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Abstract

Weight gain is a side-effect commonly associated with drugs used for headache prophylaxis. Weight gain can adversely affect patient health, exacerbate comorbid metabolic disorders and encourage noncompliance. Few studies have been conducted specifically on the effect of headache medications on weight, and it is important for physicians to have accurate information about weight-gain side-effects when identifying appropriate pharmacological regimens. This review discusses the potential effects on weight of the more common headache medications.

Keywords

Migraine weight preventive medicines side-effects

Introduction

Treatment-related weight gain is an important side-effect of headache therapy that often adversely affects general health, self-esteem, and quality of life. Treatment-related weight gain can exacerbate common physical and psychological comorbidities, and can aggravate noncompliance in many patients (1). Since headache preventives are often administered chronically, their widespread use may also contribute to the prevalence of obesity. However, very little information has been documented in the medical literature on headache drugs and their effect on weight.

Obesity, as defined by a body mass index of ≥ 30 kg/m², is already a significant public health concern in many industrialized countries. Approximately 20% of adults in the US are obese, and another 36% are overweight (BMI ≥ 25 kg/m²) (2). Similarly, 58% of adults in Britain are overweight or obese, as are 54% in Russia (3). Overweight and obesity are associated with increased risks of heart disease, diabetes, and cancer, and may exacerbate other diseases such as hypertension, osteoarthritis, stroke, and gallstones (4). In the US, obesity is associated with 9% of health care expenditures (5), while the direct and indirect costs associated with diabetes alone were $98 billion in 1997 (6).

Headache affects a significant proportion of the population in industrialized countries. Migraine headaches affect about 6% of men and 18% of women in the US (7). Chronic daily headache affects between 4% and 5% of the US population (8), with approximately one half having chronic daily migraine (also called transformed migraine). Drugs used for migraine prevention are typically divided into several categories: antidepressants, antiepileptic drugs, beta-blockers, calcium channel antagonists, and other agents such as serotonin receptor blockers; tension-type headache treatment generally involves antidepressants and muscle relaxants. Many of the drugs used as headache preventives have an effect on body weight. Accurate information is necessary to help physicians and patients appropriately assess and avoid the effect that preventive treatment may have on weight.

Antidepressants

Tricyclic antidepressants

Tricyclic antidepressants (TCAs) have historically been used in the treatment of depression, but they have also been used adjunctively for additional neurological indications, including neuropathic pain and migraine (9, 10). The acute and chronic effects of TCAs on weight in the treatment of psychiatric disorders are well documented (11–14). However, there is substantial disagreement regarding the degree of effect associated with individual drugs. It has been stated that some TCAs, such as amitriptyline and imipramine, are more often associated with weight gain than others, such as desipramine and nortriptyline (15). In a recent study of 217 patients treated for up to 2 years for depression, both amitriptyline and mirtazapine were associated with reports of weight gain; the per cent of patients exhibiting a ≥ 7% increase in body weight was higher for amitriptyline (22%) than mirtazapine(13%) (16). In a smaller study, Hinze-Selch et al. (14) found that patients treated with either amitriptyline or nortriptyline gained an average of 3.5 kg over 6 weeks, and that weight gain was associated with increased plasma levels of tumour necrosis factor alpha, a cytokine associated with weight regulation.

However, a 6-month study of agoraphobic patients treated with imipramine found no evidence of long-term weight gain (17). A study of 1157 elderly antidepressant users treated for at least 6 months found that TCAs were not generally associated with weight gain, nor were selective serotonin reuptake inhibitors (SSRIs) generally associated with weight loss (18). Protriptyline is a TCA with little serotonin reuptake inhibition that can induce weight loss and has shown efficacy in headache. A study by Cohen (19) demonstrated that patients with chronic tension-type headache taking protriptyline experienced 86% fewer headaches and had an average weight loss of 1.5 kg. In the clinic, if a patient has responded to a TCA but is complaining of weight gain, switching them to protriptyline may maintain their headache benefit and promote weight loss.

