Put a Drop of Timolol Into Each Eye and Call Me in the Morning
Invited Commentary
Invited Commentary
Put a Drop of Timolol Into Each Eye and Call Me in the Morning Bradley J. Katz, MD, PhD
Migraine is the most common, chronic, serious neurologic condition worldwide, affecting more than 11% of the world’s population.1 In the United States, it affects approximately 16% of women and 6% of men.2 Although migraine is a neurologic illness, it is associated with a number of ocular and visual Related article symptoms, including visual aura, photophobia, eye pain, and visual snow.3 As a result, it is not uncommon for patients with migraine to consult an ophthalmologist because they perceive their problem to be an eye problem and not a brain problem. The pathophysiology of migraine is incompletely understood, but most experts agree that migraine affects the trigeminovascular system, which consists of neurons in the trigeminal nerve that innervate cerebral blood vessels.4 Because the pathophysiology is incompletely understood, progress in developing treatments has been slow. Recently, several highly effective new drugs have been approved for the prevention of migraine attacks and the short-term treatment of migraine attacks. These drugs all affect the neuropeptide calcitonin generelated peptide and its receptors.5 These new drugs have another thing in common: they can be prohibitively expensive,6 limiting their use outside of high-income countries. In this issue of JAMA Ophthalmology, researchers at the Chaithanya Eye Hospital in Thiruvananthapuram, India, have repurposed an inexpensive ophthalmic medication for the treatment of migraine. Kurian et al7 present preliminary evidence that timolol, 0.5%, eyedrops, the same medication that has been used by ophthalmologists to treat glaucoma since 1978, may be an effective treatment for migraine headaches. In this investigation, the authors randomized 50 patients with migraine to use timolol, 0.5%, eyedrops or a placebo eye drop (artificial tears) to treat migraine headaches for 3 months. At the end of 3 months, patients completed a 1-month washout period and then crossed over to use the other treatment for an additional 3 months. Patients were instructed to put 1 drop of the study medication into each eye at headache onset. If patients did not have relief of their pain at 10 minutes, they were instructed to put another drop into each eye. Patients assessed their pain level 20 minutes after instillation of the drops and recorded their headaches in a diary. At the con-
ARTICLE INFORMATION Author Affiliations: Department of Ophthalmology, John A. Moran Eye Center, University of Utah Health Sciences Center, Salt Lake City; Department of Neurology, John A. Moran Eye Center, University of Utah Health Sciences Center, Salt Lake City. Corresponding Author: Bradley J. Katz, MD, PhD, Departments of Ophthalmology and Neurology, John A. Moran Eye Center, University of Utah
jamaophthalmology.com
clusion of the trial, the 50 patients had recorded a total of 619 migraine attacks. Just under half of the attacks were treated with timolol, and just under half of the attacks were treated with the placebo. The authors report that 233 timolol-treated attacks (82%) were associated with a clinically significant reduction in pain scores 20 minutes after instillation of the eyedrops, compared with 38 placebo-treated attacks (14%). β-Blockers, especially oral propranolol, can be very effective for migraine prevention but have never been found to be useful for acute treatment.8 The authors hypothesize that first-pass metabolism and the relatively slow absorption of oral β-blockers might explain their inability to treat an acute headache. Although the amount of timolol in two 0.5% eyedrops is approximately 0.5 mg, the authors hypothesize that the effectiveness of the treatment might be ascribed to its rapid absorption by the nasal mucosa. Another migraine treatment, sumatriptan, is available as a nasal spray to increase bioavailability and to make absorption more rapid. The authors concede that further research is required to confirm timolol’s effectiveness in migraine treatment. Clinical researchers who study migraine treatment will want to see better characterization of patients (eg, episodic migraine vs chronic migraine and migraine with aura vs migraine without aura), as well as other clinically relevant end points, such as pain relief at 2 and 4 hours. The authors are to be complimented for including adolescents in their study. Despite the fact that migraine affects approximately 7.7% of children,9 this age group is often excluded from clinical research. As a result, there are a very limited number of US Food and Drug Administration– approved migraine treatments for children and adolescents. Although a subgroup analysis was not conducted, based on the results presented here, future trials of timolol eyedrops in this age group might be warranted. Timolol is inexpensive and has a very good adverse event profile and safety profile.10 If the results presented here can be replicated in future studies, timolol eyedrops could be a safe, simple, and inexpensive treatment for a common, global condition associated with significant disability.
