The lower and upper ends of the whisker represent minimum and maximum pain scores for each group. The lower border of the box represents the 25th percentile; the upper border represents the 75th percentile.
eFigure 1. ICHD-III Beta Diagnostic Criteria for Migraine
eFigure 2. Crossover Diagram
eFigure 3. Overall Comparison of Primary Outcome After Treatment With Timolol and Placebo
eFigure 4. Distribution of Potentially Clinically Relevant Outcome (Aborted Attacks) in the Groups Based on the Period of Treatment
eAppendix. Migraine Diary
eTable 1. Study Procedures at Each Visit
eTable 2. Analysis of Systemic Side Effects
Data Sharing Statement.
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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. 2020;138(11):1160–1166. doi:10.1001/jamaophthalmol.2020.3676
Can topical timolol maleate ophthalmic solution reduce pain scores after an acute migraine attack better than placebo eyedrops?
In a randomized crossover clinical trial involving 50 patients, topical timolol was more likely to reduce pain scores 20 minutes after instillation compared with placebo.
These findings support consideration of timolol eyedrops in the management of acute migraine attacks, but confirmation for longer follow-up with larger groups at multiple sites is warranted.
Oral β-blockers used for the prevention of migraine headache are not effective for the treatment of acute pain. Small case series have suggested that topically applied β-blockers may be useful in the management of acute migraine pain, warranting evaluation with randomized clinical trials.
To evaluate the short-term efficacy and safety of topically applied timolol maleate ophthalmic solution, 0.5%, compared with topically applied placebo eyedrops in the treatment of acute migraine attacks.
Design, Setting, and Participants
In this randomized, masked placebo-controlled crossover trial conducted from May 27, 2015, to August 28, 2017, 50 patients with migraine were randomized to receive either timolol eyedrops, 0.5%, or a placebo eyedrop (carboxymethyl cellulose, 0.5%). After a 3-month treatment period, patients completed a 1-month washout period and were crossed over to receive the opposite treatment for a final 3 months. Analysis was performed on a modified intent-to-treat basis.
After random assignment, patients were instructed to use 1 drop of the assigned medication in each eye at the earliest onset of migraine.
Main Outcomes and Measures
The main outcome measure was reduction in pain score with treatment. The primary end point was reduction of pain score by 4 points, or to zero, 20 minutes after instillation of the eyedrop.
Of the 50 patients, 42 (84%) were females and the mean (SD) age was 27.3 (11.3) years. Of a total of 619 migraine attacks, 284 (46%) were treated with timolol, 271 (44%) were treated with the placebo, and 64 (10%) occurred during the washout period when no study medications were used. Seven patients (14%) withdrew after randomization. A total of 233 of the timolol-treated migraine attacks (82%) were associated with a reduction in pain score by 4 points, or to zero, at 20 minutes compared with 38 of the placebo-treated attacks (14%), with a difference of 68 percentage points (95% CI, 62-74 percentage points). A generalized estimating equation analysis revealed that pain score reduction at 20 minutes was greater in the timolol group compared with the placebo group by a mean (SE) of 4.63 points (0.34) (P < .001).
Conclusions and Relevance
This randomized crossover trial supports consideration of timolol eyedrops in the acute treatment of migraine. Further research is warranted to determine if the improvements observed are sustained for a longer follow-up and with larger groups.
CTRI/2015/05/005829, UTN: U1111-1167-6439
Migraine is characterized by recurrent episodes of headache that last for 4 to 72 hours, often associated with an aura that is most commonly visual. It is more common in females and peaks at age 30 to 40 years. Studies report global prevalence rates of migraine between 2.6% and 21.7% (mean, approximately 12%).1,2 The community-based prevalence of migraine in studies from India is estimated as 14.1%, which is similar to that observed in other countries.2 The Global Burden of Disease Study 2013 reported migraine as the sixth-highest cause of disability worldwide.3
Headache is a primary requirement for diagnosing migraine in many classifications. The Headache Classification Committee of the International Headache Society provides comprehensive classification and treatment guidelines for headache disorders including migraine.4,5
Oral timolol maleate is 1 of the 4 drugs approved by the US Food and Drug Administration for migraine prophylaxis, but studies have shown oral β-blockers to be ineffective for acute migraine.6-8 On the other hand, topical timolol is a time-tested drug widely used in the treatment of glaucoma. Literature on using β-blocker eyedrops to treat migraine headaches is sparse and consists of only isolated case reports.9-12 A 2014 case report by Migliazzo and Hagan13 substantiated the success of using β-blocker eyedrops to treat acute migraine but was a small case series of only 7 patients.