Assessing the pathophysiology of TCA-associated weight gain is complicated due to the diverse pharmacological profiles exhibited by TCAs, but likely includes activity at histaminergic and adrenergic receptor subtypes, and perhaps the tumour necrosis factor-α (TNF-α) signalling system. Activation of histamine receptors in the hypothalamus is associated with reduced food intake (20), and several TCAs act as antagonists at histamine receptor subtypes. Furthermore, leptin, which is associated with anorectic behaviour in animal models, may act through H₁ histamine receptors in the hypothalamus (21). Adrenergic receptors in the hypothalamus regulate feeding behaviour (β, α₁ = decreased feeding; α₂ = increased feeding) (22, 23), and the increased synaptic availability of norepinephrine produced by TCAs could impact appetite through these mechanisms. More recent studies indicate that tricyclic antidepressants are associated with increases in a soluble TNF receptor (p75) whose activity may be associated with obesity (24).

Selective serotonin reuptake inhibitors

In addition to tricyclic antidepressants, SSRIs have been used with some success for migraine prophylaxis (25–28). While conventional thinking suggests that SSRIs are associated with weight loss, the weight changes associated with SSRIs appear to differ between individual drugs and across treatment duration.

SSRIs such as paroxetine and sertraline appear to be associated with a greater incidence of weight gain than fluoxetine. In a study of 284 patients with clinical depression, Fava et al. (29) found that after 26–32 weeks of treatment, treatment with paroxetine was associated with a significantly greater percent weight change (3.6%) than either sertraline (1.0%) or fluoxetine (−0.1%). Furthermore, a greater percentage of patients (26%) treated with paroxetine gained at least 7% of body weight than those treated with either sertraline (4.2%) or fluoxetine (6.8%). Additional data suggest that up to 18% of patients treated with paroxetine for 1 year or more gain over 7% of their body weight (30).

Several other studies suggest that short-term treatment with sertraline was associated with weight loss. In a 6-week study of patients diagnosed with clinical depression, treatment with sertraline was associated with a mean weight loss of 0.6 kg (31). In an 8-week study examining the antidepressant efficacy and effects on sexual functioning of sertraline and bupropion, treatment with sertraline was associated with a mean weight loss of 0.8 kg (32).

Short-term treatment with venlafaxine, an antidepressant that inhibits the reuptake of both serotonin and norepinephrine (33), was associated with weight loss in 41/42 patients who suffered from migraine (34), while another case series reported weight gain associated with mammoplasia in female patients suffering from depression (35).

More recent studies suggest that while SSRIs may indeed be associated with acute weight loss, chronic treatment may lead to weight gain (36). In a 1-year trial of fluoxetine, patients treated with fluoxetine experienced mean weight gain of 3.1 kg, which was not significantly different from placebo, and was thought to reflect an improvement in clinical depression (37). Additional reports state that as many as 25%−30% of patients taking SSRIs chronically may gain weight (38). A study in elderly patients concluded, however, that neither TCAs nor SSRIs were disproportionately associated with either weight gain or loss with chronic treatment (18).

The diverse effects of SSRIs on body weight are not surprising, considering that there are currently over a dozen serotonin receptor subtypes, organized into several families based on structural and pharmacological characteristics. The 5-HT_2C receptor subtype, in particular, appears to mediate serotonin-related effects on appetite in the hypothalamus (39). Drugs that block the 5-HT_2C receptor increase food intake, and animals where the 5-HT_2C receptor gene has been knocked out exhibit hyperphagia, and develop insulin resistance and impaired glucose tolerance (40). Interestingly, chronic administration of paroxetine in an animal model resulted in reduced responsiveness of 5-HT₂ receptors (41), which could partially explain the apparent biphasic nature of weight change associated with some SSRIs.

Antiepileptic drugs (AEDs)

The use of AEDs in migraine preventive therapy has grown significantly in the past few years. Many of the typical AEDs cause weight gain, so it is important for physicians to take into account the full range of potential pharmacological side-effects when prescribing these medications to migraine sufferers.

