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.