Antidepressants for Migraine Prophylaxis

Transcription

1 EUROPEAN NEUROLOGICAL JOURNAL REVIEW ARTICLE Antidepressants for Migraine Prophylaxis Christian Lampl and Christine Schweiger Affiliation: Department of Neurology and Pain Medicine, Konventhospital Barmherzige Brüder Linz, Linz, Austria ABSTRACT The objectives of this review are to provide a comprehensive critical analysis of published reports of randomized controlled trials of antidepressants for reducing headache burden among adults with migraine, and to determine whether efficacy varies according to important patient characteristics, such as coexisting depression. The mechanism whereby amitriptyline and other antidepressants produce their analgesic effects is unknown, but the blockade of serotonin and norepinephrine re-uptake has been hypothesized to play a pivotal role. Concerning amitriptyline, there is some evidence that this tricyclic antidepressant may be beneficial in the prophylaxis of migraine in some patients. For selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs), beneficial effects are equivalent to those seen in the placebo group within 2 months of therapy. To conclude, there is limited evidence for a clinical superiority of amitriptyline and SSRIs over other treatments with ß-blockers, anticonvulsants, or calcium channel blockers in preventing migraine. Antidepressants in migraine should be considered if other first- or second-line drugs have not reduced the number of monthly attacks or if concomitant depression exists. Therefore, antidepressants are second- or (even) third-line prophylactic agents in patients with migraine alone. Keywords: Migraine, antidepressants, prophylactic treatment, SSRIs, SNRIs Correspondence: Christian Lampl, Department of Neurology and Pain Medicine, Konventhospital Barmherzige Brüder Linz, Seilerstätte 2, Linz, Austria. Tel: (43) ; Fax: (43) ; christian.lampl@bblinz.at INTRODUCTION Migraine is one of the most frequently observed neurological problems at primary healthcare centers. Recurrent migraines can be disabling, and the cost of missed workdays and impaired performance associated with migraines exceeds the direct costs of medical intervention. In western countries, community-based studies of migraine prevalence using standardized diagnostic criteria give 1-year prevalence estimates of around 10 12% [1, 2], with the highest rates reported in the age range years; women account for the majority of patients with migraine [3]. Notwithstanding appropriate management of acute migraine, preventive therapy may reduce the frequency of migraines by 50% or more, and patients should be evaluated for initiation of preventive therapy. Factors that should prompt consideration of preventive therapy include severe impairment of quality of life, job duties, or school attendance, frequency of attacks per month, non-response of migraine attacks to acute drug treatment, or occurrence of frequent, very long, or uncomfortable auras [4]. First-line agents for the prophylaxis of migraine include the non-selective betablocker propranolol [5, 6] and the beta-1-selective betablocker metoprolol [7]. Bisoprolol is probably also effective, but has only been examined in two studies [8, 9]. From the group of calcium antagonists, only flunarizine has been confirmed as effective [10 12]. A dose of 5 mg is probably as effective as 10 mg [13]. In several prospective studies, the anticonvulsive valproic acid has been shown to be effective [14 16]. Topiramate has migraine prophylactic properties confirmed in three large placebo-controlled studies [17 19]. Except for bisoprolol, all the above-mentioned drugs are recommended substances (drugs of first choice) for the prophylactic treatment of migraine [4]. ANTIDEPRESSANTS A CRITICAL APPROACH TO THE MATTER As the mechanisms underlying migraine headache are still not fully understood, various types of medication have been used for migraine prophylaxis so far. New research on migraine pathophysiology has brought forward new concepts for the prevention of migraine. The mechanism of action for the alleviation of migraine headache pain is thought to be due to the inhibition of reuptake of serotonin and norepinephrine within the dorsal horn; however, other possible mechanisms of action include alfa-adrenergic blockade, sodium channel effects, and N-methyl-D-aspartic acid (NMDA) receptor antagonism. Therefore, the drugs involved should converge mainly on two targets: inhibition of cortical excitation and restoration of nociceptive dysmodulation. The antiepileptics, calcium channel blockers such as verapamil, and inhibitors of cortical spreading depression are some examples of drugs that reduce neuronal hyperexcitability. On the other hand, modulators of the serotonergic and adrenergic systems and cholinergic-enhancing drugs may restore descending nociceptive inhibition and play a role in migraine prevention. However, the administration of all other drugs, except betablockers and anticonvulsants, is based more on empirical data rather than on proven pathophysiological concepts. ENJ 2010; 000:(000). Month

