Clinical review: A giant leap for migraine?

Learning objectives

After reading this feature you should be able to:

• Discuss the role inflammatory peptides play in a migraine attack
• Identify medications that may make people particularly prone to migraine and other severe headaches
• Address widespread misunderstandings about migraine.

In space, no-one can hear you … complain about your headache. Yet headaches are common even among those with a surfeit of the Right Stuff. 

A recent study of 24 astronauts reported that 92 per cent developed headaches during space flight. Just 38 per cent had experienced headaches on Earth. Ninety per cent of the headaches were tension-type; the remainder were migraines.¹

“Changes in gravity caused by space flight affect the function of many parts of the body, including the brain,” said study author Dr Willebrordus van Oosterhout, Leiden University Medical Centre, the Netherlands. “The vestibular system, which affects balance and posture, has to adapt to the conflict between the signals it is expecting to receive and the actual signals it receives in the absence of normal gravity. 

“This can lead to space motion sickness in the first week, of which headache is the most frequently reported symptom. Our study shows that headaches also occur later in space flight and could be related to an increase in pressure within the skull.”¹ 

Investigations into astronauts’ headaches may help understanding of how the vestibular system influences terrestrial headaches. About 3 per cent of adults live with vestibular migraine, while motion-induced sickness, sensitivity and nausea are typical migraine symptoms. 

In addition, children who experience motion sickness seem to be especially prone to migraines in adulthood. Animal studies suggest that blocking calcitonin gene-related peptide (CGRP), a transmitter we will return to, alleviates vestibular migraine and motion-induced nausea.² 

CGRP and hormones 

NICE estimates that about 4.5 million people in England experience migraines, which typically develop in five phases: prodrome, aura, headache, postdrome and interictal. Not everyone experiences every phase. For example, only a third of people with migraine experience aura³ – and aura can develop without headache. Some people experience aura and headache simultaneously.³ 

The headache phase of migraine seems to arise after activation of the trigeminovascular pathway. Essentially, peripheral trigeminal afferent nerves convey messages from the dura mater (Latin for ‘tough mother’), the outermost layer of the meninges, and large cerebral arteries to areas of the brain involved in pain processing. Stimulation of trigeminal afferent nerves releases neuropeptides, notably CGRP, that affect blood vessels.³

Numerous strands of evidence implicate CGRP in migraine. For example, CGRP levels increase during a migraine attack and decrease between attacks. Infusions of CGRP can trigger migraine attacks. Further research revealed that CGRP promotes migraine through various mechanisms, including arterial vasodilation, triggering inflammation in the dura mater, augmenting nerve signalling and modulating transmission of pain signals.³

In April, NICE approved atogepant, an oral treatment that prevents episodic and chronic migraine. Eligible patients should experience at least four headache days a month and at least three previous migraine treatments should have failed. NICE estimates that up to 170,000 people in England could benefit from atogepant, which is one of several drugs that block the rise in CGRP levels during migraines. 

To complicate matters, certain factors, including hormones, seem to mediate the relationship between CGRP and migraines. 

For example, in animal models, female hormones, especially oestrogen, influence CGRP release.⁴ Hormonal differences may help explain why women are about three times more likely to experience migraines as men. 

According to a recent study, CGRP concentrations in plasma and tears were significantly higher during menstruation in females with episodic migraine and regular menstrual cycles compared with age-matched female controls without migraine. 

CGRP levels were similar in the migraine and the control groups in participants taking combined oral contraception and postmenopausal women. The study did not include women with ‘pure’ menstrual migraine who may show a more marked hormonal response.⁴

“When oestrogen levels drop immediately before the start of a menstrual period, migraine patients release more CGRP,” study lead Dr Bianca Raffaelli of the Headache Centre, Universitätsmedizin Berlin, commented. “This could explain why these patients suffer more migraine attacks just before and during their monthly period. 

“The data will still need to be confirmed by larger studies, but our findings do suggest that the release of CGRP depends on hormonal status in humans, as it does in the animal model,” she continued.

Future studies also need to ascertain if CGRP inhibitors’ efficacy depends on where a person is in their cycle. 

