Antidepressants for Migraine ProphylaxisChristian Lampl and Christine Schweiger

Affiliation: Department of Neurology and Pain Medicine, Konventhospital Barmherzige Bruder Linz, Linz, Austria

A B S T R A C T

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 Bruder Linz, Seilerstatte 2,Linz, Austria. Tel: (43)-732-780-625320; Fax: (43)-732-780-625398; e-mail: christian.lampl@bblinz.at

INTRODUCTION

Migraine is one of the most frequently observed neurolo-gical problems at primary healthcare centers. Recurrentmigraines can be disabling, and the cost of missed workdaysand impaired performance associated with migraines exceedsthe direct costs of medical intervention.

In western countries, community-based studies of migraineprevalence using standardized diagnostic criteria give 1-yearprevalence estimates of around 10–12% [1, 2], with thehighest rates reported in the age range 25–55 years; womenaccount for the majority of patients with migraine [3].

Notwithstanding appropriate management of acutemigraine, preventive therapy may reduce the frequency ofmigraines by 50% or more, and patients should be evaluatedfor initiation of preventive therapy. Factors that shouldprompt consideration of preventive therapy include severeimpairment of quality of life, job duties, or school attendance,frequency of attacks per month, non-response of migraineattacks to acute drug treatment, or occurrence of frequent,very long, or uncomfortable auras [4]. First-line agents for theprophylaxis of migraine include the non-selective beta-blocker propranolol [5, 6] and the beta-1-selective beta-blocker metoprolol [7]. Bisoprolol is probably also effective,but has only been examined in two studies [8, 9]. From thegroup of ‘‘calcium antagonists’’, only flunarizine has beenconfirmed as effective [10–12]. A dose of 5 mg is probably aseffective as 10 mg [13]. In several prospective studies, theanticonvulsive 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 arerecommended substances (drugs of first choice) for theprophylactic treatment of migraine [4].

ANTIDEPRESSANTS—A CRITICAL APPROACHTO THE MATTER

As the mechanisms underlying migraine headache are stillnot fully understood, various types of medication have beenused for migraine prophylaxis so far. New research onmigraine pathophysiology has brought forward new conceptsfor the prevention of migraine. The mechanism of action forthe alleviation of migraine headache pain is thought to be dueto the inhibition of reuptake of serotonin and norepinephrinewithin the dorsal horn; however, other possible mechanismsof action include alfa-adrenergic blockade, sodium channeleffects, and N-methyl-D-aspartic acid (NMDA) receptorantagonism. Therefore, the drugs involved should convergemainly on two targets: inhibition of cortical excitation andrestoration of nociceptive dysmodulation. The antiepileptics,calcium channel blockers such as verapamil, and inhibitors ofcortical spreading depression are some examples of drugsthat reduce neuronal hyperexcitability. On the other hand,modulators of the serotonergic and adrenergic systems andcholinergic-enhancing drugs may restore descending noci-ceptive inhibition and play a role in migraine prevention.

However, the administration of all other drugs, except beta-blockers and anticonvulsants, is based more on empiricaldata rather than on proven pathophysiological concepts.

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Because migraine is currently considered a neurovasculardisorder with a main central nervous system (CNS) compo-nent, efforts now focus on attempting to prevent migraineattacks by modulating neurotransmitter systems rather thanby changing intracranial vascular tone [20]. For this reason,antidepressant drugs could be valuable treatment options formigraine prophylaxis.

Lance and Curran [21], in 1964, as part of an exploratorystudy, first showed that amitriptyline had a prophylactic effecton tension-type headache in a group of 27 headache patients.Over the past decade, subsequent studies have shown thatseveral classes of antidepressant are effective in preventingchronic headache. As a result, such therapy has become anaccepted treatment for these patients [22, 23], although it isnot approved for that indication in the US or Europe.

However, the results of antidepressant studies for prophy-lactic treatment in headache have to be viewed with caution.In a published meta-analysis of 38 studies, the authorsconcluded that the use of antidepressants in chronic headacheshould be supported [24]. With regard to migraine, only sixstudies used the 1988 International Headache Society (IHS)criteria [25], whereas the recommendation of the 1962 AdHoc Committee on Classification of Headaches [26] was usedin 11 studies. The remaining 23 studies used varyingdefinitions, and no two studies defined their outcome inthe same way. In such a meta-analysis, it is impossible todifferentiate whether the effects of antidepressant medica-tions on migraine were independent of their effects ondepression. It is obvious that depressed patients experienceimprovement in somatic complaints as their underlyingdepression is successfully treated and, moreover, that patientswith depression have more headaches. In longitudinalstudies, evidence further supports a bidirectional relationshipbetween migraine and depression, with each disorderincreasing the risk of the other [27]. It obviously followsthat antidepressant drugs may have a benefit for chronicheadache patients.

