Inexpensive Off-Label Drug May Offer Relief From Acute Migraine: Doctors

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A beta blocker eye drop that costs less than $10 may be able to help acute migraine sufferers by stopping the acute attacks from worsening or at least lessening their intensity, according to several ophthalmologists.

The doctors find that timolol eye drops (0.5 percent) that are approved for a certain eye disorder, when used off-label, are an effective and relatively safe treatment for patients with acute migraine when used immediately after symptom onset.

Dr. John C. Hagan, an ophthalmologist with over 50 years of experience said that for some people, treating their acute migraines involves using timolol in combination with other medications.

“So most of the people that we call success, don’t use the beta blocker drops as sole therapy,” Hagan told The Epoch Times. “They use like an analgesic, Tylenol or aspirin, or they use a non-steroidal anti-inflammatory like Advil or something like that.”

Dr. Melissa Toyos, an oculofacial plastic surgeon who developed migraines in her late 20s, relies on several different medications to abort the acute migraine attacks.

“I have access to all of the migraine meds including many of the pricier ones and ironically, the triptans have caused chest pain and minimal improvements while otc [over-the-counter] Excedrin and beta blockers (along with CGRP inhibitors and anti-nausea sublingual tablets) have become my mainstay,” Toyos said in an email to The Epoch Times.

She said that the beta blocker eye drops help with “nipping the migraine in the bud before it becomes full-blown and avoiding some of the less desirable side effects of other headache medications.”

Beta blockers, also known as beta-adrenergic blocking agents, have been around since the 1960s (pdf) and were initially approved to treat cardiovascular disorders. They work by blocking the action of adrenaline—a stress hormone released by the adrenal glands—to allow the heart rate to slow down and the blood vessels to relax, thus improving blood circulation.

“When doctors prescribe beta blockers in pill forms for heart palpitation [patients], many of them reported that their migraines got better,” Hagan said.

This accidental finding has led to beta blockers becoming one of the main therapy options in preventing chronic migraines (15 or more headaches per month) when the drug is taken in pill form. Yet, while the pills are successful in treating chronic migraine, they are not effective for acute pain.

Other conditions that these medications can treat include tremors, anxiety, and high blood pressure.

Eureka Moment

In 1978, a liquid form of a beta blocker, timolol eye drop, was approved by the FDA (pdf) to treat glaucoma, an eye disease that can lead to vision loss.

Patients who were being treated for glaucoma reported that their “migraines got better when they were putting their beta-blocker eye drops in every day,” Hagan said.

Dr. John C. Hagan. (Courtesy of John Hagan/The Epoch Times)

In 2013, Hagan’s colleague, a glaucoma specialist, shared his clinical experiences using timolol eye drops for treatment of acute migraines and suggested Hagan’s daughters, who had developed migraines in their 30s, try the medication as soon as symptoms of a migraine began.

The conversation sparked an interest in Hagan who wanted to know why the eye drops were effective for acute migraine but pills weren’t. Hagan dove into the literature and the limited studies on beta blocker eye drops, and after many hours of poring through the data and discussions, he and his colleague experienced a eureka moment.

“Then, it sort of dawned on us. It didn’t take that long [to realize] that if you take a pill, a migraine pill, it has to go through the stomach, be digested, and then go through the liver where some of it’s drained off,” Hagan said. “It takes a long, long time to get a therapeutic level, if a therapeutic level is reached at all.”

“And that was why it doesn’t work [for acute migraine] when it’s taken in pill form.”

In a 2014 study of seven patients with acute migraines treated with beta blocker eye drops, in which Hagan is co-author, the eye drops are effective because they achieve therapeutic blood levels “within minutes” of being administered to the patients. The eye drops are quickly absorbed through the tear duct onto the nasal mucosa and into the veins where they go into circulation.

The largest double-masked randomized trial to date on treatment of acute migraine with timolol eye drops was a study from India. Researchers examined a total of  619 acute attacks in 50 patients. The study, published in JAMA Ophthalmology on Oct. 1, 2020, found that timolol was effective in alleviating migraine pain compared to placebo.