To our knowledge, no controlled prospective or retrospective study has been performed on acute migraine treatment with β-blocker eyedrops.13 In August 2018, a research letter by Cossack et al14 described a pilot study that also had a randomized crossover design similar to ours but was not masked and had only 10 patients; the results reported, although supporting timolol eyedrops, could not be considered conclusive. Hence, this larger prospective, masked, placebo-controlled study with a crossover design was formulated, and we report the results herein.
We conducted a single-center, randomized, double-masked, placebo-controlled clinical trial with a crossover design from May 27, 2015, to August 28, 2017, at Chaithanya Eye Hospital and Research Institute, Trivandrum, India (the full study protocol is in Supplement 1). The trial conformed to the tenets of the Declaration of Helsinki15 and was registered prospectively in the Clinical Trial Registry, India. The Chaithanya Eye Hospital and Research Institute Ethical Committee approved the study, and written informed consent was obtained from all recruited participants. In addition, written parental assent was obtained from participants younger than 18 years. The participants were not offered any compensation or incentives for their participation. This study followed the 2010 Consolidated Standards of Reporting Trials (CONSORT) reporting guideline.
The patients found to be eligible after screening for inclusion and exclusion criteria (Box16 and eFigure 1 in Supplement 2) on baseline evaluation were enrolled in the study. Enrolled patients were randomly allocated to group A (treatment group: timolol maleate, 0.5%, plus hydroxypropyl methylcellulose, 0.3%, eyedrops; 1 drop of 0.5% timolol ophthalmic solution contains 0.25 mg of the drug) or group B (control group: placebo eyedrops; carboxymethyl cellulose, 0.5%, eyedrops, which are artificial tears often used over the counter for treatment of dry eye disease).
Male or female patients at least 12 years of age
A negative urine pregnancy test result at enrollment on day 1 for women of childbearing potential
Written informed consent obtained
Clinical diagnosis of migraine classified under the following subtypes according to the ICHD Beta diagnostic criteria16 (eFigure 1 in Supplement 2)
Migraine without aura (ICHD classification, 1.1)
Typical aura with headache (ICHD classification, 184.108.40.206) (subtype of migraine with aura; ICHD classification, 1.2)b
Probable migraine without aura (ICHD classification, 1.5.1)
Probable migraine with aura (ICHD classification, 1.5.2) (corresponding to the subgroup typical aura with headache; ICHD classification, 220.127.116.11)c
Not taking any antimigraine medications for at least 1 month
Ability to understand and follow the study instructions
Willingness to undergo 7 months of follow-up
Known allergy or hypersensitivity to the study medications
Female patients who are pregnant, breastfeeding, or planning to become pregnant during the study
Female patients of childbearing age not using a reliable means of contraception
Patients with bronchial asthma, bradyarrhythmias, and cardiac dysfunction
Patients with coexistent glaucoma, in whom use of topical β-blockers is anticipated
Patients taking systemic β-blockers for any indication
Patients taking medications for migraine, not willing to stop existing treatment for at least 1 month
Obstruction of lacrimal drainage system detected on baseline evaluation
Abbreviation: ICHD, International Classification of Headache Disorders, 3rd edition.
a Patients with chronic migraine according to the ICHD Beta diagnostic criteria were not included in the study, as it would be impossible to distinguish the individual episodes of headache in patients with such frequent or continuous headaches. Such patients are extremely difficult to keep medication free for 1 month, which was a prerequisite of the study.
b From the migraine with aura group (ICHD classification, 1.2), only the subtype of migraine with typical aura (ICHD classification, 1.2.1) and, within that subtype, only the subgroup of typical aura with headache (ICHD classification, 18.104.22.168) were included.
c In the probable migraine with aura group (ICHD classification, 1.5.2), only patients fulfilling the criteria for the subgroup of typical aura with headache (ICHD classification, 22.214.171.124) were included in the study to prevent confusion in recording the pain score, which was required at the onset of headache.
Quiz Ref IDThe randomization was based on a computer-generated random sequence; masking was ensured by sealed envelopes, and each patient was assigned to group A or group B. After randomization, a randomization number was allotted to each patient, and the medication was issued to the patient by assigned staff at the pharmacy in prepacked sealed kits for each randomization number and for each visit in identical-looking containers with labels removed to maintain masking. The same procedure was followed at each visit. The patients continued in the same group for the first 3 months of the study and, after a medication-free fourth month, were crossed over to the other group (eFigure 2 in Supplement 2). After day 1, medications were issued at the month 1, month 2, month 4, month 5, and month 6 visits. The study procedures at each visit are outlined in eTable 1 in Supplement 2.
