Well, it has been just 1 year since the first anti-CGRP medication came on the market, approved by the FDA for both episodic and chronic migraine for patients over the age of 18 years. I have heard from adult providers that these medications have been really helpful for their patients, especially with chronic migraine. We have a few young adults on Aimovig who are mostly doing well, but our exposure is limited due to the age limit. We get asked all the time about these medications, and I will bet that pediatric offices are also getting questions about them. I thought I would cover the basics and review the current recommendations from the pediatric neurology/headache group associated with the American Headache Society.
What are these medications and what do they do?
CGRP stands for calcitonin gene-related peptide, a protein. CGRP does a number of jobs in the body, including pain transmission through the brain along the trigeminal nerve into the brain stem. Research has revealed increased levels of CGRP in both blood and saliva during a migraine attack. People with chronic migraine (more than 15 migraine days/month) had chronically elevated levels of CGRP. Researchers hypothesized that blocking CGRP and its receptor might play a role in migraine therapy. During migraine, CGRP can cause pain, nausea/vomiting, dizziness, photophobia, phonophobia and osmophobia.
There have been 3 medications developed with the purpose of blocking the release of CGRP proteins and its receptor. These medications work by using monoclonal antibodies, which target the neurotransmitter’s communication with the brain to block the CGRP release. With this process, the anti-CGRP medications block inflammation in the trigeminal nerve cells, prevent blood vessel dilation which causes pain, and inhibits pain signals.
These monoclonal antibodies are large molecules, reportedly too large to cross the blood brain barrier, and are not metabolized by the liver or excreted by the kidneys, decreasing the adverse renal or hepatic effects. They do not interact with other medications.
Aimovig (erenumab) came to market first in May 2018. It targets the CGRP receptor, and is given in monthly self-administered injections. Side effects reported are injection site irritation and constipation. Both Ajovy (fremanezumab) and Emgality (galcanezumab) came out in September 2018, both target the CGRP protein, and are also monthly self-administered injections. Side effects are injection site irritation, but not constipation. All are approved for both episodic and chronic migraine. Clinical trials are ongoing, assessing for long term effects, as well as suitability for other populations (such as adolescents).
The researchers report that many patients have a reduction in migraine frequency, reducing by 4-6 migraine/month. Some patients have achieved a reduction of 50% fewer headache days. Some patients, called super-responders, experience up to 75% fewer headache days or even go into remission completely. If there is a partial response over the first 2 months, improvement in frequency may continue. However, if there is no response in the first 3 months, then the medication is not likely to be effective. Some have proposed that if there is no response to one of these medications, then another could be tried, as it might be effective.
What about using these medications in the under 18 population?
In a fall 2018 issue of Headache (journal of the AHS), a group of pediatric headache providers produced an expert opinion paper, giving their recommendations for the use of anti-CGRP monoclonal antibodies in children and adolescents. I will briefly summarize their recommendations.
- CGRP is significantly involved with CNS maturation and nervous system recovery after injury. These peripherally acting medications could reduce central CGRP levels and have a negative effect on brain development.
- Recommend against use in children or adolescents with a potentially compromised blood-brain barrier (recent meningitis, stroke, neurosurgery, shunt) or recent peripheral nerve injury.
- CGRP plays a role in utero-placental functions, and may affect the fetus in the 2nd or 3rd trimester. Few pregnant women were included in the clinical trials.
- Recommend against use in women who are pregnant, breastfeeding, or planning to become pregnant within the next 6 months, due to possible teratogenic effects.
- CGRP is involved in bone development, but the data in humans is limited. In mice models, there was evidence of decreased bone mass. Twenty-five percent of adult bone mass is acquired during peak velocity growth during adolescence.
- Recommend cautious use in patients with known bone diseases or osteopenia, close monitoring of height and linear growth if used, and/or waiting until puberty is complete.
- CGRP can modulate glucose-stimulated insulin release, and obesity may be associated with elevated CGRP levels. The clinical trials did not report significant weight loss benefits of these medications. Anti-CGRP medications could also theoretically affect pituitary function (growth hormone secretion).
- Recommend weight monitoring, lab testing for pituitary function if symptoms arise.
- CGRP plays a role in immune function, being present in many areas of the body involved in the immune system with possible negative effects. This has not been seen in adult trial participants.
- Recommend avoiding use in those with known immunodeficiency or receiving immunosuppressive medications.
- CGRP is a vasodilator and has a significant presence in the cardiovascular and peripheral vascular nervous system. While there has been no evidence, there are concerns about blocking CGRP on the CV system.
- Recommend avoiding use in those with structural heart defects, cardiomyopathy, pulmonary hypertension, coronary artery disease and risk factors for stroke.
Their overall recommendation is that the anti-CGRP medications can be considered for post-pubertal adolescents experiencing frequent to chronic migraine (over 8 per month or more) plus moderate to severity disability. There would need to be adequate trials of other medications and interventions, such as cognitive-behavioral therapy and supplements. There needs to be clinical trials specific to the pediatric population as well, which somehow takes into account the placebo effect/response rate.
To quote the expert opinion paper: “Well-designed trials of the anti-CGRP mAbs for migraine prevention in children and adolescents are needed not only to allow practitioners to make informed therapeutic decision, but also to allow better access to, and insurance coverage of, these medications in this age group.” I couldn’t agree more. There are significant barriers to access to these medications, especially cost and insurance approval.
As a point of interest, Botox for chronic migraine appears to operate within the CGRP system as well. There may be less concern for the above listed considerations with Botox, as it is given locally rather than systemically. Apart from a general aversion to receiving multiple injections, my patients who receive Botox for chronic migraine tolerate the procedure well. They have shown an excellent response, with the majority of patients achieving the 50% reduction mark or more after 1-2 procedures. Again, access is limited to age and insurance barriers. Considering the positive benefits and less likely serious side effects or consequences, perhaps fighting for more access to Botox for chronic migraine for younger patients would be an even more worthy endeavor.
We are always looking for the next big thing or shiny object to cure our troubles….. what if we already had an answer and just need more access to it?