By John C. Hagan III, MD

If you are a fan of pharma, you might want to skip this article. Some pharma enthusiasts will call it a rant. By pharma, I mean avaricious pharmaceutical (a pleonasm) companies collectively. On the other hand, those of you who treat acute migraines will learn of a highly effective, innovative, inexpensive, and relatively safe way to help many of your migraineurs. Those of you who believe that pharma is interested in anything beyond big profits will be seriously disabused.

Sir James W. Black, MD, a 1988 Nobel Prize-winning researcher, invented beta blockers (BBs) in the 1960s. They came to the United States in the early 1970s. Even after over 60 years, BBs remain one of the ten most prescribed drugs worldwide. Although initially developed to treat angina, BBs were found to be therapeutic for a broad spectrum of diseases.

It was noted that glaucoma patients taking BBs orally for cardio-vascular indications had an auspicious decline in their intra-ocular pressure. Timolol, a potent BB, was converted into an eyedrop and became, and remains, one of the most important medications for treating open angle glaucoma.

Carl V. Migliazzo, MD, a well-known Kansas City glaucoma specialist, serendipitously noted some of his patients reported their migraines got better when they started timolol eyedrops. I joined Dr. Migliazzo as a co-researcher in 2013 and we reported a case series of his patients using timolol 0.5% to their eyes as successful, long-term treatment of acute migraines. A fuller elaboration of our first literature report is found in the 2014 article.

The BBs, timolol, and propranolol are FDA-approved for migraines and are common, useful preventive drugs for chronic migraine (15 or more headaches per month). Taken orally for acute migraine, BBs have not been effective. Incredibly, no one seems to have questioned why. We determined oral BBs are slowly absorbed from the gut and never reach effective blood levels. Liquid timolol applied to a normal eye descends through the tear duct onto nasal mucosa, where it is extremely rapidly absorbed. By this route, timolol achieves therapeutic blood levels in 10-15 minutes. Instilling eye drops is difficult for many people and there are some eye/eyelid/tear duct conditions that contra-indicate drops to the eye. Since timolol works by nasal absorption, from the beginning we postulated direct nasal spray application was ideal.

Subsequently, our favorable timolol eyedrop studies were affirmed by many placebo-controlled studies.

Shortly after the 2014 publication, I began a worldwide, 10-year effort to have pharma fund studies leading to an FDA-approved nasal spray-delivered solution of 0.5% timolol for acute migraine. I will not name companies as I do not want to spend the rest of my life paying legal bills. Over three dozen companies were contacted. Some did not respond, and some responded they were not into migraine medications. Many responded they didn’t think there was enough profit or that a low-priced, effective BB nasal spray would compete with their much more profitable acute migraine products. A de facto collective “We pass.”

The closest I came to success was a medium size drug company flush with cash from the sale of a drug they developed. The director of research, a PhD, contacted me. I explained the rapid BB nasal absorption, and he immediately “got it.” He asked if he could set up a conference call with the company’s largest shareholder. That also went well. There was concern about getting so-called intellectual property, or new art, code for a patent. They were able to find an academic who had an active patent that could serve as a carrier of the BB molecule. They took the proposed development to their board. The board rejected their favorable recommendation. The board felt they could make more money elsewhere. I have heard this so often the words “not enough profit’ haunt me in my dreams.

Frustrated by this pharma beatdown I wrote in a journal I have edited since 2001, of my frustration I challenged pharma to develop nasal timolol or a large neurology department willing to write a likely successful, grant application for larger studies. I also mentioned that I had found a second researcher with a very successful commercial patent that felt he could use a nano molecule-carrier to get another timolol patent.

The only person that contacted me was Steven C. Kosa, MD a highly respected neurologist with special interest in headaches. We contacted a high-quality national compounding pharmacy, with offices in Kansas City. They agreed to prepare a 0.5% timolol nasal spray. Dr. Kosa used this product for treatment of refractory acute migraine patients referred to his headache clinic. In the January/February 2024 journal issue, Dr. Kosa and I reported the first world literature case series of nasal BB used successfully to treat 10 of 16 (62.5%) referred acute migraine patients. No significant side effects occurred. These patients continue to use the BB nasal spray as a first-line treatment for their acute migraines.

Unlike many initial favorable responses of experimental drugs, physicians wishing to use timolol 0.5% nasal spray can now prescribe it off-label by prescription.

So, what is the take-away after investing several minutes of your valuable time on my manuscript? If you treat acute migraines, the use of Timolol 0.5% nasal spray is worth considering. Usual BB contra-indications apply, as does monitoring for side effects, which are less frequent than daily oral BBs. Like any medication, BB nasal spray doesn’t always work, but it does often enough, in my experience and that of others, to make it useful for first-line treatment of the most prevalent neurological disease in the world.

As for pharma, don’t try to interest them in anything that will not produce enough profit to make Bill Gates or Jeff Bezos blush.

John C. Hagan III is an ophthalmologist.