Migraine and the pharmaceutical industry

Current medicines for the treatment of migraine

Medicines used in the treatment of migraine can be divided into several distinct groups:

• medicines which help control the pain,
• products that reduce the symptoms of nausea and vomiting,
• medicines that reduce the frequency of attacks, and
• those used to abort or treat an acute attack.

Medicines for pain control: The analgesics are used in a variety of painful conditions and were not developed specifically for migraine. Most are available without a prescription from high street chemists. They are used by a remarkably large number of people who manage their attacks by self-medication – recent research suggests that even in countries with well-developed health care systems, fewer than 50 per cent of women and 30 per cent of men are diagnosed by their GP, the majority relying on non-prescription medicines. These have a real place and provide some relief, especially when combined with anti-sickness medicines or other products such as caffeine, ergot alkaloids or anti-nausea medicines.

The commonest analgesics used are paracetamol, codeine, aspirin, ibuprofen, diclofenac, naproxen and tolfenamic acid. They are all used to control pain, although only tolfenamic acid is specifically indicated for migraine. The first two change pain perception in the brain, while the others act differently. They belong to a group of medicines called non-steroidal anti-inflammatory drugs (NSAIDs). These work by blocking the formation of chemicals called prostaglandins involved in the fluid leakage and swelling in inflamed tissues and probably act on the sterile inflammatory phase of migraine, though this remains unproven.

Compounds for nausea and vomiting: The compounds used to control nausea in migraine have mostly been available since the 1950s or 1960s. They include metoclopramide (Sanofi-Synthélabo), domperidone (Servier), and prochlorperazine (Reckitt & Colman). Some antihistamines also have an anti-nausea action, including buclizine (Pfizer), cyclizine (Glaxo Wellcome), and cyproheptadine (Merck Sharp & Dohme). These compounds act on a variety of receptors involved in the nausea response and also modify gastric contractions with an overall calming action. Most are formulated as combinations with ergot alkaloids, caffeine, or analgesics such as paracetamol.

 

How medicines are licensed Initial research on new compounds is carried out in the laboratory, using a wide variety of techniques. Promising compounds are then studied in animals, to investigate effects that cannot currently be predicted from the computer and test tube studies. A sequence of phases of clinical assessment in humans follow strict guidelines. Phase 1 : a small number of healthy volunteers is given the compound. These trials will determine some aspects of how it works in humans and help to establish the dose required. Phase 2 : a small number of patients with the condition are given the medicine to assess both that it works and that it does not produce unacceptable side-effects. Phase 3 : many more patients, perhaps several thousand, take the medicine under supervision for an appropriate period. It is tested in comparison with an established treatment and/or a placebo. These studies are used to establish the efficacy of the new medicine. If the results prove satisfactory in terms of quality, efficacy and safety, the data gathered are presented to the medicines evaluation authorities. If the authorities are satisfied by the evidence, a marketing authorisation is issued. Phase IV : the newly-licensed medicine may be studied in large numbers of patients in general practice to assess its clinical effectiveness. SAMM (Safety Assessment of Marketed Medicines) studies are sometimes initiated after the medicine has been made available for doctors to prescribe and to help identify any unforeseen side-effects. These may involve many thousands of patients. GP databases are also used to identify medicine safety issues and to explore the potential for new and better uses of medicines once the product is available for prescription.

The individual obviously has a problem to know how much, when and which of the various analgesics, antihistamines or anti-nausea medicines to take and in which combinations. This problem has been specifically addressed in two products, Migraleve (Pfizer) and MigraMax (Elan Pharma). The former is manufactured as either pink or yellow tablets. The pink tablet contains two analgesics and buclizine for nausea, while the yellow one contains two analgesics only. The patient takes the pink tablet at the first sign of a migraine and follows this with the yellow tablet if symptoms persist. MigraMax is available in a sachet to dissolve in water and contains lysine acetylsalicylate (LAS) and metoclopramide. LAS is a form of aspirin that dissolves readily in water and is taken up quickly into the body. Metoclopramide controls symptoms of nausea.

Medicines that reduce the frequency of attacks: Several compounds originally developed to treat high blood pressure are also used to prevent migraine, especially in individuals who get many attacks (minimum of four attacks a month). These include clonidine (Boehringer-Ingelheim) and a group of compounds called beta-blockers. The first beta-blocker licensed for migraine was propranolol (AstraZeneca). Three others are now available, namely metoprolol (AstraZeneca and Novartis), timolol (Leo Pharmaceuticals) and nadolol (Sanofi-Synthélabo).

In addition, pizotifen (Novartis), sodium valproate, methysergide (Alliance), and occasionally the antidepressant amitriptyline are used in migraine prevention. The use of such medicines is usually reserved for people whose problem has not been successfully brought under control through other methods.

Pizotifen acts in two main ways: firstly, on brain blood vessels to stop fluid leakage and hence the chemicals that trigger the pain receptors and secondly, to keep blood levels of serotonin closer to normal. Serotonin is also involved in depression (though in different parts of the brain and using different receptors) which may explain the apparent value of amitriptyline in migraine prevention.

Valproate has been used for many years to control epileptic seizures. It has several actions, including binding to GABA receptors in the brain and has been found useful in the prevention of migraine. This supports the suggestion that epilepsy and migraine are part of a broad spectrum of disturbances of the central nervous system. Finally, another molecule, derived from the ergot fungus, methysergide (Alliance), has some use in migraine prevention. It is largely free of the unwanted ergotamine-like effects and can thus be given for longer periods, but its use is still limited by other unwanted actions.

It is important to note that these medicines are not ideal and their success rate in migraine is limited. Individual response is very variable and at best, 55 per cent of patients will achieve a 50 per cent or more reduction in attack frequency.

Medicines for acute attacks: Alkaloids from the ergot fungus are much less used today than 10 years ago, and have been largely supplanted by the triptans. A major reason is that ergotamine binds to various types of receptors other than those involved in migraine – it is not specific. This causes problems through the constriction of blood vessels in the heart and it cannot be used in people with pre-existing heart complaints. Its use is mainly in young and otherwise healthy individuals. Triptans act considerably more selectively on the brain, but are nevertheless restricted in their use in people who have had a heart attack, or suffer from certain heart or circulatory conditions.

Ergotamine is available from Alliance, CP Pharmaceuticals, Novartis and Sanofi-Synthélabo – in some cases combined with caffeine (Novartis) or caffeine plus an anti-histamine. It tends to be used mostly in cases unresponsive to analgesics or the triptans, or for people who react badly to them.

The side effects are somewhat reduced in dihydroergotamine (Novartis), the most recent addition to the UK ergot medicines, which became available here in early 1999 as a nasal spray. Another alternative is isometheptine (Manx Pharma) which has been available for many years and acts to constrict over-enlarged brain blood vessels.