A Randomized Controlled Trial of High Rate rTMS Versus rTMS and Amitriptyline in Chronic Migraine

BACKGROUND: The patients with chronic migraine (CM) respond poorly to pharmacological agents including tricyclic antidepressants, beta-blockers, anticonvulsants, calcium channel blockers, flunarizine, and melatonin. The combination of 2 or more pharmacological agents has not shown better efficacy but increased side effects. High rate repetitive transcranial magnetic stimulation (rTMS) has been reported effective in episodic migraine and converts CM to episodic migraine. A combination of high rate rTMS with a pharmacological agent may be more effective compared to rTMS alone. OBJECTIVES: We evaluate the efficacy and safety of 10 Hz rTMS compared to rTMS and amitriptyline in CM. STUDY DESIGN: Randomized controlled trial. SETTING: Tertiary care teaching institute in India. METHODS: Patients with CM as per International Classification of Headache Disorder third edition (ICHD-3) beta criteria were included whose age was between 18 years and 55 years. CM was defined if there were 15 headache days per month and at least 8 of these attacks having migraine characteristics for a period of more than 3 months. Patients with major psychiatric, other neurological or systemic disease, and those on migraine prophylaxis were excluded. The demographic details, frequency of headache attacks and headache days per month, migraine triggers, and associated symptoms were noted. The severity of headache was noted using a 0-10 Visual Analog Scale and the number of abortive drugs per month was noted. CM patients were randomly assigned to rTMS (group I) or rTMS and amitriptyline (group II). 10 Hz rTMS was applied using a figure of eight magnetic stimulation coil. The coil was placed over the left frontal cortex corresponding to the hot spot of the right abductor digiti minimi, which is approximately 7 cm lateral from the midline and 2 cm anterior to interaural line. The motor threshold was measured, and 70% of it was used for rTMS. Ten trains of 10 Hz rTMS, each train comprising of 60 pulses with an inter-train interval of 45 seconds were delivered in one session. Three such sessions were delivered on an alternate day and were repeated every month for 3 months. Amitriptyline was prescribed in a dose of 10mg, increased to 25mg after 2 weeks; thereafter increase in dose to 50 mg was optional. The primary outcome was > 50% reduction in headache days, and secondary outcomes were the reduction in severity of headache, abortive drug, and side effects. RESULTS: Forty-one patients were included in group I and 42 in group II, and their baseline characteristics were comparable. A higher proportion of group II patients had more than 50% reduction in headache days at 3 months (76.2 vs 31.7%; P < 0.001) compared to group I. More than 50% reduction in headache severity was also greater in group II compared to group I at 3 months (47.6% vs 19.5%; P = 0.01). Side effects were comparable, and none had to be withdrawn. LIMITATIONS: A higher proportion of patients was shifted from group I to group II. CONCLUSION: Combination of rTMS and amitriptyline is safe and more effective in CM compared to rTMS alone. KEY WORDS: Headache, migraine, chronic migraine, transcranial magnetic stimulation, amitriptyline, prophylaxis, noninvasive stimulation, nonpharmacological treatment