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Major headache

Migraine is one of the most common disorders encountered in GP's surgeries and emergency departments, affecting around 20 per cent of people

Treatments for migraine are maturing, promising a brighter future for sufferers

Migraine is one of the most common disorders encountered in GP's surgeries and emergency departments, affecting around 20 per cent of people.

Primarily, this condition presents with recurring episodes of throbbing and, most commonly, unilateral severe head pain that can last for between four and 72 hours. Patients also frequently complain of associated symptoms of migraine, such as nausea, vomiting and sensitivity to light, sound and movement.

About one-third of migraine patients also describe experiences of aura - a visual disturbance characterised by visions of flashing lights or black spots - that appear five to 20 minutes prior to the onset of head pain and can last for up to an hour.

As well as impacting significantly on patients' quality of life, this disorder also presents a high socio-economic burden, as it affects mainly young working adults and is associated with high rates of work and school absenteeism.

The pathogenesis of this chronic and disabling disorder has puzzled researchers for decades, with earlier models of migraine circulating around a primarily vascular hypothesis.

However, recent evidence has indicated that migraine should be viewed as a neurological condition.

As the majority of the brain lacks pain receptors, those components that are capable of generating pain are implicated in migraine - the cranial and intracranial blood vessels and the dura mater (the outermost layer covering the brain and the spinal cord), which are supplied by branches of the trigeminal cranial nerve.

Those fibres that innervate cerebral blood vessels contain substance P and calcitonin gene-related peptide (CGRP) - neuromodulators associated with the regulation of pain.

Current therapies for acute migraine consist primarily of the serotonin1B/1D receptor agonists (more commonly known as triptans), such as sumatriptan, that have been shown in experimental studies to block CGRP release and action, inhibiting trigeminovascular nociceptive transmission.

What's new
Boehringer Ingelheim's CGRP receptor antagonist olcegepant (BIBN 4096) is currently undergoing phase II development in Europe and the US as a potential therapy for acute migraine.

In a multicentre, randomised, double-blind study, 126 patients with migraine received intravenous olcegepant 2.5mg or placebo. Some 66 per cent of the olce-gepant recipients demonstrated a clinical response, compared with 27 per cent of those treated with placebo (p = 0.001).

The pain-free rate at two hours, sustained response over 24 hours, headache recurrence and secondary headache symptoms of photophobia, phonophobia and nausea were significantly better in BIBN 4096 compared with placebo recipients, with a treatment effect observed from 30 minutes onwards.

Inhibitors
Civamide (Winston Laboratories) is a vanilloid receptor agonist and neural calcium channel blocker. This drug, which is applied intranasally, inhibits neuronal release of excitatory neurotransmitters, such as substance P and CGRP, making it a prime candidate for migraine treatment.

In a double-blind study, where 34 patients with acute migraine were treated with civamide 20g or 150g, 56 per cent had a decrease in migraine pain severity at two hours post-dose and 22 per cent of patients were pain-free at this time.

At four hours post-dose, 73 per cent of patients experienced a decrease in their pain severity, while 33 per cent achieved pain-free status. However, civamide has been associated with nasal burning and tearing of the eyes, as it is a cis-isomer of capsaicin, the substance that gives hot peppers their burn.

Old versus new
Opioids have been used for centuries to control pain. However, these drugs do not rate highly in modern migraine management as, beside being highly addictive, they mask the pain associated with migraine leaving the patient exposed to the cognitive deficits that are characteristic of migraines and the aforementioned associated symptoms.

As a rule, the use of opioids should be limited to rescue medication in severe cases where maximal doses of other migraine-specific medications have not resulted in adequate pain control.

Intranasal Therapeutics is developing butorphanol, an intranasal opioid, for the treatment of migraine and acute pain.

In an emergency department study that included 25 patients with migraine, butorphanol was associated with significant improvements in pain intensity at 15 minutes post-dose, with 60 per cent of patients requiring no further treatment.

Adverse events were observed in 75 per cent of patients however, most of these were mild-to-moderate in severity.

Elan's zonisamide (Zonegran) is an approved anti-epileptic drug, undergoing phase II development as a prophylactic therapy for migraine.

In a prospective study, 34 migraine sufferers took once-daily oral zonisamide 100-400 mg/day for three months. The results revealed significantly decreased severity score, duration of headache and frequency of attacks per week following treatment with zonisamide.

Zonisamide appears to have wide-reaching possibilities, as it is also in clinical development as a treatment of Parkinson's disease, manic episodes of bipolar disorders, obesity and neuropathic pain.

Public health issues
Migraine presents a substantial public health problem, affecting quality of life and leading to poor self-rated health, and psychological and somatic symptoms.

However, with new therapies for the prevention and treatment of this condition, the future for migraine sufferers looks brighter.

The Author
Pipeline is written by Anna Mett of Adis International, using information derived from Adis Clinical Trials Insight and R&D Insight.

2nd September 2008

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