Migraine prevention: what the AAN evidence review will actually support

Design

Systematic review of randomised trials with duplicate screening and modified GRADE certainty rating, informing a joint AAN and American Headache Society guideline

Population

Adults with episodic or chronic migraine across 217 included randomised trials

Primary outcome

Change in monthly headache days, 50% responder rate, and validated quality-of-life measures

Effect

High certainty for galcanezumab and erenumab in episodic migraine, and fremanezumab, galcanezumab and onabotulinumtoxinA in chronic; moderate for propranolol, topiramate and valproate; comparative evidence low or very low

The systematic review underpinning the joint American Academy of Neurology and American Headache Society guideline screened randomised trials from database inception to June 2024 and included 217 studies, with duplicate screening, dual risk-of-bias assessment and a modified GRADE approach to certainty. Outcomes were monthly headache days, the 50% responder rate and validated quality-of-life instruments.

For episodic migraine, high-certainty evidence supports galcanezumab and erenumab over placebo; moderate certainty supports atogepant, eptinezumab, fremanezumab, propranolol, topiramate and valproate. For chronic migraine, high certainty supports fremanezumab, galcanezumab and onabotulinumtoxinA; moderate certainty supports atogepant, eptinezumab, erenumab, topiramate and valproate. Amitriptyline, flunarizine, metoprolol, bisoprolol, levetiracetam and several others reached only low certainty. Quality-of-life gains were shown for the CGRP-targeted agents, rimegepant, topiramate and onabotulinumtoxinA.

The finding that should change a conversation is the one about comparison. Evidence putting one active preventive against another was limited and mostly low or very low certainty, so the review cannot rank these drugs against each other. That means a preventive choice is properly made on comorbidity, pregnancy plans, tolerability and cost — not on a claim that the newer agent is better, which this evidence does not make. Where CGRP monoclonals are out of financial reach, propranolol and topiramate sit at the same moderate certainty as atogepant and eptinezumab. Valproate carries the same certainty and is not an option for a woman who could become pregnant.

• Choose a preventive on comorbidity, pregnancy plans, tolerability and cost — the head-to-head evidence does not rank them.
• Do not describe a CGRP agent as more effective than propranolol or topiramate; that comparison was not established.
• Exclude valproate in women of childbearing potential regardless of its efficacy rating.
• Set the trial period and the target — monthly headache days, or a 50% reduction — before starting, so failure is definable.
• Reserve onabotulinumtoxinA for chronic, not episodic, migraine; that is where the high-certainty evidence sits.

The statistics, in plain English

Certainty grading is a statement about how much the evidence could still move, not about how large the effect is. A high-certainty finding for galcanezumab means further trials are unlikely to overturn the conclusion that it beats placebo; it does not mean the reduction in headache days is bigger than topiramate's. Because almost all 217 trials compared a drug with placebo rather than with another drug, comparing effect sizes across those trials would mean comparing different populations, baselines and eras — which is why the review rates the comparative evidence low to very low and declines to rank. The absence of a ranking is the result here, and it is a useful one.

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