Irrigation of the nasolacrimal duct was performed at baseline to confirm its patency, which was a prerequisite for the topical medication to reach the nasal mucosa to ensure adequate absorption to attain the required blood level.
The patients were instructed to use 1 drop of the assigned medication in each eye at the earliest onset of migraine (aura or headache). They were instructed to use another drop at 10 minutes if there was no relief with the first drop. If the patient had no pain relief at 20 minutes after pain onset, they were free to use any other oral medication for pain relief. The rescue medications used were only those for treatment of acute migraine and included acetaminophen, metoclopramide, and prochlorperazine. Prophylactic antimigraine medications were not allowed.
For each acute migraine attack, patients were asked to record the details in a diary (eAppendix in Supplement 2), which was collected at each visit. Patients were asked about adherence to treatment and to report any serious medical event or adverse event encountered during the intervening period.
Patients were asked to grade the migraine headache on a pain scale of 0 to 10 before and after the use of study medication (eAppendix in Supplement 2 for scale and definition). The main outcome measure was reduction in pain score 20 minutes after the use of study medication. The primary end point was reduction of the pain score by 4 points, or to zero, 20 minutes after instillation of the eyedrop. The secondary end point was nonuse of an oral rescue medication. A reduction in pain score to 0 or of at least 4 points on the pain scale when measured at 20 minutes, without the use of any oral rescue medication, was considered a potentially clinically relevant outcome.
Individuals in the migraine with aura–typical aura with headache subgroup were instructed to use the eyedrops at the onset of aura and to measure the pain score at the onset of headache. In this group, attacks that started as aura, in which a headache did not develop in the 20 minutes after the aura, were not included for analysis because the pain score and primary end point could not be recorded for these episodes. The episodes that were aborted in the aura stage itself after use of the study eyedrops were also not taken up for analysis because the pain score and primary end point also could not be recorded for these episodes. The secondary measures analyzed were the presence of adverse effects or systemic adverse effects due to use of study medication.
Power was calculated as for a binary outcome superiority trial with crossover design at 90% power at a significance level of 5%, assuming 10% treatment success in the control group and 60% in the experimental group. This yielded a total sample size of 36. To adjust for an assumed potential dropout of 25%, a sample size of 50 was the goal. Accumulated data were subjected to both qualitative and quantitative analysis (Microsoft Office Excel 365; Microsoft Corp, and IBM SPSS Statistics, version 20; IBM Inc). Data were evaluated using a modified intent-to-treat analysis that included data from all 43 patients for whom postbaseline data were available.
A preliminary analysis of the 2 treatment groups was performed by unpaired t test to rule out any crossover effect. This overall analysis was based on individual migraine episodes rather than at the patient level. Because migraines within an individual are correlated, not accounting for the correlation may artificially inflate the power of the study to find a difference. Hence, an analysis was also performed at the patient level by aggregating the scores for each patient.
An analysis using generalized estimating equations was performed to account for the correlations in the data owing to repeated measures for migraine incidences. The generalized linear model with independent covariance structure was used, with the pain score difference in 20 minutes as the dependent variable and the time period (binary variable), treatment (binary variable), and their interaction as independent variables. Correlation between data sets (between headache severity and response to treatment) was analyzed by calculating the correlation coefficient using the CORREL function of Excel (Microsoft Corp).
To assess the systemic adverse effects, baseline parameters including resting heart rate, systolic and diastolic blood pressure, and respiratory rate were compared with the mean value of these parameters after intervention, in both the timolol and placebo groups, by a 1-way repeated-measures analysis of variance.
A 2-sided P ≤ .05 was considered statistically significant for the primary outcome only. There were no adjustments to P values for multiple analyses.
The study, including recruitment and follow-up, was conducted from May 27, 2015, to August 28, 2017. The patient flowchart is shown in Figure 1. A total of 50 patients were enrolled in this trial after screening for the eligibility criteria. Of these, 7 patients withdrew after the randomization visit; because no data were available for postbaseline analysis, those patients were excluded from the primary analysis. A modified intent-to-treat analysis that included observed data from the remaining 43 patients was performed.
Of these 43 patients, 38 completed the 7-month follow-up. For the 5 patients who withdrew with incomplete follow-up, only the observed data were used. None of the 43 patients reported any nonadherence to the protocol or medication use during any of the reported migraine attacks. Baseline demographic characteristics are shown in Table 1.