Valproic acid

Valproate is approved for the treatment of epilepsy, as well as for the treatment of migraine (42–46) and bipolar mania (47, 48). Owing to the nature of these disorders, chronic pharmacological treatment is often required. As with many conventional AEDs, weight gain is one of the most common side-effects associated with the use of valproic acid and divalproex sodium (an oligomeric complex of valproic acid and valproate sodium) (49–51). The weight gain associated with valproate is often cause for discontinuation of the drug (38, 52). In a retrospective review of 70 epilepsy patients, 71% experienced at least a 5% gain in body weight while on valproate therapy (49). Forty-seven per cent gained at least 10% of their body weight, and patients with no history of weight problems experienced the greatest initial increases. Verrotti et al. (53) evaluated 40 female epilepsy patients who were administered valproate therapy for 1 years. Fifteen patients gained weight, from a mean baseline BMI of 24.6–29.3 kg/m² at the end of the study. These patients also had significantly higher serum levels of leptin and insulin after 1 years. The other treated patients exhibited relatively stable BMIs.

A recent randomized, double-blind study compared weight changes associated with either valproate or lamotrigine in 133 epilepsy patients. After 32 weeks, patients on valproate had gained an average of 5.9 kg, while those on lamotrigine had gained 0.5 kg (54). In a retrospective study of 65 female patients with epilepsy, Isojärvi et al. (51) found that 50% of the women treated with valproate gained an average of 20.9 kg, and 64% developed hyperandrogenism, polycystic ovaries, or both. In a follow-up study, the BMI, fasting serum testosterone concentrations, and total number of polycystic ovaries decreased after 12 months in women who substituted other pharmacological therapy for valproate (55). Additionally, Novak et al. (56) studied valproate-associated weight gain in 55 children treated for epilepsy, and found that most experienced a significant increase in both BMI and body weight. In a retrospective chart review, Freitag et al. (57) evaluated the efficacy of valproate in the treatment of chronic daily headache. Six hundred and forty-two charts were analysed and weight gain was demonstrated in 7% of patients. The average weight gain was 1.3 kg, although a broad range of weight increase was reported(4.5–9.1 kg), with men gaining more weight than women.

Silberstein and Collins (46) in a study looking at the adverse event profile of long-term valproate use in migraine prevention found that 19% of 163 patients complained of weight gain. Seven female patients had weight gain of 10.9 kg or more (range 10.9–14.5 kg). Weight gain was cited as the reason for discontinuation of valproate in 2% of the patients.

Valproate and divalproex sodium are thought to increase concentrations of gamma-aminobutyric acid (GABA) in the CNS through the inhibition of a transaminase enzyme responsible for degrading GABA. Microinjection of muscimol, an agonist at the GABA_A receptor subtype, stimulates feeding in animal models (58). However, it is unclear if these increased concentrations of synaptic GABA are responsible for the weight gain associated with valproate use.

Newer antiepileptic drugs

Lamotrigine

The FDA approved lamotrigine in 1993 as adjunctive therapy in adults for the treatment of partial seizures and for Lennox–Gastaut syndrome. Lamotrigine is also approved as monotherapy for patients converting from certain other AEDs. Lamotrigine inhibits voltage-gated sodium channels in a state-dependent fashion (59–62) and inhibits glutamate and aspartate release from presynaptic terminals (61, 63), possibly through inhibition of voltage-gated calcium channels (64).

