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Join us for a conversation with John C. Hagan III, an ophthalmologist, as we delve into the innovative use of beta-blockers for treating acute migraines. Discover the journey behind the discovery of Timolol’s efficacy in migraine relief and the challenges faced in securing pharmaceutical support. Gain insights into the potential future of beta-blocker nasal sprays and the importance of pursuing innovative, low-cost treatments in the medical field.

John C. Hagan III is an ophthalmologist.

He discusses the KevinMD article, “Big pharma ignores low-cost migraine solution.”

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Transcript

Kevin Pho: Hi, and welcome to the show. Subscribe at KevinMD.com/podcast, and get CME for this episode by clicking on the CME link in the show notes. Today we welcome John C. Hagan III. He’s an ophthalmologist, and today’s KevinMD article is “Big pharma ignores low-cost migraine solution.” John, welcome to the show.

John C. Hagan III: Thank you, Kevin. It’s an honor to be here and I appreciate the opportunity.

Kevin Pho: First off, let’s briefly share your story and journey.

John C. Hagan III: As you know, beta blockers are among the most widely prescribed medications, even 60 years after they were developed by Dr. James Black. Our story with this unique and effective treatment of acute migraines began with my colleague Carl Milatoo, who is one of Kansas City’s most stellar glaucoma specialists.

Timolol became available to ophthalmologists in the late 70s and rapidly became the drug of choice. Dr. Milatoo noticed that when he put patients on timolol, those that had migraines, often their migraines got a lot better. And when the medicine was stopped or switched to something else, the migraines came back. So some of the patients used their leftover glaucoma medicine when they had their migraines, and they told Dr. Milatoo about this. And he tried it empirically on patients, nurses, ophthalmic assistants, and some of his family members, and it worked. And that was as long as 20 years ago, 25 years ago.

About 2018 or so, both of my daughters developed migraine, and I happened to mention this to Carl, who’s a good friend of mine. And he said, why don’t you try timolol eye drops? And me being me, I said, Carl, you know that beta blockers don’t work for acute migraine, they work for prevention but not acute migraine. He said, no, they do. And he told me his experience, and I said, whoa, Carl, we need to research this, this is a great paper and great finding.

So very quickly we found out the mechanism is that when you take a beta blocker every day it maintains a therapeutic blood level. But when you take an oral beta blocker at first onset of acute migraine, it never reaches therapeutic levels, the migraine spins out of control and the medication never catches up with it. However, if you take timolol in liquid form and you put it on a normal eye, it travels very quickly from the eye to the tear duct on to the nasal mucosa, where it’s extremely rapidly absorbed and therapeutic levels are achieved in 10 to 15 minutes. And this is basically why it works.

So we retrospectively found a series of about seven of his long-term successful patients and reported that in 2014 in Missouri Medicine medical journal. And at that time Carl and I thought that we would win a Nobel Prize and make a million dollars. But ten years later the medication, while it’s available in compounding pharmacies, has not been picked up by either a large grant or the pharmaceutical companies.

So our first literature report, as I said, was in 2014. Subsequently our work was verified by Gratton and colleagues in JAMA Neurology in 2018. They continue to be very enthusiastic users. And then in the largest study published to date, in JAMA Ophthalmology, Cuan and others did a placebo controlled study of 43 patients and also found statistical significance. When that was published, one of the world’s leading neuro-ophthalmologists, Dr. Katz, was very, very enthusiastic about it.

But again, while we were doing this, there was no traction in pharma. I was frustrated that this was happening, especially when I knew this medication was very effective. So I wrote an editorial in Missouri Medicine, that I edit, and I challenged pharma and researchers to step forward and test this on larger groups of people.

The only person that responded was Steve Kosa. Dr. Kosa is a neurologist and headache specialist and runs a specialty headache clinic at North Kansas City Hospital. And he was very interested, and we approached a compounding pharmacy here in Kansas City, O’Brien Pharmacy, and they agreed to make up a 0.5 percent nasal spray. And Dr. Kosa used this in his practice and found it very effective from the get-go, so he came on board as a total enthusiast.

So in January of this year, Dr. Kosa and I, in a first world literature report in Missouri Medicine, reported on 16 refractory migraine patients referred to his clinic because of failure to respond to standard therapy, that responded to the medication. Again, 10 out of 16 or so.

The frustrating part is that for ten years I have been bringing the data that I’ve just discussed with your physician audience to pharma. And basically the response I get is, we’re not interested. Or more common, yeah, it’s a great idea but we don’t think we can make enough money on it. Or the last one, yeah, it probably would work and we understand the mechanism, but why would we want to have a low price effective product in our product line that would compete with our very expensive medications?

