If you are a fan of pharmaceuticals, you may want to skip this article. Some pharmaceutical industry enthusiasts will call this a rant. By pharma, I collectively mean greedy pharmaceutical companies (a pleonasm). On the other hand, those of you who deal with acute migraines will discover a very effective, innovative, inexpensive and relatively safe way to help many of your migraine sufferers. Those of you who believe that the pharmaceutical industry is interested in anything other than big profits will be seriously disillusioned.
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 more than 60 years, BBs remain one of the ten most prescribed drugs in the world. Although initially developed to treat angina, BBs have been shown to be therapeutic for a wide range of conditions.
It was noted that glaucoma patients taking oral BBs for cardiovascular indications showed a promising drop in their intraocular pressure. Timolol, a potent BB, was transformed into eye drops and became, and remains, one of the most important drugs to treat open-angle glaucoma.
Carl V. Migliazzo, MD, a well-known glaucoma specialist in Kansas City, incidentally noted that some of his patients reported that their migraines improved when they began using timolol eye drops. I joined Dr. Migliazzo as a co-investigator in 2013 and we reported a case series of his patients using timolol 0.5% in their eyes as an effective long-term treatment for acute migraines. A more complete elaboration of our first literature report can be found in the Missouri Medicine 2014 article.
BBs, timolol, and propranolol are FDA approved for migraines and are common and useful preventative medications for chronic migraine (15 or more headaches per month). Taken orally for acute migraine, BBs were not effective. Surprisingly, no one seems to have asked why. We have determined that oral BBs are slowly absorbed from the intestine and never reach effective blood levels. Liquid timolol applied to a normal eye travels down the tear duct to the nasal mucosa, where it is absorbed extremely quickly. By this route, timolol reaches therapeutic blood levels within 10 to 15 minutes. Instilling eye drops is difficult for many people, and certain conditions of the eyes, eyelids, and tear ducts contraindicate the administration of eye drops. Since timolol acts by nasal absorption, we postulated from the beginning that direct application by nasal spray was ideal.
Subsequently, our favorable studies of timolol eye drops were confirmed by placebo-controlled studies reported in JAMA NeurologyAnd JAMA Ophthalmology.
Shortly after the publication of Missouri Medicine in 2014, I launched a 10-year global effort to fund pharmaceutical studies leading to an FDA-approved nasal spray solution of timolol 0.5%, for the treatment of acute migraine. I won't name any companies because I don't want to spend the rest of my life paying legal bills. More than three dozen companies were contacted. Some did not respond and others responded that they did not take migraine medication. Many responded that they didn't think there was enough profit or that a low-cost, effective BB nasal spray could compete with their much more profitable acute migraine products. A de facto collective “We pass”.
The closest I got to success was a mid-sized pharmaceutical company that had cash from the sale of a drug it had developed. The research director, a doctor, contacted me. I explained the rapid nasal absorption of BB, and he immediately “got it.” He asked if he could set up a conference call with the company's largest shareholder. This also went well. There were concerns about obtaining an intellectual property, or new art, code for a patent. They managed to find an academic with an active patent that could serve as support for the BB molecule. They presented the development project to their board of directors. The board rejected their favorable recommendation. The board felt he could make more money elsewhere. I have heard the words “not enough profit” so often that haunt me in my dreams.
Frustrated by this pharmaceutical crackdown I wrote in Missouri Medicine, a journal I have edited since 2001, out of my frustration I challenged the pharmaceutical industry 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 who thought he could use a nano-carrier molecule to obtain another patent on timolol.
The only person who contacted me was Steven C. Kosa, MD, a well-respected neurologist with a 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 has used this product for the treatment of patients with refractory acute migraines referred to his headache clinic. In the January/February 2024 issue of Missouri Medicine, Dr. Kosa and I reported the first case series published in the world literature 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 BB nasal spray as first-line treatment for their acute migraines.
Contrary to many initial positive responses to experimental drugs, doctors wishing to use timolol 0.5% nasal spray can now prescribe it off-label with a prescription.
So, what to remember after investing several minutes of your precious time on my manuscript? If you are treating acute migraines, the use of Timolol 0.5% nasal spray should be considered. The usual contraindications for BBs apply, as does monitoring for side effects, which are less common than daily oral BBs. Like any medication, BB nasal spray does not always work, but it does often enough, in my and others' experience, to make it useful in the first-line treatment of the most common neurological disease in the world.
As for the pharmaceutical industry, don't try to interest them in something that won't produce enough profits to make Bill Gates or Jeff Bezos blush.
John C. Hagan III is an ophthalmologist.