“The results observed give further support to the hypothesis that topically applied beta blockers may be an effective and inexpensive abortive migraine medication for some patients, with fewer adverse effects,” the authors wrote.

Struggle to Get FDA Approval

Hagan and his colleague, for the past eight years, have reached out to academic institutions and more than 50 drug manufacturers who have the capacity to develop and fund a phase 3 randomized trial to demonstrate and confirm that timolol is effective, safe, and beneficial for acute migraine. A large clinical trial is needed prior to applying for FDA approval.

While timolol eye drops may be used off-label for acute migraine, doctors may still be put off from prescribing it due to lack of information regarding how to best use it outside of what it’s approved for. But that may be remedied if the FDA approves it for a new indication, such as acute migraine, as all the necessary information will be available to help the physician make a decision.

The responses from pharmaceuticals were not what Hagan had expected, with many initially expressing interest but later rejecting their proposal.

“As of February 2022, the response from pharma has been almost uniform,” Hagan said in an article published in Missouri Medicine, adding that the three reasons given for the rejection were that it would be difficult to patent the medicine, the drug company didn’t want to develop a cheaper product that would compete with their “existing more expensive product line,” and that there is not “enough profit in this product with or without intellectual property to fund it.”

Without profit to make, neuro-ophthalmologist Dr. Bradley Katz said, pharmaceuticals won’t fund the study.

“No drug company is going to co-sponsor it because it’s generic, so there’s no money to be made. That’s probably the biggest thing,” Katz told The Epoch Times.

Off-Label Use

Off-label use is when a drug is used for any other medical condition, or given in a different manner or dose than what it’s federally approved for.

Since 2013, Hagan has been prescribing timolol eye drops to acute migraine patients. Two years ago, he worked with a family-owned pharmacy, O'Brien Pharmacy, to develop a compounded timolol nasal spray to use off-label that would allow for even faster absorption to provide pain relief.

A nasal spray would be the “easiest, fastest, and most effective way to deliver” the medication and it would also help people who have difficulty properly using the eye drops, Hagan said.

“The absorption of beta blockers topical to the eye, sublingual, and nasal has been studied,” Hagan and his co-authors wrote in an article published in the International Journal of Pharmaceutical Compounding in 2020. “Nasal is the fastest (100 percent) being equal to intravenous administration in a study of 80 healthy volunteers.”

Katz has been using the beta blocker eye drop to treat his own migraines and also prescribing it to patients. He advises that acute migraine sufferers discuss with their doctor if they should try timolol.

“For some patients, it can be very effective ... it’s so inexpensive,“ Katz said, adding that the side effects are very few in healthy people. ”It’s an eye drop that I often will recommend to patients as like a first-line treatment if they feel like they’re starting to get a [migraine] headache.” 

“They can just pop in a couple of drops, wait 20 minutes. If they’re not getting better, they can put in another set of drops. And if it works, great, and if it doesn’t work, well then you haven’t really lost anything,” he added.

Dr. Sean Gratton, an ophthalmologist and a co-author of a 2018 small study that examined whether timolol was effective in aborting acute migraines, said in an article published in EyeNet magazine that the has “found them [timolol eye drops] to be effective in a subset of patients who take them as needed.”

While relatively safe to use, timolol can cause some common side effects such as dry eyes, burning in the eye, or red eyelids. Timolol is not recommended for people with conditions like asthma, emphysema, or an irregular heartbeat, according to Katz. There is concern that the medication may worsen their condition.

In addition, people who’ve had a negative reaction to beta blockers should avoid this medication, according to Hagan.

Lanette Todd, an ophthalmic technician, has used timolol eye drops off-label for more than seven years without any issue although she has asthma.

“I don’t have any underlying issues, so it was never a problem for me,” Todd told The Epoch Times.

Todd was diagnosed 18 years ago with ocular migraine that causes temporary vision problems in one eye that lasts for about an hour.

Prior to using timolol eye drops, Todd said she took an aspirin and caffeine and “just wait it out.”