So that’s it. Our biggest vehicle has been the compounding pharmacists. We’ve had two articles published in the International Journal of Pharmaceutical Compounding.

The thing for your audience is that most of the time when people come on here and they talk to you, especially if they’re researchers, they’re in the beginning of clinical trials, and even if it moves forward it’s going to be 10, 15 years before the average physician can sit down and write a prescription for it. But timolol nasal spray is available right now for use by physicians from at least two compounding pharmacies, one in New England and one here in Kansas City, O’Brien Pharmacy. And they’ll mail this compounded nasal spray to people in the United States, along with instructions on receiving a valid prescription. And although the medicine’s not likely to be covered by insurance, it’s very inexpensive, at this time $74 for a 15 milliliter spray, which will treat multiple migraines.

Kevin Pho: So what would be the prescription instructions and doses for this intranasal form of timolol?

John C. Hagan III: Well, first of all, standard beta blocker contraindications exist. One of the nice things is that almost all physicians use beta blockers, so they’re familiar with this. And then observation for reactions is appropriate. I will say parenthetically that episodic beta blockers are much, much more tolerated than taking a beta blocker every day.

So what they would do is they write a prescription, send it to O’Brien Pharmacy or the pharmacy in New England, or they have a local compounding pharmacy. The instructions for compounding this have been published twice, so any local compounding pharmacy can do this.

So the signature, or the directions, would be, take one spray in each nostril at earliest onset of headache. If no improvement in 10 to 15 minutes, take a second spray in each nostril. Do not use more than four sprays in 24 hours.

In using this medication for over a decade, we found that it’s synergistic and it works with many other of the acute migraine medications. So it works well with analgesics, anti-inflammatories, and some of the other prescription medications.

Kevin Pho: Now, do you find the efficacy of the intranasal timolol, is it comparable to say something like an Imitrex or a sumatriptan type medication that people typically use for acute onset of migraines?

John C. Hagan III: Those studies have not been done, and I would be overstepping my expertise if I said they had. Dr. Kosa, who again is a headache neurologist and all the patients he sees are refractory, has found this extremely useful. As I said, it’s part of his basic beginning therapy of acute migraines. But to answer your question specifically, those haven’t been studied.

Kevin Pho: And does Dr. Kosa or the other physicians using this form, are they first line, or are they more second, third line after traditional medications have been used first?

John C. Hagan III: The majority of them are used by patients that are unhappy with their existing acute treatment. There’s no reason to try this on a happy patient. But if you look at some of the statistics, about 65 percent of patients that have migraines are either unhappy with their present treatment or would accept additional treatment that would be helpful to them.

Kevin Pho: Tell us about some of the side effects and potential risks that the timolol nasal spray may have.

John C. Hagan III: OK, well again, if you put it on the eye, you put it under the tongue, liquid beta blockers, or you take it by nasal spray, it’s the same indications, contraindications as timolol. So you would not want to use it in patients that have had a previous bad reaction to beta blocker. If a patient is on beta blockers orally for some other indication, it won’t work because that patient’s already in beta blockade. Reactive airway disease, severe bradycardia, severe hypotension, orthostatic hypotension.

And then monitoring, telling the patients, like stuffy nose, runny nose, trouble breathing, wheezing, fatigue, cold feet, all those types of things. But again, I want to emphasize that if a patient is taking a beta blocker once or twice a day, they have a much greater chance of having side effects than a person that’s taking it just when they have an acute migraine.

I would add parenthetically that in about four months Dr. Kosa and I are also publishing a first literature report on a patient with essential tremor. So essential tremor is treated with beta blockers, and this particular nice lady was on oral beta blockers and it controlled her tremors extremely well, but she began to have side effects of profound fatigue and slow pulse and so forth, so the medication was stopped. And her hands shook, and this bothered her a great deal, especially when two things, her grandchildren came over, or she went to play bridge.

So Dr. Kosa tried using the nasal beta blocker just on those occasions. So if she was going to play bridge she would take the nasal spray, or if a grandchild were coming over. And it worked just fine, and she’s happy, and there’s been none of the side effects that she had when she was taking it every day.

Kevin Pho: Now, do you have to worry about the hypotensive effects that beta blockers would have if you use it intranasally?

John C. Hagan III: Yes, yes. You know, I’m an ophthalmologist, and when timolol came out in the late 70s that was a wonder drug, we just could not believe it. And when it first came out, basically it was sold as, there’s no side effects, this is a wonderful medication. And that didn’t last very long. We found that some patients were having the whole gamut of beta blocker side effects.