“Taking birth control pills and the end of menopause … bring relief for some female migraine patients but, as our study also shows, there are women who suffer from migraine even without any hormonal fluctuations,” Dr Raffaelli said. “We suspect that other processes in the body play a role in triggering attacks in those patients. After all, CGRP isn’t the only inflammatory peptide that can cause a migraine attack.”

Acid-suppressing drugs and migraine

Changed levels of inflammatory peptides is not the only mechanism that can influence migraines. For example, people who take proton pump inhibitors (PPIs), histamine H2-receptor antagonists or antacids may be particularly prone to migraine and other severe headaches, according to US researchers.⁵ 

Twenty-five per cent of those on PPIs had migraine or severe headache in the three months before being asked, compared with 19 per cent of controls. Similarly, 25 per cent of those taking H2-blockers had severe headache, compared with 20 per cent of those not taking those drugs, while 22 per cent of those taking antacids had severe headache, compared to 20 per cent of controls.⁵

Adjusting for other factors that could affect migraine risk, such as age, sex and use of caffeine and alcohol, people taking PPIs were 70 per cent more likely to have migraine in the previous three months than controls. Those taking H2-blockers or antacids were 40 and 30 per cent more likely to experience migraine than controls.⁵

Other studies show that people with gastrointestinal conditions, such as Helicobacter pylori infection, IBS, coeliac disease, peptic ulcers or gastroparesis, may be more likely to experience migraine than the general population. 

The authors suggest that gastrointestinal ailments are unlikely to fully explain the association between acid-reducing drugs and migraine; other changes may contribute. For instance, the reduction in gastric pH may inhibit digestion, slow gastric emptying, decrease nutrient absorption and alter the gut microbiome.⁵

The study was cross-sectional and so does not prove that acid-reducing drugs cause migraine. It also did not include use of OTC preparations.5 “Given the wide usage of acid-reducing drugs and these potential implications with migraine, these results warrant further investigation,” said study author Dr Margaret Slavin, University of Maryland in College Park. 

“Many people do need acid-reducing medications to manage acid reflux or other conditions, and people with migraine or severe headache who are taking these drugs or supplements should talk with their doctors about whether they should continue.” 

New treatments

Meanwhile, research into new treatments continues apace. Ketamine (which is, depending on the dose, a sedative, stimulant and psychedelic) numbs bodily sensations and dissociates the user from their environment.

Ketamine is a long-established veterinary and medical anaesthetic, and more recently found a growing number of roles in, for instance, perioperative and chronic pain, depression and headache. Notably for people with migraine, ketamine’s plethora of pharmacological actions includes antagonising CGRP receptors.⁶ 

A recent study assessed intranasal ketamine in 242 patients with refractory chronic migraine. Participants reported a median of 30 headache days a month and had tried four classes of preventive medications before ketamine. 

Of these, 49 and 40 per cent regarded intranasal ketamine as ‘very effective’ or ‘somewhat effective’ respectively, while 36 and 42 per cent reported that their quality of life was ‘much better’ or ‘somewhat better’. Seventy-four per cent reported at least one adverse event.

“Well-designed prospective placebo-controlled trials are necessary to demonstrate the efficacy and safety of intranasal ketamine in patients with migraine,” the authors concluded.

The opioid crisis has given the search for better treatments for chronic pain extra impetus. For example, researchers at Northwestern University, Illinois, have developed a device that surgeons implant next to a peripheral nerve. The device electrically stimulates the nerve at high frequency to block transmission. 

The Northwestern team also pioneered wrapping a microscopically fine tube around the nerve. Researchers can inject drugs that evaporate at a controlled rate to numb pain without damaging the nerve. Importantly, both devices are resorbable and degrade when no longer needed. 

Initially, researchers are focusing on implantation to treat acute, post-surgical pain when patients are already under the scalpel⁷ but the approaches exemplify the innovative chronic pain treatments – including for migraine – that are in the pipeline. 

<sup>References
1.    Neurology 2024; 102:e209224
2.    Cephalalgia 2024; 44: DOI:10.1177/03331024231223971
3.    Cmaj 2023; 195:E153-e158
4.    Neurology 2023; 100:e1825-e1835
5.    Neurology Clinical Practice 2024; 14:e200302
6.    Regional Anesthesia and Pain Medicine 2023; 48:581-587
7.    American Scientist 2024; 112:74-76</sup>