Health Sciences Center, 65 N Mario Capecchi Dr, Salt Lake City, UT 84132 ([email protected]. edu). Published Online: October 1, 2020. doi:10.1001/jamaophthalmol.2020.3837 Conflict of Interest Disclosures: Dr Katz reports grants from Research to Prevent Blindness; CEO of Axon Optics outside the submitted work; has a patent for methods, systems, and apparatus issued, licensed, and with royalties paid; and a patent for nanoparticle light filtering issued and licensed.
REFERENCES 1. Global Burden of Disease Study 2013 Collaborators. Global Burden of Disease Study 2013 Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015;386(9995):743-800. doi:10. 1016/S0140-6736(15)60692-4
(Reprinted) JAMA Ophthalmology Published online October 1, 2020
© 2020 American Medical Association. All rights reserved.
Downloaded From: https://jamanetwork.com/ by a University of Canberra User on 10/04/2020
E1
Invited Commentary
Put a Drop of Timolol Into Each Eye and Call Me in the Morning
2. Stewart WF, Lipton RB, Celentano DD, Reed ML. Prevalence of migraine headache in the United States. Relation to age, income, race, and other sociodemographic factors. JAMA. 1992;267(1): 64-69. doi:10.1001/jama.1992.03480010072027 3. Schwartz DP, Robbins MS. Primary headache disorders and neuro-ophthalmologic manifestations. Eye Brain. 2012;4:49-61. 4. Goadsby PJ, Holland PR, Martins-Oliveira M, Hoffmann J, Schankin C, Akerman S. Pathophysiology of migraine: a disorder of sensory processing. Physiol Rev. 2017;97(2):553-622. doi:10.1152/physrev.00034.2015
E2
5. Russo AF. Calcitonin gene-related peptide (CGRP): a new target for migraine. Annu Rev Pharmacol Toxicol. 2015;55:533-552. doi:10.1146/ annurev-pharmtox-010814-124701 6. Loder E, Renthal W. Calcitonin gene-related peptide monoclonal antibody treatments for migraine. JAMA Intern Med. 2019;179(3):421-422. doi:10.1001/jamainternmed.2018.7536 7. Kurian A, Reghunadhan I, Thilak P, Soman I, Nair U. Short-term efficacy and safety of topical β-blockers (timolol maleate ophthalmic solution, 0.5%) in acute migraine: a randomized crossover trial. JAMA Ophthalmol. Published online October 1, 2020. doi:10.1001/jamaophthalmol.2020.3676
8. Goadsby PJ, Lipton RB, Ferrari MD. Migraine: current understanding and treatment. N Engl J Med. 2002;346(4):257-270. doi:10.1056/NEJMra010917 9. Abu-Arafeh I, Razak S, Sivaraman B, Graham C. Prevalence of headache and migraine in children and adolescents: a systematic review of population-based studies. Dev Med Child Neurol. 2010;52(12):1088-1097. doi:10.1111/j.1469-8749. 2010.03793.x 10. Zimmerman TJ, Leader BJ, Golob DS. Potential side effects of timolol therapy in the treatment of glaucoma. Ann Ophthalmol. 1981;13(6):683-689.
JAMA Ophthalmology Published online October 1, 2020 (Reprinted)
© 2020 American Medical Association. All rights reserved.
