Transformative Pain Relief for Management of the CGRP Migraine


New research from Harvard Medical School could be a game changer for the management of headaches associated with anti-CGRP migraine therapy.

The launch of the first anti-calcitonin gene-related peptide (CGRP) therapy for migraine in 2018 was the biggest therapeutic advance in 30 years. Very little can touch this treatment for efficacy, more than halving monthly headache days for many of the worst affected patients.

The big pain point has been that approximately 50% of migraine patients do not respond to anti-CGRP therapy. Until recently, it was impossible to know which 50% would or would not respond before taking the drug.

Now, for the first time, a patient- and clinician-friendly non-invasive test has prospectively demonstrated in a clinical trial. In research published in Cephalalgia,1 the test showed the ability to accurately predict anti-CGRP response before initiation of treatment with more than 80% accuracy, which may potentially transform migraine management.

Results from the study demonstrated that non-ictal cephalic allodynia—a certain type of pain sensitivity experienced during a specific period of time—determined before interventional treatment is a statistically significant predictor of response to anti-CGRP therapy. This was present in 84% of the 19 non-responders, but absent in 79% of the 24 responders, for an overall accuracy rate of 86% (p<0.0001).

Anti-CGRP medications work by neutralizing the CGRP peptide or by blocking CGRP receptors in the dura, which is a part of the meningeal membrane that protects the brain and spinal cord. Successful blockade of CGRP signaling in the meninges prevents dilation of blood vessels as well as activation and sensitization of pain fibers that mediate the headache phase of migraine.

However, because anti-CGRP drugs are too large to cross the blood-brain barrier, they can only prevent migraine in patients whose headache is triggered by CGRP signaling outside the brain. The study published in Cephalalgia utilized a novel proprietary quantitative sensory testing (QST) algorithm to determine the presence or absence of cephalic allodynia during the "non-ictal" phase of migraine (>12 hours after a migraine attack and >12 hours before the next attack).

Importantly, the study also confirmed that manifestation of non-ictal extracephalic (peripherally governed) allodynia was less successful in identifying non-responders, and that non-ictal cephalic allodynia was consistently predictive of response across the chronic migraine (CM) as well as high-frequency episodic migraine (HFEM) groups.

The concept of predicting treatment response to anti-CGRP treatment by testing for absence or presence of non-ictal cephalic allodynia among patients diagnosed with chronic or high-frequency episodic migraine was developed by Rami Burstein, PhD, professor of Anesthesia at Harvard Medical School and President-Elect of the International Headache Society (IHS), in collaboration with CGRP Diagnostics.

The Harvard authors, Drs. Ashina, Burstein, and colleagues, wrote that: “Key fundamental differences in the disease pathology of responders and non-responders have been identified” and that “detection of non-ictal allodynia with a simplified paradigm of Quantitative Sensory Testing (QST) may provide a quick, affordable, non-invasive, and patient-friendly way to prospectively distinguish between responders and non-responders to the prophylactic treatment of chronic and high-frequency episodic migraine with drugs that reduce CGRP signaling.”

This could be a boon for patients, clinicians, and payers alike. In fact, according to neurologist, David Greeley, MD, FAAN, who leads the Northwest Neurological clinical practice in Spokane, Washington, it could be transformative for migraine treatment.

“CGRP antagonists have been a huge advance in the treatment of migraine headaches—but to know with precision which patients will respond to one of these potent drugs would be a game-changer. The teams at Harvard and CGRP Diagnostics appear to have done just that with a quick, affordable and non-invasive test,” Greeley said.

Payers seem to agree, as some of the biggest managed care organizations revealed consistent alignment that this precision medicine opportunity “fits into our desire to tailor the right drug to the right patient” and that “it would be a ‘no brainer’ to prefer a product that came with the test."

“It is better to see which patients will respond to therapy than waste up to six months of time, cost and suffering, before they fail," said Thomas Lundquist, MD, former senior vice president and chief medical officer for alarge regional health plan and a large multi-state Blues Plan.

This significant advance in knowledge also presents an opportunity for manufacturers who align their product with the test.

“The ability to largely prevent treatment failures not only enables earlier use of anti-CGRP therapy in migraine treatment protocols for tested responders, but also provides the potential for excellent formulary positioning and increased brand loyalty,” said Mark Hasleton, PhD, CEO of CGRP Diagnostics. “We now have an objective tool to accurately predict response before treatment initiation, enabling clinicians to prescribe early and with confidence of treatment success, reducing the need for prior treatment failures with generics. Equally important though, It also enables non-responders to rapidly transition to other treatment strategies, preventing a great deal of suffering and frustration for all.“


1. Ashina S, Melo-Carrillo A, Szabo E, Borsook D, Burstein R. Pre-treatment non-ictal cephalic allodynia identifies responders to prophylactic treatment of chronic and episodic migraine patients with galcanezumab: A prospective quantitative sensory testing study (NCT04271202). Cephalalgia. 2023;43(3). doi:10.1177/03331024221147881

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