2 European Neurological Journal Because migraine is currently considered a neurovascular disorder with a main central nervous system (CNS) component, efforts now focus on attempting to prevent migraine attacks by modulating neurotransmitter systems rather than by changing intracranial vascular tone [20]. For this reason, antidepressant drugs could be valuable treatment options for migraine prophylaxis. Lance and Curran [21], in 1964, as part of an exploratory study, first showed that amitriptyline had a prophylactic effect on tension-type headache in a group of 27 headache patients. Over the past decade, subsequent studies have shown that several classes of antidepressant are effective in preventing chronic headache. As a result, such therapy has become an accepted treatment for these patients [22, 23], although it is not approved for that indication in the US or Europe. However, the results of antidepressant studies for prophylactic treatment in headache have to be viewed with caution. In a published meta-analysis of 38 studies, the authors concluded that the use of antidepressants in chronic headache should be supported [24]. With regard to migraine, only six studies used the 1988 International Headache Society (IHS) criteria [25], whereas the recommendation of the 1962 Ad Hoc Committee on Classification of Headaches [26] was used in 11 studies. The remaining 23 studies used varying definitions, and no two studies defined their outcome in the same way. In such a meta-analysis, it is impossible to differentiate whether the effects of antidepressant medications on migraine were independent of their effects on depression. It is obvious that depressed patients experience improvement in somatic complaints as their underlying depression is successfully treated and, moreover, that patients with depression have more headaches. In longitudinal studies, evidence further supports a bidirectional relationship between migraine and depression, with each disorder increasing the risk of the other [27]. It obviously follows that antidepressant drugs may have a benefit for chronic headache patients. The main questions to be raised are whether antidepressant efficacy varies according to the specific headache diagnosis or potentially important patient characteristics, such as coexisting depression; whether antidepressants are as effective for non-depressed patients; and whether they achieve a direct analgesic effect in addition to treating concomitant depression. In general, it must be stated that analysis of preventive migraine therapy with antidepressants poses some methodological issues that need to be focused on: definition and diagnostic criteria of migraine (trials before and after 1988); quality of trials; definition of primary outcome parameters (specific migraine score vs reduction of migraine frequency); population of included patients (US patients vs European comparisons between study populations); as well as information on quality of life and comorbidity (e.g., depression and anxiety). Primarily, the diagnostic criteria of migraine should conform to those of the IHS [28]. Concerning quality of trials, the Clinical Trials Subcommittee of the IHS published its first edition of the guidelines on controlled trials of drugs for migraine in With the current trend for huge multinational trials, there was a need for increased awareness among clinical investigators of methodological issues in clinical trials of drugs for migraine. Therefore, new guidelines were developed to improve the quality of controlled clinical trials in migraine, because only quality trials can form the basis for international collaboration on drug therapy [29]. Secondary, headache days with moderate or severe intensity, migraine days, or frequency of migraine episodes should be the primary efficacy measures. The evaluation of efficacy should be based on a headache diary, which captures the key assessment measures for each study. To evaluate the total impact of headache and headache therapies on the individual sufferer, outcomes research is emerging as an important tool. Of increasing importance is the impact of clinical measures on patient-perceived quality of life, including comorbidity, work performance, and economic cost. Health-related quality of life (HRQOL) represents the net effect of an illness and its consequent therapy on a subject s perception of his or her ability to live a useful and fulfilling life [30]. HRQOL can be measured with a variety