Health professionals

Where are we with migraine?
The state of play in the science of migraine

Migraine – to recap

Migraine is a largely inherited disorder. It is now believed to be primarily nervous in origin, by way of the central nervous system. From the scientist’s perspective, it is the complex pattern of dysfunction in sensory nervous processing that is typical of the condition.

For people with migraine, there are the all too familiar symptoms of repeating attacks with intense head pain of some duration with nausea. Other symptoms that come before the head pain are typically: photophobia (sensitivity to light); phonophobia (sensitivity to sound); osmophobia (sensitivity to smell); and eerie sensory distortions of the vision, sound and smell perceptions. Any of these symptoms may be present and may instil a sense of fear and foreboding in a child or an adult about to experience their first episode of migraine.

In advance of all those symptoms, however, is usually a premonitory period in which people can experience tiredness, reduced concentration, irritability and pronounced yawning. Such warning signs may occur several hours or even sometimes days before the full onset of the migraine episode.

For the majority of the twentieth century medical opinion was inclined towards viewing the condition as vascular in origin. Attempts in research and in pharmacology to identify and treat the cause as largely vascular have only just recently produced reliable evidence to the contrary. Scientists now believe, (as was believed in the nineteenth century) that migraine originates in the nervous system.

Aura and cortical spreading depression

A sub group of migraineurs sometimes experience the visual so-called ‘aura’, typically before the head pain commences. The term cortical spreading depression (CSD) describes a local disturbance of the brain function that is characterised by a transient and local suppression (depression) of the spontaneous electrical activity in the cortex (cortical) that moves slowly across this brain region (spreading). Aura would seem to be a symptomatic manifestation of CSD, something which non-aura patients would not be aware of, even when CSD is happening. Aristides A P Leão was the first to describe this phenomemon in 1944 and it has now been proven to exist using electrophysiological methods and human imaging studies.

Could CSD be the immediate progenitor (biologically related precursor) of migraine? Some studies suggested it might activate head pain via the meningeal branch of the trigeminal nerve. For a while it was considered at least worth attempting to stave off an attack by interrupting the migraine build up pattern using Tonabersat, a blocker and an inhibitor of CSD. Disappointingly for migraine sufferers whilst the treatment did prevent aura in those patients prone to experience this, it could not prevent the subsequent migraine.

Dural plasma protein extravasation

When still searching for a vascular cause, at least as far as the headache component of migraine was concerned, attention was turned to a known phenomenon: the pain–causing leakage of plasma proteins from the dura (the outer meningeal layer) or ‘extravasation’. This takes place with excessive trigeminal nerve stimulation and is one part of the cycle of an impending migraine episode. Sumatriptan, often effective when taken as an acute treatment for attacks, actually blocks this process. Reasonably it was surmised that the blocking of extravasation was helping the pain. Unfortunately it was discovered that other compounds able to block this extravasation were not successful in controlling the pain, and hence the dural plasma protein extravasation in the event was not providing a key to the actual mechanism of migraine headache symptoms.

Brainstem origin of migraine

Although the resolution of PET scans is pushed to the limit in pinpointing precisely where in the brainstem this takes place, there is certainly some activation registering in an area of the dorso-lateral brainstem during acute migraine attacks.

Regional structures almost certainly implicated include one or both of:

• the periaqueductal grey matter – involved in neurological pain inhibition/suppression
• the locus coeruleus – known to modulate response to sensory neural transmission in critically regulating cortical function.

In other words dysfunction of such brainstem structures and networks could account not only for the headache component, but also for the auditory, olfactory and visual components. Plus locus coeruleus dysfunction also could account for the symptoms of anxiety and distractibility which people with migraine can experience.

New pharmacological approaches to reducing attack frequency and severity in migraine

1. Prevention medication
   

   Currently the mechanisms by which preventative treatments take effect are not at all well understood. Drugs proven to benefit both aura and no-aura migraine are: beta blockers (such as propranolol), anti-depressants (such as amitriptyline), anti-convulsants (such as valproate or topiramate), calcium channel blockers (such as flunarizine) and serotonin antagonists (such as methysergide). It is reasoned that these drugs probably target activity in modulatory circuits as well as in the neuronal activity of the trigeminal system.

   As migraine is such an individual condition there is an inevitable trial and error process in finding out which drug works for each individual – a frustrating and often time consuming business for the migraine sufferer. Equally each drug has side effects and contraindications which need to be weighed up carefully for each person adding to the complex nature of migraine management.

   New approaches currently undergoing trials include: Botulinum toxin; stimulation of the occipital nerve, which can modify central processing of pain signals in the thalamus; and other neuromodulational approaches any of which may prove to be effective preventatives in the future.

2. Acute medication
   

   On the one hand there are non-specific anti-pain compounds NSAIDS, analgesics and the like, on the other there are more migraine specific approaches such as ergot-derivatives and the triptans. The choice of an acute medication on the basis of attack characteristics has been shown to be superior to stepped care. Triptans have proved to be most effective and are therefore the typical drug of choice for more severe migraine attacks. Better tolerability by the patient also means triptans have superceded ergotamine in most cases.

   There are still situations where triptans cannot be prescribed because of the vasoconstrictor effects they have. This makes them unsafe for patients who have cerebro-vascular and/or cardiovascular conditions. This is where the new Gepant drugs could come into their own. These are CGRP (calcitonin gene-related peptide) receptor antagonists that have shown promise in effectiveness comparable to triptans only without the unwanted vascular constriction.

   Several more options may follow in their wake such as nitric oxide synthase inhibitors, vanilloid TRPV1 receptor agonists and glutamate, AMPA/kainite receptor as well as pure kainite receptor antagonists. Migraine specific drugs that are usable in the acute stage will soon benefit patients more and more as the choices become broader and the drawbacks that limit currently used drugs are overcome.

Conclusion

Neural treatments of the sensory dysfunction show most promise for present and future pharmacological care of migraine sufferers.

In addition to new treatments, improved discovery and diagnosis of who can benefit best from already available treatments is likewise a huge way forward bringing hope to the millions who suffer from this disabling condition.

Adapted from the mini review ‘Migraine pathogenesis and state of pharmacological treatment options’,
by Till Sprenger and Peter J Goadsby, published in BMC Medicine, 16th November 2009.