The cusp of a different era in migraine management

Attendees at the Irish Neurological Association and the Association of British Neurologists Joint Meeting 2023 received a comprehensive update on various aspects of migraine from several speakers, that included its pathologies, diagnosis, management, and the latest in genomic and hormonal research. In his discussion on ‘Neurogenetics and the pathology of migraine’, Consultant Neurologist Prof Zameel Cader, Director of the Oxford Headache Centre, UK, called the disorder a “big deal” and “a fascinating condition”, because of its varied manifestations. He described how one-third of patients experience migraine aura, and gave an insightful outline of the data linking the phenomenon of migraine aura to spreading depolarisation. “Depolarisation is the substrate of an aura,” he said. 

Moving on to what activates pain during migraine, Prof  Cader said he did not have the answer, but that understanding of the disorder is evolving. He went on to examine the flaws in the theories of migraine to date, from vascular theories to the neurogenic and neuroinflammatory hypotheses, and how genetic studies have “turned our understanding” of the condition. Telling the room that the calcitonin gene-related peptide (CGRP) molecule in particular “has really taken centre stage” in the last five years, he described the rationales for targeting this neuropeptide in migraine therapy and research. Evidence for this included the findings that migraine sufferers exhibited elevated CGRP versus control, that CGRP levels decreased following triptan administration, and that CGRP, along with other molecules, is able to provoke a migraine-like headache in some, but not all migraineurs. “We are at the cusp of a completely different era of neurology and I think it’s a brilliant time to be a neurologist,” he said, as he described the emerging data on CGRP-targeted therapy.

“Migraine CGRP antibodies and CGRP small molecules that are targeted against the CGRP receptors in clinical trials have been shown to be very efficacious and very safe. What’s still a mystery is where they are working.” Describing challenges ahead, Prof Cader told the meeting that despite the positive data, the treatments are costly and are not disease-modifying, before acknowledging that despite a large group of “super-responders”, not all patients experience improvements. “There is still a substantial burden of headache that needs to be dealt with… my job as a research scientist is not over.”

Consultant Neurologist Dr Shazia Afridi, Guy’s and St Thomas’ NHS Foundation Trust, London, UK, also addressed the disorder in her comprehensive overview of the ‘hormonal aspects of migraine’, focusing primarily on the role of oestrogen fluctuation in migraine throughout the female lifespan. She highlighted the high prevalence of the condition in women, noting a 3:1 women-to-men ratio, and how one-in-four females of child-bearing age will experience migraine. Acknowledging that “we don’t know how it [oestrogen] works”, she echoed the sentiments of Prof Cader, saying “oestrogen can modulate CGRP expression” in animal studies, and outlined recently published findings of elevated CGRP levels in the tears of women with menstrual migraine versus control.

Dr Afridi also discussed the areas of the brain believed to play a role in migraine, such as the hypothalamus, brain stem, and trigeminal nucleus caudalis, and how they all express oestrogen receptors, before looking at data linking oestrogen and migraine in transgender women, pregnancy, the combined oral contraceptive pill (COCP), and menopause. She told her colleagues that 50 per cent of female migraine sufferers will experience menstrual exacerbation, and that management depends on whether the woman’s cycle is regular or not. In patients with a regular cycle, she discussed the evidence supporting the use of non-steroidal anti-inflammatories, describing the two days before menstruation as the “therapeutic window” for treatment. She also told the room that reliable evidence exists to support the use of triptans and oestrogen gel during this period. For those with an irregular cycle, Dr Afridi outlined the current data supporting tricycling the COCP, the use of vaginal rings, and GnRH analogues. She also discussed various other forms of hormonal manipulation, prophylactics, vagus nerve stimulation, and the current use of magnesium in managing menstrual migraine.

Addressing the use of contraception for migraineurs, Dr Afridi said it “is difficult to predict if it is safe” before looking at links between COCP oestrogen doses and stroke risk. She described the relationship between migraine and stroke as “a topic in its own right” and noted the higher incidence of stroke in migraine with aura. Taking into account the additional risks of stroke in COCP, she said this is “where concern comes in” before describing how migraine with aura carries a two-fold relevant risk of stroke, and how migraine with aura and the COCP combined present a six-fold risk, saying that this data “has to be taken seriously”. She did acknowledge the deficit in up-to-date studies on the risks associated with the COCP, especially in view of the major changes in oestrogen doses and pill formulations since links between it and stroke were first established, but concluded that the guidance still dictates that the COCP should not be offered to this patient group until new, valid, and reliable data becomes available.