A potential new paradigm for treating acute migraine: Timolol nasal spray

Affecting more than 1 billion people worldwide, migraine is among the most common neurological diseases. During their lives, 43% of women and 18% of men develop migraine.

Migraine is often more severe in young people. Thus, it is a leading cause of absences, inefficiency, errors and presenteeism at work and school.

Although a variety of old and new medications exist to treat migraine, prior research estimates that 40% to 80% of patients would welcome a more effective medication to replace or supplement those they currently use. The reasons include lack of efficacy, side effects and financial burden, especially with new-generation medications that do not have generic formulations. A safe, effective, available and inexpensive acute migraine medication is urgently needed.

We believe that the beta blocker (BB) timolol 0.5% eye drops, delivered topically to normal eyes or by nasal spray, meets these ideal criteria and will be a new treatment paradigm. Timolol is approved by the FDA for the treatment of migraine and glaucoma. What is “new” with this “old” drug is administering it as a liquid rather than pills.

Background on BBs

Introduced in the late 1960s for cardiovascular disease (CVD), BBs remain among the 10 most prescribed medications. There are two serendipitous discoveries that underlie its new use.

First, when patients with CVD and migraine were placed on BBs, they often reported improvements in migraine. Neurologists tested daily oral BBs for migraine prevention and found them to be effective. However, when taken at first onset of a migraine, oral BBs were ineffective. It seems no researchers sought to explore the reason for this paradox.

Second, when patients with CVD and glaucoma were placed on BBs, they often had significant reductions in intraocular pressure, the major goal of therapy. Ophthalmologists successfully tested timolol eye drops for primary open angle glaucoma. Approved by the FDA, timolol eye drops were introduced in 1979 and became, and remain, a mainstay of glaucoma therapy.

Emerging evidence of timolol for migraine

In the 1980s, Carl Migliazzo, MD, a Kansas City glaucoma specialist, was told by his patients that timolol eye drops improved their migraine. He empirically tried timolol 0.5% eye drops for acute migraine on family members, colleagues and patients and reported excellent results.

In 2012, John C. Hagan III, MD, collaborated with Migliazzo after his two daughters had developed migraine and learned of Migliazzo’s success with timolol drops. They began by asking why BB pills did not work for acute migraine but the drops did. The discrepancy was ultimately attributed to liquid BB quickly reaching therapeutic blood levels (10-15 minutes), which is something oral BBs never achieve.

Applied to normal eyes, timolol drops pass quickly from the eye through the tear duct into the nose and are absorbed by the nasal mucosa almost as fast as IV administration. Pills are absorbed slowly through the gut into the liver where first-pass metabolism occurs and only then circulate to the brain.

In 2014, Migliazzo and Hagan published the first case series of long-term successful treatment of acute migraine using timolol eye drops. Since the mechanism is nasal absorption, and some patients have trouble putting in eye drops and certain ophthalmic conditions preclude topical BBs, nasal administration is ideal.

Several subsequent studies of topical timolol support its effectiveness in migraine. In 2018, Matthew Cossack, MD, and colleagues published the first successful prospective, placebo-controlled study in JAMA Neurology. In 2020, Abraham Kurian, MS, DO, and colleagues reported in JAMA Ophthalmology that their prospective study of 43 participants with acute migraine demonstrated a statistically significant reduction in pain scores with timolol eye drops. In 2023, Shimaa Elgamal and colleagues published a study in Mansoura Medical Journal showing a significant improvement with timolol eye drops over other common acute migraine therapies in 57 participants who were randomly assigned to the drops or over-the-counter medications.

It is important to note that one of the studies is small, retrospective in design and without placebo control. The others are prospective, placebo-controlled studies with somewhat larger numbers of patients. The authors of all these studies concluded that larger, multicenter, prospective placebo studies are needed.

There was one study that found no improvement of acute migraine with timolol drops. However, the methodology and results of that study were flawed. For example, the study cohort included non-BB-naive participants, the researchers did not instruct participants to take the eye drops as quickly as possible with migraine onset and the study was not powered enough to allow reliable statistical validity.

Our experience

We contacted the national compounding pharmacy O’Brien Pharmacy to develop a nasal spray device delivering a metered 0.1 ml of timolol 0.5% solution. When we prescribe this to patients, we instruct them to spray each nostril quickly at first onset of headache. If they are still symptomatic, patients can use the spray again 10 to 15 minutes later. The maximum number of sprays in 24 hours is four.

The usual BB contraindications and adverse effect monitoring apply. We do not administer this solution to patients who are already on BBs or who have experienced treatment failure with oral BB for migraine prevention.

It is important to keep in mind that BBs lower blood pressure, slow the pulse and have anti-anxiety properties that are generally beneficial. We have not observed adverse interactions in patients who take the timolol 0.5% solution with other standard migraine medications.

In an article published earlier this year in Missouri Medicine, we presented a case series of 16 patients with refractory migraine, 63% of whom (n = 9) were pleased with the nasal timolol and added it to their preferred treatment. No significant adverse events were noted. We presented these encouraging results in a scientific poster at the 2024 American Headache Society meeting in San Diego.

A huge advantage of this treatment is that it is presently available from O’Brien Pharmacy in Kansas City and Bayview Pharmacy in Rhode Island by proper prescription. The formulation has been published in the International Journal of Pharmacy Compounding, so other local compounding pharmacies should be able to prepare it. The medicated sprayer is mailed to patients. Thankfully, it is inexpensive. Timolol eye drops that can be used topically to the eye range from about $8 to $15 per bottle, and the 15 ml nasal spray, which can be used to treat multiple migraine attacks, is about $75.

The bottom line is that the molecule timolol has been approved for migraine, glaucoma and multiple cardiovascular indications for more than 40 years with a long track record of safety. In the here and now, for your patients with acute migraine who are not responding satisfactorily to standard medications, nasal spray timolol 0.5% deserves your serious consideration.

References:

• Aggarwal D, et al. Kans J Med. 2020;10.17161/kjm.v13i.13495.
• Cossack M, et al. JAMA Neurol. 2018; doi: 10.1001/jamaneurol.2018.0970.
• Elgamal S, et al. Mansoura Med J. 2023;doi:10.58775/2735-3990.1370.
• Gratton S, Cossack M. Mo Med. 2018;115(6):520-521.
• Hagan JCIII. Kans J Med. 2020; doi:10.17161/kjm.vol1315733.
• Hagan JCIII, et al. Int J Pharm Compd. 2024;28(4):286-290.
• Katz BJ. JAMA Ophthalmol. 2020;doi:10.1001/jamaophthalmol.2020.3837.
• Kosa SC, et al. Nasally delivered timolol for acute migraine treatment, case series. Presented at: American Headache Society Annual Scientific Meeting; June 13-16, 2024; San Diego.
• Kosa SC, Hagan III JC. Moi Med. 2024;121(1):33-36.
• Kurian A, et al. JAMA Ophthalmol. 2020; doi:10.1001/jamaophthalmol.2020.3676.
• Migliazzo CV, Hagan III JC. Mo Med. 2014;111(4):283-288.
• National Headache Foundation survey shows majority of people with migraine are unable to control disease and dissatisfied with current preventive treatment options. https://headaches.org/national-headache-foundation-survey-shows-majority-of-people-with-migraine-are-unable-to-control-disease-and-dissatisfied-with-current-preventive-treatment-options/. Accessed Oct. 2, 2024.