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Table.  
Summary and Participants’ Survey Responses While Using Placebo and Timolola
Summary and Participants’ Survey Responses While Using Placebo and Timolola
1.
Bobik  A, Jennings  GL, Ashley  P, Korner  PI.  Timolol pharmacokinetics and effects on heart rate and blood pressure after acute and chronic administration.  Eur J Clin Pharmacol. 1979;16(4):243-249. doi:10.1007/BF00608402Google ScholarCrossref
2.
Urtti  A, Rouhiainen  H, Kaila  T, Saano  V.  Controlled ocular timolol delivery: systemic absorption and intraocular pressure effects in humans.  Pharm Res. 1994;11(9):1278-1282.PubMedGoogle ScholarCrossref
3.
Korte  J-M, Kaila  T, Saari  KM.  Systemic bioavailability and cardiopulmonary effects of 0.5% timolol eyedrops.  Graefes Arch Clin Exp Ophthalmol. 2002;240(6):430-435.PubMedGoogle ScholarCrossref
4.
Migliazzo  CV, Hagan  JC  III.  Beta blocker eyedrops for treatment of acute migraine.  Mo Med. 2014;111(4):283-288.PubMedGoogle Scholar
5.
Chiam  PJT.  Topical beta-blocker treatment for migraine.  Int Ophthalmol. 2012;32(1):85-88.PubMedGoogle ScholarCrossref
6.
Headache Classification Committee of the International Headache Society. The international classification of headache disorders, 3rd edition (beta version). https://www.ichd-3.org/wp-content/uploads/2016/08/International-Headache-Classification-III-ICHD-III-2013-Beta-1.pdf. Accessed June 1, 2016.
Research Letter
August 2018

Timolol Eyedrops in the Treatment of Acute Migraine Attacks: A Randomized Crossover Study

Author Affiliations
  • 1University of Missouri–Kansas City School of Medicine, Kansas City
JAMA Neurol. 2018;75(8):1024-1025. doi:10.1001/jamaneurol.2018.0970

Several oral β-blockers are US Food and Drug Administration–approved for migraine prophylaxis, but their gradual absorption and modification by first-pass metabolism delays effective plasma levels for hours to days, limiting their use in acute migraines.1 Timolol eyedrops provide a rapid route of delivery with the maximum plasma concentration achieved within 15 minutes of administration.2,3 This pharmacokinetic advantage supports a potential role for timolol eyedrops in managing acute migraine.4,5

Methods

We conducted a randomized, crossover, placebo-controlled pilot study of timolol eyedrops as an abortive migraine treatment in adults. The study was approved by the institutional review board of the University of Missouri–Kansas City (Trial Protocol in the Supplement). Participants were recruited via our neurology and ophthalmology clinics, a listing on clinicaltrials.gov (NCT02630719), and flyers. Participants provided written consent.

Men and women who were at least age 18 years and met the International Headache Society criteria for migraine with or without aura6 were eligible for the study. All patients underwent a screening, which included complete neurological and ophthalmological examinations and a pregnancy test for women of childbearing potential. Participants were randomized to receive timolol maleate, 0.5%, or artificial tears at 1 drop in both eyes at onset and 30 minutes after. Participants were seen monthly for 5 visits over 4 months and crossed over at the 2-month mark with a 3-day washout period.

A data sheet for each migraine instructed participants to rate their migraine attacks on a scale of 0 to 3 in terms of severity. At the conclusion of the study, the participants were also asked to rate the effectiveness of each drop on a scale of 1 to 4 to decide whether they would use the timolol in place of or in addition to current treatments. The aim of this pilot study was to determine the effect size of timolol on migraine headaches.

