Timolol eye drops may help abort acute migraine attack, finds Study

The Headache Classification Committee of the International Headache Society provides comprehensive classification and treatment guidelines for headache disorders including migraine. Oral timolol maleate is 1 of the 4 drugs approved by the US Food and Drug Administration for migraine prophylaxis, but studies have shown oral β-blockers to be ineffective for acute migraine. On the other hand, topical timolol is a time tested drug widely used in the treatment of glaucoma.

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.

A study was conducted by Abraham Kurian and team 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.

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.

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.

A total of 50 patients were enrolled in this trial after screening for the eligibility criteria. Of these, 7 patients withdrew after the randomization visit, those patients were excluded from the primary analysis.

Migraine attacks in which headache followed the aura more than 20 minutes later (14 attacks) and attacks aborted in the aura stage itself (12 attacks) were excluded from analysis. After excluding these, the 43 patients had a total of 619 eligible migraine attacks during the study period, of which 284 (46%) were treated with timolol eyedrops, 271 (44%) with placebo eyedrops, and the remaining 64 (10%) were during the washout period when no study medications were used. Of the 619 attacks, 359 (58%) were on both sides of the head, while the rest were unilateral.

To analyze the primary outcome in general, the 284 attacks treated with timolol were compared with the 271 attacks treated with placebo.

Primary analysis showed that 233 (82%) of the attacks treated with timolol were associated with a reduction in pain score by 4 points or to zero at 20 minutes compared with 38 (14%) attacks treated with placebo.

The difference between the groups was 68 percentage points (P < .001). A total of 120 (42%) of the attacks treated with timolol required a second administration of drops after 10 minutes.

Oral rescue medications were required in 74 attacks, all of which belonged to the group of 284 attacks that did not have a potentially clinically relevant outcome. Oral rescue medications were not required in any of the attacks with the potentially clinically relevant outcome.

To account for the crossover design and to look for any carryover effect, the number of attacks and mean reduction in pain score with intervention at 20 minutes were assessed at the patient level and compared between the 2 groups by an unpaired t test. The mean (SD) reduction in pain score with timolol was 4.58 for group A and 5.04 for group B. The mean (SD) reduction in pain score with placebo was 0.84 (1.35) for group A and 1.00 (1.40) for group B. It was concluded that there was no significant carryover effect due to the crossover, and data from both periods were considered for all further analysis.

The mean (SD) pain score at the onset of attacks was 6.01 (1.40) for the 284 migraine attacks treated with timolol and 5.93 (1.42) for the 271 migraine attacks treated with placebo. Only 10 (4%) of the attacks treated with timolol and 11 (4%) of the attacks treated with placebo recorded a pain score of 3 or less; hence, floor effects were only minimal.

Adverse reactions or systemic adverse effects of timolol eyedrops were not seen in any patient during the study period.

The factor precluding the use of oral β-blockers in acute migraine attacks is proposed to be its high first-pass metabolism and time taken to achieve peak plasma levels. Topically administered β-blockers are thought to overcome this, and plasma levels, although 100 to 250 times less than the orally administered dose, have been shown in studies to cause pharmacologic effects and hence could be beneficial in aborting acute migraine attacks.

The study showed that patients treated with timolol eyedrops at the onset of a migraine attack had a statistically significant chance of a potentially clinically relevant outcome compared with the patients treated with placebo eyedrops and confirmed it as a useful treatment option for aborting acute migraine attacks.

The results observed give further support to the hypothesis that topically applied β-blockers may be an effective and inexpensive abortive migraine medication for some patients, with fewer adverse effects. The study supports consideration of timolol eyedrops in aborting acute migraine attacks compared with placebo eyedrops.

Source: Abraham Kurian; Iodine Reghunadhan; Pratibha Thilak et al ; JAMA Ophthalmol. 2020;138(11):1160-1166.

doi:10.1001/jamaophthalmol.2020.3676