Lamotrigine has been found to be effective for the control of migraine aura (65–67), but not for migraine headache, although early studies were limited by a high dropout rate associated with rapid dose escalation. Evidence to date suggests that lamotrigine has little or no effect on body weight. A recent retrospective review of 463 patients across 32 clinical trials for epilepsy reported minimal change in body weight associated with lamotrigine therapy (68). Isojärvi et al. (55) substituted lamotrigine for valproate in a study of 12 women who had received chronic valproate treatment for epilepsy. The mean BMI for these patients had increased from 24 to 31 kg/m² during valproate therapy (mean duration 9 years). One year following lamotrigine substitution, the mean BMI decreased to 28 kg/m². An increase in serum HDL-cholesterol and a decrease in serum triglyceride levels accompanied this decrease in BMI. In a controlled trial of lamotrigine in 195 patients with bipolar depression, no significant change in body weight was observed after 7 weeks of lamotrigine monotherapy (69). More recently, Biton and colleagues compared the weight changes associated with valproate or lamotrigine monotherapy in 133 patients with partial or generalized seizures (54). After 32 weeks of treatment, patients treated with valproate experienced a mean weight gain of 5.9 kg, while those patients treated with lamotrigine gained an average of 0.5 kg.

Gabapentin

Gabapentin was approved in 1994 as adjunctive treatment for partial or secondary generalized seizures in adults. The mechanism of action through which gabapentin exhibits its antiepileptic effect is not entirely clear, although proposed mechanisms include competitive inhibition of the system L amino acid transport protein (70, 71), increased GABA synthesis (72), inhibition of l-type calcium channels (73, 74), inhibition of monoamine neurotransmitter release (75, 76), increased serum serotonin concentrations (77), and competitive inhibition of branched-chain amino acid aminotransferase (BCAA-T) (78), an enzyme partially responsible for glutamate synthesis.

Weight gain has not typically been widely reported as an adverse event associated with gabapentin. However, there are some reports that suggest weight gain associated with chronic use or higher doses. Asconapé and Collins (79) reported that among 57 epilepsy patients treated with gabapentin for at least 3 months, 46% experienced weight gain ranging from 5% to 20%. King and Bayles (80) reported that 58 epilepsy patients gained an average of 7.3 kg while receiving gabapentin as add-on therapy. In a retrospective study, 44 patients who had been treated with an average dose of 3520 mg/day of gabapentin for at least 12 months exhibited a mean weight gain of 2.3 kg (81). Twenty-two per cent of the patients studied gained 10% or more of their body weight, and 57% gained at least 5%. Weight gain appeared to stabilize after 6–9 months of treatment. Mathew et al. (82) reported weight gain in 3.1% of patients receiving gabapentin for migraine prophylaxis, although the amount of weight gain was not documented.

Although one of the proposed mechanisms of action of gabapentin is increased GABA synthesis, it is unclear if gabapentin produces this effect with sufficient potency to attribute it to an effect on appetite or body weight.

Topiramate

Topiramate was approved in 1996 for adjunctive treatment of partial seizures in adults, in 1999 for treatment of partial seizures in children 2 years and older, and in 2001 for the treatment of Lennox–Gastaut syndrome. Topiramate has several mechanisms of action that may contribute to its antiepileptic efficacy, including state-dependent inhibition of voltage-gated sodium and calcium channels (83–85), inhibition of glutamate-mediated neurotransmission at the AMPA/kainate receptor subtype (86, 87), and enhancement of GABA_A receptor–mediated chloride flux (88). Additionally, Shank et al. (89) have speculated that topiramate may affect the phosphorylation state of the receptors or ion channels with which it interacts, shifting a greater proportion toward a dephosphorylated state.

Unlike most antiepileptic drugs, topiramate pharmacotherapy is typically associated with weight loss rather than weight gain. In a summary of 1809 patients treated with topiramate, Shorvon reported that the mean weight loss was dose-dependent, and ranged from 1.1 to 5.9 kg (90). In another study, patients who weighed more than 100 kg prior to therapy experienced a mean weight loss of 9.5 kg, while those who weighed less than 60 kg before treatment lost an average of 1.3 kg (91). In a study of 34 epilepsy patients, Smith et al. (92) reported that topiramate-associated weight loss was accompanied by improvements in glucose tolerance, insulin, and lipid levels. McElroy et al. (93) conducted an open-label study of adjunctive topiramate in the treatment of bipolar disorder, and found that among 37 patients treated with topiramate for 1 year, the mean weight loss was approximately 5.9 kg, which correlated with a 6% change in BMI. More recently, Chengappa et al. (94) reported a case series of obese bipolar patients who had received adjunctive topiramate therapy for 1–2 years. Mean body weight decreased from 132 kg to 111 kg after 12 months, mean BMI decreased from 42 kg/m² to 35 kg/m², and fasting blood glucose levels decreased from 15.0 mmol/l to 7.9 mmol/l (270.3 mg/dl to 142.3 mg/dl).

