A landmark international guideline reviewed hundreds of clinical trials to determine which medications work best for migraine - both for stopping attacks and preventing them. Here's what it means for patients.
What This Guideline Is - and Why It Matters
If you or someone you love lives with migraine, you know how hard it can be to find relief. With dozens of medications available - old standbys and exciting new drugs - it can be overwhelming to know which ones are actually worth trying.
A major new international medical guideline, published in early 2025 in the journal Cephalalgia, set out to answer that question definitively. Created jointly by the Italian Society for the Study of Headaches and the International Headache Society, the guidelines brought together dozens of migraine specialists from around the world to systematically review the evidence from hundreds of clinical trials.
The result is a comprehensive, 326-page document that rates every major migraine medication - assessing both the strength of the recommendation (strong vs. weak) and the quality of evidence behind it (high, moderate, low, or very low). The goal, in the authors' own words, is to "standardize migraine treatment and promote high-quality care across different healthcare settings."
This article breaks down what those guidelines say, in plain language.
Two kinds of migraine treatment: The guidelines cover two separate categories of medication. Acute treatments (sometimes called "abortive" treatments) are taken at the start of a migraine attack to stop it. Preventive treatments are taken regularly - daily or monthly - to reduce how often attacks happen.
Part One: Stopping a Migraine Attack
When a migraine strikes, the goal is to get pain-free as quickly as possible. The guideline evaluated medications based on whether patients were pain-free at 2 hours and whether they had meaningful pain relief at 2 hours - the two outcomes most important in clinical trials.
The Everyday Options: NSAIDs and Paracetamol (Tylenol)
For many people, the first line of defense against a migraine is a medication they can buy at any pharmacy. The guidelines confirm that several over-the-counter options are genuinely effective.
Paracetamol (acetaminophen, also sold as Tylenol in the US) at 1,000 mg - a higher dose than most people realize is needed - received a strong recommendation with high-quality evidence. It is one of the most frequently used over-the-counter medications for treating acute pain, including headaches, and has a lower risk of gastric bleeding compared to other analgesics.
Ibuprofen (also sold as Advil and Motrin in the US) (200, 400, and 600 mg) also received a strong recommendation, though the quality of evidence was rated lower than for paracetamol. Aspirin (acetylsalicylic acid) at 1,000 mg received a strong recommendation with moderate-quality evidence.
A well-known combination - aspirin 500 mg + paracetamol 500 mg + caffeine 130 mg - received a strong recommendation backed by high-quality evidence. The caffeine component, frequently included in over-the-counter migraine products, appears to genuinely enhance the effectiveness of the other ingredients.
A word of caution about overuse: The guidelines emphasize that NSAIDs carry a risk of "medication overuse headache" (MOH) - a paradoxical condition where taking pain medication too frequently can itself cause more headaches. For NSAIDs, this risk applies when they are used on 15 or more days per month for at least 3 months. Using any acute migraine medication too often is something to discuss with your doctor.
Triptans: The First Migraine-Specific Medications
For decades, triptans have been the cornerstone of migraine-specific treatment. The guidelines describe them as "a significant advancement in the acute treatment of migraine." They work by activating certain serotonin receptors in the brain and nervous system, narrowing blood vessels in the brain's lining and blocking pain signals from the trigeminal nerve - the main pain pathway in migraine.
Multiple triptans received strong recommendations with high-quality evidence, including:
The guidelines suggest that for people with severe, disabling migraine attacks, triptans should be considered first-line treatment from the outset. For those with milder attacks, doctors may reasonably try an NSAID first and move to a triptan if the simpler medication doesn't work.
Triptans do have important limitations, however. Because they cause constriction of blood vessels, they are not recommended for people with cardiovascular disease, a history of stroke, or certain other cardiovascular risk factors. They also carry a risk of medication overuse headache - the guidelines suggest limiting their use to fewer than 10 days per month to reduce this risk.
Lasmiditan: A New Option for People Who Can't Use Triptans
One of the most clinically important sections of the guideline covers a newer class of drug called ditans, represented by a single approved medication: lasmiditan.
Lasmiditan works on a different serotonin receptor (5-HT1F) than triptans, and crucially, it does not cause blood vessel constriction. Clinical studies have confirmed it is safe and effective even in patients with cardiovascular risk factors or cardiovascular disease - a population for whom triptans are typically off-limits. The guidelines note that lasmiditan "may address important unmet needs in patients with cardiovascular risk factors, cardiovascular diseases, or patients who respond poorly to other acute treatments."
