentage of patients (26%) experienced reduced frequency of headache at rates higher than 50%, and side effects were more frequent than in our patients, with 68% of patients experiencing paresthesias, taste alterations reported by 37%, and both anorexia and memory disturbances in 21% of patients.

Mathew and colleagues[17] examined topiramate for the prevention of episodic migraine (n = 70), chronic migraine (n = 96), and cluster headache (n = 12). The patients with chronic migraine were allowed to use other migraine prophylaxis, and those with episodic migraine used topiramate monotherapy as the first choice of treatment. This was a retrospective analysis with an average daily topiramate dose of 87.5 mg, and thus, comparisons with our study observations are limited. Furthermore, Mathew and colleagues[17] assessed different parameters than we assessed. Nonetheless, the results are instructive. A total of 53% of patients with chronic migraine and 61% of those with episodic migraine experienced a substantial or moderate improvement. With regard to patients with cluster headache, 9 of the 12 achieved substantial or moderate improvement in symptoms and 3 patients experienced no improvement. These latter 3 patients suffered chronic cluster headaches whereas those obtaining relief had episodic cluster headaches. The most common adverse effects included paresthesias (12%), cognitive disturbances (11%), and dizziness (6%). Eight patients (4.5%) discontinued the drug, and average weight loss oscillated ranged between 2.3 and 54.5 kg, during a nonspecific study period.

In a 26-week multicenter study, Brandes and colleagues[18] assessed 483 patients, randomized to receive placebo or topiramate 50 mg, 100 mg, or 200 mg daily. The primary assessment parameter was average reduction in monthly frequency of migraine headaches and reductions in headache frequency above 50%. Reductions in headache frequency were already observed at the end of the first month of treatment, with 39% of the patients receiving 50 mg daily and 49% of those on 100 mg daily noting a reduction greater than 50% after 26 weeks of the study. Average weight loss was 4.8% of baseline body weight. In this study, paresthesias, asthenia, nausea, and abdominal pain were the most reported side effects, but the investigators did not provide specific percentages.

Topiramate prophylaxis of other primary headaches is also being studied. Two recent open-label studies have indicated that it may be useful for preventing cluster headache attacks. Controlled studies with longer treatment periods are required to establish this utility and are under way.[19,20]

Topiramate and Weight Loss

Topiramate has been found to be associated with weight loss of up to 15% to 18% of the baseline weight. The amount of weight loss appears to be greater as the baseline weight rises, and it continues for the time patients are using the drug. A recent study evaluated topiramate's weight loss efficacy and tolerability with obese subjects and demonstrated that the weight loss associated with topiramate therapy lasted the entire period of 76 weeks of treatment.[21]

The mechanism underlying this side effect is still uncertain but seems to be related to neuropeptide Y a neuropeptide abundantly and widely distributed in the mammalian central nervous system (CNS). Centrally administered neuropeptide Y markedly reduces pharmacologically induced seizures and induces antidepressant-like activity as well as feeding behavior. Two other peptides, galanin and corticotropin-releasing hormone have also been proposed to play a modulatory role in mood, appetite, and seizure regulation, and may be involved in topiramate's effect of promoting weight loss.[22]

In a study focusing on topiramate-related weight loss, 15 patients who had gained weight after using selective serotonin reuptake inhibitors for anxiety disorder received topiramate, starting at a dose of 50 mg and titrating up to a target daily dose of 100 mg to a maximum dose of 250 mg daily. Subjects' weights were measured at baseline and after 5 and 10 weeks of treatment. Before topiramate treatment, these subjects had gained a mean of 13.0 ± 8.4 kg (28.6 ± 18.5 lb). After the addition of a mean daily topiramate dose of 135.0 ± 44.1 mg for approximately 10 weeks, subjects lost a mean of 4.2 ± 6.0 kg (9.3 ± 13.3 lb), therefore higher than with our patients.[23]

Ben-Menachem and colleagues[24] reported a magnitude of weight loss similar to our patients with epilepsy treated with topiramate. For 38 patients who completed 1 year of topiramate treatment, baseline weight declined 82% at 3 months and 86% at 1 year. Mean body weight was reduced by 3.0 kg (3.9% of baseline) at 3 months and 5.9 kg (7.3%) at 1 year. For obese patients in this study [body mass index ≥ 30 kg/m²], mean weight loss was 4.2 kg (4.3%) at 3 months and 10.9 kg (11.0%) at 1 year.

Despite the fact that overall tolerability of the drug was good in our study, the emotional and cognitive effects may represent factors that will limit adherence in clinical practice. The CNS side effects and other cognitive adverse events that emerged from the trials with topiramate were mainly transient and tended to resolve spontaneously, although some patients discontinued medication because of these side effects. Furthermore, CNS complaints may be minimized by initial slow titration or small reductions in other medications with sedative effects. There is no evidence that the CNS side effects persist after therapy is discontinued, and the patients who remained in our study experienced a diminution in these effects over time.[18,25,26]

The limitations of this open-label and uncontrolled study are clear and include the selection bias in choosing patients from a last-resort tertiary care center. This also presents drawbacks for data interpretation and does not allow for comparisons against other agents used for migraine prophylaxis. Although comparisons with other studies may be hindered by the differences and drawbacks in the methodologies used, topiramate appears to be a promising drug for migraine prophylaxis. Adherence to its use and weight loss were observed in the majority of patients despite the lack of formal indication, at the time of the study, for migraine prophylaxis and weight loss. Placebo-controlled studies with different patient populations are needed to confirm these findings.