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Migraine is a common unilateral throbbing headache that occurs periodically and lasts 4–72 hours. The first clear classification that migraine with and migraine without aura are separated was published in 1988 (see Tables 1 and 2).(1) This separation is important for research purposes, as there is genetic and epidemiologic evidence that both types differ.(2–5) The majority of patients who suffer from common migraine have never suffered an aura, whereas those with classical migraine with aura often suffer from additional attacks of migraine without aura. There is no difference between migraine with and migraine without aura with regard to efficacy of antimigraine drugs.
Twin studies have indicated that there is a genetic component to migraine.(6) The fact that migraine is a common condition suggests that a predisposition is more likely to be caused by genetic polymorphisms than mutations in candidate genes. Although it is known that migraine is associated with altered serotonin metabolism, screening for mutations or polymorphisms in the 5-HT(2A) and 5-HT(2C) receptors of migraineurs has been negative.(7) Similarly, no association was found between migraine and polymorphisms in cytochrome p450 2d6,(8) glutathione S-transferase M1,(9) and nitric oxide synthase genes.(10) One study demonstrated an association between migraine and dopamine D(2) receptor alleles,(11) although these findings have been challenged . An association between migraine and endothelin type A receptor gene polymorphisms has been reported.(12)
There is a strong environmental influence on the expression of migraine. Predisposing factors include certain foods, hormonal environment and psychosocial stressors. The latter has been interpreted as the reduced ability of the brain of migraineurs to adapt to physiological changes such as altered circadian rhythm or irregular mealtimes. Migraineurs may also have interictal physiological and biochemical abnormalities(13–15) that may lower their “threshold” for developing an attack,(16) which may then be precipitated by either CNS-based factors such as stress or bright lights, or exogenous factors such as fasting or particular foods.
Pathophysiology of migraine
It is thought that the painful components of migraine with and migraine without aura are identical with respect to pathophysiology, but that the two forms differ with respect to the mechanism of attack onset.
There have been significant advances in understanding the physiology and pharmacology of migraine. The “vascular” theory of migraine has been superseded by a more complex model in which the primary event is neurogenic, characterised by an alteration in neuronal excitability, followed by the development of a self-limiting meningeal irritation.
In classical migraine, the headache is preceded by a defined aura. This is thought to be due to the development of a wave of “spreading depression”(17) associated with an increased extracellular concentration of potassium and glutamate.(18) This activates the perivascular nerve terminals surrounding the cerebral vessels and venous sinuses, which project to the trigeminal nucleus caudalis, and from there to the cortical pain areas via the thalamus. Depolarisation of the trigeminal ganglion and perivascular nerve terminals activates the trigeminovascular system, which also results in retrograde perivascular release of vasoactive neuropeptides. This is thought to be the mechanism of the headache in both migraine with aura and migraine without aura.
A number of positron emission tomography (PET) studies during attacks of migraine have demonstrated regions of the brain that are activated during the attack, termed “cortical generators”, and which remain active following successful treatment of the headache.(19) Such generators are thought to represent the sites of initiation of the migraine attack. However, the relationship between these regions and the subsequent generation of the migraine headache remains unclear.
Further elucidation of the mechanisms of migraine will lead to the development of new and more effective drugs for both symptomatic and prophylactic use.
Pharmacotherapy of migraine
Many of the “standard” pharmacological therapies for migraine have not been validated by randomised placebo-controlled trials. The American Academy of Neurology (AAN) recently published a series of evidence- based reviews and recommendations with respect to the management of migraine.(20–23) The salient aspects of these reviews are outlined below.
