Discussion:
The overall global prevalence of RP is approximately 10% in women (partly due to hormonal variations) and 4-14% in men(4). Migraine and RP were found to co-exist in 26% (29 of 111) of migraine patients in one study (4). Although the pathophysiology of RP is not well understood, a combination of neuronal and vascular factors (including intravascular anomalies) are known to play a role. Vasoconstriction is believed to be a major feature of RP and can be triggered by external stimuli, including cold water or weather. RP can also be triggered mainly by neural mediated changes(4).
CGRP is a ubiquitous 37 amino acid neuropeptide found in two isoforms: α- CGRP (mainly localized to the peripheral nervous system) and β- CGRP (predominantly localized to enteric nervous system). Both isoforms are efficient vasodilators (2, 3, 5). Evidence suggests the presence of increased CGRP in sites undergoing inflammatory response(5). Elevated CGRP levels are observed in saliva, CSF and serum during migraine attacks and reduces after these bouts subside(2).. Targeting the CGRP receptor with monoclonal antibodies is effective in the management of migraine(3, 5). It is believed that activation of the trigeminovascular system by migraine specific triggers causes vasodilation of cranial blood vessels, thereby activating sensory nerve fibres of the trigeminal system (2, 3). Pain is conveyed to the brainstem where several different neurotransmitters including CGRP and substance P are released, and bind to the functional receptors causing neuronal inflammation, degranulation of mast cells and leakage of blood vessels (2, 5).
Although the CGRP monoclonal antibodies, including erenumab, fremanezumab, galcanezumab, eptinezumab, were found to be safe and effective in clinical trials, more data is emerging regarding their safety profile and potential side effects in clinical practice(3). RP is becoming a relatively rare recognized side effect of CGRP monoclonal antibodies in patients with migraine(4). It has been recently reported in three patients (two females- 33 yrs & 45 yrs and one male- 65 yrs) undergoing CGRP monoclonal antibody treatment. Two patients were treated with monoclonal antibodies against the ligand (fremanezumab and galcanezumab) and in one case, the monoclonal antibody targeted the receptor (erenumab)(4). There is a consensus now that the most likely mechanism by which CGRP monoclonal antibodies cause RP is primarily due to vasoconstriction, but this can only occur in conjunction with several other factors, including genetic and hormonal influences. CGRP monoclonal antibodies therefore antagonise CGRP’s role as a potent vasodilator in this context (2, 3). When administered, erenumab binds to the functional receptor, subsequently blocking its function (3, 4). This prevents the cascade of reactions within the cell responsible for vasodilation, presumably leading to the development of RP in a small number of cases(3, 4).
In summary, we report a case of a chronic daily headache with migraine features who developed RP after receiving treatment with a CGRP receptor antagonist, further supporting the theory that RP is now a recognised rare side effect of CGRP monoclonal antibodies. This information did not emerge from clinical trials. The presence of significant or debilitating RP in a small proportion of patients with migraine who are treated with CGRP monoclonal antibodies has clinical implications, including the necessity for cessation of treatment in some patients. Furthermore, this class of drugs could exacerbate the symptoms of RP in patients with a previous history of this condition.