Introduction
Calcitonin gene-related peptide (CGRP) is a 37 amino acid long protein with a strong role in the pathophysiology of migraine. CGRP’s other roles in the body include acting as a vasodilator (helping to widen blood vessels) and helping with bone formation. Monoclonal antibodies to CGRP, or one of its receptors, have been developed and shown to decrease migraine frequency in adults, including those with chronic migraine and those who have not responded to previous preventive trials.
CGRP pathway monoclonal antibodies for migraine prevention
For patients and families
As of early 2021, there are not yet randomized trials on the use of CGRP pathway monoclonal antibodies in children or adolescents. That said, since the first of these treatments, erenumab, was FDA approved for migraine prevention in adults in 2018, some U.S. pediatric headache specialists have been using CGRP pathway monoclonal antibodies “off label” to treat adolescents who have difficult to treat headaches that have not responded to other treatments. In deciding whether or not these treatments are right for you (or your child), the two main things to consider are (1) what are the possible side effects? and (2) what are the possible benefits, relative to how severe my/my child’s headache problem is and what treatments have already been tried? In terms of side effects, the most commonly seen are constipation and injection-site reactions. Constipation can often be managed with diet changes, physical activity, or use of stool softeners and fiber supplements. The injection-site reactions are typically mild and short-lived. Rarely, new or worsened high blood pressure has occurred in adults treated with erenumab.
Since these treatments have only been in use for a few years (as of the time of this writing), the main question when considering whether to use them in a young person might be, Is there a risk to their use in young people that we don’t yet know about? Unfortunately, the only way to answer this question adequately is with careful observations made over the passage of time. In the meantime, in consultation with your/your child’s clinicians, you will need to decide how much to weigh the theoretical risk of an unknown side effect against the real and likely (if you are considering these treatments) substantial impact and disability that headache is having on you/your child right now. How to weigh these things and integrate them into a treatment plan that is right for you/your child is a very personal decision and speaking with your/your child’s headache specialist about your/your child’s individual situation is highly advisable.
For primary care providers
Prescribing and managing CGRP pathway monoclonal antibodies in adolescents is probably best left to headache specialists (as least as of our current state of knowledge in 2021). However, having a basic familiarity with CGRP pathway monoclonal antibodies will be helpful in that, your patients may reach out to you for advice when considering whether to start one of these, and being familiar with them can inspire confidence. It is also helpful to understand how other treatments you may be prescribing or managing might interact with the CGRP pathway monoclonal antibody your patient is taking. Monoclonal antibodies are eliminated through the endothelial cells lining the blood vessels. They are not hepatically or renally metabolized, so typical “drug–drug” interactions are generally not a concern. If constipation was already an issue for your patient, it may worsen when they go on a CGRP pathway monoclonal antibody and they may need more assistance with managing this. Constipation can also arise for the first time on these therapies. As CGRP is a vasodilator, the rare side effect of new or worsened hypertension that can be seen in adults treated with erenumab may also be possible in adolescents, and may also be possible with the CGRP pathway monoclonal antibodies other than erenumab. The author has not seen hypertension arise, or worsen, in adolescents treated with CGRP pathway monoclonal antibodies. However, for youth with pre-existing hypertension, it may be prudent to increase blood pressure monitoring if they do start one of these treatments. There have also been rare reports of hypersensitivity reactions as well.
It is prudent to avoid these treatments in people who are pregnant, or in those who have had a stroke or thromboembolic event.
For headache specialists
Given that the CGRP pathway monoclonal antibodies are still relatively new, relatively costly, and not yet formally studied in children and adolescents other than in retrospective chart review, they are generally not considered first-line migraine preventive therapy in youth. However, pediatric headache experts have suggested that they be considered for adolescents with migraine who have significant headache-related disability and who have not responded to other preventive treatments. In the table are some suggested criteria for when to consider offering these treatments. If the patient is also taking medications that predispose to constipation, such as tricyclic antidepressants, consider weaning these off if possible or at least giving good anticipatory guidance about constipation management ( Table 1 ) .
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Once the decision to treat with a CGRP pathway monoclonal antibody has been made, the question then is which one to prescribe. Sometimes this decision comes down to which one the patient’s insurance will cover, as these treatments are relatively costly (approximately $600/month out of pocket for the injectables, presumably more for the intravenous option). Erenumab blocks the canonical CGRP receptor but does not bind CGRP itself (i.e., the ligand). It has been available in the U.S. the longest, hence there may be more clinical experience with its use in adolescents relative to the others. The other three CGRP pathway monoclonal antibodies (fremanezumab, galcanezumab, and eptinezumab) bind to CGRP itself. Erenumab, galcanezumab, and fremanezumab are given by subcutaneous injection, while eptinezumab is given by intravenous infusion. If a patient has a strong preference not to do subcutaneous injections at home, but is comfortable getting intravenous infusions, eptinezumab may be a good option. The dosing interval for the three injectable ones are every 28 days, although fremanezumab was studied both as 225 mg SC monthly and as 675 mg SC quarterly. If the patient is going to be traveling abroad for several months, or going away to camp for the summer, quarterly dosing may be advantageous.
If a patient does not respond to one CGRP monoclonal pathway antibody, they may respond to another. How long a treatment trial has to be conducted before assessing for treatment efficacy is not empirically known. While adult trials with these agents suggest that benefit in the first month or two is possible, some may take more time to respond. It is important to note that, generally speaking, people with chronic migraine who are experiencing daily, continuous headache have been excluded from treatment trials. Therefore, how long it might take to know if a preventive is helpful in this population is unknown, and it may be longer than the duration needed in the migraine population overall. Whether to try a third or even fourth CGRP pathway monoclonal antibody if the first two did not work is also not known. On the one hand, it may seem futile. On the other hand, often patients who have gotten to this point in treatment have already had 9 or 10 preventive trials, as well as copious lifestyle advice and cognitive behavioral therapy and often nerve injections and headache-related hospitalizations. Whether it is “worth it” to try another one may depend on patient and family preference, as well as what other treatment options are still available for them to try. The box below shows one possible approach to choosing and progressing through CGRP pathway monoclonal antibodies in adolescents:
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