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Arquivos de Neuro-Psiquiatria

Print version ISSN 0004-282X

Arq. Neuro-Psiquiatr. vol.72 no.11 São Paulo Nov. 2014 


Amitriptyline and aerobic exercise or amitriptyline alone in the treatment of chronic migraine: a randomized comparative study

Amitriptilina e exercício aeróbico ou amitriptilina isolada no tratamento da migrânea crônica: um estudo randomizado e comparativo

Michelle Dias Santos Santiago

Deusvenir de Souza Carvalho

Alberto Alain Gabbai

Mariana Machado Pereira Pinto

Andrea Regina Correa Moutran

Thais Rodrigues Villa

1Departamento de Neurologia e Neurocirurgia, Universidade Federal de São Paulo, Sao Paulo SP, Brazil


To compare the preventive treatment benefits of amitriptyline and aerobic exercise or amitriptyline alone in patients with chronic migraine.


Sixty patients, both genders, aged between 18 and 50 years, with a diagnosis of chronic migraine, were randomized in groups called amitriptyline and aerobic exercise or amitriptyline alone. The following parameters were evaluated: headache frequency, intensity and duration of headache, days of the analgesic medication use, body mass index (BMI), Beck Depression Inventory (BDI) and Beck Anxiety Inventory (BAI) scores.


In the evaluated parameters, was observed decrease in headache frequency (p=0.001), moderate intensity (p=0.048), in headache duration (p=0.001), the body mass index (p=0.001), Beck Depression Inventory (p=0.001) and Beck Anxiety Inventory scores (p=0.001), when groups were compared in the end of third month.


In this study, the amitriptyline was an effective treatment for chronic migraine, but its efficacy was increased when combined with aerobic exercise.

Key words: chronic migraine; adults; prophylaxis; amitriptyline; aerobic exercise


Comparar os benefícios do tratamento preventivo em pacientes com migrânea crônica utilizando a amitriptilina associada ao exercício aeróbico ou amitriptilina isolada.


Sessenta pacientes de ambos os sexos com idade entre 18 e 50 anos e com diagnóstico de migrânea crônica foram randomizados para receber amitriptilina e orientados a: praticar exercícios aeróbicos ou somente a amitriptilina isolada. Os seguintes parâmetros foram avaliados: frequência, intensidade e duração da cefaleia, dias de uso de medicação analgésica, índice de massa corporal (IMC), e pontuação nas escalas de Beck Depression Inventory (BDI) e Beck Anxiety Inventory (BAI).


Nos parâmetros avaliados, houve redução na frequência da cefaleia (p=0,001), intensidade moderada (p=0,048), na duração (p=0,001), no índice de massa corporal (p=0,001), e pontuação nas escalas Beck Depression Inventory (p=0,001) e Beck Anxiety Inventory (p=0,001), quando os grupos foram comparados ao final do terceiro mês.


A amitriptilina foi um tratamento eficaz para a migrânea crônica, mas sua eficácia foi maior quando combinada com exercício aeróbio.

Palavras-Chave: migrânea crônica; adultos; profilaxia; amitriptilina; exercício aeróbio

Chronic migraine is a disabling disease, with a negative impact on the individual's ability to perform daily activities1 affecting 2% to 3% of the general population2 and with the prevalence in Brazilian population of 5%3.

The quality of life in patients with chronic migraine have significant impairments compared to the healthy population and also when compared to other chronic conditions4, and 85% of these patients have disabling attacks, justifying the introduction of prophylactic treatment5.

In episodic migraines, amitriptyline has been used as prophylactic therapy in the last 45 years, and is generally accepted as an effective drug6.

In addition to reducing the frequency, duration and intensity of headache attacks, therapy with amitriptyline may improve the response to acute treatment, reduce disability, and reduce associated economic costs7,8.

The use of amitriptyline for treatment of migraine resulted in 50% reduction in the headache frequency. Studies demonstrated reduction in headache intensity and frequency of amitriptyline group compared to the group venlafaxine9, reduction in the frequency and duration of headache compared to placebo7. Others studies observed similar results10,11.

A significant reduction in the use of analgesic medication was related after prophylaxis with topiramate (50-100 mg/day) associated with amitriptyline (10-20 mg/day) in migraneurs with overuse of analgesic medicines12 .

The use of amitriptyline for treatment of migraine requires initial doses of 10 to 25 mg, and the effective therapeutic dose ranges from 25 to 200 mg13.

Studies with amitriptyline demonstrate limited evidence that the treatment may be beneficial for patients with chronic migraine14.

