Over-the-Counter Painkillers vs Gepants and Lasmiditan: What a 25-Trial Analysis Found

What the Study Looked At

The authors searched PubMed, Embase and the Cochrane trials register for placebo-controlled randomized trials published between 1990 and July 2025 in adults with episodic migraine. They included five treatments: the acetaminophen, aspirin and caffeine combination (often shortened to AAC), ibuprofen, lasmiditan (Reyvow, since discontinued), ubrogepant (Ubrelvy) and rimegepant (Nurtec ODT). Triptans were left out by design.

Twenty-five trials published between 1997 and 2025 qualified. Each one compared a single drug against placebo, so the analysis builds its comparisons between drugs indirectly, through their shared placebo groups. Outcomes were measured two hours after the dose: pain relief (moderate or severe pain down to mild or none), pain freedom, and relief of light sensitivity, sound sensitivity and nausea. The authors focused their interpretation on FDA-approved doses.

Pain Relief and Pain Freedom

For pain relief at two hours, the acetaminophen, aspirin and caffeine combination had the largest effect compared with placebo (relative risk 1.76, 95% CI 1.61 to 1.94), followed by ibuprofen 400 mg (1.68) and ibuprofen 200 mg (1.63).

For pain freedom at two hours, three treatments were nearly tied: the combination (2.20), ibuprofen 400 mg (2.19) and lasmiditan 200 mg (2.15). Rimegepant and ubrogepant beat placebo at their approved doses, but with smaller effect sizes than these three.

Light, Sound and Nausea

The combination product also ranked first for light sensitivity (relative risk 1.99) and sound sensitivity (1.53) at two hours. Ibuprofen 400 mg in liquid-gel form and rimegepant 75 mg followed.

Nausea was the one outcome where a prescription drug led. Rimegepant 75 mg ranked highest (1.15), with ibuprofen liquid gel 400 mg (1.16) and the combination (1.11) close behind. Lasmiditan did not improve nausea at any approved dose.

Side Effects

The trials reported side effects too inconsistently for the authors to compare them statistically, so the safety findings are descriptive. Lasmiditan stood out. At the 200 mg dose, the trials recorded 995 adverse events among 2,002 participants, mostly dizziness, sleepiness, nausea, tingling and fatigue. The over-the-counter options and the gepants had fewer reported side effects.

The authors point out that these trials looked at single attacks treated over a short period. They did not capture the risks of using these drugs often, such as stomach bleeding with aspirin and ibuprofen, kidney strain from NSAIDs in people who are susceptible, and medication overuse headache.

Why the Ranking Needs Context

Who ran the analysis

Three of the five authors work for Haleon, the company that sells both Excedrin and Advil. The other two work for a research services firm. The review was registered in advance with PROSPERO and followed standard methods, but the company that sells the top-ranked products designed and reported the analysis.

Trials from different decades

All but one of the over-the-counter trials date from 1998 to 2007, while the gepant and lasmiditan trials ran from 2012 to 2025. Placebo response in migraine trials has been rising over time, as a 126-trial analysis we covered showed. A drug tested against a stronger placebo will show a smaller relative risk even if it works just as well, which tilts this kind of comparison toward the older trials.

Who was enrolled

Some of the older over-the-counter trials, including the original trials of the combination product, excluded people whose attacks usually involved vomiting or confined them to bed. People in those trials may have had milder attacks on average than people in the newer prescription trials, so the treatments may have been tested on different kinds of attacks.

What was left out

Triptans, the most widely prescribed migraine-specific drugs, were not included. The analysis also only covers episodic migraine and single attacks, and it says nothing about combining treatments, which many people do.

What This Means for You

Ibuprofen and the acetaminophen, aspirin and caffeine combination are effective for many people with episodic migraine, and they belong at the start of the list. That matches existing guidelines, which already list them among the first options for mild to moderate attacks.

The newer drugs earn their place for people who cannot take NSAIDs or aspirin safely, such as people with stomach ulcers, kidney disease or a high bleeding risk, and for people whose attacks do not respond to simple painkillers. Lasmiditan is no longer one of those options, since Lilly has discontinued it. If you were relying on it, gepants are one alternative worth asking your doctor about, and like lasmiditan they do not narrow blood vessels, which matters for people with heart disease. Rimegepant may be worth considering when nausea is a major part of your attacks.

Whichever you use, frequency matters. Taking simple painkillers on 15 or more days a month, or combination painkillers on 10 or more days a month, can lead to medication overuse headache. If you are reaching for any acute treatment that often, talk to your doctor about prevention. Our guide to simple analgesics and combination products covers dosing and safety in more detail.