By Ryan J. Cady, MS; J. Kent Dexter, MD; Roger K. Cady, MD of The Headache Care Center in Springfield, Missouri
In the annals of migraine, one of the most fascinating stories is how, in 1966, a physician named Robert Rabkin observed that the drug propranolol could prevent migraine. Dr. Rabkin was actually conducting a study using a beta-blocker (propranolol) to treat heart pain (angina) and fortuitously observed that one of his research subjects had a remarkable reduction in the frequency of his migraine attacks. A decade later, Drs. Seymour Diamond and John Graham presented their experience treating 86 migraine patients with daily propranolol to the Food and Drug Administration (FDA), and demonstrated that propranolol was indeed efficacious and safe for migraine prophylactic therapy. Subsequently, propranolol became the first FDA-approved medication for the prevention of migraine.
As one of many beta blockers used commonly to prevent migraine, propranolol currently, is probably the most widely prescribed medication in the world for prevention of migraine. Beta blockers are used to treat multiple diseases including high blood pressure, heart pain, and irregularities of the heart as well as conditions such as anxiety and certain types of tremors. Beta blockers have been so successful that they are considered one of the most important medical discoveries of the 20th century.
In 1978, a second beta blocker, timolol, also received FDA approval as the first topical beta blocker for the treatment of glaucoma. Although clinical trials demonstrated a very strong benefit from using timolol as a migraine preventive, neither it nor propranolol have demonstrated efficacy as an acute treatment for migraine. However, these previous studies have focused on oral preparations of these drugs and the drug was not absorbed quickly enough to be effective as an acute treatment. Interestingly, since the 1980s, there have been rare case reports of patients with glaucoma being treated with timolol eye drops who experienced migraine relief.
Considering the history of these beta blockers, two ophthalmologists—John Hagen and Carl Migliazzo—recently made a startling observation. During a game of golf, these ophthalmologists had an “eureka” moment while discussing possible treatment options for Dr. Hagen’s daughters who experience migraine. They observed that some of their patients treated for glaucoma with timolol eye drops reported that if the timolol eye drops were instilled during a migraine, the headache would be rapidly terminated.
Following their discussion on the use of beta blocker eye drops for the treatment of acute migraine, Drs. Hagen and Migliazzo reported on a series of seven patients who had successfully treated acute attacks of migraine with timolol eye drops, which was published in The Journal of the Missouri State Medical Association in 2014. The seven patients in these case reports were all female, ages 38 to 76, who presented with migraine syndromes, with and without aura. Five of the seven patients reported complete pain relief, with one patient reporting complete pain relief within 10 minutes of treatment. The two remaining patients reported pain relief of 8 and 9.5 on a 1 to 10 scale, with 10 representing complete relief. These patients were all instructed to use 1 or 2 drops of their beta blocker eye drops as early as possible during their acute migraine attacks. Patients were advised to blink several times to encourage the eye drop to pass into the lacrimal drainage duct. Interestingly, one patient used timolol drops sublingually and reported receiving pain relief. The dye drops were generally well-tolerated with only one reported side effect of shortness of breath which only occurred if eye drops were used in both eyes. Drs. Hagen and Migliazzo stress all patients underwent a complete medical history and ophthalmic examination prior to the initiation of topical beta blockers. Patients were advised to read the package insert and inform their primary care physicians of their acute use of beta blocker eye drops.
Since the publication of these reports, Drs. Hagen and Migliazzo have received multiple messages and phone calls from fellow physicians who have reported success with patients using beta blocker eye drops for migraine relief. Although these represent only a few case reports, they provide additional evidence of the use of topical beta blockers in acute migraine, and the treatment appears to be well-tolerated. The physicians are hopeful to see the development of well-controlled studies to validate the efficacy of beta blocker eye drops for acute migraine relief.
How would beta blockers work in acute treatment of migraine?
The exact mechanism of beta blockers in the treatment or prevention of migraine is unknown. Beta blockers work primarily by blocking the stimulating or activating effects of adrenalin. Considering that individuals with migraine have inherited a nervous system that is more excitable than those without migraine, it is easy to assume that beta blockers may in some way reduce this inherent excitability. In other words, the beta blockers may make the nervous system less vulnerable to migraine. While this likely explains the migraine prevention benefits, it also may provide a rationale for their use in the acute treatment of migraine headaches.