Although several studies addressing prophylactic treatment for episodic migraine6,7,8,9,10,11,12,13,14, only topiramate15 and the botulinum toxin16 were effective in placebo-controlled studies for the prophylactic treatment of patients with chronic migraine.

In addition to the prophylactic drug therapies, multiple studies have shown benefits of non-pharmacological interventions such as aerobic exercise17,18,19,20,21,22,23,24. Exercise of moderate intensity and practiced regularly can promotes muscle relaxation, improved cardiovascular fitness and also reduces the frequency, intensity and duration of headache attacks19.

Hypotheses for the mechanisms by which exercise may reduce headache include decreased peripheral sensitization and activation of descending inhibitory pathways25.

Studies where the exercise was supervised by a physical therapist demonstrated higher patient compliance18,19,20. However, even the studies without supervision, with exercises performed at home, positive results have been reported20,21. Despite of positive findings, these studies showed some limitations as a lack of control groups and subjective endpoints.

The aim of this study was to compare the combination of amitriptyline and aerobic exercise with amitriptyline alone in the prophylactic treatment of patients with chronic migraine, in a randomized controlled open label trial. The following parameters were evaluated: headache frequency, intensity and duration of headache, days of the analgesic medication use, body mass index (BMI), Beck Depression Inventory (BDI) and Beck Anxiety Inventory (BAI) scores.


Over a 2-year period (June 2010 through June 2012), patients newly admitted to the out-patient Division of Investigation and Treatment of Headaches (DITH) of the Universidade Federal de São Paulo (Unifesp), both genders, aged between 18 and 50 years, all diagnosed with chronic migraine by the criteria of “The International Classification of Headache Disorders (ICHD-II, 2004)”26, were included in the studies.

Inclusion criteria: patients diagnosed with chronic migraine, normal cardiac and neurological examination, who had not been practicing exercise for at least 3 months.

Exclusion criteria: previous use in the last year of medication with action in the central nervous system, including migraine prophylactics, other systemic, neurological and psychiatric disorders, inability to understand verbal commands and to perform aerobic exercise, not treatment compliance during the study.

In neurological evaluation, patients with medication overuse were instructed to perform a washout of all analgesic medicines and an abortive therapy with naproxen sodium 550 mg maximum twice a week and non-pharmacological practices were oriented. In psychological evaluation, patients were instructed to fill out Beck Depression Inventory and Beck Anxiety Inventory. After neurological and psychological evaluation patients were simple randomized, using computer-generated random numbers, in two groups:

  • Amitriptyline alone: patients using amitriptyline (25 mg/day);

  • Amitriptyline and aerobic exercise: patients using amitriptyline (25 mg/day) combined with aerobic exercise.

In the aerobic exercise program patients were instructed to perform a 40 minutes fast walk outdoors with a frequency of 3 times/week for 12 consecutive weeks27 and daily, fill out a headache questionnaire. All patients received written instructions and performed a training session with physiotherapist.

Instruments used in the amitriptyline group and aerobic exercise: headache questionnaire, explanatory leaflet about the warm-up exercises, spreadsheet with hours of exercise performance, Borg scale28 and measurement of heart rate on the initial and final walk.

Instruments used in the amitriptyline group alone: headache questionnaire.

The following parameters were evaluated: headache frequency (days/month), headache intensity 1 (mild), 2 (moderate) and 3 (disabling), duration/day of headache (6h, 12h, 18h e 24h), analgesic medication use (days/month), body mass index, Beck Depression Inventory and Beck Anxiety Inventory at baseline and in the end of the 3rd month. Also the patients were weekly assessed by telephone calls and informed the study authors about the evolution of proposed therapies.

The study was submitted and approved by the local Ethic Committee in Research, and all participants signed an informed consent form, but they were able to leave the study anytime and for any reason.

Statistical analysis

For statistical analysis, Student's t-test was used. The significance level was p≤0.05. The Minitab was Statistical Software utilized.


Sixty patients were randomized for the study, 30 in amitriptyline alone group and 30 amitriptyline and aerobic exercise group.

In amitriptyline alone group 4 withdrew from the study for not using the medication correctly or not could tolerate the medication side effects (drowsiness and dry mouth) and in amitriptyline and aerobic exercise group 6 withdrew for non-adherence to proposed physical treatment.

The comparison of mean age, gender, and onset time of migraine between the groups were shown in Table 1.

Table 1 Patients in amitriptyline alone (n=30) and amitriptyline and aerobic exercise group (n=30) according to the average age, gender and average onset migraine. 

