Migraine affects about one in seven people worldwide1 and is the leading cause of disability among people aged under 50 years, often impacting negatively on education, employment, and family relationships.2 The discovery of calcitonin gene-related peptide (CGRP) as a key player in migraine pathophysiology, and the subsequent development of drugs that target this system, represents a triumph in bench-to-bed medicine and has revolutionised both migraine prevention and acute medication strategies.3 CGRP therapies have been shown to be highly effective at reducing migraine and overall are said to benefit at least 50% of patients by at least 50%.4,5 Guidance issued by the Medicines and Healthcare products Regulatory Agency states that topiramate, a commonly used migraine preventive in primary care, is now contraindicated in pregnancy and under the ‘Pregnancy Prevention Programme’,6 and furthers the need for new alternatives to be made available in primary care. Sooner or later most GPs will be in the position to prescribe some form of CGRP therapy. Knowledge of these drugs and when to prescribe them is briefly reviewed below.
Anti-CGRP monoclonal antibodies and gepants
Anti-CGRP monoclonal antibody (mAb) therapy either targets the CGRP molecule (fremanezumab, galcanezumab, and eptinezumab) or CGRP receptor (erenumab). Eptinezumab is given as an intravenous infusion 3-monthly, while the others are self-administered subcutaneously via an autoinjector once monthly. Gepants (rimegepant and atogepant) are CGRP receptor antagonists and given orally as tablets. Rimegepant is available as an orally disintegrating tablet and, although not absorbed orally, this offers convenience to patients.
When to give CGRP therapies?
The National Institute for Health and Care Excellence (NICE) has provided guidance for use of CGRP mAbs as migraine preventives, and gepants as migraine preventives and as an acute migraine medication in adults (Table 1).
Table 1.
Available CGRP mAbs and gepants
| Drug (trade name) [TAG]a | Indication | Route | Dose and frequency |
|---|---|---|---|
| Fremanezumab (Ajovy) [TA764] | EM, CM | SC | Monthly |
| Erenumab (Aimovig) [TA682] | EM, CM | SC | Monthly |
| Galcanezumab (Emgality) [TA659] | EM, CM | SC | Monthly, loading dose required |
| Eptinezumab (Vyepti) [TA871] | EM, CM | IV | 3-monthly |
| Rimegepant (Vydura) [TA906, TA919] | AM, EM | PO | 75 mg, as required or alternate day |
| Atogepant (Aquipta) [TA973] | EM, CM | PO | 60 mg, once daily |
Technology appraisal guidance (TAG) can be viewed via the NICE website: https://www.nice.org.uk. AM = acute migraine. CM = chronic migraine. EM = episodic migraine. IV = intravenous. NICE = National Institute for Health and Care Excellence. PO = per os. SC = subcutaneously.
For the purposes of treatment, episodic migraine is defined as 4–14 headache days per month and chronic migraine as more than 15 days of headache (of which 8 have features of migraine) per month.
To qualify for CGRP mAbs and gepants on the NHS, patients are required to have not benefited from at least three conventional migraine preventatives (for example, amitriptyline, propranolol, candesartan, pizotifen, and topiramate). This has been predicted to apply to 13% of patients with episodic migraine and 35% of patients with chronic migraine.7 In the case of gepants for acute migraine treatment, NHS patients are required to have not benefited from at least two triptans (for example, sumatriptan and rizatriptan). This has been predicted to apply to 4.8% of patients who have been prescribed triptans.7
Rimegepant has two indications: prevention of episodic migraine (given alternate days); and acute medication (given as required, maximum once per day).
Although rimegepant is not licensed to be used as a preventive in chronic migraine, it can be used as an acute medication (suggested less than 10 days per month) in chronic migraine. It is safe to use rimegepant as an acute medication in patients receiving atogepant, CGRP mAbs, or any another migraine preventives. Patients who benefit from triptans may also continue to use them when gepants or CGRP mAbs are used as preventives.
CGRP mAbs and gepants should be prescribed according to local policy.
When not to give CGRP mAbs and gepants
Because of lack of safety data, CGRP mAbs and gepants should be avoided during pregnancy, breastfeeding, and if there is a recent history of significant vascular disease.
Clinical trials for gepants and CGRP mAbs have not included sufficient older patients (aged over 65 years) to determine tolerance, efficacy, or safety. In practice, regardless of age, it is safer to avoid gepants and CGRP mAbs in any patients who are at significant risk of cardiovascular or cerebrovascular disease. If in doubt, advice should be sought from a cardiologist or stroke physician.