The main questions to be raised are whether antidepressantefficacy varies according to the specific headache diagnosis orpotentially important patient characteristics, such as coexist-ing depression; whether antidepressants are as effective fornon-depressed patients; and whether they achieve a directanalgesic effect in addition to treating concomitant depres-sion.

In general, it must be stated that analysis of preventivemigraine therapy with antidepressants poses some methodo-logical issues that need to be focused on: definition anddiagnostic 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 Europeancomparisons between study populations); as well as informa-tion on quality of life and comorbidity (e.g., depression andanxiety).

Primarily, the diagnostic criteria of migraine shouldconform to those of the IHS [28]. Concerning quality of

trials, the Clinical Trials Subcommittee of the IHS publishedits first edition of the guidelines on controlled trials ofdrugs for migraine in 1991. With the current trend for hugemultinational trials, there was a need for increasedawareness among clinical investigators of methodologicalissues in clinical trials of drugs for migraine. Therefore, newguidelines were developed to improve the quality ofcontrolled clinical trials in migraine, because only qualitytrials can form the basis for international collaboration ondrug therapy [29].

Secondary, headache days with moderate or severe intensity,migraine days, or frequency of migraine episodes should bethe primary efficacy measures. The evaluation of efficacyshould be based on a headache diary, which captures the keyassessment measures for each study.

To evaluate the total impact of headache and headachetherapies on the individual sufferer, outcomes research isemerging as an important tool. Of increasing importance isthe impact of clinical measures on patient-perceived quality oflife, including comorbidity, work performance, and economiccost. Health-related quality of life (HRQOL) represents the neteffect of an illness and its consequent therapy on a subject’sperception of his or her ability to live a useful and fulfillinglife [30]. HRQOL can be measured with a variety of genericand specific questionnaires such as the Migraine DisabilityAssessment (MIDAS) questionnaire, which has been used inone trial [31] and proven useful.

AMITRIPTYLINE

The beneficial use of amitriptyline in migraine was reportedin the late 1960s by Friedman [32] and Mahloudji [33]. One ofthe early clinical studies conducted by Gomersall and Stuartin 1973 [34] showed efficacy of amitriptyline as a prophylactictreatment for migraine in 26 patients. The number of attackswas reduced by more than 50% in about half of the subjects,and by more than 70% in a quarter of them. Total attackswere reduced by 42%, which was statistically significant(P,0.001).

In 1979, Couch and Hassanein [35] showed that 75 mg ofamitriptyline reduced a specific migraine score (reflectingfrequency, severity, and duration of attacks) by more than50% in 55% of amitriptyline-treated patients, compared with34% of placebo-treated patients. The therapeutic gain in thatparticular study was 21%. However, data on migrainefrequency were not presented, and patients with comorbiddepression were not excluded.

Ten years later, Ziegler et al [36] presented the results of aplacebo-controlled trial comparing amitriptyline and propra-nolol. They concluded that amitriptyline, as well as propra-nolol, is effective in reducing a specific headache score andthat the positive results of amitriptyline are unrelated todepression. All these early trials used loose criteria to definemigraine; they did not exclude patients with comorbid anxietyand depression and were limited by their use of global clinicalratings, rather than daily headache recordings, to assessoutcome.

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Rafieian-Kopaei et al [37] reported a significant reduction inmigraine frequency, duration, and intensity when usingamitriptyline. However, amitriptyline reduced the frequencyof migraine attacks during treatment; after discontinuation,the rebound effect was higher than in the control group.

Two recently published studies compared amitriptyline withtopiramate. The first examined the prophylactic efficacy ofcombined amitriptyline and topiramate in patients with 3–12migraine episodes, compared with that of monotherapy witheach drug [38]. All treatments resulted in significantimprovement in all efficacy measures but, again, patientswith mild to moderate depression were not excluded.

The second study was performed by Dodick and colleagues[39]. In that long-term, multicenter, randomized, double-blind, double-dummy, parallel-group, non-inferiority study,the primary efficacy outcome was the change from prospec-tive baseline in the mean monthly number of migraineepisodes. The intent-to-treat population included 331 sub-jects, and change from baseline in the mean monthly numberof migraine episodes did not differ significantly between thetopiramate and amitriptyline groups. The authors concludedthat topiramate was at least as effective as amitriptyline interms of reducing the rate of mean monthly migraineepisodes and all prespecified secondary efficacy endpoints.Topiramate was associated with improvement in somequality-of-life indicators compared with amitriptyline andwas associated with weight loss and improved weightsatisfaction.