of generic and specific questionnaires such as the Migraine Disability Assessment (MIDAS) questionnaire, which has been used in one trial [31] and proven useful. AMITRIPTYLINE The beneficial use of amitriptyline in migraine was reported in the late 1960s by Friedman [32] and Mahloudji [33]. One of the early clinical studies conducted by Gomersall and Stuart in 1973 [34] showed efficacy of amitriptyline as a prophylactic treatment for migraine in 26 patients. The number of attacks was reduced by more than 50% in about half of the subjects, and by more than 70% in a quarter of them. Total attacks were reduced by 42%, which was statistically significant (P,0.001). In 1979, Couch and Hassanein [35] showed that 75 mg of amitriptyline reduced a specific migraine score (reflecting frequency, severity, and duration of attacks) by more than 50% in 55% of amitriptyline-treated patients, compared with 34% of placebo-treated patients. The therapeutic gain in that particular study was 21%. However, data on migraine frequency were not presented, and patients with comorbid depression were not excluded. Ten years later, Ziegler et al [36] presented the results of a placebo-controlled trial comparing amitriptyline and propranolol. They concluded that amitriptyline, as well as propranolol, is effective in reducing a specific headache score and that the positive results of amitriptyline are unrelated to depression. All these early trials used loose criteria to define migraine; they did not exclude patients with comorbid anxiety and depression and were limited by their use of global clinical ratings, rather than daily headache recordings, to assess outcome. ENJ 2010; 000:(000). Month

3 Antidepressants for migraine prophylaxis Rafieian-Kopaei et al [37] reported a significant reduction in migraine frequency, duration, and intensity when using amitriptyline. However, amitriptyline reduced the frequency of migraine attacks during treatment; after discontinuation, the rebound effect was higher than in the control group. Two recently published studies compared amitriptyline with topiramate. The first examined the prophylactic efficacy of combined amitriptyline and topiramate in patients with 3 12 migraine episodes, compared with that of monotherapy with each drug [38]. All treatments resulted in significant improvement in all efficacy measures but, again, patients with mild to moderate depression were not excluded. The second study was performed by Dodick and colleagues [39]. In that long-term, multicenter, randomized, doubleblind, double-dummy, parallel-group, non-inferiority study, the primary efficacy outcome was the change from prospective baseline in the mean monthly number of migraine episodes. The intent-to-treat population included 331 subjects, and change from baseline in the mean monthly number of migraine episodes did not differ significantly between the topiramate and amitriptyline groups. The authors concluded that topiramate was at least as effective as amitriptyline in terms of reducing the rate of mean monthly migraine episodes and all prespecified secondary efficacy endpoints. Topiramate was associated with improvement in some quality-of-life indicators compared with amitriptyline and was associated with weight loss and improved weight satisfaction. We performed a trial to examine the prophylactic benefit of two doses of amitriptyline extended release (ER) over a 6- month observational period without a placebo arm in real-life situations [40]. The study hypothesis was that amitriptyline is effective in preventing migraine attacks and that 50 mg of ER amitriptyline is more effective than 25 mg of ER amitriptyline. Furthermore, we were interested in determining possible predictive factors for therapeutic responsiveness. Change in median number of migraine days from baseline to the end of the intent-to-treat period of 6 months was adducted as a primary efficacy measure. A statistically significant reduction in median migraine days was found between baseline and months 3 and 6. However, no significant difference in treatment efficacy was observed between treatment with amitriptyline ER 25 mg/day and with amitriptyline ER 50 mg/ day at any time period. In contrast to other similar studies, we used the number of headache days as a primary efficacy outcome instead of the recommended number of attacks per 4 weeks, because we considered the number of headache days to be a more robust and conservative parameter. When looking at the secondary outcome measures, migraine days were able to be reduced by >30% in 39% of the patients by the end of the study. However, only 14% of the study patients experienced a reduction of >50% in migraine headache days, whereas none of the patients benefited by more than 70%. This study shows that