6 March 2019

Is there light at the end of the tunnel for migraineurs?

Chronic Disease Clinical

“Migraine is an incurable disease of unknown cause” is a sentence that sums up the two inconvenient truths about the world’s most common severe headache – but there is fresh hope for sufferers in the form of monoclonal antibodies.

Neurologist Dr Paul Spira, speaking about the history and latest developments in migraine research at the HealthEd Women and Children’s Health Update late last month, said while the first written descriptions of migraine dated back millennia, the condition had probably been around for as long as humanity.

Even now there is contention between two theories of migraine – is it vascular or neural, or both?

Dr Spira, from the Institute of Neurological Sciences at Sydney’s Prince of Wales Hospital, said Australian researchers had been at the forefront of solving the migraine puzzle, and paid tribute to the late Australian neurologist James Waldo Lance, who died only days before the conference.

About 15% of the world’s population experience migraines, while an unfortunate 2% have chronic migraine, or as many as 15 days of headache per month. Prevalence in women is two to three times higher than in men.

Effective therapies have been elusive.

Trepanning, or drilling a hole into the skull, is thought to have been the Neolithic fix for the blinding pain of an evil-spirit-induced headache and was still being recommended as late as the 17th century. Around that time, the disease was determined to have a vascular aetiology. Ergotamine, a vasoconstrictor derived from a fungus (and also a non-specific serotonin agonist), has been prescribed since the 1920s. 

But the medication does have significant although rare risks including gangrene and, cruelly, severe headaches.

It also can’t be given to patients with cardiovascular disease.

Then in the 1960s, work by Lance and colleagues focussed on serotonin, after increased levels of serotonin’s main metabolite were found in the urine of patients experiencing  an acute migraine.

However, early treatment with serotonin agonists, while relieving the headache, made some subjects so sick they preferred the pain, Dr Spira told the conference attendees.

The triptan class of drugs were developed on the basis that both the blood vessels and serotonin are central to migraine pathophysiology. Sumatriptan, introduced in 1991, and following second-generation triptans, target serotonin receptor subtypes with greater efficacy and safety than ergotamine; but they don’t work on everyone and are still contraindicated for CVD patients.

A student and colleague of Dr Lance, Peter Goadsby, more recently established that another neurotransmitter, calcitonin gene-related peptide or CGRP, a powerful vasodilator that inflames the meninges, played an important role in migraines.

The gepant class of drugs, non-vasoconstrictive CGRP antagonists, were then developed. The first of these, telcagepant, was effective in relieving migraines, Professor Spira said, but was so hepatotoxic it had to be withdrawn. However, other safer gepants, like ubrogepant and rimegepant, are on their way to market or still in development.

Other classes of drug in use include botulinum toxin injections, anticonvulsants, beta-blockers and antidepressants, with varying rates of efficacy and side effects.

Now, in what Professor Spira called a “situation of great promise”, researchers are turning their attention to monoclonal antibodies, identical immunoglobulins that specifically target one binding site on a given antigen.

These monoclonal antibodies can be generated to target almost any substance, and are currently revolutionising treatment across the full spectrum of clinical medicine from cancer and inflammatory diseases to asthma and viruses such as hepatitis C.

The first monoclonal antibody for migraine has been approved by the FDA and TGA, after positive results in safety and efficacy trials with no significant side effects or interactions reported.

Erenumab, marketed as Aimovig, has been approved for preventive use against migraine.

The listing follows results of the STRIVE trial, led by Professor Goadsby, which showed monthly injections of the medication substantially reduced the frequency and severity of migraines among almost 1000 chronic migraineurs over a six month period. 

Of course, no one therapy was going to cure everybody, Dr Spira conceded. But migraineurs will no doubt appreciate having yet another option to get some relief from this miserable condition.