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Beta Blocking Eye Drops in Acute Migraine: A Novel Use of an Old Drug

By Brandi R. French, MD & Niranjan N. Singh, MD

Migraine affects 29.5 million Americans and according to the American Migraine Prevalence and Prevention study (AMPP), the largest study of migraine sufferers, approximately 12% American have migraines with higher prevalence in woman than man, 17% vs. 6% respectively.¹ Migraine is usually characterized by one-sided pulsating pain with nausea, vomiting and sensitivity to light and noise. A minority of the migraine sufferers have aura, visual displays before or during attack. Estimates vary anywhere from two to sixty-one working days lost per patient per year due to migraine, depending on the population studied.² Numerous print and online resources are dedicated to those seeking permanent disability due to migraine. From these data, it is clear that both long term preventive and acute abortive therapy must continue to advance, and novel therapies must be sought.

In this issue of Missouri Medicine, Migliazzo and Hagan present a series of seven of their own patients who were treated with topical beta blocker eye drops for treatment of acute migraine attacks. All patients were long-standing migraine sufferers with well-established patterns of pain and response to standard acute abortive medications. There was rough equivalency of migraine patients with and without aura, with only one patient having additional neurologic deficits (garbled speech) associated with attacks. All patients were screened with a medical history and ophthalmological evaluation prior to instituting therapy, and were advised of the possibility of systemic side effects. Patients reported, via questionnaire, that there was relief of pain within minutes of instilling eye drops, with infrequent need for repeat drops though some used coincident NSAIDS. The authors correctly point out that this is a novel use of beta blocker eye drops with only sporadic reports in the literature of similar use. Of these, only one was a small series of four patients, the rest being case reports.^{3, 4, 5}

It is noted in this paper that the use of oral beta blockers is useful in, and FDA approved for, migraine prophylaxis,⁶ though ineffective in acute abortive treatment.^{7, 8} It is postulated that this differing usefulness of beta blockers in migraine treatment depending upon the route of administration is due to the speed by which the medication achieves a therapeutic blood level. It can take hours to days for oral administration though only minutes with the eyedrop route.^{8, 9}

Current acute abortive therapy consists of conservative over-the-counter analgesics and NSAIDS, as well as newer caffeine-containing “for migraine” preparations combined with analgesics; these can be associated with unwelcome side-effects, particularly in those with GI illness. Prescription medications such as ergotamine and triptans have several limitations, most important being patients with coronary disease, stroke and peripheral vascular disease. This presents a unique challenge when treating older patients, or those with significant vascular disease, who suffer persistent migraine pain. The abuse potential of some of prescription remedies, or propensity for rebound phenomenon also poses unique challenges in the acute and chronic treatment of migraine. There is an ongoing search for an effective antimigraine treatment which works faster, can be used at home and is devoid of these unwanted side effects.^{1, 10}

Off-label rapidly acting intravenous medications include valproate and verapamil. It is postulated that the rapid attainment of therapeutic levels of these medications is responsible for the rapid resolution of migraine pain. Small trials of intravenous valproate provide conflicting results regarding efficacy.^{11, 12} Case series of verapamil primarily address hemiplegic rather than common or classic migraine, though tend to be supportive.^{13, 14} We have located no reports thus far regarding the use of intravenous beta blocker agents for acute migraine control. However, the intravenous form of delivery is inconvenient, necessitating office, or more commonly emergency department visits, and by its very nature patients will have suffered hours prior to achieving any form of relief. A fast-acting alternate form of delivery could be ideal.

The authors of this paper emphasize the safety of beta blocker drops, and all patients were given a medical history interview and ophthalmological examination. The only reported side effect in the authors’ population was shortness of breath with multiple drops. The literature indicates additional common side effects being generally mild hypotension and bradycardia, which occasionally can be dose-limiting.^{9, 15}

There are several strengths of this paper. This is the largest case series review of patients treated with beta blocking eye drops for the indication of acute migraine, with no stronger study designs available in the literature. There is a clear demonstration of efficacy in a well-established migraine population, with documentation of the duration of migraine history and prior response, or importantly lack of response to traditional acute abortive therapies. Compelling argument is made for the efficacy of beta blockers possibly due to route of administration and lack of first pass effect,¹⁶ with coincident rapid escalation of plasma level of drug.⁹ Further mechanism of action is unknown or unclear and parallels the lack of clear known mechanism for other off label agents.

The weaknesses of this paper involve study design with it being a case series, with a small number of patients, and lack of an available control. The authors have described seven cases of migraine, five of them are more than 60 years of age. Timolol eye drops has been used in five of them while levobunolol in two patients. Five of seven patients have also used NSAIDs acutely. The frequency of use of the eye drops is not reported. Beta blockers are known to have prophylactic properties for migraine. Additionally, while there was no neurologist’s documentation of the migraine diagnosis, the description of symptoms provided for each patient helps the reader draw the diagnostic conclusion of migraine with or without aura.

This therapy is attractive due to its possible efficacy as a novel agent for the acute treatment of migraine. The widespread use of beta blocking eye drops do indicate that it is safe across a broad spectrum of the population.^{9, 15} The route of administration is both easy and convenient, with the added benefit of being inexpensive and widely available. Additionally and importantly, it may be more generalizable to the elderly or those with cerebrovascular or cardiovascular disease, a known contraindication to triptans or other sympathomimetics.¹⁰ While migraine tends to wane in the elderly, a significant subset of older patients do continue to have migraine pain.

Given substantial prevalence, morbidity and disability, these results are compelling. However, to have more definitive answers, the beta blocker eye drops need to be tried against placebo without any supplemental nonsteroidal anti-inflammatory medications. Their use as a prophylactic agent should also be investigated. Further aspects of this treatment to explore include the possibility of rebound effect with multiple or frequent doses. Additionally, its sustained efficacy in large populations of patients will need to be verified, though the case reports provided by the authors provide preliminary support to efficacy over time. As called for in 1999 further studies are warranted.⁴ The NIH has issued a call for research on migraine (http://grants.nih.gov/grants/guide/pa-files/PA-14-069.html) and this could pose an attractive and feasible area for study of a new use of an old medication to address a pervasive problem throughout the population, particularly in the important subset of those with vascular disease in whom treatment options become more limited. We would anxiously await institution of trials to explore expanding our therapeutic repertoire.

Brandi R. French, MD, (top) is Assistant Professor of Clinical Vascular Neurology and Medical Director of Inpatient Neurosciences Unit. and Niranjan N. Singh, MD, DM, is Associate Professor of Neurology and Director of the Missouri Stroke Program. Both are at the University of Missouri.

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