As detailed in the Methods, migraine attacks in which headache followed the aura more than 20 minutes later (14 attacks) and attacks aborted in the aura stage itself (12 attacks) were excluded from analysis. After excluding these, the 43 patients had a total of 619 eligible migraine attacks during the study period, of which 284 (46%) were treated with timolol eyedrops, 271 (44%) with placebo eyedrops, and the remaining 64 (10%) were during the washout period when no study medications were used. Of the 619 attacks, 359 (58%) were on both sides of the head, while the rest were unilateral.
Quiz Ref IDTo analyze the primary outcome in general, the 284 attacks treated with timolol were compared with the 271 attacks treated with placebo. The mean (SD) number of attacks treated with timolol was 2.3 (1.3) and with placebo was 1.3 (1.3). According to the definition of the potentially clinically relevant outcome as detailed in the Methods, primary analysis showed that 233 (82%) of the attacks treated with timolol were associated with a reduction in pain score by 4 points or to zero at 20 minutes compared with 38 (14%) attacks treated with placebo (eFigures 3 and 4 in Supplement 2). The difference between the groups was 68 percentage points (95% CI, 62-74 percentage points; P < .001). A total of 120 (42%) of the attacks treated with timolol required a second administration of drops after 10 minutes.
Oral rescue medications were required in 74 attacks, all of which belonged to the group of 284 attacks that did not have a potentially clinically relevant outcome. Oral rescue medications were not required in any of the attacks with the potentially clinically relevant outcome. This finding equated the primary and secondary end points of our study to a common primary outcome measure.
To account for the crossover design and to look for any carryover effect, the number of attacks and mean reduction in pain score with intervention at 20 minutes were assessed at the patient level and compared between the 2 groups by an unpaired t test. The results are reported in Table 2. The mean (SD) reduction in pain score with timolol was 4.58 (1.77) for group A and 5.04 (1.65) for group B, with a difference of −0.46 (95% CI, −1.49 to 0.57; P = .38). The mean (SD) reduction in pain score with placebo was 0.84 (1.35) for group A and 1.00 (1.40) for group B, with a difference of −0.16 (95% CI, −0.98 to 0.66; P = .69). Hence, it was concluded that there was no significant carryover effect due to the crossover, and data from both periods were considered for all further analysis.
The mean (SD) pain score at the onset of attacks was 6.01 (1.40) for the 284 migraine attacks treated with timolol and 5.93 (1.42) for the 271 migraine attacks treated with placebo. Only 10 (4%) of the attacks treated with timolol and 11 (4%) of the attacks treated with placebo recorded a pain score of 3 or less; hence, floor effects were only minimal. A box and whisker plot depicting the pain scores before and after timolol and placebo separately is shown in Figure 2 and shows results on an attack-specific level.
The difference in pain scores before and after interventions was compared between timolol and placebo after integrating the mean (SD) reduction in pain scores for each patient by paired t test (5.98 [2.54] for timolol and 0.93 [1.37] for placebo). The difference of 5.05 (95% CI, 4.19-5.91) was significant at P < .001 (Table 2).
Quiz Ref IDA generalized estimating equation analysis revealed that pain score reduction at 20 minutes was a mean (SE) of 4.63 (0.34) points greater in the timolol group compared with the placebo group (P < .001). The generalized linear model was also used for analyzing the parameter estimates, that is, the time period and its interaction with treatment. A correlation between the pain score at onset and response to intervention yielded a correlation coefficient of −0.04, indicating no correlation between the severity of the attack and a positive or negative outcome.
Adverse reactions or systemic adverse effects of timolol eyedrops were not seen in any patient during the study period. A 1-way analysis of variance for repeated measures did not reveal any significant difference between the groups for any of these parameters (eTable 2 in Supplement 2).
The factor precluding the use of oral β-blockers in acute migraine attacks is proposed to be its high first-pass metabolism and time taken to achieve peak plasma levels. Topically administered β-blockers are thought to overcome this, and plasma levels, although 100 to 250 times less than the orally administered dose, have been shown in studies to cause pharmacologic effects6,16 and hence could be beneficial in aborting acute migraine attacks.
A review of the literature shows that all previous publications describing the beneficial effects of β-blocker eyedrops for the treatment of migraine headaches are sporadic isolated case reports. The literature collectively9-12 suggests that the success of β-blocker eyedrops in treating acute migraine may be a result of the rapidity of eyedrops in achieving effective blood levels when instilled shortly after symptom onset.