Serotonin metabolism is disturbed in migraineurs, although the precise mechanism remains unclear. The observation that serotonin metabolism is important in migraine has led to the development of a new generation of specific antimigraine agents that have revolutionised the acute management of migraine. The triptans are 5-HT derivatives that display highly-selective agonist activity at the 1B, 1D, 1F and 1A 5HT receptors.(24) Three hypotheses have been proposed to account for the actions of the triptans: inhibition of dural neurogenic inflammation; reduction in the excitability of the cells in the trigeminal nucleus (the prototype drug, sumatriptan, does not act on these cells, as it does not cross the blood–brain barrier); and vasoconstriction of meningeal, dural and pial vessels.
Sumatriptan, the prototype triptan, has had a significant impact in the management of acute migraine. When administered orally, 75% of patients have relief of headache and other symptoms within four hours. However, the headache may recur in up to 44% of patients, and a second dose of 100mg may be effective. Subcutaneous administration produces a more rapid response, with maximal therapeutic response within one hour. The side-effects of the triptans include chest tightness (not related to cardiac ischaemia),(25) flushing, nausea and dizziness. There have been a small number of reports of cardiac events following triptan administration, and it is contraindicated in patients with a history of heart disease. Sumatriptan can be administered orally, intranasally or subcutaneously.
Since the launch of sumatriptan, there have been a number of other similar drugs, including zolmitriptan, rizatriptan, eletriptan, almotriptan and naratriptan. All of these have been compared with oral sumatriptan in randomised double-blind clinical trials, with minimal difference between the oral formulations. Subcutaneous sumatriptan has the most rapid onset of action of all triptans currently available.
Many patients experience recurrence of headache after a primary successful response. Administration of a second dose is usually effective. Failure of one of the triptans to control migraine does not imply that all will fail, and it is worth trying a substitute. Similarly, not all migraines respond to the triptans, and the failure of the drug to control a headache does not necessarily indicate that all migraines will be refractory to the drug.
Ergotamine with caffeine is effective orally or rectally. Dihydroergotamine can be administered by nasal spray, subcutaneously, intravenously or intramuscularly. The ergot alkaloids are associated with a higher incidence of side-effects than the triptans and a slower onset of action. Side-effects include nausea, vomiting and peripheral vasoconstriction. The ergot derivatives are significantly cheaper than the triptans.
Non-steroidal anti-inflammatory drugs (NSAIDs)
Oral NSAIDs and combination analgesics containing caffeine are recommended as first-line treatment for mild-to- moderate migraine attacks. Paracetamol is usually ineffective.
Opiates and other medications
Opiates should be used sparingly for the management of migraine as they are addictive, sedating, and the pain-modulating effect may be limited owing to the disruption in serotoninergic metabolism. They can be used as “rescue” agents for management of acute intractable headache, but should be avoided where possible.
Steroids can be used as rescue therapy for status migrainosus. There are anecdotal reports of the effective use of other drugs and agents in the management of migraine. The majority are unvalidated.
The goal of preventive therapy is to reduce the frequency, severity and duration of attacks, and to improve quality of life. The decision to use a preventive drug should be taken following discussion with the patient. Indications for preventive therapy include:
The choice of preventive drug should be determined by the efficacy and the possible side-effect profile. An adequate trial duration should be encouraged; at least 2–3 months are required in many cases to achieve clinical benefit. Patients should be encouraged to keep a diary, and treatment should be re-evaluated in 3–6 months. A list of potential preventive drugs is provided in Table 3.
German Migraine and Headache Society (DMKG)
T:+49 941 9413070
F:+49 941 9413075
International Headache Society
Italian Society for Headache Studies
Migraine Association of Ireland
T:+353 (0)1 8724137
F:+353 (0)1 8724157
Olesen J, Theur-Hansen P, Welch M. The headache. Philadelphia: Lippincott, Williams & Wilkins; 2000
Silberstein S, Lipton RB, Goadsby P. Headache in clinical practice. Oxford: ISU Medical Media; 1998
22–26 June 2002
European Neurological Society 12th Meeting
26–30 June 2002
European Headache Federation 6th Headache Congress Istanbul, Turkey
T:+90 312 3095293
F:+90 312 4461099 E:firstname.lastname@example.org