Variable Group Amitr alone±SD Group Amitr and exer±SD p-value
Average age (y)±SD 35±8 31±9 0.170
Gender (%) – F:M 88:12 79:21 0.370
Average onset of migraine (y)±SD 17±10 13±11 0.189

Fifty patients reached the end of study. In the evaluated parameters, was observed decrease in headache frequency (p=0.001), duration of headache attacks (p=0.001) intensity moderate (p=0.048), the body mass index (p=0.006), Beck Depression Inventory (p=0.001) and Beck Anxiety Inventory scores (p=0.001) between the groups amitriptyline alone (n=26) and amitriptyline and aerobic exercise group (n=24), as summarized on Table 2.

Table 2 Results of headache frequency (days/month), duration and intensity of headache attacks (attacks/month), use of analgesic medication (days/month), body mass index (BMI), Beck Depression Inventory (BDI) and Beck Anxiety Inventory (BAI) scores at baseline and the end of the 3rd month in amitriptyline alone (n=26) and amitriptyline and aerobic exercise group (n=24). 

Variable Evaluation Group Amitr alone±SD Group Amitr and exer±SD p-value
Frequency initial 25±6.31 23±6.11
3rd month 13±6.41 5±2.21 0.001**
Duration (6h) initial 1±3.14 4±9.74
3rd month 4±2.94 3±1.79 0.017*
Duration (12h) initial 13±7.50 3±12.1
3rd month 1±4.62 6±1.74 0.001**
Duration (18h) initial 5±9.13 2±3.26
3rd month 3±2.53 1±1.02 0.733
Duration (24h) initial 20±13.9 20±11.0
3rd month 3±6.19 0 0.001**
Intensity 1 (mild) initial 10±8.68 8±8.38
3rd month 5±3.18 3±2.16 0.528
Intensity 2 (moderate) initial 13±6.89 14±7.57
3rd month 6±4.75 3±1.86 0.048*
Intensity 3 (disabling) initial 6±5.50 6±6.55
3rd month 2±2.65 0 0.093
Analgesic Medication initial 20±9.63 16±8.95
3rd month 3±2.99 1±1.48 0.752
BMI initial 24±2.66 24±2.57
3rd month 25±2.92 23±2.64 0.006**
BDI initial 14±11.45 10±6.70
3rd month 10±11.20 6±5.69 0.001**
BAI initial 16±15.85 15±8.91
3rd month 10±12.10 8±7.17 0.001**




This study showed that the combination of a prophylactic drug therapy amitriptyline with a non-pharmacological treatment aerobic exercise was effective as a preventive therapy as compared with amitriptyline alone.

There is no consensus in the literature about how patients with chronic migraine should be instructed to perform aerobic exercise19, so the parameters of intensity, frequency and duration of exercise were based on the parameters used for the healthy population27.

The regular practice of aerobic exercise seems to benefit patients with migraine17,18,19,20,21,22,23,24. These benefits could be related to increased production of beta-endorphins18 or changes in levels of nitric oxide during aerobic exercise17. Controlled studies are needed to define the optimal frequency and intensity of exercise20.

Studies showed difference in pain intensity between groups19,24 and this study also showed a significant reduction in these evaluated groups.

Despite of findings of decreased intensity, duration and frequency of headache in physically active people, there are few studies about the real influence of exercise in patients with headache21.

Many patients with chronic migraine report that exercise exacerbates their headaches20. However, in this study was not observed worsening of headache in chronic migraine patients.

Obesity is a risk factor to migraine chronicity29. Despite the weight gain, the amitriptyline group alone had a reduced frequency of headache attacks. The combination of amitriptyline and aerobic exercise resulted in no increase in body mass index, therefore, in addition to resulting in greater efficacy of headache prevention, exercise can also prevent the adverse effect of weight gain associated with the use of amitriptyline.

This study had some limitations such as the small samples of patients evaluated, the aerobic exercise have been done by patients without supervision. However other studies without supervision and with the exercises performed at home led to similar results18,19,20,21.

In conclusion, the therapy with amitriptyline was effective as a prophylactic treatment for patients with chronic migraine, however the combination of amitriptyline and aerobic exercise resulted in an even greater reduction in the frequency, duration and intensity of headache, in body mass index, Beck Depression Inventory and Beck Anxiety Inventory scores.


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Received: March 17, 2014; Revised: July 11, 2014; Accepted: July 31, 2014

Correspondence: Thais Rodrigues Villa; Rua Dr. Bacelar 231, cj. 17; 04026-000 São Paulo SP, Brasil; E-mail:

Conflict of interest: There is no conflict of interest to declare.

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