FDA Approves Botox for Treatment of Chronic Migraine

Hope or Hype?

On October 15,  2010, just weeks after the drug manufacturer Allergan was fined $600 million by the FDA for promoting Botox® (botulinum toxin) for unapproved indications, the medication was approved by the same agency for the treatment of one of those indications, chronic migraine.
 
First, the story, then the science. Dermatologists and cosmetic surgeons used Botox for many years for the treatment of facial wrinkles. One Beverly Hills dermatologist heard some of his patients say that their migraines were disappearing along with their wrinkles. This led to a frenzy of scientific as well as commercial interest – the typical set of injections can cost $1000 - $2000, takes a physician a few minutes, and is repeated every 3 months. The first study of Botox compared doses of 25u and 75u to placebo, and found a modest benefit of the 25u dose but not the 75u dose.  Future studies upped the ante, looking at doses between 100-200u, and consistently failed to meet the primary endpoint, which is the stated goal for the study. They finally were able to find a primary endpoint for which they could best placebo – the number of headache days in patients with “chronic migraine,” defined as more than 15 migraine days/month.

How effective is Botox? It required a pooled analysis of two studies of over 1000 patients to show a difference from placebo, and the difference was small: mean frequency of headache days fell 8.6 days in the Botox® group and 6.8 days in the placebo group, a difference of 1.8 headache days/month. The study used doses of 150 – 200u. In a small study from Brazil, 250u Botox  was no more effective than the older tricyclic antidepressant amitriptyline.

Meanwhile, across the Atlantic . . .
Two days before the FDA approval of Botox®, the prestigious British Medical Journal (BMJ) published a meta-analysis of reboxetine, a newer antidepressant approved in Europe, and based on unpublished as well as published data, found it to be not only no better than placebo, but harmful. To receive approval, the company published data on 1000 patients, but the authors of the BMJ study found that over 4000 patients had actually been studied. When results for all patients were analyzed, the drug was clearly no better than placebo. In an accompanying editorial, co-editors of BMJ suggested that this and similar articles "…must call into question the entire evidence synthesis enterprise. Meta-analyses are generally considered the best form of evidence, but is that a plausible world view any longer when so many of them are likely to be missing relevant information?"

I use Botox® on occasion in clinical practice, usually as a last resort or for patients who have failed numerous preventives or have contra-indications to preventives. I have observed the technique of several of the leading proponents of Botox® in this country, from New York City to San Diego, and found they all used different techniques and dosages, with no seeming difference in results. I am a pragmatist, and with headache, I have found that the more tools I have to offer a patient, the more likely I am to succeed.

What you should know as a patient. First, currently Medicare is the only provider in the state of North Carolina to cover Botox®, although that is likely to change with the FDA approval. The scientific data for Botox® shows it to be no better than standard preventives, but it may have a role in the treatment of chronic migraine – most patients with chronic migraine have headache every day, and migraine-like headaches 15 days/month. Botox® is not approved for the more common, episodic migraine.

Back to basics. Many patients with chronic migraine suffer from “drug rebound headache (DRH)” – the frequent or daily use of headache remedies, including pain pills, butalbital (Fioricet and others), and triptans (Imitrex and others). Caffeine, but in beverages and medicines (Excedrin, Goody’s, BC powders) also cause frug rebound headache. Patients with DRH do best when they withdraw from these medicines. Don’t try to do this on your own, but only under medical supervision.