Although considered safe in most patients, they should be avoided in certain situations (Box 1).
Box 1.
Contraindications
| CGRP mAbs | Gepants |
|---|---|
| Pregnancy and breastfeeding | |
| Known sensitivity to drug (avoid erenumab if latex sensitivity) | |
| Significant cardiovascular/cerebrovascular/peripheral vascular disease (including severe Raynaud’s disease) within the last 6 months | |
| Significant renal or liver impairment | |
| Certain antibiotics, certain seizure medications, and grapefruita | |
For drug interactions, please refer to the British National Formulary (or equivalent). CGRP = calcitonin gene-related peptide. mAbs = monoclonal antibodies
Common side effects
CGRP mAbs and gepants are generally considered well tolerated. The most common reported side effects in patients receiving CGRP mAbs are constipation and local skin irritation. Commonly reported side effects with gepants include fatigue, nausea, dizziness, tiredness, and dry mouth.
How to monitor clinical effectiveness and when to stop
It is important that patients keep a simple headache diary and that baseline monthly migraine/headache days are documented when preventive medication is commenced.
Patients should be reviewed at 3 months and then 12-monthly thereafter. According to NICE, treatment should be stopped if:
in episodic migraine (less than 15 headache days a month), the frequency does not reduce by at least 50%; and
in chronic migraine (15 headache days a month or more with at least 8 of those having features of migraine), the frequency does not reduce by at least 30%.
Some patients with chronic migraine may continue to get daily headaches, but significantly fewer migraine days and medication is best continued in these patients. Because of the natural history of migraine, it is good practice to consider stopping treatment at 1 year and to review the patient. At each visit patients should also be asked about pregnancy and relevant contraindications.
Who can prescribe CGRP therapy?
Frustratingly for many patients with migraine, despite qualifying for these newer drugs, they often remain difficult to access. They are costly when prescribed through private health care, and access to specialist prescribing clinics (neurologists or headache clinics) is often limited by long waiting times. It remains unclear if (or when) CGRP mAbs will be available in primary care. NICE has recently issued guidance and indicated that gepants (rimegepant and atogepant) can be prescribed in primary care, although this remains dependent on local health policy.
The future
Geographical inequalities and the availability of newer treatments have long frustrated patients with migraine. Gepants and CGRP mAbs are more effective and have lower adverse effect profiles compared with many drugs in current use and should be prescribed in primary care where possible. A satisfactory response to these newer drugs should not exclude attention to lifestyle and psychosocial factors that are increasingly important with high-frequency and chronic migraine.
Provenance
Freely submitted; externally peer reviewed.
Competing interests
Benjamin R Wakerley is the founder of Ceftronics Limited and has received speaker fees from AbbVie. Katherine Phillips has no disclosures or conflicts of interest.
References
- 1.Stovner LJ, Hagen K, Linde M, Steiner TJ. The global prevalence of headache: an update, with analysis of the influences of methodological factors on prevalence estimates. J Headache Pain. 2022;23(1):34. doi: 10.1186/s10194-022-01402-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Ashina M, Katsarava Z, Do TP, et al. Migraine: epidemiology and systems of care. Lancet. 2021;397(10283):1485–1495. doi: 10.1016/S0140-6736(20)32160-7. [DOI] [PubMed] [Google Scholar]
- 3.Ho TW, Edvinsson L, Goadsby PJ. CGRP and its receptors provide new insights into migraine pathophysiology. Nat Rev Neurol. 2010;6(10):573–582. doi: 10.1038/nrneurol.2010.127. [DOI] [PubMed] [Google Scholar]
- 4.Oliveira R, Gil-Gouveia R, Puledda F. CGRP-targeted medication in chronic migraine — systematic review. J Headache Pain. 2024;25(1):51. doi: 10.1186/s10194-024-01753-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Moreno-Ajona D, Villar-Martínez MD, Goadsby PJ. New generation Gepants: migraine acute and preventive medications. J Clin Med. 2022;11(6):1656. doi: 10.3390/jcm11061656. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Medicines and Healthcare products Regulatory Agency Topiramate (Topamax): introduction of new safety measures, including a Pregnancy Prevention Programme. 2024. https://www.gov.uk/drug-safety-update/topiramate-topamax-introduction-of-new-safety-measures-including-a-pregnancy-prevention-programme (accessed 2 Oct 2024).
- 7.NICE . Rimegepant for treating migraine. TA919. London: NICE; 2023. https://www.nice.org.uk/guidance/ta919/resources (accessed 2 Oct 2024). [Google Scholar]