Results

A total of 198 migraine attacks were studied among 10 participants. The overall effectiveness of timolol was 2.4 compared with 1.4 with the placebo (Table). Four participants found timolol highly effective compared with placebo while 1 participant found the opposite. The average percentage of headaches with a severity of none or mild at 2 hours was 57% with placebo compared with 78% with timolol (a Wilcoxon match paired test was conducted to account for repeated measurements and this difference was not found to be significant, with P = .26 as expected with a small pilot study). A 2-tailed χ2 statistic suggests that 172 randomized participants or 86 crossover participants would be needed to power a study with α ≤ .05 and β ≤ 0.2. One participant developed a branch retinal artery occlusion while using placebo, which was believed to be unrelated to the study. No other adverse events, including hypotension or bradycardia, were observed.

Discussion

This pilot study successfully explored the effect size of timolol eyedrops on migraine headaches. Several participants responded extremely well to the timolol. Further research is needed to determine what patient factors might predict responsiveness to timolol.

Limitations

Study limitations include a small sample size, a lack of investigator masking, and an imperfect placebo, as artificial tears tend to cause less of a burning sensation than timolol. With a half-life of 4 hours, timolol ophthalmic is unlikely to have had an association with repeated headaches or beyond the 3-day washout period. Four 50-μL drops of timolol, 0.5%, represent 1 mg of timolol, which compares with an oral prophylactic dosage of 10 to 30 mg of timolol daily. Future research should aim for a target enrollment of more than 86 participants and explore optimal dosing regimens.

Conclusions

Timolol is an effective abortive treatment for some patients with migraines. Future research should focus on identifying which patients will respond and at what dosage.

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Article Information

Accepted for Publication: February 23, 2018.

Corresponding Author: Sean Gratton, MD, University of Missouri–Kansas City School of Medicine, 2301 Holmes St, Kansas City, MO 64108 (grattons@umkc.edu).

Correction: This article was corrected online July 16, 2018, for errors in the Table and Results section and September 4, 2018, for an error in the Results section.

Published Online: May 14, 2018. doi:10.1001/jamaneurol.2018.0970

Author Contributions: Dr Cossack had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Cossack, Abraham, Gratton.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: All authors.

Critical revision of the manuscript for important intellectual content: Cossack, Gratton.

Statistical analysis: Cossack, Nabrinsky.

Administrative, technical, or material support: Turner, Abraham, Gratton.

Supervision: Gratton.

Conflict of Interest Disclosures: None reported.

Trial Registration: ClinicalTrials.gov Identifier: NCT02630719

Additional Contributions: We thank statistician An-Lin Cheng, PhD, University of Missouri–Kansas City, for her help with the statistical analysis and John Hagan, MD, Discover Vision Centers, and Carl Migliazzo, MD, Shawnee Mission Medical Center, for assisting with the conception of the study and patient recruitment. None of these individuals were compensated for their contributions.

References
1.
Bobik  A, Jennings  GL, Ashley  P, Korner  PI.  Timolol pharmacokinetics and effects on heart rate and blood pressure after acute and chronic administration.  Eur J Clin Pharmacol. 1979;16(4):243-249. doi:10.1007/BF00608402Google ScholarCrossref
2.
Urtti  A, Rouhiainen  H, Kaila  T, Saano  V.  Controlled ocular timolol delivery: systemic absorption and intraocular pressure effects in humans.  Pharm Res. 1994;11(9):1278-1282.PubMedGoogle ScholarCrossref
3.
Korte  J-M, Kaila  T, Saari  KM.  Systemic bioavailability and cardiopulmonary effects of 0.5% timolol eyedrops.  Graefes Arch Clin Exp Ophthalmol. 2002;240(6):430-435.PubMedGoogle ScholarCrossref
4.
Migliazzo  CV, Hagan  JC  III.  Beta blocker eyedrops for treatment of acute migraine.  Mo Med. 2014;111(4):283-288.PubMedGoogle Scholar
5.
Chiam  PJT.  Topical beta-blocker treatment for migraine.  Int Ophthalmol. 2012;32(1):85-88.PubMedGoogle ScholarCrossref
6.
Headache Classification Committee of the International Headache Society. The international classification of headache disorders, 3rd edition (beta version). https://www.ichd-3.org/wp-content/uploads/2016/08/International-Headache-Classification-III-ICHD-III-2013-Beta-1.pdf. Accessed June 1, 2016.
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