Topiramate has been shown in single-centre, placebo-controlled trials to be effective as a migraine preventive. In these trials topiramate also induced weight loss in patients. Edwards et al. (95) using topiramate as a migraine preventive (200 mg/day), noted a significant decrease in weight vs. placebo in migraineurs taking topiramate (topiramate −2.8 kg, placebo −0.3 kg). Storey et al. (96) also noted substantial, statistically significant weight loss vs. placebo in topiramate-treated migraine patients (topiramate −2.2 kg, placebo +0.03 kg). In recent multicentre, placebo-controlled trials for migraine prevention, topiramate was associated with up to a 4.8% reduction in mean body weight compared to placebo (97).

Animal studies have shown that stimulation of the lateral hypothalamus by glutamate and glutamate agonists, including kainate/AMPA agonists, are associated with an increase in food intake (98, 99). Topiramate is an antagonist at kainate/AMPA glutamate receptors, and this may contribute to its anorectic properties. Topiramate also potentiates GABA-mediated activity at the GABA_A receptor subtype, which is typically associated with increased feeding behaviour, but this activity may be produced with less efficacy or potency than those mechanisms associated with appetite suppression and weight loss.

β-adrenergic receptor blockers (beta-blockers)

Beta-blockers were initially used primarily for hypertension and myocardial ischemia, but have also been used for migraine prophylaxis (100), with propranolol, timolol, metoprolol, atenolol, and nadolol among the drugs most commonly used. Interestingly, the exact mechanism of action through which beta-blockers exhibit their prophylactic activity is not entirely clear. A meta-analysis of over 2400 patients suggested that propranolol was associated with a 44%−65% reduction in migraine activity (101), although some smaller individual studies have not supported the therapeutic efficacy of propranolol or metoprolol in migraine prophylaxis (102–104).

An underreported aspect of chronic therapy using beta–blockers is their association with weight gain in some patients. A number of small, short-term studies have reported on the use of beta-blockers for migraine prophylaxis without noting clinically significant weight gain. For example, in a comparison study of pizotifen and metoprolol for migraine prophylaxis, it was noted that treatment with pizotifen was associated with weight gain of ≥ 2 kg in 16/30 (53%) patients, while only 2/32 (6%) reported that degree of weight gain on metoprolol (105). However, the crossover design of the study was such that patients were treated with each drug for only 8 weeks. In a long-term study of over 3800 patients who had survived a recent myocardial infarction, treatment with propranolol was associated with a mean weight gain of 3 kg after 24 months. Another recent review evaluated the use of beta-blockers in 8 controlled studies that lasted at least 6 months, and found that beta-blockers were associated with a weight gain of up to 3.4 kg over placebo (106). Clearly, the degree of weight gain associated with beta-blockers is variable; while some studies report little or no weight gain, others cite substantial weight increases. A case study of a woman treated for 9 months with propranolol for migraine prevention reported what appeared to be a medication-related weight gain of 9 kg (107).

β-adrenergic receptors are involved in stimulation of lipolysis, while α₂-adrenergic receptors are thought to inhibit lipolysis (108, 109). Weight gain produced by chronic use of beta-blockers may be caused in part by interference with catecholamine-induced lipolysis. Other studies have suggested that beta-adrenergic receptors in the hypothalamus contribute to the anorectic effects of catecholamines and selective beta-adrenergic receptor agonists (23). It is not clear whether there is any difference in associated weight gain between beta-blockers that nonselectively block both β₁ and β₂ receptors (e.g. propranolol, nadolol) and those that are selective β₁ receptor antagonists (e.g. metoprolol).