One can imagine that during a migraine, the threshold for nervous system activation has already been surpassed and hence the process of migraine occurs. Beta blocker eye drops enter the nasal cavity through the lacrimal duct (a small passageway from the eye to the nose that drains tears from the eye) very quickly. Once in the nose, the eye drops are rapidly absorbed into the blood. Conceivably, they could block the activating effects of adrenaline and allow the nervous system to reverse migraine. Beyond the speed of entry into the blood, another major advantage of nasal absorption is that medications do not have to pass through the liver before entering the systemic circulation, thus avoiding their metabolism by the liver and allowing a much smaller dose of medication to be effective. Beta blockers have also been found to reduce the electrical excitability of nerve cells, and this too may be part of their potential mechanism.
When oral preparations of beta blockers are used to prevent migraine, levels build up slowly in the blood. This action works well for prevention but during migraine, these levels would increase too slowly to be effective. Using an eye drop with rapid absorption through the nose circumvents that problem. Also, nerves in the nasal cavity may become activated and potentially, beta blockers could act directly on these nerves. Finally, it is possible that some of the beta blocker eye drop could be absorbed into the brain and exert their beneficial effect in that manner.
Would beta blocker eye drops be a breakthrough for the acute treatment of migraine?
Currently, the medications used to treat acute migraine generally are either triptans or nonsteroidal anti-inflammatories (NSAIDs). Triptans act by constricting blood vessels and blocking the release of calcitonin gene-related peptide (CGRP) from the nerves activated during migraine. CGRP cause blood vessels to swell and initiates the cascade of inflammatory events leading to pain. The NSAIDs are believed to work primarily by blocking the synthesis of another inflammatory pathway mediated by prostaglandins. If beta blockers are found to be an effective acute treatment for migraine, their efficacy would likely be due to a novel mechanism(s) and provide a third line of potential treatment success. This finding would undoubtedly represent a major medical advancement for the acute treatment of migraine.
Also, because beta blockers are already used on a daily basis to prevent migraine, it is likely that their frequent use to treat acute migraine would be associated with medication-overuse headache. This finding would welcome news for those individuals with high treatment requirements. The beta blocker eye drops also would likely have a good tolerability profile as the dose of actual medication received would be quite low relative to oral beta blocker therapy. Clearly, the need to obtain good clinical trials is indicated before making claims for their use of safety.
What are the risks and limitations?
Oral beta blocker therapy is not tolerated by everyone. Beta blockers can lower blood pressure and slow the heart rate. These effects have been occasionally noted with beta blocker eye drops as well. Rarely, beta blockers can have an adverse effect on asthma. Finally, for those patients with diabetes who are prone to hypoglycemia (low blood sugar), beta blockers can mask some of the warning symptoms and would have to be used with caution. However, beta blockers, and in particular timolol, have been used for decades on a daily basis for treatment of glaucoma, and are generally well-tolerated even with daily use. It is assumed that as an acute treatment for migraine, the beta blocker eye drops would be used on an intermittent basis which should increase their tolerability. In the future, studies may be conducted on the administration of beta blockers as a nasal spray.
What are the next steps?
As with any new potential treatment, the next step is rigorous clinical studies. However, much of the initial work has probably been accomplished, and can be extrapolated from completed studies of beta blocker in glaucoma patients and in migraine patients using beta blockers for migraine prevention. However, the initial step is to undertake a pilot study to establish a proof of concept that timolol eye drops are indeed effective as acute treatment of migraine. If that conclusion can be established, large clinical trials must be undertaken to further establish efficacy and safety of their use in acute migraine. Efforts are currently underway to conduct a pilot proof of concept study. If the proof of concept is established, then involvement of the FDA will be needed before the beta blocker eye drops could be approved treatment of acute migraine.
Hagan JC III. Are drops the ‘solution’? A Eureka moment? Beta blocker eye drops for acute migraines. Missouri Me 2014; 111:281-283
Migliazzo CV, Hagan JC III. Beta blocker eye drops for treatment of acute migraine. Missouri Med 2014; 111:284-289.
Dexter JK, Cady RK. Ophthalmic beta blockers: Treatment for acute migraine? Missouri Med 2014; 111:293-294.