A Popperian View on Anti‐CGRP Biologics in Migraine

The recent approval of monoclonal antibodies against the calcitonin gene-related peptide (CGRP) or its receptor (also defined as “anti-CGRP biologics”) for migraine prevention represents a pharmaceutical revolution in the field of headache therapy. Three of these antibodies (eptinezumab, fremanezumab, and galcanezumab) are directed against CGRP, whereas the fourth antibody (erenumab) selectively binds to the canonical CGRP receptor containing the calcitonin-like receptor (CLR) and receptor activity-modifying protein (RAMP1) subunits. In spite of this remarkable therapeutic advancement, migraine pathogenesis is still unresolved, and the “peripheral” and “central” hypoth eses of migraine origin remain actively debated. Although intracerebral vasodilation now appears irrelevant to migraine pathogenesis, no doubts that the peripheral hypothesis is receiving great momentum from consolidated evidence that anti-CGRP biologics are efficacious migraine preventive medicines. Indeed, their therapeutic efficacy, along with the well-known inability of antibodies to easily permeate the bloodbrain barrier (BBB), suggest that anti-CGRP biologics must exclusively operate outside of the brain and therefore migraine is mostly peripheral in origin. This latter interpretation will be here referred as the peripheral theory. At first glance, the logic of the peripheral theory is unquestionable and welcomed by those that had been struggling for decades in an attempt to decipher the molecular and cellular basis of migraine pain. However, Sir Karl Popper, among the greatest philosophers of science of the last century and founder of the method of empirical falsification, might have disagreed about such epistemological absolutism. Popper’s critical rationalism claims that an incontestable reasoning is, in itself, evidence that it is wrong. Here, standing Headache doi: 10.1111/head.13695 © 2019 American Headache Society Published by Wiley Periodicals, Inc. ISSN 0017-8748