Calcium channel blockers

Although calcium channel blockers such as verapamil were initially used in the treatment of cardiac arrhythmias, they have also been used in migraine prophylaxis. The efficacy demonstrated by some members of this drug class for prophylaxis of migraine and cluster headache is not surprising; recent genetic studies indicate that mutations in P/Q-calcium channel subtypes may contribute to familial hemiplegic migraine (110–113). Both verapamil and flunarizine (114–117) have demonstrated some efficacy in migraine prevention. The effect of a given calcium channel blocker on body weight may depend on pharmacological activity other than calcium channels. For example, flunarizine also acts as a dopamine receptor antagonist, which may contribute to its propensity to cause weight gain.

Flunarizine has been approved in many countries outside the US for both migraine prophylaxis and for vestibular vertigo. The association between flunarizine and weight gain has been evident from the earliest clinical studies. In a 4-month study of migraine prophylaxis, flunarizine was associated with a mean weight gain of 4.3 kg in 8/38 (21%) patients (114). During a double-blind study of flunarizine and pizotifen in migraine prophylaxis, 6/21 (29%) patients treated with flunarizine for 4 months gained an average of 4.5 kg (118). In a larger study of 149 migraineurs, 23/72 patients treated with flunarizine experienced weight gain, with an average gain of 1.9 kg over 5 months (115). More recently, in a 4-month study of 94 migraine patients the mean BMI for patients treated with flunarizine increased significantly (119).

However, this effect on body weight does not necessarily apply to calcium channel blockers as a class; verapamil is not typically associated with weight gain or loss.

Mixed serotonergic/histaminergic agents

Several drugs that bind to and block serotonin and histamine receptors have been used for migraine prophylaxis, including pizotifen and cyproheptadine. While clinical studies report mixed results regarding their efficacy in migraine prophylaxis, chronic use of these compounds is strongly associated with weight gain.

Pizotifen

Pizotifen has been used for years in migraine prophylaxis, with varying degrees of success. Pizotifen exhibits several biochemical activities that are possibly relevant to its efficacy and side-effects, including blockade of 5HT₂ and 5HT_1C serotonin receptors and weak inhibition of H₁ histamine receptors and muscarinic cholinergic receptors (120), although it is more selective for the serotonin receptors. The utility of pizotifen for migraine prophylaxis is limited by its marked side-effects, of which weight gain is the most prevalent.

In a study in which pizotifen was added to sumatriptan therapy, almost 2 out of 3 patients gained an average of 4.1–5 kg during an initial 12-week exposure to pizotifen (121). Most patients retained the weight gain, or gained additional weight with continued treatment. In a double-blind, crossover study involving 27 migraine patients, treatment with pizotifen was associated with a mean weight gain of 4.1 kg over 2 months (122). Rascol and colleagues reported in a comparison study that 29% of patients taking pizotifen over 4 months experienced a mean weight gain of 3.8 kg, while 29% of those patients taking the calcium channel blocker flunarizine gained 4.5 kg (118). Another double-blind crossover study found that 50% of migraine patients treated with pizotifen for 8 weeks gained at least 2 kg, with a maximum gain of 10.5 kg (105). Louis and colleagues found that approximately 20% of migraineurs treated with either pizotifen or flunarizine gained weight during a 4-month study, with a mean weight gain of 4 kg and 9.1 kg, respectively (114).

At least part of the weight gain produced by pizotifen may be due to the weak antihistaminergic or anticholinergic activities of the drug. Many TCAs also exhibit weak anticholinergic activity, and many other drugs with these activities are known to both stimulate appetite and increase sedation.

