Calcitonin gene-related peptide
CGRP, alpha-CGRP, CALCA gene product, beta-CGRP (CALCB)
Calcitonin gene-related peptide is a 37-residue peptide produced by alternative splicing of the calcitonin gene and released from trigeminal sensory nerves. It is the most potent microvascular vasodilator known and is the single most therapeutically productive neuropeptide target in modern medicine, underpinning eight approved migraine drugs. The evidence here is genuinely strong.
Mechanism
The CALCA gene generates calcitonin in thyroid C cells and alpha-CGRP in neurons through tissue-specific alternative RNA processing, a discovery that established alternative splicing as a mechanism for generating protein diversity. A separate gene, CALCB, yields beta-CGRP, predominant in the enteric nervous system. The canonical CGRP receptor is unusual: it requires calcitonin receptor-like receptor (CLR) in obligate complex with receptor activity-modifying protein 1 (RAMP1) plus the intracellular receptor component protein. CLR alone with RAMP2 or RAMP3 becomes an adrenomedullin receptor instead, so RAMP identity determines pharmacology.
The CGRP receptor couples to Gs, raising cyclic AMP and activating protein kinase A, opening ATP-sensitive potassium channels in vascular smooth muscle and stimulating endothelial nitric oxide production. In migraine, CGRP is released from trigeminal afferents innervating the dura, producing meningeal vasodilatation, mast cell degranulation, neurogenic inflammation and sensitisation of second-order trigeminocervical neurons. Jugular CGRP concentrations rise during spontaneous attacks, and intravenous CGRP infusion triggers delayed migraine-like headache in people with migraine but not reliably in controls.
What the research shows
The causal human experiment came first: intravenous CGRP infusion induced delayed migraine-like attacks in migraine patients, establishing more than correlation. Blocking the pathway then worked repeatedly. In the STRIVE trial, erenumab, a monoclonal antibody against the CGRP receptor, reduced monthly migraine days in episodic migraine against placebo over six months. Oral small-molecule antagonists followed: ubrogepant and rimegepant demonstrated superiority to placebo for two-hour pain freedom and freedom from the most bothersome symptom in acute treatment, and atogepant reduced monthly migraine days in prevention in the ADVANCE trial. Fremanezumab, galcanezumab, eptinezumab and intranasal zavegepant have added to the class.
The boundaries matter. Erenumab failed in episodic cluster headache and galcanezumab failed in chronic cluster headache, so the mechanism is not a general headache mechanism. Effect sizes in migraine are real but moderate, typically one to two fewer migraine days per month than placebo, and a substantial minority of patients do not respond. Long-term concerns include constipation and blood pressure elevation with erenumab, and the theoretical loss of a protective vasodilator reserve in ischaemia, which remains under post-marketing observation.
Evidence assessment
High-quality evidence
Six citations survived audit with all identifiers verified, including four separate pivotal phase 3 randomised trials published in the New England Journal of Medicine and a human causal provocation study. Multiple agents hold regulator-approved labelling in both the US (FDA) and UK (MHRA). This is the highest evidence tier in the class and it is earned.
Tiers are applied consistently across the library and re-checked when new trials read out. Read the grading method.
Key studies
Alternative RNA processing in calcitonin gene expression generates mRNAs encoding different polypeptide products Preclinical only
Discovery that the calcitonin gene generates CGRP by alternative splicing, establishing both the peptide and the principle of alternative RNA processing.
CGRP may play a causative role in migraine Preclinical only
CGRP infusion induced delayed migraine-like headache in migraine patients, providing causal rather than correlational human evidence.
A Controlled Trial of Erenumab for Episodic Migraine Preclinical only
Erenumab reduced monthly migraine days versus placebo in episodic migraine. A pivotal registration trial for CGRP receptor antibodies.
Ubrogepant for the Treatment of Migraine Preclinical only
Ubrogepant increased two-hour pain freedom and freedom from the most bothersome symptom versus placebo, supporting oral CGRP antagonism for acute attacks.
Rimegepant, an Oral Calcitonin Gene-Related Peptide Receptor Antagonist, for Migraine Preclinical only
A single oral dose produced significantly greater pain freedom and freedom from the most bothersome symptom at two hours than placebo.
Atogepant for the Preventive Treatment of Migraine Preclinical only
Atogepant significantly reduced mean monthly migraine days versus placebo, establishing oral CGRP antagonism for prevention as well as acute use.
Safety
CGRP itself is not a therapeutic; infusion causes flushing, headache and hypotension. For the licensed antagonists, the most consistent issues are constipation, which can be severe with erenumab, injection site reactions, and blood pressure increases reported post-marketing. Hepatic monitoring applies to some gepants. Because CGRP is a protective vasodilator in ischaemia, caution is advised in significant cardiovascular or cerebrovascular disease, and the drugs are generally avoided in pregnancy.
Regulatory status
| Jurisdiction | Status |
|---|---|
| United Kingdom | MHRA has authorised erenumab, fremanezumab, galcanezumab, eptinezumab, rimegepant and atogepant, with NICE appraisals for migraine prevention or acute treatment and criteria typically requiring prior preventive failures. Ubrogepant and zavegepant are not UK-authorised. The peptide itself is unlicensed. |
| United States | CGRP itself is not approved. FDA has approved erenumab, fremanezumab, galcanezumab and eptinezumab (antibodies) and ubrogepant, rimegepant, atogepant and zavegepant (small-molecule antagonists) for migraine. |
| WADA (sport) | CGRP-targeted migraine drugs are not on the WADA Prohibited List. The peptide itself, being unapproved for human therapeutic use, would fall under section S0. |