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Case 5

JW is a 63-year-old female who had the onset of migraines 27 years ago. She describes a sudden, left-sided, pounding and throbbing temple pain that radiates into her left ear and jaw. Associated nausea, vomiting, and sound sensitivity will occasionally occur. She had previously tried many different oral medications and alternative treatments for her migraines including acupuncture, chiropractic manipulation, various diets, and a nasal-palatine block. Oral medications would take up to 60 minutes to obtain partial or complete relief of symptoms. She is currently taking duloxetine and topiramate for migraine prophylaxis which has reduced the frequency of her attacks. Approximately six years ago she began using topical levobunolol 0.5% ophthalmic solution two drops in each eye at the first onset of symptoms. She will repeat the drops in 15 minutes if she doesn’t get meaningful relief after the first set. She gets complete relief of symptoms in about 70 to 80% of acute migraine attacks with levobunolol eye drops alone. If she obtained no relief, she would use oral medication. She tried using daily, topical levobunolol prophylactically, but it did not eliminate her attacks, so daily use was discontinued. No systemic or ocular side effects have been noted with topical beta blocker use.

Case 6

VB is a 57-year-old female with onset of frequent migraines at age five. She describes sparkling light aura lasting 10 to 20 minutes followed by severe right-sided pain above the eye, radiating into the temple and head. She had photophobia, nausea and difficulty with thinking clearly. The migraine would often last four to six hours followed by a “migraine hang-over” lasting a day or two. She treated these with Excedrin and lying quietly in a dark room. In her mid 30s she began using timolol 0.5% ophthalmic solution one or two drops sublingually at the first onset of her aura. She experienced improvement of her symptoms in about 10 minutes with complete relief in 30 to 45 minutes. Although she has asthma, she experienced no breathing problems or other side effects. She used the beta blocker eye drops till her mid to late 40s when she ceased to have further migraines.

Case 7

SW is a 76-year-old female whose migraines began in high school. Her typical attack begins with a visual aura of a “broken glass/mirror” followed by a left temporal pain that increases in intensity and radiates to both sides of her head. Nausea, vomiting, garbled speech, and post-migraine fatigue are often associated with her headaches. Symptoms would typically last from 24 to 72 hours. She began using topical timolol 0.5%, one drop in each eye, approximately five years ago. If she instills the drops within a few minutes from the onset of an aura, her symptom relief is immediate and complete. If there is a delay in eye drop instillation, she rates her relief as an 8 on a scale of 1 to 10. She does not take any oral medications along with her drops and she has not had any side effects.

Discussion

The literature on using beta blocker eye drops to treat migraine is sparse. A 1980 report stated that topical timolol 0.5% relieved symptoms of Horton cluster headaches compared with placebo in four patients.¹ In 1999, a 59-year-old female with migraine and glaucoma had no improvement in migraine over 10 years on timolol drops although it controlled her glaucoma. She had a dramatic improvement of her migraines when carteolol beta blocker eye drops were substituted for timolol for better glaucoma control.² In 2000, a 4-year-old girl with ophthalmoplegic migraine was treated successfully with 0.25% timolol maleate bid.³ A 64-year-old woman with classic migraine resistant to standard oral therapy was started on timolol maleate 0.5% eye drops to both eyes. She had been migraine free for 18 years when the case was reported in 2004.⁴ Lastly, a 52-year-old male with “normal tension glaucoma” and migraines had relief from his headaches when placed on Timoptol-LA once per day for glaucoma therapy.⁵

Physicians often consider migraine prophylaxis when three or more attacks occur per month. Other indications include intolerable migrainous side effects that may constitute a danger to the patient or unsuccessful acute migraine therapy.^{6, 7} Two of the four FDA approved oral drugs for migraine prophylaxis are beta blockers (timolol and propranolol).⁷ The non-beta blockers are topiramate and divalproex.⁷ Three other beta blockers are often used ‘off label’ (atenolol, metroprolol and nadalol) for chronic migraine prevention. Neurologists and general practitioners preferentially used oral beta blockers for migraine prophylaxis in a European study.⁸ However, two double-blind, and placebo controlled studies have shown that oral propranolol has no significant effect in aborting acute attacks of migraine when compared with placebo.^{10, 11}

Timolol ophthalmic solution was the first topical beta blocker approved by the FDA for the treatment of glaucoma in 1978.⁹ It is a highly effective glaucoma medication with few ocular side effects and was for years the first line treatment for glaucoma world-wide. Several other ophthalmic beta blocking eye drops were subsequently approved. All of them have been used extensively (see Table 1). Beta blocker eye drops achieve pharmacologically active concentrations in the plasma.⁴ Ophthalmic beta blocker solutions applied topically to the eye are rapidly absorbed into the systemic circulation primarily by lacrimal duct transit into nasopharyngeal mucosa and, to a lesser extent, the conjunctival epithelium and the gastrointestinal tract.¹² Pharmacokinetic analysis has shown that one drop of timolol ophthalmic solution 0.5% in each eye will reach a plasma concentration of 2 ng/ml within 10 to 15 minutes.¹⁰ Beta 1 and beta 2 receptor blockade has been calculated to be approximately 80% with this plasma concentration.¹⁰ Our case reports support these observations with acute migraine symptom relief within minutes of beta blocker eye drop instillation especially if the drops are instilled as soon as possible after symptom onset.

Our cases and the literature collectively^1-12 suggest that the success of beta blocker eye drops in treating acute migraine may be due to the rapidity of eye drops in achieving effective blood levels. Oral beta blocker medication is subject to the “one pass effect,”¹⁶ i.e. inactivation of alimentary beta blocker by bacterial, gut and gut wall enzymes and hepatic metabolism (see Figure 1). In chronic migraine therapy, daily oral beta blocker medication attains effective blood levels for migraine prevention within hours to days. This would also explain the effectiveness of oral beta blockers on chronic migraine prevention.

Figure 1 The success of beta blocker eye drops in treating acute migraine may be due to the rapidity of eye drops in achieving effective blood levels.  Eye drops pass directly into circulation. Therapeutic blood levels occur in 4-10 minutes.  Oral beta blocker medication is subject to first pass metabolism and takes several hours to reach therapeutic blood levels. Source: http://intranasal.net

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