Q:Recently I had occasion to visit my GP as a migraine attack had occurred, far worse than I had experienced previously, shortly followed by another.
The GP took my blood pressure and prescribed Imigran (sumatriptan). On arriving home I had breakfast and took one. Nothing prepared me for what was to follow. I collapsed and came to some seven hours later, able to do very little. Breathing difficulties, a lack of appetite and a feeling of total lethargy followed for the next three days.
After this experience I refused to take any more, preferring to suffer the pain of migraine, which I experience about once a year. J M, Newhaven, East Sussex.
A:As you know from the patient information leaflet you were given with your drug, Imigran, generically known as sumatriptan, is a new migraine drug, called a 5-HT agonist, which supposedly works by reducing the swollen blood vessels around the brain.
It is chemically related to 5-hydroxytryptamine, or serotonin, a chemical in the brain, and was developed after scientists revised their thinking about what causes migraine. Dr Frank Clifford-Rose of the Charing Cross Hospital, who helped coordinate many of the studies of sumatriptan, says that migraine, rather than being initiated by the blood vessels in the brain itself, is now believed to be a biological disease of the nervous system, and that serotonin plays a key role. It has long been known that 5-HT can cause headaches, and experiments have shown that 5-HT is released during migraine attacks.
Glaxo was the first to come up with a drug which was chemically related to 5-HT, but supposed to selectively block the receptors for this hormone, causing the blood vessels in the brain to constrict without affecting what could be as many as 15 other 5-HT receptors, which affect blood clotting, activity in the lungs and the gastrointestinal system in the central nervous system.
In 1991, Glaxo enthusiastically launched sumatriptan as "a revolutionary acute therapy in migraine" after a number of studies showed highly promising results in patients injected with the drug under the skin (the faster route) or given it in tablets.
In two studies testing sumatriptan against a placebo in a total of 1600
patients, within two hours, 81-86 per cent of patients had their headaches disappear or lessen to the point of being mild (N Engl J Med, 1991; 325: 316-21 and JAMA, 1991; 265: 2831-5).
In the wake of a great deal of noisy fanfare over what was thought to be one of the first real breakthroughs for migraine, medicine has begun to retrench, now that the reports are flooding in demonstrating that patients taking this drug may be trading one health problem for another or, indeed, making the problem worse.
The latest studies show that at least 5 per cent of users of sumatriptan experience chest pain. Because the drug works on blood vessels, it has always been assumed that the chest pain had to do with the heart. But a new study (The Lancet, 8 October 1994) shows that the pain may start in the esophagus (the canal from your mouth to your stomach). A double-blind study of 24 volunteers randomly injected with either sumatriptan or saline found that there were no electrocardiogram changes. However, studies of the esophagus showed that contractions of the esophagus were significantly increased by sumatriptan.
Five of the subjects (21 per cent) developed chest pain, lasting from two to 45 minutes, although there seemed to be no relation in time between onset of the pain and the abnormal recordings of movement of the esophagus.
A number of doctors writing from the Department of Medicine and Therapeutics, Western Infirmary, University of Glasgow, argued that the study results should be regarded with caution, particularly since the changes were seen only when three times the normal amount of the drug was given. They also point out that changes in the blood have been shown with the standard therapeutic dose of sumatriptan; blood pressure in the lungs and aorta rises by 40 per cent and 20 per cent, respectively, which could mean that the chest tightness arises from the veins in the lungs or those running the breadth of the body rather than in the esophagus (The Lancet, 26 November 1994).
Dr K M A Welch, from the Department of Neurology, Henry Ford Hospital and Health Sciences Center, in Detroit, Michigan, concluded that in rare cases heart arterial spasms have occurred (N Engl J Med, 329; 1476-83). A Lancet commentary (19 June 1993) added there is a small risk of poor blood flow to the heart, and a Dutch postmarketing study says that angiographies of patients showed that sumatriptan does indeed constrict arteries (BMJ, 6 November 1993).
The bottom line is that medicine doesn't really have a clue what causes the chest pain or what it really means. What doctors do know is that one woman with no previous history of vascular disease suffered a fatal heart attack after injecting herself with sumatriptan (The Lancet 1993; 341: 861-2) and two patients developed serious irregular heartbeat (19 September 1992). Furthermore, in some the chest pressure or pain radiates out to the left arm and head, in the manner of angina (N Engl J Med, 11 November 1993).
The other problem is the possibility of rebound migraines, setting up increased dependence on the drug. The Gothenburg Migraine Clinic in Sweden found that 102 of 193 (53 per cent ) patients given sumatriptan by injection had recurrences of migraine within five to 10 hours after nearly every treated attack. Another study of 21 patients found that all but one had a headache the next day (The Lancet, 10 October 1992).
Researchers at the Department of Neurology, University of Essen in Germany also reported on seven patients who after an average of nine months found that they had to use the drug nearly every day to prevent their headaches from recurring.
In another case, a patient who'd only suffered from migraines once a month began getting them every morning after he'd began taking sumatriptan (BMJ, 8 January 1994).
Glaxo denies that there is any evidence of dependence on the drug, and points out that the drug is only approved for short-term intermittent treatment of acute migraine attacks, and not for daily prevention.
Besides the problems mentioned, sumatriptan can cause dizziness, vertigo, malaise, fatigue, drowsiness and a feeling of heaviness.
In the Gothenburg Clinic, 70 per cent of patients experienced one or more side effects, including neck pain, chest symptoms, tiredness, tingling and a reaction at the injection site. The oral variety can also cause nausea and vomiting.
Besides this multitude of side effects a question mark hangs over sumatripan's genuine effectiveness in times of need. Although as many as 90 per cent have responded to the drug over three treatment courses, only about 50-60 per cent will respond to it during any one attack (The Lancet, 23 January 1993).
As usual, medicine has rushed in shouting about its "breakthrough" far too early, without fully understanding what the role of serotonin is in the onset of migraine, what blocking could do to you or whether sumatriptan is as "selective" as first thought. (The not fully understood role of this hormone is also behind the many side effects reported with Prozac and cholesterol-lowering drugs). It also demonstrates that in studying the body microscopically and looking for a specific means to block the action in the body which specifically sets off the pain, medicine has once again missed the forest for the trees.
Without looking at the body as a whole, the approach fails to consider what exactly sets off the serotonin and the migraine pain in the first place.