Migraine

Migraine – what is it and why research is needed

Migraine is a common disabling, episodic brain disorder, typically characterised by recurring, usually incapacitating attacks of severe pulsating head pain and associated symptoms such as nausea, vomiting, photophobia and phonophobia, and changes in mood or energy levels (migraine without aura).1 Migraine attacks last between 4‐72 hours (median one day).2,3 In one‐third of patients, attacks are associated with neurological aura symptoms (migraine with aura).3 Migraine is a clinically heterogeneous disorder. None of the features occur in all patients who meet a definition of migraine, and no single symptom is required for diagnosis.1

Treatments are failing

There is a huge unmet need of effective and tolerated treatments for migraine. Triptans, also known as serotonin (5-HT) agonists, are the only available option for the acute treatment of migraine. However, 30–40% of patients do not respond to triptans and a wide range of inter-individual efficacy and tolerability has been described, leaving more than 50% of migraine triptan users dissatisfied.4 For prophylactic treatments, aimed at reducing attack frequency, the situation is worse. Apart from the new antibodies targeting the calcitonin gene-related peptide (CGRP) pathway (which are prohibitively expensive at ~AU$7,000-10,000 per year), all migraine prophylactics were originally designed for other indications and were accidentally found to show “some efficacy” in “some patients” for “some time”. In Australia, the two most common prophylactic agents prescribed for migraine are pizotifen (a 5-HT antagonist and antihistamine) and propranolol (an antihypertensive β-blocker), both of which were developed over 50 years ago. More recently, topiramate, an anticonvulsant (antiepileptic) was first approved in 2004 (USA) for the prophylaxis of migraines in adults, and is listed on the Australian Pharmaceutical Benefits Scheme (PBS) as a second-line option, after propranolol and pizotifen. However, contraindications and adverse effects exist for all antimigraine drugs, and most patients undergo a long trial‐and‐error prescription process before they may experience at least some relief.

Most recently, botulinum toxin type A (commonly known as Botox) and some anti-CGRP treatments were approved and listed on the Australian PBS. However, to qualify, patients must suffer chronic migraine (i.e., experience an average of 15 or more headache days per month, with at least 8 days of migraine, over a period of at least 6 months) and have experienced an inadequate response, intolerance or a contraindication to at least three prophylactic migraine medications prior to commencement of treatment. Moreover, patients must be appropriately managed by their practitioner for medication overuse headache and maintain a ≥50% reduction (responder rate) from baseline in the number of headache days per month. Unfortunately, Botox therapy is considered ineffective and thus not recommended for the preventive treatment of episodic migraine and 26% and 42% of chronic migraine patients discontinue Botox treatment after two and four 12-week treatment cycles, respectively;19 while anti-CGRPs have a similar ≥50% responder rate of ~50% in both episodic and chronic migraine patients (with or without previous preventive treatment failures and medication overuse).20  Hence, there is a huge pool of episodic and chronic migraine patients for whom current treatments are failing and who stand to benefit from new and improved therapeutics.

Migraine is a highly prevalent disorder with frequent attacks

Nearly one in four people (up to 33% of women and 13% of men), will have recurring attacks of migraine during their life.3 The vast majority of migraine attacks start at young age (5–25 years). In at least two-thirds of patients, attacks will continue to recur for many decades, often into very old age.2,3 The 2015 Global Burden of Disease (GDB) study estimated the global prevalence of “active migraineurs” (i.e., attacks in the past year) at 13.6% (17.7% of women and 9.5% of men); in Australia, the prevalence was estimated at 19.3% (26.5% of women and 11.7% all men). The peak age is between 20 and 50 years, when most people start families and build their professional career. The median migraine attack frequency is around two per month and the median duration of attacks is about one day.2,3 One in ten migraineurs will develop chronic migraine with migraine headaches on at least 15 days a month.2

The personal and socio-economic burden of migraine is enormous

Migraine is the seventh leading cause of years of life lost to disability worldwide, and the third cause of disability in under 50s.5 Migraine is the leading cause of disability among neurological disorders, accounting for over half of all years lived with disability.5 In high-income countries like Australia, the total disability due to migraine is more than 1.5 times that due to multiple sclerosis and Parkinson’s disease combined and almost 3 times that due to epilepsy.6 The economic burden due to migraine is the highest of all neurological conditions in Europe.7 The total annual economic cost of migraine in Australia is $35.7bn, comprising $14.3bn in health system costs, $16.3bn in productivity costs, and $5.1bn in other costs. There are also significant wellbeing costs for migraine patients and their families.8

People with migraines increases risk of other incapacitating disorders

Migraine co-occurs with several disorders including anxiety, asthma, depression, endometriosis, epilepsy, motion sickness and obesity,9-11 which may affect treatment adherence, increase risk of medication overuse and transform migraine to a more chronic form. I have shown that the co-occurrence of migraine with depression9, endometriosis10 and epilepsy12 can be explained, at least partly, by shared underlying genetically determined mechanisms. My more recent results, indicate that in migraine patients with comorbid depression, migraine may be a symptom or consequence of depression, and that ‘pure’ and depression-related migraine may be aetiologically different disorders.13

Migraine is impacted by genetic and environmental factors

The heritability for migraine is estimated at 46%,14 indicating both genetic and environmental factors play an important role in its development. Indeed, migraine attacks rarely occur spontaneously in the absence of any possible environmental trigger factors. A recent study found 95% of migraineurs associate trigger factors with their migraine attacks.15 Common triggers are: stress and negative emotions; sensory triggers; hunger; lack/excess of sleep; food and drink; alcohol; menstruation; and weather.