So ophthalmologists did blood level studies on glaucoma patients and found that yeah, they’re getting a lot in it. So when we treat glaucoma patients, we don’t want it in blood, so we have them put it in the eye, block their tear duct, hold it like that for 10 minutes. And then also timolol was compounded in a gel formula, which takes a lot longer to get in the blood.

Kevin Pho: So you mentioned various reasons why pharmaceutical companies may not take up timolol and the intranasal form of timolol, and this isn’t the first story I’ve heard. I think that the reasons that you said are certainly valid, they’re not going to make any money on things that are already generic, or if it competes with something that’s proprietary, right? So what does that say about our current pharmaceutical system, and the difficulty you’ve had getting any interest from them?

John C. Hagan III: Well, I’m not going to name names because I don’t want to get letters from lawyers tomorrow. But the first big disappointment was that the national companies that publicly say they’re about repurposing generics or marketing generics or lowering the cost of medication worldwide, there was no interest and the door was shut in our face.

It would be one thing if they said, hey, this is not going to work. But they all said, hey, that’s absolutely brilliant, yeah, we can see how it worked, but we’re not going to make enough money.

So there was one pharmaceutical company that contacted me, and the director of research was a PhD, and he had read our publications and he was hot to trot. I mean, he thought this was just absolutely wonderful. He was worried about getting a patent, and on his own he was able to find a university professor that had a carrier that was actively patented in the United States, Europe, and China. And he arranged a second phone call with the largest shareholder, and he was hot to trot, he thought this was wonderful.

So the company had a lot of money, they just sold a drug, they had $100 million to invest. And they went to their board with the recommendation of their director of research and their largest shareholder, and the board said, yeah, it’s a wonderful idea, but we think we can make more money elsewhere, so that’s where we’re going.

So I have lost almost all the respect that I had for pharma. I just, you know, they’re about money, they’re about money, and they’re about money. And they don’t put patients first.

Kevin Pho: For those physicians who aren’t familiar with how compounding pharmacies work, just give us a word on that and your experience with compounding pharmacies, and specifically the safety of compounding pharmacies in general.

John C. Hagan III: Well, prior to this I had not had much experience with compounding, until in the 1980s I was doing a great deal, I was doing about a thousand cataract operations a year, and a medication called hyaluronidase that we used to spread the anesthetic. There was only one drug company that made that, and they closed their plant down. So the world essentially was without this hyaluronidase, and immediately we started to see complications, primarily permanent double vision after cataract surgery.

So someone told me that a local compounding pharmacy could make up a solution of hyaluronidase. So I approached O’Brien and yes, they could. And I watched, I went through the pharmacy, looked at their sterile techniques and everything, and they made up hyaluronidase, which I used for a couple months in eye surgery, didn’t have any complications. I went to a national meeting, presented it, and long story short, this compounding pharmacy for about three years was the world’s largest source and only source of hyaluronidase. So I was familiar with the capabilities of this, and they said yeah, we can do this.

So the compounding medications are generally not FDA approved, they don’t go through that particular route. But if you look at the market, there are many, many people that use them, and there are many of those of us in orthodox medicine that use compounding pharmacies to create special solutions, injections, medications that are not available from pharma. And they’re scattered across the country, there’s usually one in every area. And they have their own standards, they’re monitored by, it’s a federal agency that comes in and inspects for cleanliness and sterility and so forth.

O’Brien Pharmacy, it’s headquartered here in Kansas City but they have branches across the country. And I have no financial interest in any of this, none at all. All they have to do is contact O’Brien Pharmacy and send them a prescription, and the patient’s in business.

Kevin Pho: We’re talking to John C. Hagan III. He’s an ophthalmologist. Today’s KevinMD article is “Big pharma ignores low-cost migraine solution.” John, we’ll end with some of your take-home messages that you want to leave with the KevinMD audience.

John C. Hagan III: Yes. If you take care of migraines, and most of us do, and your patient with acute migraine has been tried on standard medication, is not happy or it’s not working, and there’s no contraindication to using beta blockers, I would suggest that you read the literature that’s been published on nasal beta blocker and topical to the eye, and try them on your patients. We have family members, other physicians, daughters, wives, and we’ve been using this medicine for ten years, and we have some really, really happy patients.

Kevin Pho: John, thank you so much for sharing your insight and perspective, and thanks again for coming on the show.

John C. Hagan III: Thank you, Kevin, for having me.