Peter Goadsby, M.D, Ph.D.
Director of the UCSF Headache Program
Studies have shown that a day with a migraine — a disorder that affects 15 percent of the U.S. population — can be as debilitating as a full day of quadriparesis. Still, headache is a little-appreciated condition, often relegated to the category of side effect or symptom. And many migraine sufferers remain undiagnosed, under-treated or untreated.
Until the 1990's, specific migraine therapies were limited to ergotamine derivatives. The triptan eraserotonin 5-HT1B/1D receptor antagonists began with sumatriptan in 1991. Now, there are six oral triptans available in the United States. Triptan medication revolutionized migraine treatment by stopping headaches and related symptoms, rather than just providing pain relief.
Triptans have transformed many patients' lives by providing relief from migraines for the first time and are regularly prescribed in practice. However, they are ineffective in about a third of migraine sufferers. And because they constrict blood vessels, they cannot be used in patients who have had a heart attack or stroke, and should be used with caution by those who are at risk.
Recently, two innovative treatments, including a novel class of drugs and combination therapy, have been shown to have significant clinical advantages compared to triptans and other drugs, ushering in a new era of migraine treatment. The development of new therapies will benefit many patients whose lives remain blighted by a condition that is reversible with proper treatment.
Calcitonin Gene-Related Peptide (CGRP) Receptor Antagonists
Recent trials found that MK-0974 — belonging to a potential new class of drugs known as calcitonin gene-related peptide (CGRP) receptor antagonists — effectively treats migraines in the majority of people tested. The drug also was well tolerated, and most importantly, unlike triptans, does not have any cardiovascular side effects.
The brain chemical, calcitonin gene-related peptide (CGRP), transmits pain signals during a new migraine attack. This discovery was made by my research group, leading to the development of new drugs, such as MK-0974 that work by blocking CGRP.
The safety and effectiveness of MK-0974 was tested in a randomized, double-blind, placebo-controlled study, involving 330 people who suffer one to six migraines a month. Study patients kept a diary to record pain relief two hours after taking the medication, pain freedom two hours after taking the medication, and freedom from pain 24 hours later.
More than two-thirds (68.0 percent) of those who took the 300 mg dose of MK-0974 experienced pain relief two hours after the dose, compared to 69.5 percent of those who took the FDA-approved triptan called rizatriptan, and 46 percent who took a placebo. Nearly half (45.2 percent) of those who took MK-0974 were free of pain after two hours, compared to 33.4 percent who took rizatriptan (Maxalt) and 14.3 percent who took the placebo.
More than a third of study participants (39.6 percent) were pain free 24 hours after taking MK-0974, compared to 18.4 percent who took rizatriptan and 11 percent who took the placebo. Common side effects included nausea, dizziness and sleepiness.
MK-0974 has not yet been approved by the Food and Drug Administration (FDA). Results from the large Phase III study were presented at the American Headache Society meeting in Boston in June 2008.
Symptoms of migraine headaches are caused by multiple pathological mechanisms. A new fixed-dose tablet combining sumatriptan and naproxen (Treximet, Prozen Inc./GlaxoSmithKline) targets more than one of these mechanisms. Some doctors have been clinically combining the two drugs for some time. However, results of two recent randomized trials assessing the efficacy and safety of the combination drug suggest that it provides greater clinical benefits compared to either drug alone. It was well tolerated, with minor side effects including dizziness, paresthesias and somnolence.
The combination therapy was tested in two randomized, double-blind, parallel-group studies in a total of 2956 patients at 118 U.S. clinical centers. Patients aged 18 to 65 with at least a six month history of migraine headache and a monthly average of two to six moderate or severe episodes were randomized to one of four treatments taken after migraine onset: a single tablet containing either sumatriptan (85 mg) plus naproxen sodium (500 mg), sumatriptan only, naproxen only, or placebo.
After two hours, the combination therapy was significantly more effective than the placebo for headache relief, defined as reduction of pain from moderate or severe to mild or none without use of rescue medications (65 percent versus 28 percent), absence of photophobia (58 percent versus 36 percent), and absence of phonophobia (61 percent versus 38 percent). Absence of nausea at two hours was significantly more common with combined therapy than with placebo in study 1 (71 percent versus 65 percent), but not in study 2 (65 percent versus 68 percent).
The incidence of sustained (less than or equal to 24 hours) pain-free response was significantly higher with combined therapy (25 percent) than with sumatriptan (16 percent), naproxen (10 percent), or placebo (8 percent). Although all groups had low rates (less than 5 percent) of adverse events, the overall incidence of adverse events was higher with combined therapy (27 percent) than with placebo (12 percent) or naproxen (13 percent), but not sumatriptan (24 percent).
Study results were published in the April 4, 2008 issue of the Journal of American Medicine (JAMA).
UCSF Medical Center has established the UCSF Headache Center, which is primarily a consult service for headache sufferers for whom treatment has failed. Experts work with the referring primary care doctors of patients to develop an individualized treatment plan to significantly improve quality of life. For those who suffer from more complex disorders, inpatient and outpatient treatments are available.
In addition, the center conducts basic and clinical research, exploring the basic mechanisms of headache and how existing and novel therapies might treat the debilitating disorder. In the last five years, migraine research has identified several mechanisms that underlie regulating migraines. We now have a better understanding of the complex interplay of certain ion channel disruptions that are integral to triggering head pain. Under the right circumstances, technologies like functional MRI and other imaging procedures have allowed us to actually see how the larger structures in the brain are involved during migraine and headache.
For more information, contact the Physician Referral Service at UCSF Medical Center:
|Phone||(888) 689-UCSF or (888) 689-8273|