amitriptyline is probably not effective in a dose of up to 50 mg; the prophylactic effect seen in our study did not reach beyond well-known placebo response rates of 20 30%. To conclude, there is some evidence that amitriptyline may be beneficial in the prophylaxis of migraine in some patients. Previous reports, exclusively from the US, have shown that migraine patients may respond to amitriptyline used for prophylactic therapy. Most of these studies had poor scientific quality. Many of the trials considered in this review had limited sample size (median of 50 randomized patients, with a mean dropout rate of 20%), which leaves the findings unclear for many outcome measures. Length of follow-up was often too short (mean length, 12 weeks; recommended, 24 weeks), and the clinical outcomes measured (scales or indices) often did not have a well-established rationale and were not prespecified. The appropriateness of statistical analyses was a frequent matter of concern, particularly in light of multiple treatment comparisons, repeated measurements over time, and questionable subgroup analyses. In the past few years, the association between migraine and depression has been described in both clinic- and community-based populations. Many researchers maintain that chronic migraine pain can induce a reactive depression that becomes more evident the more chronic the pain is. To explain a development from migraine to depression, it has been hypothesized that unpredictable attacks of severe pain might lead to anxiety and depression. In longitudinal studies, the evidence supports a bidirectional relationship between migraine and depression, with each disorder increasing the risk of the other [27, 41]. In such cases amitriptyline may provide more benefit than other drugs. However, this approach is not successful in all migraine patients, and finding a means of identifying patients who are likely to respond to amitriptyline is a high-priority research goal. In some cases, the benefits gained must be weighed against the risks incurred. The most important adverse effects are drowsiness and anticholinergic symptoms such as dry mouth, constipation, and tachycardia. Weight gain occurs in many patients together with elevated levels of leptin, insulin, and C peptide [42], and can be a limiting factor leading to impaired compliance and discontinuation. Occasionally, amitriptyline may provoke glaucoma, PQ and QT interval prolongation on electrocardiogram (ECG), as well as benign prostate hypertrophy, which should be excluded prior to treatment. Amitriptyline is metabolized by cytochrome P450 (CYP) isoenzymes, particularly CYP2D6, which is responsible for multiple interactions (e.g., class Ia and IIIa antiarrhythmics, warfarin, opiates, propranolol, diuretics, insulin). Therefore, its use is further limited by age. SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIS) SSRIs currently used in migraine comprise citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline. When compared with placebo, SSRIs did not show any superiority in patients with migraine. When compared with other active treatments, specifically tricyclic antidepressants, SSRIs were not superior in migraine [43]. There is some evidence that SSRIs are better tolerated than other active treatments with respect to minor adverse events. This 3 ENJ 2010; 000:(000). Month 2010

4 European Neurological Journal tolerability has no impact on the total number of patients withdrawing as a result of adverse effects [44]. Patients taking tricyclic antidepressants for headache are as likely to continue taking a tricyclic as patients treated with an SSRI are to continue taking the SSRI. The issue of long-term treatment (.3 months) with respect to efficacy and tolerability should still be addressed, as in real-life conditions. Fluoxetine is certainly the most extensively studied SSRI in migraine prevention. A loss of habituation of visually evoked potentials in migraine patients was normalized on fluoxetine 20 mg/day; in addition, migraine attack frequency diminished significantly [45]. In a prospective study by Krymchantowski et al [46] in patients with transformed migraine, amitriptyline 40 mg was found to be equally effective as a combination of amitriptyline and fluoxetine, which argues against a strong efficacy of fluoxetine. No significant effect of fluoxetine mg daily compared with placebo was found after 3 months of intake on headache self-assessment scales, a proprietary headache index, or number of severe headache days per week [47]. Another double-blind, placebo-controlled study demonstrated a significant improvement on a proprietary headache index [48], but the withdrawal rate was high, the overall number in each group was low [n58], and the results were not corrected for multiple