We performed a trial to examine the prophylactic benefit oftwo doses of amitriptyline extended release (ER) over a 6-month observational period without a placebo arm in real-lifesituations [40]. The study hypothesis was that amitriptyline iseffective in preventing migraine attacks and that 50 mg of ERamitriptyline is more effective than 25 mg of ER amitriptyline.Furthermore, we were interested in determining possiblepredictive factors for therapeutic responsiveness. Change inmedian number of migraine days from baseline to the end ofthe intent-to-treat period of 6 months was adducted as aprimary efficacy measure. A statistically significant reductionin median migraine days was found between baseline andmonths 3 and 6. However, no significant difference intreatment efficacy was observed between treatment withamitriptyline ER 25 mg/day and with amitriptyline ER 50 mg/day at any time period. In contrast to other similar studies, weused the number of headache days as a primary efficacyoutcome instead of the recommended number of ‘‘attacks per4 weeks’’, because we considered the number of headachedays to be a more robust and conservative parameter. Whenlooking at the secondary outcome measures, migraine dayswere able to be reduced by >30% in 39% of the patients bythe end of the study. However, only 14% of the study patientsexperienced 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 effectivein a dose of up to 50 mg; the prophylactic effect seen in ourstudy did not reach beyond well-known placebo responserates of 20–30%.

To conclude, there is some evidence that amitriptyline maybe beneficial in the prophylaxis of migraine in some patients.Previous reports, exclusively from the US, have shown thatmigraine patients may respond to amitriptyline used forprophylactic therapy. Most of these studies had poor scientificquality. Many of the trials considered in this review hadlimited sample size (median of 50 randomized patients, witha mean dropout rate of 20%), which leaves the findingsunclear for many outcome measures. Length of follow-up wasoften too short (mean length, 12 weeks; recommended,24 weeks), and the clinical outcomes measured (scales orindices) often did not have a well-established rationale andwere not prespecified. The appropriateness of statisticalanalyses was a frequent matter of concern, particularly inlight of multiple treatment comparisons, repeated measure-ments over time, and questionable subgroup analyses.

In the past few years, the association between migraine anddepression has been described in both clinic- and commu-nity-based populations. Many researchers maintain thatchronic migraine pain can induce a reactive depression thatbecomes more evident the more chronic the pain is. Toexplain a development from migraine to depression, it hasbeen hypothesized that unpredictable attacks of severe painmight lead to anxiety and depression. In longitudinal studies,the evidence supports a bidirectional relationship betweenmigraine and depression, with each disorder increasing therisk of the other [27, 41]. In such cases amitriptyline mayprovide more benefit than other drugs. However, thisapproach is not successful in all migraine patients, andfinding a means of identifying patients who are likely torespond to amitriptyline is a high-priority research goal.

In some cases, the benefits gained must be weighed againstthe risks incurred. The most important adverse effects aredrowsiness and anticholinergic symptoms such as dry mouth,constipation, and tachycardia. Weight gain occurs in manypatients together with elevated levels of leptin, insulin, and Cpeptide [42], and can be a limiting factor leading to impairedcompliance and discontinuation. Occasionally, amitriptylinemay provoke glaucoma, PQ and QT interval prolongation onelectrocardiogram (ECG), as well as benign prostate hyper-trophy, which should be excluded prior to treatment.Amitriptyline is metabolized by cytochrome P450 (CYP)isoenzymes, particularly CYP2D6, which is responsible formultiple 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 sertra-line. When compared with placebo, SSRIs did not show anysuperiority in patients with migraine. When compared withother active treatments, specifically tricyclic antidepressants,SSRIs were not superior in migraine [43]. There is someevidence that SSRIs are better tolerated than other activetreatments with respect to minor adverse events. This

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tolerability has no impact on the total number of patientswithdrawing as a result of adverse effects [44]. Patients takingtricyclic antidepressants for headache are as likely to continuetaking a tricyclic as patients treated with an SSRI are tocontinue taking the SSRI. The issue of long-term treatment(.3 months) with respect to efficacy and tolerability shouldstill be addressed, as in real-life conditions.