How genes and the environment interplay in migraine

Common complex diseases such as migraine are the result of the combined effect of genes, environmental factors, and their interactions. Given an individual’s genotype remains constant throughout life, the fact that individual migraine patients experience a great variation in attack frequency and symptomatology during their lifetimes,16 provides strong support for the importance of an interplay between genetics (risk factors) and environment (trigger factors) (i.e., G×E interaction) in migraine.

Our research vision

SGEL has led and played major roles in multiple large-scale International Headache Genetics Consortium (IHGC) studies to identify genetic risk factors robustly associated with migraine. In 2016, we published the then largest migraine genome-wide association study (GWAS) of 59,674 migraine cases and 316,078 controls, and identified 44 independent risk variants for migraine, 34 of which have not previously been reported.17 Most recently, in 2022 we published the largest ever migraine genome-wide association study (GWAS) of 102,084 migraine cases and 771,257 controls, and identified 123 (86 new) GWAS loci harbouring 170 independent risk variants for migraine.18 Despite our success in identifying genetic risk factors for migraine, the interpretation of GWAS findings is not straight-forward and the substantial inter-individual heterogeneity (differences) in migraine symptoms and triggers, comorbid disorders, and treatment response, is impeding our understanding of the aetiology of migraine and our ability to prevent and treat attacks. SGEL uses a multi-themed approach to generate new knowledge that will directly address these impediments.

Our research aims to 1) find novel risk variants and identify the likely causal DNA sequence variants at migraine risk loci; 2) integrate multi-omic data to unravel the functional consequences of existing risk variants/loci and identify new genes, pathways and metabolites associated with migraine; 3) identify interactions between genetic risk and environmental trigger factors (G×E) associated with migraine, comorbid traits and treatment response; and 4) perform pharmacogenomic studies of drug response in migraine. Our research, aimed at identifying and understanding the molecular mechanisms of migraine, will significantly improve our ability to prevent, treat and manage attacks, and will identify new targets for drug therapy.

References

  1. Headache Classification Committee of the International Headache Society. The International Classification of Headache Disorders: 2nd edition. Cephalalgia 24(Suppl 1), 1-160 (2004).
  2. Jensen, R. & Stovner, L.J. Epidemiology and comorbidity of headache. Lancet Neurol 7, 354-61 (2008).
  3. Launer, L.J., Terwindt, G.M. & Ferrari, M.D. The prevalence and characteristics of migraine in a population-based cohort: the GEM study. Neurology 53, 537-542 (1999).
  4. Loder, E. Triptan therapy in migraine. N Engl J Med 363, 63-70 (2010).
  5. GBD 2015 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet 388, 1545-1602 (2016).
  6. Collins, P.Y. et al. Grand challenges in global mental health. Nature 475, 27-30 (2011).
  7. Linde, M. et al. The cost of headache disorders in Europe: the Eurolight project. Eur J Neurol 19, 703-11 (2012).
  8. Deloitte Access Economics. Migraine in Australia Whitepaper, Prepared for Novartis Australia. From https://www2.deloitte.com/au/en/pages/economics/articles/migraine-australia-whitepaper.html. Accessed 3 Dec 2018.
  9. Ligthart, L., Nyholt, D.R., Penninx, B.W. & Boomsma, D.I. The shared genetics of migraine and anxious depression. Headache 50, 1549-60 (2010).
  10. Nyholt, D.R. et al. Common genetic influences underlie comorbidity of migraine and endometriosis. Genet Epidemiol 33, 105-13 (2009).
  11. Bigal, M.E. & Lipton, R.B. The epidemiology, burden, and comorbidities of migraine. Neurol Clin 27, 321-34 (2009).
  12. Brainstorm Consortium, et al. Analysis of shared heritability in common disorders of the brain. Science 360, eaap8757 (2018).
  13. Ligthart, L. et al. Genetic risk score analysis indicates migraine with and without comorbid depression are genetically different disorders. Hum Genet 133, 173-86 (2014).
  14. Mulder, E.J. et al. Genetic and environmental influences on migraine: a twin study across six countries. Twin Res 6, 422-31 (2003).
  15. Kelman, L. The triggers or precipitants of the acute migraine attack. Cephalalgia 27, 394-402 (2007).
  16. Eriksen, M.K., Thomsen, L.L. & Russell, M.B. Prognosis of migraine with aura. Cephalalgia 24, 18-22 (2004).
  17. Gormley, P. et al. Meta-analysis of 375,000 individuals identifies 38 susceptibility loci for migraine. Nat Genet 48, 856-66 (2016).
  18. Hautakangas, H. et al. Genome-wide analysis of 102,084 migraine cases identifies 123 risk loci and subtype-specific risk alleles. Nat Genet 54, 152-160 (2022).
  19. Stark, C. et al. Real-world effectiveness of onabotulinumtoxinA treatment for the prevention of headaches in adults with chronic migraine in Australia: a retrospective study. J Headache Pain 20, 81 (2019).
  20. Torres-Ferrús, M. et al. The impact of anti-CGRP monoclonal antibodies in resistant migraine patients: a real-world evidence observational study. J Neurol 268, 3789-3798 (2021).