Early observations and pilot data that first suggested a new direction
Migraine prevention relied for decades on repurposed drugs — beta-blockers, antidepressants, and anticonvulsants — none designed specifically for migraine. These agents offered modest efficacy with significant side effects, leading to poor adherence. The discovery of calcitonin gene-related peptide (CGRP) as a key mediator of migraine pathophysiology in the 1990s opened the door to the first migraine-specific preventive therapies.
Proof
Landmark RCTs and pivotal trials that established the evidence base
STRIVE (2017) demonstrated erenumab (anti-CGRP receptor antibody) reduced monthly migraine days by 3.2-3.7 versus 1.8 with placebo in episodic migraine. EVOLVE-1 (2018) showed galcanezumab reduced monthly migraine days by 4.7 versus 2.8 with placebo. Fremanezumab (PROMISE trials) confirmed the class effect. These monoclonal antibodies offered the first preventive treatments designed specifically for migraine, with monthly or quarterly subcutaneous injections and minimal systemic side effects.
Follow-up studies, subgroup analyses, and real-world validation
CGRP-targeting gepants (small molecule antagonists) expanded the therapeutic options with oral administration. Ubrogepant (ACHIEVE, 2019) and rimegepant were approved for acute treatment, while atogepant became the first oral CGRP-pathway preventive. This provided patients who preferred oral medications over injections with a migraine-specific preventive option for the first time.
Integration into clinical practice guidelines and recommendations
AAN/AHS 2021 guidelines endorsed CGRP monoclonal antibodies for episodic and chronic migraine prevention, positioning them alongside traditional preventives. European Headache Federation guidelines similarly recommended anti-CGRP therapies. Many guidelines now suggest CGRP-targeted therapy when one or two traditional preventives have failed.
AAN/AHS Migraine Prevention Guidelines
CGRP monoclonal antibodies recommended for episodic and chronic migraine prevention
Now
Current standard of care and ongoing research directions
Migraine prevention has been transformed by CGRP-targeted therapies. Four monoclonal antibodies (erenumab, galcanezumab, fremanezumab, eptinezumab) and oral gepants (atogepant, rimegepant) provide migraine-specific options with favourable tolerability. Current research explores dual prevention-acute use of gepants, combination strategies, and neuromodulation devices as non-pharmacological alternatives.
CGRP (calcitonin gene-related peptide) inhibitors are the first class of drugs designed specifically to prevent migraines. They include monoclonal antibodies (erenumab, galcanezumab, fremanezumab, eptinezumab) given as monthly/quarterly injections, and gepants (atogepant, rimegepant) taken orally. STRIVE showed erenumab reduced monthly migraine days by about 50% compared to placebo.
How do CGRP drugs compare to older migraine preventives?+
Unlike older preventives (propranolol, amitriptyline, topiramate) which were repurposed from other indications and have significant systemic side effects, CGRP-targeted therapies were designed specifically for migraine. They offer better tolerability with fewer cognitive, metabolic, and cardiovascular side effects, leading to better adherence. The main limitation is cost.