Our study showed that patients treated with timolol eyedrops at the onset of a migraine attack had a statistically significant chance of a potentially clinically relevant outcome compared with the patients treated with placebo eyedrops and confirmed it as a useful treatment option for aborting acute migraine attacks. This finding was comparable with those from similar studies.13,14
Analyzing our results, most patients were adults younger than 30 years; 16 patients (32%) were between 12 and 18 years of age. Because data from this age group were included in our study, one could postulate that timolol eyedrops may be useful in adolescents as well as adults, without any systemic effects. However, because no subgroup analysis was performed, this possibility needs validation by additional studies.
Unlike oral administration, ophthalmically administered β-blockers bypass first-pass metabolism by the liver.17,18 Because the pharmacokinetics of nasopharyngeal absorption may be similar to those of an intravenous bolus, plasma levels are achieved very quickly with topical administration. As a result, high plasma levels may be achieved from an eyedrop even though a large portion of the drop overflows onto the eyelids.19,20
A review of pharmacokinetic data has shown that when timolol solution was administered topically, peak plasma levels of 0.5 ng/mL were attained in 10 minutes, with a decrease to 0.3 ng/mL after 4 hours.17-20 In contrast, a single oral dose of 20 mg of timolol attained a peak plasma level of 50 to 103 ng/mL 1 to 2 hours after oral administration. Detectable plasma levels of oral timolol occur in 30 minutes, and the mean plasma half-life after oral dosing is 4 hours.21 The highest plasma concentration will occur soon after entry into the circulation, before significant dilution occurs and the drug is spread over its known volume of distribution. Guidelines state that abortive therapy for migraine should be used as early as possible after the onset of symptoms.22,23 Hence, the use of timolol as eyedrops had the advantage of attaining peak plasma levels quickly at levels high enough to abort the acute migraine attacks effectively.
Quiz Ref IDOur study had some limitations, including that of being a crossover study, in which a carryover effect is possible. However, with an adequate washout period of 1 month, this effect was considered insignificant. Another limitation was that we could include only the group of patients with migraine who had a headache. Although rare, other migraine subgroups were excluded. In the subgroup of migraine patients having typical aura with headache (International Classification of Headache Disorders classification, 126.96.36.199), our study design had some shortcomings. We could not include migraine attacks that started as aura and progressed to headache only after 20 minutes. Similarly, attacks that were aborted in the aura stage were also excluded from analysis. These exclusions lowered the total number of attacks used for analysis. However, because there were only 12 migraine attacks that started as aura and progressed to headache only after 20 minutes and 14 attacks that were aborted in the aura stage, which could have accounted for only 4% of the total attacks (26 of 645), it was thought that these should be excluded. Also, the effects of the study drug on ancillary symptoms in migraine such as nausea and vomiting were not graded or assessed. Our study also had the limitation that we assessed only the quick response (at 20 minutes) to the eyedrops. Improvements at the 2-hour and 4-hour end points were not studied. In addition, the physical examinations were performed well outside the treatment effect period and therefore are unlikely to have identified any systemic adverse effects. With our investigation being a single-center study, our study population was also limited to a single region. We suggest that future studies address these aspects and include 2-hour and 4-hour end points and confirmation for longer follow-up with larger groups at multiple sites.
The results observed give further support to the hypothesis that topically applied β-blockers may be an effective and inexpensive abortive migraine medication for some patients, with fewer adverse effects. The study supports consideration of timolol eyedrops in aborting acute migraine attacks compared with placebo eyedrops. Use of topical β-blockers can at least theoretically abolish confounding factors such as high first-pass metabolism and holds the promise to be a welcome addition to existing medications for abortive pharmacotherapy of acute migraine.
Accepted for Publication: August 10, 2020.
Corresponding Author: Abraham Kurian, MS, DO, Chaithanya Eye Hospital and Research Institute, Kesavadasapuram, Trivandrum, Kerala 695004, India (firstname.lastname@example.org).
Published Online: October 1, 2020. doi:10.1001/jamaophthalmol.2020.3676
Author Contributions: Drs Kurian and Reghunadhan had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Kurian, Reghunadhan, Nair.
Acquisition, analysis, or interpretation of data: Kurian, Reghunadhan, Thilak, Soman.
Drafting of the manuscript: Kurian, Reghunadhan, Thilak.
Critical revision of the manuscript for important intellectual content: Kurian, Reghunadhan, Soman, Nair.
Statistical analysis: Reghunadhan, Soman.
Administrative, technical, or material support: Kurian, Thilak.
Supervision: Kurian, Nair.
Conflict of Interest Disclosures: None reported.
Data Sharing Statement: See Supplement 3.