Downloaded From: https://jamanetwork.com/ by a University of Canberra User on 10/04/2020
jamaophthalmology.com
Invited Commentary
Invited Commentary
Put a Drop of Timolol Into Each Eye and Call Me in the Morning Bradley J. Katz, MD, PhD
Migraine is the most common, chronic, serious neurologic condition worldwide, affecting more than 11% of the world’s population.1 In the United States, it affects approximately 16% of women and 6% of men.2 Although migraine is a neurologic illness, it is associated with a number of ocular and visual Related article symptoms, including visual aura, photophobia, eye pain, and visual snow.3 As a result, it is not uncommon for patients with migraine to consult an ophthalmologist because they perceive their problem to be an eye problem and not a brain problem. The pathophysiology of migraine is incompletely understood, but most experts agree that migraine affects the trigeminovascular system, which consists of neurons in the trigeminal nerve that innervate cerebral blood vessels.4 Because the pathophysiology is incompletely understood, progress in developing treatments has been slow. Recently, several highly effective new drugs have been approved for the prevention of migraine attacks and the short-term treatment of migraine attacks. These drugs all affect the neuropeptide calcitonin generelated peptide and its receptors.5 These new drugs have another thing in common: they can be prohibitively expensive,6 limiting their use outside of high-income countries. In this issue of JAMA Ophthalmology, researchers at the Chaithanya Eye Hospital in Thiruvananthapuram, India, have repurposed an inexpensive ophthalmic medication for the treatment of migraine. Kurian et al7 present preliminary evidence that timolol, 0.5%, eyedrops, the same medication that has been used by ophthalmologists to treat glaucoma since 1978, may be an effective treatment for migraine headaches. In this investigation, the authors randomized 50 patients with migraine to use timolol, 0.5%, eyedrops or a placebo eye drop (artificial tears) to treat migraine headaches for 3 months. At the end of 3 months, patients completed a 1-month washout period and then crossed over to use the other treatment for an additional 3 months. Patients were instructed to put 1 drop of the study medication into each eye at headache onset. If patients did not have relief of their pain at 10 minutes, they were instructed to put another drop into each eye. Patients assessed their pain level 20 minutes after instillation of the drops and recorded their headaches in a diary. At the con-
ARTICLE INFORMATION Author Affiliations: Department of Ophthalmology, John A. Moran Eye Center, University of Utah Health Sciences Center, Salt Lake City; Department of Neurology, John A. Moran Eye Center, University of Utah Health Sciences Center, Salt Lake City. Corresponding Author: Bradley J. Katz, MD, PhD, Departments of Ophthalmology and Neurology, John A. Moran Eye Center, University of Utah
jamaophthalmology.com
clusion of the trial, the 50 patients had recorded a total of 619 migraine attacks. Just under half of the attacks were treated with timolol, and just under half of the attacks were treated with the placebo. The authors report that 233 timolol-treated attacks (82%) were associated with a clinically significant reduction in pain scores 20 minutes after instillation of the eyedrops, compared with 38 placebo-treated attacks (14%). β-Blockers, especially oral propranolol, can be very effective for migraine prevention but have never been found to be useful for acute treatment.8 The authors hypothesize that first-pass metabolism and the relatively slow absorption of oral β-blockers might explain their inability to treat an acute headache. Although the amount of timolol in two 0.5% eyedrops is approximately 0.5 mg, the authors hypothesize that the effectiveness of the treatment might be ascribed to its rapid absorption by the nasal mucosa. Another migraine treatment, sumatriptan, is available as a nasal spray to increase bioavailability and to make absorption more rapid. The authors concede that further research is required to confirm timolol’s effectiveness in migraine treatment. Clinical researchers who study migraine treatment will want to see better characterization of patients (eg, episodic migraine vs chronic migraine and migraine with aura vs migraine without aura), as well as other clinically relevant end points, such as pain relief at 2 and 4 hours. The authors are to be complimented for including adolescents in their study. Despite the fact that migraine affects approximately 7.7% of children,9 this age group is often excluded from clinical research. As a result, there are a very limited number of US Food and Drug Administration– approved migraine treatments for children and adolescents. Although a subgroup analysis was not conducted, based on the results presented here, future trials of timolol eyedrops in this age group might be warranted. Timolol is inexpensive and has a very good adverse event profile and safety profile.10 If the results presented here can be replicated in future studies, timolol eyedrops could be a safe, simple, and inexpensive treatment for a common, global condition associated with significant disability.
