ILLUSTRATIVE CASE
A 35-year-old woman with no significant past medical history presents for follow-up of migraine. At the previous visit, she was prescribed sumatriptan for abortive therapy. However, she has been having significant adverse effect intolerance from the oral formulation, and the nasal formulation is cost prohibitive. What can you recommend as an alternative abortive therapy for this patient’s migraine?
Migraine is among the most common causes of disability worldwide, affecting more than 10% of the global population.2 The prevalence of migraine is between 2.6% and 21.7% across multiple countries.3 On a scale of 0% to 100%, disability caused by migraine is 43.3%, comparable to the first 2 days after an acute myocardial infarction (42.2%) and severe dementia (43.8%).4
Abortive therapy for acute migraine includes nonsteroidal anti-inflammatory drugs (NSAIDs), triptans, ergots, and antiemetics. However, these options are predominantly administered by mouth; non-oral formulations tend to be cost prohibitive and difficult to obtain.
Nausea and vomiting, common components of migraine (that are included in International Classification of Headache Disorders, 3rd edition [ICHD-3] criteria for migraine5) present obstacles to effective oral administration if experienced by the patient. In addition, for migraine refractory to first-line treatments, abortive options—including the recently approved calcitonin gene-related peptide (CGRP) receptor antagonists ubrogepant and rimegepant—are also cost prohibitive, potentially costing more than $1000 for 10 tablets (100 mg), depending on insurance coverage.6
Two oral beta-blockers, propranolol and timolol, are approved by the US Food and Drug Administration for migraine prophylaxis. Unfortunately, oral beta-blockers are ineffective for abortive treatment.7 Ophthalmic timolol is typically used in the treatment of glaucoma, but there have been case reports describing its benefits in acute migraine treatment.8,9 In addition, ophthalmic timolol is far cheaper than medications such as ubrogepant.10 A 2014 case series of 7 patients discussed ophthalmic beta-blockers as an effective and possibly cheaper option for acute migraine treatment.8 A randomized, crossover, placebo-controlled pilot study of 198 migraine attacks in 10 participants using timolol eyedrops for abortive therapy found timolol was not significantly more effective than placebo.9 However, it was an underpowered pilot study, with a lack of masking and an imperfect placebo. The trial discussed here was a controlled, prospective study investigating topical beta-blockers for acute migraine treatment.
STUDY SUMMARY
Crossover study achieved primary endpoint in pain reduction
This randomized, single-center, double-masked, crossover trial compared timolol maleate ophthalmic solution 0.5% with placebo among 43 patients ages 12 or older presenting with a diagnosis of migraine based on ICHD-3 (beta) criteria. Patients were eligible if they had not taken any antimigraine medications for at least 1 month prior to the study and were excluded if they had taken systemic beta-blockers at baseline, or had asthma, bradyarrhythmias, or cardiac dysfunction.
Patients were randomized 1:1 to treatment with timolol maleate 0.5% eyedrops or placebo. At the earliest onset of migraine, patients used 1 drop of timolol maleate 0.5% or placebo in each eye; if they experienced no relief after 10 minutes, they used a second drop or matching placebo. Patients were instructed to score their headache pain on a 10-point scale prior to using the eyedrops and then again 20 minutes after treatment. If a patient had migraine with aura, they were asked to use the eyedrops at the onset of the aura but measure their score at headache onset. If no headaches developed within 20 minutes of the aura, the episode was not included for analysis. All patients were permitted to use their standard oral rescue medication if no relief occurred after 20 minutes of pain onset.
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