Short-term Efficacy and Safety of Topical β-Blockers (Timolol Maleate Ophthalmic Solution, 0.5%) in Acute Migraine: A Randomized Crossover Trial

Importance: Oral β-blockers used for the prevention of migraine headache are not effective for the treatment of acute pain. Small case series have suggested that topically applied β-blockers may be useful in the management of acute migraine pain, warranting evaluation with randomized clinical trials.

Objective: To evaluate the short-term efficacy and safety of topically applied timolol maleate ophthalmic solution, 0.5%, compared with topically applied placebo eyedrops in the treatment of acute migraine attacks.

Design, setting, and participants: In this randomized, masked placebo-controlled crossover trial conducted from May 27, 2015, to August 28, 2017, 50 patients with migraine were randomized to receive either timolol eyedrops, 0.5%, or a placebo eyedrop (carboxymethyl cellulose, 0.5%). After a 3-month treatment period, patients completed a 1-month washout period and were crossed over to receive the opposite treatment for a final 3 months. Analysis was performed on a modified intent-to-treat basis.

Intervention: After random assignment, patients were instructed to use 1 drop of the assigned medication in each eye at the earliest onset of migraine.

Main outcomes and measures: The main outcome measure was reduction in pain score with treatment. The primary end point was reduction of pain score by 4 points, or to zero, 20 minutes after instillation of the eyedrop.

Results: Of the 50 patients, 42 (84%) were females and the mean (SD) age was 27.3 (11.3) years. Of a total of 619 migraine attacks, 284 (46%) were treated with timolol, 271 (44%) were treated with the placebo, and 64 (10%) occurred during the washout period when no study medications were used. Seven patients (14%) withdrew after randomization. A total of 233 of the timolol-treated migraine attacks (82%) were associated with a reduction in pain score by 4 points, or to zero, at 20 minutes compared with 38 of the placebo-treated attacks (14%), with a difference of 68 percentage points (95% CI, 62-74 percentage points). A generalized estimating equation analysis revealed that pain score reduction at 20 minutes was greater in the timolol group compared with the placebo group by a mean (SE) of 4.63 points (0.34) (P < .001).

Conclusions and relevance: This randomized crossover trial supports consideration of timolol eyedrops in the acute treatment of migraine. Further research is warranted to determine if the improvements observed are sustained for a longer follow-up and with larger groups.

Trial registration: CTRI/2015/05/005829, UTN: U1111-1167-6439.