Note: The Newsletter will be running a series of guest editorials in future editions. Dr. John Hagan has graciously agreed to be the first contributor to this series.

About the author: Dr. Hagan is a Kansas City ophthalmologist, and a long-time medical researcher with over 250 articles published in peer-reviewed journals. He is the Editor of Missouri Medicine, contributing editor of Kansas City Medicine and past President of many local and state physician associations. In 2021, The Kansas City Medical Society gave him its "Medical Innovator Award". Over the past 12 years, he has published more articles on liquid beta blockers for acute migraine than any other researcher.

During my long career as an ophthalmic surgeon and clinical researcher, I have had the opportunity to collaborate with many talented individuals and distinguished institutions. Among my most enjoyable and fruitful research projects have been those with the compounding pharmacists at O'Brien Pharmacy, headquartered in Kansas City. I thank Dr. Loyd Allen, the editor of The International Journal of Pharmaceutical Compounding for the opportunity to share two notable research projects. Both of these successful and lauded endeavors highlight how physicians and compounding pharmacists can, and should, work together for the benefit of our patients. Each of these two professions embody special expertise that, skillfully integrated, can synergistically produce results superior to single profession research.

The Great Hyaluronidase Shortage: Compounding Pharmacies to the Rescue

Hyaluronidase is an enzyme with multiple uses. It has a long and distinguished history. The action of hyaluronidase was described in 1936 and given its present name in 1939. Ophthalmologists have used hyaluronidase since 1949. The primary use in eye surgery is as a spreading enzyme for local anesthesia. Besides improving the speed and depth of anesthesia, hyaluronidase also protects extraocular muscles and orbital nerves from toxic and ischemic damage by failure of the anesthetic agent to diffuse throughout the orbit. This prevents pressure mediated or neuro/myotoxic mechanisms which often causes paresis or fibrosis of extraocular muscles; thus hyaluronidase is considered a vital component of the injected anesthetic.

Despite the importance and ubiquity of hyaluronidase, only one company, Wyeth, produced the FDA approved product under the brand name Wydase. And Wydase was produced in only one, rather old, factory. In the late 1990's, the FDA did an inspection and outlined a long list of problems with the physical facility that needed to be corrected. Given the expense involved, Wyeth chose not to make these repairs and advised customers that they would soon be unable to fill orders. There was no alternate source for the important enzyme.

I was one of the thousands of ophthalmic surgeons affected by this development. Like virtually every other surgeon in the United States, I elected to continue doing cataract surgery without hyaluronidase in the local anesthetic. Almost immediately my patients began to complain of post-operative double vision. In some cases, the double vision took many months to resolve; in other instances, it did not resolve and required eye muscle surgery and/or prism glasses. With a University of Kansas neuro-ophthalmologist, we were the second authors in the world to report this new problem. Nationally, many cases followed, and it became apparent that hyaluronidase was the agent preventing anesthetic damage to vital orbital structures.

I learned that compounding pharmacists had access to hyaluronidase and met with Eric Everett, PharmD of O'Brien's staff. With a prescription, he could prepare a sterile solution of hyaluronidase identical to the unavailable Wydase. I believe I was the first surgeon in the United States to try this compounded enzyme. Post operative double vision immediately ceased. I teamed with a respected surgeon in Arizona to accumulate a large series of compounded hyaluronidase cases done without operative or post-operative problems. Our paper, entitled “Is O'Brien Pharmacy Hyaluronidase as Good as the Frequently Unavailable Wydase: Yes, It's Better!�, was presented in 2001 at the largest meeting of cataract surgeons in the country; later our manuscript was published in the Journal of Cataract & Refractive Surgery.

Compounding pharmacies were the only source of vital hyaluronidase from about 2001 to 2005 when alternative methods and sources were found for FDA approved hyaluronidase. Given there are about four million cataract surgeries done yearly in the US, compounding pharmacists saved tens of thousands of patients from permanent double vision and additional treatment or surgery. Kudos to your profession!

Nasal Spray Timolol 0.5%: A New Paradigm in Acute Migraine Treatment

In IJPC (May/June 2020 V24 (3)194-197) with Eric Everett, RPh and Tyler Chamberlain, PharmD, I described for the first time the use of a compounded timolol 0.25% nasal spray for the treatment of acute migraine. I will not describe the development of this in detail as it was covered in that article and reviewed again in another scientific article scheduled for the July/August 2024 issue of IJPC. It is extremely important to note that in a small, unpublished series of patients that had used timolol 0.5% successfully topical to their eyes or sublingual, they found the 0.25% timolol nasal spray much less effective than 0.5%. An addendum stating this important change in concentration to 0.5% timolol was published in IJPC (Mar/Apr 2024 V28 (2)129).