She said taking the eye drop sublingually, or underneath her tongue, provided quicker relief than as eye drops.

“So I started out putting them in my eye, like one drop in each eye, and it helped a little bit,” Todd said. “Then we discovered if you put it under your tongue, put the drops in, then it would go to your system faster, kind of get in your bloodstream a lot faster through your saliva.”

Todd’s teenage daughter and sister also suffer from migraines and the beta blocker eye drops have helped with the acute attacks.

The National Library of Medicine says that migraines “result from a combination of genetic, environmental, and lifestyle factors.” In addition, “variations in many genes have been found to be associated with the development of migraines with or without aura.”

Carolyn Csongradi has suffered from migraines for over 40 years and said the eye drops were very effective in treating her acute attacks. But she’s had to discontinue the medication because of the sinus congestion she experienced as a side effect.

Csongradi is taking a daily anti-seizure drug, topomax, that is also used off-label to prevent migraine headaches. However, the drug doesn’t stop a migraine headache that has already begun.

Prevalence and Characteristics

A screenshot of a chart showing the percentage of adults with a severe headache or migraine in the past three months as part of the 2018 National Health Interview Survey. (CDC/Screenshot by The Epoch Times)

Migraine is one of the most prevalent neurological diseases, affecting about 1 billion people globally, according to the American Headache Society. In the United States, at least 39 million people suffer from the disorder.

One in five women live with migraines, whereas one in 16 men experience them.

Between 2.5 percent to 4 percent of children under the age of 8, and about 10 percent of children ages 5 to 15 (pdf), suffer from recurrent migraines. When they are very young, boys are far more likely than girls to develop migraines, but by adolescence, girls outnumber boys in terms of the prevalence of migraines.

Katz said that children with migraines don’t necessarily experience headaches like adults.

“In kids sometimes they don’t get headaches as much as they get car sickness,” Katz said. “So, a lot of people who have migraines as adults are carsick as children.”

He added that some children who get stomach cramps or stomach pain for no apparent reason may be a “pediatric manifestation of migraine.”

Migraine is considered a chronic, debilitating condition where headaches are only one of its symptoms that can last for a few hours to several days. Other accompanying symptoms may include extreme sensitivity to light and sound, nausea, and vomiting. Some people also see an aura that occurs prior to or with a headache.

According to a 1999 study, migraine cost American companies roughly $13 billion annually due to decreased productivity and lost workdays. Eleven years later, in a different study, researchers estimated that the total indirect cost of migraine in the United States was $19.3 billion due to 81 percent of missed workdays.

Federally Approved Drugs

Several newer drugs for acute migraine have been approved in the past several years.

Three medications, which involve targeting a protein in the brain and nervous system called calcitonin gene-related peptide (CGRP) that “can cause blood vessels to dilate and cause inflammation and migraine headache pain,” were approved in 2019 to decrease the number of acute attacks. They are monoclonal antibodies administered under the skin once every month. The three drugs cost from $696.75, $640, and $696.90 for a one-time monthly dose for people without health insurance.

A different class of drug known as serotonin 5-HT-receptor agonists, which bind to the 5-HT-receptors in the brain “to inhibit the release of serotonin to reduce pain, nausea, and other symptoms of migraine,” is a nasal spray approved by the FDA in 2019 for acute migraine with or without aura in adults.

Patients may have to dish out $626 for a supply of six sprays if their insurance doesn’t cover the drug, according to drugs.com, an online resource for comprehensive drug information.

Also approved in 2019, CGRP pills used to treat acute migraine with or without aura in adults are listed for $996 for a supply of 10 pills.

Toyos said she has “tried almost everything for migraine” and knows how important it is for patients to have access to all the medications that will help treat their acute migraine.

“I think what is important in this story is that our healthcare system can sometimes be oriented to the latest and greatest and good, solid, older medications might be overlooked in the market due to smaller profit margins,” she said.

“When those medications are effective, both patients and our healthcare system benefit. It is important for migraine sufferers to have access to all medications that are useful so that they, too, can get back to their busy lives and remain productive even while living with migraine.”