Health Sciences Center, 65 N Mario Capecchi Dr, Salt Lake City, UT 84132 ([email protected]. edu). Published Online: October 1, 2020. doi:10.1001/jamaophthalmol.2020.3837 Conflict of Interest Disclosures: Dr Katz reports grants from Research to Prevent Blindness; CEO of Axon Optics outside the submitted work; has a patent for methods, systems, and apparatus issued, licensed, and with royalties paid; and a patent for nanoparticle light filtering issued and licensed.
REFERENCES 1. Global Burden of Disease Study 2013 Collaborators. Global Burden of Disease Study 2013 Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015;386(9995):743-800. doi:10. 1016/S0140-6736(15)60692-4
(Reprinted) JAMA Ophthalmology Published online October 1, 2020
© 2020 American Medical Association. All rights reserved.
Downloaded From: https://jamanetwork.com/ by a University of Canberra User on 10/04/2020
E1
Invited Commentary
Put a Drop of Timolol Into Each Eye and Call Me in the Morning
2. Stewart WF, Lipton RB, Celentano DD, Reed ML. Prevalence of migraine headache in the United States. Relation to age, income, race, and other sociodemographic factors. JAMA. 1992;267(1): 64-69. doi:10.1001/jama.1992.03480010072027 3. Schwartz DP, Robbins MS. Primary headache disorders and neuro-ophthalmologic manifestations. Eye Brain. 2012;4:49-61. 4. Goadsby PJ, Holland PR, Martins-Oliveira M, Hoffmann J, Schankin C, Akerman S. Pathophysiology of migraine: a disorder of sensory processing. Physiol Rev. 2017;97(2):553-622. doi:10.1152/physrev.00034.2015
E2
5. Russo AF. Calcitonin gene-related peptide (CGRP): a new target for migraine. Annu Rev Pharmacol Toxicol. 2015;55:533-552. doi:10.1146/ annurev-pharmtox-010814-124701 6. Loder E, Renthal W. Calcitonin gene-related peptide monoclonal antibody treatments for migraine. JAMA Intern Med. 2019;179(3):421-422. doi:10.1001/jamainternmed.2018.7536 7. Kurian A, Reghunadhan I, Thilak P, Soman I, Nair U. Short-term efficacy and safety of topical β-blockers (timolol maleate ophthalmic solution, 0.5%) in acute migraine: a randomized crossover trial. JAMA Ophthalmol. Published online October 1, 2020. doi:10.1001/jamaophthalmol.2020.3676
8. Goadsby PJ, Lipton RB, Ferrari MD. Migraine: current understanding and treatment. N Engl J Med. 2002;346(4):257-270. doi:10.1056/NEJMra010917 9. Abu-Arafeh I, Razak S, Sivaraman B, Graham C. Prevalence of headache and migraine in children and adolescents: a systematic review of population-based studies. Dev Med Child Neurol. 2010;52(12):1088-1097. doi:10.1111/j.1469-8749. 2010.03793.x 10. Zimmerman TJ, Leader BJ, Golob DS. Potential side effects of timolol therapy in the treatment of glaucoma. Ann Ophthalmol. 1981;13(6):683-689.
JAMA Ophthalmology Published online October 1, 2020 (Reprinted)
© 2020 American Medical Association. All rights reserved.
Downloaded From: https://jamanetwork.com/ by a University of Canberra User on 10/04/2020
jamaophthalmology.com
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