Fluoxetine is certainly the most extensively studied SSRI inmigraine prevention. A loss of habituation of visually evokedpotentials in migraine patients was normalized on fluoxetine20 mg/day; in addition, migraine attack frequency diminishedsignificantly [45]. In a prospective study by Krymchantowskiet al [46] in patients with transformed migraine, amitriptyline40 mg was found to be equally effective as a combination ofamitriptyline and fluoxetine, which argues against a strongefficacy of fluoxetine. No significant effect of fluoxetine 20–40 mg daily compared with placebo was found after 3 monthsof intake on headache self-assessment scales, a proprietaryheadache index, or number of severe headache days per week[47]. Another double-blind, placebo-controlled study demon-strated a significant improvement on a proprietary headacheindex [48], but the withdrawal rate was high, the overallnumber in each group was low [n58], and the results werenot corrected for multiple testing.

In conclusion, current data on the use of SSRIs in migraineprevention favor the use of fluoxetine. However, it should beconsidered that these studies are partly inconsistent andlacking in numbers of patients. The Cochrane review [44]mentioned revealed that beneficial effects from SSRIs areequivalent to those seen in the placebo group within 2 monthsof therapy.

SEROTONIN NORADRENALIN(NOREPINEPHRINE) REUPTAKE INHIBITORS(SNRIS)

Duloxetine and venlafaxine have been promoted as beingespecially useful in migraine and depression. In migraine, aretrospective analysis of 65 migraine patients receiving 30–60 mg daily for at least 2 months revealed a significantreduction in attacks per month. Interestingly, those patientswith comorbid depression did not benefit significantly in asubgroup analysis, whereas those with a comorbid anxietydisorder experienced greater benefit than did all 65 migrainepatients together [49].

For venlafaxine, four studies were published, but thereported positive results are limited by an open-labelprocedure [50], the retrospective design, the fact thatconcomitant migraine prophylactics were allowed, or thatthe majority of patients had simultaneous tension-typeheadache [51]. In the only randomized, double-blind, cross-over trial, patients with migraine with and without aurareceived either amitriptyline or venlafaxine extended release.The number of attacks per month as well as the duration andintensity of the attacks decreased significantly with bothdrugs [52]. However, the small number of patients in eachgroup limits the impact of this outcome.

CONCLUSIONS

In older placebo-controlled trials, positive results could beshown for amitriptyline in the prophylactic treatment ofmigraine. The results of a study comparing amitriptyline withpropranolol suggest that propranolol is more effective inpatients with a single migraine type, whereas amitriptyline ismore beneficial for patients with mixed migraine and tensionfeatures. Compared with topiramate, amitriptyline was atleast as effective in terms of reducing the rate of meanmonthly migraine episodes. However, topiramate was asso-ciated with improvement in some quality-of-life indicatorscompared with amitriptyline and was associated with fewerside-effects.

SSRIs did not show any superiority in patients withmigraine, when compared with placebo. When comparedwith other active treatments, specifically tricyclic antidepres-sants, SSRIs were not superior in migraine prophylaxis.Furthermore, there is limited evidence for a clinical super-iority of amitriptyline and SSRIs over other treatments withbeta-blockers, anticonvulsants, or calcium channel blockersin preventing migraine.

Therefore, antidepressants in migraine should be discussedwith the patient if other drugs (beta-blockers, flunarizine,valproate, and topiramate) have not reduced the number ofmonthly attacks, are limited because of their severalimportant side-effects, or if concomitant depression (or otherpsychiatric disease) exists. Antidepressants should be con-sidered as second- (amitriptyline) or third-line (SSRIs, SNRIs)prophylactic agents in patients with migraine alone. Ourcautious recommendations for the use of antidepressantsreflect the current lack of data on most substances. Futurestudies should adopt a higher standard in terms of design andreporting by using the International Headache Societydiagnostic criteria to classify patient pain in chronic formsof either migraine and/or tension-type headache. Accordingto the Task Force of the International Headache SocietyClinical Trials Subcommittee, migraine headache days withmoderate or severe intensity, migraine days, or frequency ofmigraine episodes should be the primary efficacy measures[29]. Another heterogeneity is the fact that some of thepresented studies examined migraine preventive efficacy onlyin those patients without concomitant depression, whereasothers allowed concurrent depression. Today, some guide-lines adopt a rather strict approach recommending onlyantidepressants for migraine prophylaxis [3], whereas others,such as the US Academy of Neurology, recommend thosedrugs, albeit stressing the low quality of evidence in thecorresponding drugs [53].

Disclosure: Christian Lampl received personal compensation fromGlaxo, Pfizer Austria, Mundipharma, Grunenthal, Bayer-Shering, BiogenIdec and Astra Zeneca. Christine Schweiger has nothing to disclose.

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