Although the exact pathophysiology and origin of migraine has not been fully elucidated, there is a body of evidence supporting that the ‘migraine brain’ is hyperexcitable, hyperresponsive, and hypersensitive.1,2 There is also evidence that the origin of a migraine attack involves both peripheral and central mechanisms, wherein pain is sensed peripherally and pain signals are transmitted to the cortex where pain is perceived.3 The question of whether preventive migraine treatments work peripherally or centrally – or both – also remains unclear, but this was a topic of debate at the 2024 American Headache Society (AHS) annual congress. Rami Burstein, PhD, a scientist and Professor of Neuroscience at Harvard Medical School, presented evidence supporting peripheral actions of migraine preventive medications and Dr. Peter Goadsby, Professor of Neurology at King’s College London, UK, argued that migraine therapies exert their therapeutic actions in the brain.
Lessons learned from prodromes and triggers
To support his arguments that migraine therapies work peripherally, Dr. Burstein described a study showing that 3 months of treatment with an anti-CGRP monoclonal antibody (MAb) significantly reduced the incidence of headache after premonitory symptoms or triggers and this effect was much more pronounced in super-responders than in super non-responders.2 If this class of therapy acted within the central nervous system to directly block CGRP receptors, then no difference in headaches stemming from premonitory symptoms or triggers would have been expected. The researchers concluded that anti-CGRP MAbs reduce the magnitude and duration of pain signals that originate in the periphery and that reach the brain over many months.
Prolonged reduction in nociceptive input to the brain restores normal responsivity and reverses the hyperexcitable ‘migraine brain’
Anti-CGRP monoclonal antibodies do not cross the blood-brain barrier (BBB)
Another central part of Dr. Burstein’s argument supporting peripheral actions of migraine preventive therapies is that large MAbs do not cross the BBB. CGRP receptors are widely distributed throughout the body and are found in particularly high density along the trigeminovascular pathway, which is known to be involved in migraine attacks, and in meningeal blood vessels.4,5 Animal studies have shown that intravenously injected fluorescent labeled anti-CGRP MAb does not penetrate central anatomical areas involved in migraine including the trigeminal nucleus, thalamus, hypothalamus, or cortex when the BBB is intact.5 In contrast, there are high concentrations found in the dura, dural and pial blood vessels, trigeminal ganglion and other peripheral sites involved in migraine attacks. These observations suggest that large anti-CGRP MAbs do not cross the BBB, and they must therefore prevent migraine headaches by acting outside the central nervous system.
Anti-CGRP MAbs are too large to cross the intact blood-brain barrier and therefore their actions must be peripheral
The brain as the consequential anatomic target of anti-migraine therapies
A key theme in Dr. Goadsby’s arguments supporting central actions of migraine medications is the notion that the consequential anatomic location whose physiology is altered by agents that have clinical anti-migraine effects is none other than the brain. Indeed, all migraine preventive approaches exert their actions in the brain, including behavioural approaches, neuromodulation treatments, non-specific migraine medications, and migraine-specific agents including the anti-CGRP MAbs. Even triptans, which were originally conceptualized as acting on intracranial blood vessels, were later found to prevent sensitization of central but not peripheral trigeminovascular neurons through presynaptic serotonin 5HT1B/1D receptors.6
Migraine is a complex brain disorder that can be prevented with centrally acting medications that target the brain
Anti-CGRP MAbs enter the cerebrospinal fluid where they sequester CGRP
There is evidence to suggest that despite their large molecular size, anti-CGRP MAbs can enter the cerebrospinal fluid (CSF) and bind to their target, CGRP.7 In a small sample of healthy individuals, a single intravenous dose of anti-CGRP MAb resulted in a rapid increase in plasma and CSF concentrations, peaking after 15 days. Although the ratio of CSF to plasma anti-CGRP MAb was low, its presence in the CSF affirms the potential to access the brain and engage its target.
Peripherally administered anti-CGRP can enter the CSF and bind to its target
Migraine is more than pain
A final argument presented by Dr. Goadsby is that migraine is about more than pain. Indeed, other symptoms can be impairing and bothersome, including cognitive complaints or ‘brain fog’ defined as feeling confused, difficulty learning or remembering, or having trouble speaking or reading.8 In a real-world observational study of 94 adults receiving an anti-CGRP MAb, 80% reported never having experienced brain fog before. After treatment with anti-CGRP MAb, 86% of those patients reported an improvement in brain fog. In Dr. Goadsby’s own clinical experience, patients who respond to anti-CGRP MAb treatment often describe their ‘head being clear’ for the first time.
Improvement in cognitive burden is a potential target for preventive migraine treatment
The bottom line
Although both experts presented convincing arguments supporting peripheral and central actions of migraine preventive therapies, it is likely that both peripheral and central mechanisms are involved in migraine attacks and thus there exist peripheral and central targets for preventive therapies.3 The debaters agreed that the pathophysiology of migraine remains a grey area and further research is warranted to more fully elucidate the mechanisms and site(s) of action of migraine treatments.
Our correspondent’s highlights from the symposium are meant as a fair representation of the scientific content presented. The views and opinions expressed on this page do not necessarily reflect those of Lundbeck.