testing. In conclusion, current data on the use of SSRIs in migraine prevention favor the use of fluoxetine. However, it should be considered that these studies are partly inconsistent and lacking in numbers of patients. The Cochrane review [44] mentioned revealed that beneficial effects from SSRIs are equivalent to those seen in the placebo group within 2 months of therapy. SEROTONIN NORADRENALIN (NOREPINEPHRINE) REUPTAKE INHIBITORS (SNRIS) Duloxetine and venlafaxine have been promoted as being especially useful in migraine and depression. In migraine, a retrospective analysis of 65 migraine patients receiving mg daily for at least 2 months revealed a significant reduction in attacks per month. Interestingly, those patients with comorbid depression did not benefit significantly in a subgroup analysis, whereas those with a comorbid anxiety disorder experienced greater benefit than did all 65 migraine patients together [49]. For venlafaxine, four studies were published, but the reported positive results are limited by an open-label procedure [50], the retrospective design, the fact that concomitant migraine prophylactics were allowed, or that the majority of patients had simultaneous tension-type headache [51]. In the only randomized, double-blind, crossover trial, patients with migraine with and without aura received either amitriptyline or venlafaxine extended release. The number of attacks per month as well as the duration and intensity of the attacks decreased significantly with both drugs [52]. However, the small number of patients in each group limits the impact of this outcome. CONCLUSIONS In older placebo-controlled trials, positive results could be shown for amitriptyline in the prophylactic treatment of migraine. The results of a study comparing amitriptyline with propranolol suggest that propranolol is more effective in patients with a single migraine type, whereas amitriptyline is more beneficial for patients with mixed migraine and tension features. Compared with topiramate, amitriptyline was at least as effective in terms of reducing the rate of mean monthly migraine episodes. However, topiramate was associated with improvement in some quality-of-life indicators compared with amitriptyline and was associated with fewer side-effects. SSRIs did not show any superiority in patients with migraine, when compared with placebo. When compared with other active treatments, specifically tricyclic antidepressants, SSRIs were not superior in migraine prophylaxis. Furthermore, there is limited evidence for a clinical superiority of amitriptyline and SSRIs over other treatments with beta-blockers, anticonvulsants, or calcium channel blockers in preventing migraine. Therefore, antidepressants in migraine should be discussed with the patient if other drugs (beta-blockers, flunarizine, valproate, and topiramate) have not reduced the number of monthly attacks, are limited because of their several important side-effects, or if concomitant depression (or other psychiatric disease) exists. Antidepressants should be considered as second- (amitriptyline) or third-line (SSRIs, SNRIs) prophylactic agents in patients with migraine alone. Our cautious recommendations for the use of antidepressants reflect the current lack of data on most substances. Future studies should adopt a higher standard in terms of design and reporting by using the International Headache Society diagnostic criteria to classify patient pain in chronic forms of either migraine and/or tension-type headache. According to the Task Force of the International Headache Society Clinical Trials Subcommittee, migraine headache days with moderate or severe intensity, migraine days, or frequency of migraine episodes should be the primary efficacy measures [29]. Another heterogeneity is the fact that some of the presented studies examined migraine preventive efficacy only in those patients without concomitant depression, whereas others allowed concurrent depression. Today, some guidelines adopt a rather strict approach recommending only antidepressants for migraine prophylaxis [3], whereas others, such as the US Academy of Neurology, recommend those drugs, albeit stressing the low quality of evidence in the corresponding drugs [53]. Disclosure: Christian Lampl received personal compensation from Glaxo, Pfizer Austria, Mundipharma, Grünenthal, Bayer-Shering, Biogen Idec and Astra Zeneca. Christine Schweiger has nothing to disclose. REFERENCES 1. Breslau N, Rasmussen BK. The impact of migraine epidemiology, risk factors, and co-morbidities. Neurology. 2001;56: Lampl C, Buzath A, Baumhackl U, Klingler D. One-year prevalence of migraine in Austria: a nation-wide survey. Cephalalgia. 2003;23: ENJ 2010; 000:(000). Month

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