Timolol for Migraine Shows Efficacy as Abortive Therapy

Matthew Cossack, MD, from the University of Missouri-Kansas City School of Medicine

Matthew Cossack, MD

Timolol eye drops have shown to be effective as an abortive therapy for some patients with migraine, according to new pilot study results.¹

In drop form, the nonselective β-adrenergic blocking agent is often used to treat intraocular pressure in ocular hypertension and glaucoma, though its oral form has been explored in migraine treatment. ß-blockers, through FDA approved for migraine prophylaxis, are limited in their use in acute migraine due to their slow absorption and modification by first-pass metabolism holding up effective plasma levels for indeterminant periods of time.² The eye drop form of timolol, though, offers a more rapid route of delivery, hitting plasma concentration maximums within 15 minutes.

Led by Matthew Cossack, MD, from the University of Missouri-Kansas City School of Medicine, the group of investigators assessed the therapy in a randomized, crossover, placebo-controlled study that randomized 10 participants to either timolol maleate 0.5% or artificial tears, with patients administered 1 drop in each eye at migraine onset and 30 minutes later.

In total, 198 attacks were observed, with the mean number of attacks (standard deviation [SD]) for the timolol group being 11.9 (11) and 8 (6.7) for the placebo group.

“A 2-tailed χ² statistic suggests that 172 randomized participants or 86 crossover participants would be needed to power a study with α ≤ .05 and β ≤ 0.2,” Cossack and colleagues noted.

Patients were asked to rate the severity of their migraine attacks on a scale of 0 to 3 and were asked to rate each drop’s effectiveness at the conclusion of the trial on a scale of 1 to 4. The overall efficacy of timolol drops was rated at 2.4 (SD, 1.4) compared to 1.4 (SD, 0.9) with the placebo drops. Four of the 10 participants found timolol to be highly effective compared to placebo, and 1 participant stated the reverse.

The average percentage of headaches with a rated severity of none or mild at the 2-hour mark was 57% (SD, 34) with placebo compared to 78% (SD, 31) with timolol (P = .26). This lack of significance, the authors noted, was expected in such a small pilot study. When asked if they would use the trial treatment in place of their current treatment option, 55% (n = 5.5) said yes for timolol, compared to 25% (n = 2.5) for placebo.

“This pilot study successfully explored the effect size of timolol eyedrops on migraine headaches,” Cossack and colleagues indicated. “Several participants responded extremely well to the timolol. Further research is needed to determine what patient factors might predict responsiveness to timolol.”

Cossack and colleagues also reported a number of limitations. The small sample size, no masking of the investigators, and an imperfect placebo—artificial tears tend to cause a lessened burning sensation than timolol, they noted—were some of those mentioned. Additionally, timolol in its ophthalmic form has a 4-hour half-life, making it unlikely to have a link to repeated headaches beyond the washout period of 3 days.

The treatment therapy, in a 4-drop, 50-µL dose, represents 1 mg of timolol, comparable to a 10- to 30-mg oral prophylactic daily dose. “Future research should aim for a target enrollment of more than 86 participants and explore optimal dosing regimens,” the authors wrote.

Only a single adverse event (AE) was observed, with 1 patient developing branch retinal artery occlusion, but it was deemed unrelated to the study. No additional AEs were observed, including hypotension or bradycardia.

REFERENCES

1. Cossack M, Nabrinsky E, Turner H, Abraham A, Gratton S. Timolol eyedrops in the treatment of acute migraine attacks: A randomized crossover study. JAMA Neurol. 2018;75(8):1024-1025.

doi

:10.1001/jamaneurol.2018.0970

2. Bobik A, Jennings GL, Ashley P, Korner PI. Timolol pharmacokinetics and effects on heart rate and blood pressure after acute and chronic administration. Eur J Clin Pharmacol. 1979;16(4):243-249. doi

:10.1007/BF00608402.