Amitriptyline vs Venlafaxine for Reducing Migraine Attacks: Which Is Better?

In a noninferiority randomized trial, researchers compared the effects of amitriptyline and venlafaxine reducing severity and frequency of migraine attacks.

Amitriptyline and venlafaxine significantly improved migraine attack frequency, duration, and severity, according to noninferiority randomized trial published in Clinical Neurology and Neurosurgery.

Migraine is ranked second (12% in the general population) for disabling neurological disorders. Since the underlying migraine headache mechanisms remain elusive to researchers, prophylactic treatment is used to target frequency, duration, and severity. The objective of the current study was to compare the effects of amitriptyline (AMT) and venlafaxine (VLF) reducing severity and the frequency of migraine attacks.

Researchers conducted a noninferiority randomized, double-blind trial of 80 patients (mean 33 years of age, range 18-60; 57.5% female) with complaints of migraine attacks (mean duration of disease = 8 years) in the neurology clinic of Imam Khomeini Hospital, Urmia, Iran between July 2020 and April 2021. Patients were randomized (40) into the AMT cohort (25mg/day for 8 weeks) and (40) into the VLF cohort (37.5mg/day for 8 weeks), double-blind. There were no significant differences between cohorts regarding age, sex, disease duration, frequency of migraine, and the 6-item Headache Impact Test (HIT-6) score at baseline.

Number of attacks per month were significantly reduced by AMT (from 10.98 to 2.98), and by VLF (from 9.98 to 3.18), P <.001. The HIT-6 score was significantly reduced by AMT (from 67.78 to 49.73), and by VLF (from 66.65 to 48.88). No significant difference in results was observed between the 2 drugs. No significant relationship exists between age or disease duration with the HIT-6 score. In males, the HIT-6 decrease rate in the score was higher than that of females.

The AMT group had slightly more patients who reported adverse effects compared to patients in the VLF. Sleepiness (37.5%) and insomnia (23%) were the most common adverse effects in the AMT group and the VLF group, respectively.

There were several study limitations, the researchers noted. These included a short study period, a small sample size, and the use of a fixed dose of each drug. “It is evident that the findings of the present study are a preliminary outcome that might be related to the genetic or physiologic base of patients or the small size of the involved population which was outpatients of (a) neurology clinic,” the researchers wrote.

Patients with migraine saw clinical benefits from both AMT and VLF, leading to a reduction in frequency, intensity, and duration of headache. Furthermore, the researchers noted the decrease in migraine intensity and duration was more noticeable in male patients. The researchers stated that “The decrease rate in the score of the HIT-6 in males was higher than that of females which shows the modifier role of the gender.”

Overall, “venlafaxine could have priority over amitriptyline in migraine prophylaxis,” the researchers concluded, when taking into account adverse drug reactions.


Hedayat M, Nazarbaghi S, Heidari M, Sharifi H. Venlafaxine can reduce the migraine attacks as well as amitriptyline: A noninferiority randomized trial. Clin Neurol Neurosurg. Published online January 29, 2022. doi:10.1016/j.clineuro.2022.107151