Cyproheptadine

Cyproheptadine is another compound that may act as an antagonist at both serotonin and histamine receptors, with selectivity for serotonin receptor subtypes. Cyproheptadine has been used with success in migraine prophylaxis (123), but its appetite-stimulating properties are such that it has also been used in attempts to treat anorexia and weight loss associated with several conditions, with mixed results (124–126).

Methysergide

Methysergide is a semisynthetic ergot alkaloid derivative that is not commonly used for migraine prophylaxis due to its potential for side-effects, which include a rare, but potentially fatal fibrosis involving the retroperitoneum, lungs or endocardium (127). Methysergide blocks some serotonergic receptor subtypes, and inhibits the release of histamine from mast cells, possibly due to its activity as an antagonist at the 5HT_2A receptor subtype (128). Graham noted weight gain associated with methysergide therapy in a review of 500 headache patients, many of whom were diagnosed with migraine or cluster headache (129). Forssman et al. (130) noted weight gain in 3/17 patients treated with methysergide in a crossover study, but did not note the degree of weight gain.

It is not surprising that drugs combining both antihistaminergic and serotonergic activity are associated with significant weight gain. As previously discussed, both histamine (through H₁ receptors in the hypothalamus) and serotonin (through 5-HT_2C receptors) contribute to feelings of satiety. Drugs that block these pathways, and especially those counteracting anorectic signalling through more than one mechanism, would certainly be expected to impact appetite, feeding behaviour, and body weight.

Clinical experience

Weight is a major issue in patient satisfaction with headache drugs. Most headache preventive medications have an effect on weight (Table 1). Our clinical experience in headache patients indicates that consistent patterns of weight gain or loss can be generally attributed to individual drugs. We recently examined the weight changes experienced by outpatients who had taken one of several drugs for migraine prophylaxis for up to 9 months (131). The drugs included topiramate, fluoxetine, nortriptyline, divalproex, and riboflavin. At the end of 9 months, patients taking topiramate had lost an average of 4.9 kg, while those on fluoxetine (2.8 kg), nortriptyline (1.9 kg), or divalproex (1.7 kg) gained weight (Fig. 1). Patients on riboflavin demonstrated little or no weight change.

Figure 1

A retrospective, open-label study of weight changes experienced by headache outpatients who had taken one of several drugs for migraine prophylaxis for up to 9 months. • Topiramate, ▪ Fluoxetine, ▴ Nortriptyline, ○ Divalproex, □ Riboflavin. From Young and Loewinger (131).

Table 1

Weight gain associated with migraine prophylactics

Drug class/drug	Weight gain
Antidepressants
Amitriptyline	↑↑↑
Fluoxetine	↑↑
Nortriptyline	↑↑
Paroxetine	↑↑↑
Protriptyline	↓
Venlafaxine
Antiepileptic drugs
Divalproex sodium	↑↑↑
Lamotrigine
Gabapentin	↑
Topiramate	↓↓
Beta-blockers	↑
Calcium channel blockers
Flunarizine	↑↑↑
Verapamil
Methysergide	↑↑↑

↑ Weight increase, ↓ Weight decrease, No effect on weight.

Conclusions

It is the responsibility of the attending physician to take into account potential consequences when prescribing headache medication for patients, particularly for those patients in whom weight changes may be associated with the exacerbation (or improvement) of comorbid metabolic disorders. Increasing pharmacological choices with varying effects on weight permits clinicians to craft a personalized regimen that meets the needs of individual patients.

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Preventive Treatment of Migraine: Effect on Weight

Abstract

Keywords

Introduction

Antidepressants

Tricyclic antidepressants

Selective serotonin reuptake inhibitors

Antiepileptic drugs (AEDs)

Valproic acid

Newer antiepileptic drugs

Lamotrigine

Gabapentin

Topiramate

β-adrenergic receptor blockers (beta-blockers)

Calcium channel blockers

Mixed serotonergic/histaminergic agents

Pizotifen

Cyproheptadine

Methysergide

Clinical experience

Conclusions

References