In its most concise form, migraine patients put on oral beta blockers for cardio-vascular indications often reported their migraines got better. Neurologists tested oral beta blockers and found when taken daily they were often successful in preventing migraines. Timolol and propranolol were FDA approved for this indication. However, when taken orally at the first onset of a migraine, they were ineffective. There was no subsequent research on this disparity of efficacy.

Glaucoma patients put on oral beta blockers for cardiovascular indications often had dramatic reductions of their intra-ocular pressure, a salubrious effect for that blinding disease. Liquid timolol 0.25% and 0.5% were FDA approved for chronic open angle glaucoma and remains one of the most effective and widely used glaucoma medications in the world. My associate Carl V. Migliazzo, MD a glaucoma specialist, as long as 30 years ago found his patients with migraine often reported their headaches were better when they started timolol eye drops for glaucoma. He empirically tried timolol eye drops on his wife who had migraines and it worked fabulously as it did on a score of other friends, relatives, and patients.

In 2013, Dr. Migliazzo told me of his observations, and we began serious study of why timolol eye drops worked for acute migraines but oral timolol did not. We quickly determined that the drops applied to the eye traveled through the lacrimal duct onto nasal mucosa where absorption into the blood was extremely rapid, much faster than when oral beta blockers were used. Pills never achieve therapeutic blood levels but drops reach 80-100% beta blockade in 15-20 minutes. Since many people have trouble instilling eye drops and some eye conditions preclude use on the eye, a nasal spray seemed the ideal way to deliver the medication.

Once again, I consulted O'Brien's Compounding Pharmacy. Because I am an ophthalmologist, and this was a new use, they cautiously would only prepare with 0.25% timolol, which as mentioned was not effective. In 2022, Steven Kosa, MD a neurologist that specializes in headaches took an interest in this research and O'Brien Pharmacy agreed to produce a 0.5% timolol nasal spray. (Figure 1) Dr. Kosas referral patient base is moderate to severe migraine patients who have failed first line treatment. We authored a first world literature report in the January/February 2024 issue of Missouri Medicine: The Journal of the Missouri State Medical Association. The results were spectacular, of 16 referred migraine patients, 9 or 62.5% responded well to timolol 0.5% nasal spray and added its use to their preferred treatment for acute migraine. There were no serious side effects. While not covered by insurance the cost for a 15 mL nasal spray is $77.45 US, which is modest compared to ultra-expensive patented pharma products (e.g. CGRP inhibitors).

Pharma has shown little interest in testing and developing this product. I have spent a decade pitching scores of drug companies on the effectiveness of nasal timolol, not only for acute migraine, but when therapeutic levels of beta blocker are needed, and intravenous administration is not available or practical. The response of these companies is either “We can't make enough money� or “Why would we want an effective, inexpensive medication that would compete with our much more expensive and profitable products?� That is way beyond sad.

For the foreseeable future, compounding pharmacists will likely be the only source of this very effective migraine product. A large, prospective, placebo-controlled, cross-over study is in the making at a major Midwest university. A compounding pharmacy will be supplying the timolol 0.5% nasal spray, an identical appearing placebo saline spray, and doing the randomization. Until this formula eventually gets FDA approval, you are the only ballgame in town.

My hope is that "The word will get out� and many more physicians will prescribe compounded timolol 0.5% nasal spray for their acute migraine patients. At present, I know the product is available from O'Brien Pharmacy and Bayview Pharmacy in Rhode Island. Please consider adding nasal spray timolol to your product line. Dr. Kosa and I will do everything we can to get physicians to start prescribing it more often.

Your profession is offering great service and products to our patients. Keep up the good work.

For the foreseeable future compounding pharmacies will be the only source of nasal spray 0.5% timolol, a highly effective new treatment for acute migraine.

The IJPC team wishes to express their gratitude to Dr. Hagan for this contribution to the newsletter. It has been our pleasure to work with him, a consumate professional in every way, to bring this information to our readers.

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From Out of the Past

Said farmer Brown
Who's bald
On top
Wish I could
Rotate the crop
     Burma-Shave

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