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Original Investigation
October 1, 2020

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

Author Affiliations
  • 1Chaithanya Eye Hospital and Research Institute, Kesavadasapuram, Trivandrum, Kerala, India
  • 2Chaithanya Eye Hospital and Research Institute, Tiruvalla, Kerala, India
JAMA Ophthalmol. 2020;138(11):1160-1166. doi:10.1001/jamaophthalmol.2020.3676
Key Points

Question  Can topical timolol maleate ophthalmic solution reduce pain scores after an acute migraine attack better than placebo eyedrops?

Findings  In a randomized crossover clinical trial involving 50 patients, topical timolol was more likely to reduce pain scores 20 minutes after instillation compared with placebo.

Meaning  These findings support consideration of timolol eyedrops in the management of acute migraine attacks, but confirmation for longer follow-up with larger groups at multiple sites is warranted.


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

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