Gerry Gajadharsingh writes:

“Following on from my recent blog and podcast in regard to CGRP antagonist medications here is some more information for clinicians.”

Neurology

September 2022

Ailani et al

CGRP plays a role in gastrointestinal nociception (detection of pain), inflammation, gastric acid secretion, and motility. Nausea and vomiting are among the gastrointestinal symptoms associated with migraine, but individuals with migraine may also experience functional upper and lower gastrointestinal comorbidities, such as gastroesophageal reflux disease (GORD), gastroparesis (ineffective neuromuscular contractions of the stomach), functional diarrhoea or constipation, and irritable bowel syndrome (IBS). Although gastrointestinal symptoms in migraine can be treatment-related, they may also be attributable to increased CGRP.

Susceptibility to migraine is multifactorial. Besides photophobia (light sensitivity) and phonophobia (sound sensitivity), migraine can present with a number of gastrointestinal (GI) symptoms, such as nausea, diarrhoea, and vomiting, and is associated with GI disorders such as cyclical vomiting syndrome (CVS) and irritable bowel syndrome (IBS). There is also evidence that symptoms such as fatigue and insomnia are more common in people with chronic migraine (CM) than in those with episodic migraine (EM). The relationship between migraine and GI comorbidities is multifactorial, involving several neuropeptides, proinflammatory molecules, and the gut microbiota, among other factors.

During a migraine attack, serum CGRP concentration increases and decreases in parallel with headache intensity. The relationship between CGRP and migraine has led to the development of CGRP pathway-based therapies, including small- molecule CGRP receptor antagonists (“gepants”) and monoclonal antibodies (mAbs), which bind to either CGRP or its receptor.

Nausea and vomiting are among the symptoms associated with migraine. Among patients with migraine, 60%–95% develop nausea and 50%–62% develop vomiting during attacks.

A retrospective analysis of 1,025 patients with migraine found that headache intensity correlated significantly with nausea and vomiting, as well as with other symptoms associated with migraine

Cyclical Vomiting Syndrome (CVS) is a chronic disorder of the foregut (the section of the intestine that ends where the bile duct enters the duodenum). CVS is characterized by recurrent episodes of severe nausea and frequent vomiting. It is associated with autonomic dysfunction and has a strong association with migraine.

Abdominal migraine is usually recognized in childhood and is characterized by recurrent attacks of moderate to severe midline abdominal pain, associated with vasomotor symptoms, nausea, and vomiting, without headache. It is most commonly observed in children between ages 5 and 9 years and is rarely seen in adults. For approximately two-thirds of children, abdominal migraine resolves by their late teenage years, and 50%–70% of these individuals go on to develop migraine headaches.

Functional diarrhoea has a reported prevalence in the general population in the range 1.5%–17% and is characterized by recurrent passage of loose or watery stools; it can be associated with abdominal pain or bloating as seen in IBS. Several mechanisms seem to contribute to functional diarrhoea, including altered GI motility, brain-gut disturbances, genetics, environmental factors, prior infections, and psychosocial factors. Functional diarrhoea is among the symptoms of altered autonomic function in migraine.

Functional constipation is a functional disorder of the hindgut (the section of the gut commencing at the junction of the right and middle thirds of the transverse colon) defined by a reduction in bowel movement frequency and may be primary or secondary to an underlying disorder. Like functional diarrhoea, it can be associated with IBS if there is a component of abdominal pain or bloating. A systematic review found the median global rate of functional constipation to be 16%

IBS is a functional disorder of the hindgut with increased prevalence in women, IBS presents with recurrent episodes of abdominal pain related to defecation, associated with a change in stool frequency or in stool form. Two primary forms of IBS exist: IBS with diarrhoea (IBS-D), characterized by recurrent or chronic diarrhoea, and IBS with constipation (IBS-C), characterized by abdominal pain or discomfort associated with constipation. Some patients experience IBS with mixed bowel habits differently in the foregut (e.g., nausea and vomiting) and hindgut (e.g., diarrhoea and constipation), but both types of disorders stem from regional modulation of the enteric nervous system by afferent and efferent autonomic stimuli

The commonality of innervation in different regions of the gut and the role of CGRP in GI function may explain why migraine is associated with a range of GI symptoms and comorbidities.

Based on data from the FDA Adverse Event Reporting System (FAERS), it is estimated that 17% of patients treated with mAbs targeting CGRP or its receptor develop GI-related adverse reactions (AEs), although rates seen in clinical trials are lower.

Relatively few AEs have been recorded through FAERS for the gepants, although these drugs have been available for a shorter time than mAbs. As of March 31, 2021, nausea (12.4%) and vomiting (4.7%) associated with ubrogepant were reported among 106 GI cases (total cases, 443); 175 of 943 cases with rimegepant were GI events, with nausea

(11.2%) and vomiting (2.9%) most common.

Implications for Physicians Managing Patients with Migraine

Given that individuals receiving migraine therapies are at risk of developing GI AEs, it is important to consider how both physicians and patients can best mitigate these effects.

From the patient’s perspective, counselling about possible GI outcomes is important, and some self-care strategies are listed below; any changes or restrictions in diet should only be introduced in consultation with a health care provider. Accurate medical and treatment history taken by physicians is essential when initiating migraine treatment. A full history should also be noted if GI symptoms are subsequently reported by the patient.

Questions for the clinician to consider include the following:

  • Does the patient have a preexisting GI disorder?
  • What are the patient’s baseline bowel habits, and did these habits change after treatment initiation?
  • Does the patient have underlying risk factors for GI disorders other than migraine?
  • Is a particular class of migraine treatment likely to increase the risk of GI AEs or exacerbate an existing GI disorder?
  • What is the best route of administration of migraine medications, in light of the patient’s GI symptoms?
  • Is the patient receiving an acute therapy (especially an over-the-counter medication) that can confound or exacerbate GI events of preventive medications?
  • Is the patient taking other nonmigraine medications associated with GI AEs?