Developments in understanding migraine pathogenesis and, in particular, the role of the neuropeptide, calcitonin gene-related peptide (CGRP), have led to breakthroughs which will revolutionise treatment, especially chronic migraine (defined conventionally as over 15 headache days a month).
Migraine is a common (affecting 2% of the population), disabling condition resulting in many medical consultations. It is the second commonest cause of years lived with disability. Despite this, triptans have been the sole migraine-specific therapy developed so far.
Some of the prescribed medications for acute therapy of episodic migraine such as opiates are non-specific and are associated with a doubling in conversion to chronic migraine.
Previously, migraine prophylaxis pharmacotherapy has consisted of drugs handed down from other conditions that have demonstrated some effectiveness with migraine. These include anti-epileptics (e.g. valproate, topiramate), antidepressants (e.g. amitriptyline), antihypertensives (e.g. candesartan, calcium channel blockers), nutraceuticals (e.g. magnesium, feverfew, butterbur) and, more recently, neurotoxin (Botox).
Their mechanisms in migraine prevention is unknown. Neurologists frequently have to explain to patients why they are prescribing anti-epileptics or antihypertensives to treat their migraines. Lack of a migraine-specific mechanism also explains why they often have intolerable side effects and adherence is low, at only 25% after six months of treatment.
CGRP’s role in migraine was first suspected in the 1980s when it was shown that during migraine, levels in the cerebral circulation (and not the peripheral circulation) increased. Other trials showed that a migraine could be induced by endogenous administration of CGRP.
Efforts to target this neuropeptide have led to the development of at least three monoclonal antibodies: erenumab, fremanezumab and galcanezumab. They are humanised monoclonal antibodies that prevent nociceptive signalling via direct antagonism of CGRP receptor binding sites, likely at the trigeminal ganglion level.
These are the first migraine-specific, disease-mechanism targeted preventive therapies for patients with high-frequency episodic and chronic migraine. The Therapeutic Goods Authority (TGA) has approved them for treatment and prevention of chronic migraine.
Clinical trials have shown convincing benefits in treatments targeting CGRP including reduced number of headache days. Of the responders, 40% experienced a 75% reduction in headache days after 12 months of treatment, and 25% were free of headaches. Presumably because of their mechanism specificity, they have very little unwanted cross-mechanism effects and have shown little in terms of short-term adverse effects. They were so well tolerated in the clinical trials, that there was only single digit percentage drop-off rates (versus 30% in the topiramate trials).
For pharmacologic reasons, these drugs are administered subcutaneously (with an easy to use self-injection device) and are dosed monthly or quarterly (long half-lives) which positively effects compliance. Currently they are not PBS subsidised so cost will be the main limiting factor ($300 to $750 per month). This will obviously impact their positioning in the chronic migraine treatment hierarchy.
On the back of these new drugs, there are also disease-specific acute migraine therapies on the horizon. We have entered a new era in migraine treatment.
Key messages
- Chronic migraine is a prevalent, burdensome condition, which is currently poorly treated
- CGRP targeting drugs are well tolerated and quite effective
- New acute treatments should be licensed shortly
References available on request.
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Author competing interests: nil
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