Constipation Caused by Anti-calcitonin Gene-Related Peptide Migraine Therapeutics Explained by Antagonism of Calcitonin Gene-Related Peptide’s Motor-Stimulating and Prosecretory Function in the Intestine

Abstract

The development of small-molecule calcitonin gene-related peptide (CGRP) receptor antagonists (gepants) and of monoclonal antibodies targeting the CGRP system has been a major advance in the management of migraine. In the randomized controlled trials before regulatory approval, the safety of these anti-CGRP migraine therapeutics was considered favorable and to stay within the expected profile. Post-approval real-world surveys reveal, however, constipation to be a major adverse event which may affect more than 50% of patients treated with erenumab (an antibody targeting the CGRP receptor), fremanezumab or galcanezumab (antibodies targeting CGRP). In this review article we address the question whether constipation caused by inhibition of CGRP signaling can be mechanistically deduced from the known pharmacological actions and pathophysiological implications of CGRP in the digestive tract. CGRP in the gut is expressed by two distinct neuronal populations: extrinsic primary afferent nerve fibers and distinct neurons of the intrinsic enteric nervous system. In particular, CGRP is a major messenger of enteric sensory neurons which in response to mucosal stimulation activate both ascending excitatory and descending inhibitory neuronal pathways that enable propulsive (peristaltic) motor activity to take place. In addition, CGRP is able to stimulate ion and water secretion into the intestinal lumen. The motor-stimulating and prosecretory actions of CGRP combine in accelerating intestinal transit, an activity profile that has been confirmed by the ability of CGRP to induce diarrhea in mice, dogs and humans. We therefore conclude that the constipation elicited by antibodies targeting CGRP or its receptor results from interference with the physiological function of CGRP in the small and large intestine in which it contributes to the maintenance of peristaltic motor activity, ion and water secretion and intestinal transit.

European Headache Federation guideline on the use of monoclonal antibodies targeting the calcitonin gene related peptide pathway for migraine prevention – 2022 update

“…Constipation could be related to CGRP-mAb use due to potential inhibition of gastrointestinal motility, which is regulated by CGRP [ 79 , 80 ]. Constipation emerged as a frequent adverse event of treatment with galcanezumab and mostly with erenumab, as reported in real-world studies [ 33 , 46 , 47 ]; however, the vast majority of cases was mild and did not lead to treatment stopping.…”

Calcitonin Gene-Related Peptide (CGRP) Receptor Antagonism Reduces Motion Sickness Indicators in Mouse Migraine Models

“…Others have shown in human subjects and in mouse models that CGRP causes diarrhea by disrupting peristaltic intestinal activity and promoting ion and water secretion in the intestinal lumen, and that CGRP signaling antagonism can reverse these effects (27, 28). We have verified that OVAR rotation does further increase gastric distress in mice (increased fecal granules and diarrhea) and other indices like piloerection and a short-term tremor.…”

Preventive migraine treatment in mitochondrial diseases: a case report of erenumab efficacy and literature review

“…Although both in the previously published case and in our patient no adverse events were reported, based on the current knowledge of the physiological actions of CGRP, we can speculate on the possible risks associated with such treatments for patients with mitochondrial disease. In particular, antibodies targeting CGRP or its receptor can interfere with the function of the small and large intestine regarding the peristaltic motor activity, the intestinal transit, and the ion and water secretion [10]. Therefore, these drugs should be administered with caution in mitochondrial patients with gastrointestinal dysfunction, frequently reported in these neurogenetic disorders [11].…”