Lasmiditan (50 mg, 100 mg, and 200 mg) received a strong recommendation with high-quality evidence. The main trade-off is a set of side effects related to the brain, including dizziness, drowsiness, fatigue, tingling sensations, nausea, and vertigo. Because of these effects, patients should not drive or operate heavy machinery for at least 8 hours after taking it.
- Ornello et al., 2025
Gepants: A Newer Class with Fewer Restrictions
Perhaps the most exciting development in migraine treatment over the past several years is the arrival of a class of drugs called gepants. Gepants work by blocking the activity of a molecule called CGRP (calcitonin gene-related peptide), which plays a central role in causing migraine pain.
Unlike triptans, gepants do not constrict blood vessels, giving them a favorable safety profile. The guidelines note that "their specific mechanism of action justifies their good safety profile." Three gepants are currently approved for acute migraine treatment:
Gepants have not yet been studied in children, adolescents, pregnant women, or breastfeeding women, so they are currently not recommended in those groups. People with significant liver impairment should also use caution, as these drugs are primarily processed by the liver.
What About Opioids?
The guidelines are clear on this point: opioid pain medications (such as codeine, tramadol, or butorphanol) should be a last resort for migraine. Their use "should be considered only when all the other available options have proved ineffective." Misuse of opioids can lead to opioid use disorder and medication overuse headache, and their combination with serotonergic drugs like triptans should be avoided. They do not address the underlying mechanism of migraine and carry significant risks of dependence and worsening headache patterns over time.
A note on antiemetics: Nausea is a common and distressing part of migraine for many people. The combination of aspirin 900 mg + metoclopramide 10 mg (an anti-nausea drug) received a strong recommendation with moderate-quality evidence, making it a useful option when nausea is a significant part of the attack.
Part Two: Preventing Migraines Before They Start
For people who have frequent, severe, or disabling migraines, treating individual attacks may not be enough. Preventive medications - taken on a regular schedule to reduce how often migraines occur - are a cornerstone of long-term management.
The guideline divides migraine into two categories. Episodic migraine refers to fewer than 15 headache days per month; chronic migraine refers to 15 or more headache days per month (with at least 8 of those having migraine features). Different medications have been studied for each.
Beta-Blockers and Other Blood Pressure Medications
Several medications originally developed for heart conditions or high blood pressure have long been used to prevent migraine, and the guidelines confirm their usefulness - though generally with lower levels of evidence than the newer drugs.
Propranolol (160 mg) received a weak recommendation for preventing migraine with low-quality evidence, as did bisoprolol (5 and 10 mg) and metoprolol (200 mg), though the latter two are noted in the broader "any migraine" category. The blood pressure medication candesartan (16 mg) also received a weak recommendation with low-quality evidence.
Anti-Seizure Medications
Topiramate, an anti-seizure drug, received a strong recommendation with moderate-quality evidence for preventing episodic migraine at doses of 100 mg and 200 mg, and a weak recommendation at 50 mg. Valproate received a weak recommendation at various doses. These medications require careful management due to their potential side effects.
Antidepressants
Amitriptyline (25 mg), a tricyclic antidepressant, received a weak recommendation with moderate-quality evidence for preventing episodic migraine. Its role in migraine is separate from its antidepressant effect - it works by influencing the brain's pain control pathways.
Duloxetine (60 mg), a serotonin-norepinephrine reuptake inhibitor (SNRI), was also evaluated. The single available clinical trial did not demonstrate a benefit over placebo, and the quality of evidence was rated very low. The guideline issues a weak recommendation against duloxetine for episodic migraine prevention based on current evidence — meaning the evidence does not support its use for this purpose at this time, though that picture could change as more studies are conducted.
Botulinum Toxin (Botox) - For Chronic Migraine
One of the strongest findings in the preventive section is for onabotulinumtoxinA (the medical formulation of botulinum toxin, best known by the brand name Botox). For people with chronic migraine - meaning 15 or more headache days per month - it received a strong recommendation with high-quality evidence, at a dose of 155-195 units injected into specific muscles of the head and neck.
This is an important distinction: botulinum toxin is recommended specifically for chronic migraine prevention, not for episodic migraine. It is typically administered every 12 weeks in a clinical setting by a trained provider.
CGRP Monoclonal Antibodies: The Newest and Most Targeted Preventive Treatments
The biggest development in migraine prevention in recent years is the arrival of a class of injectable medications called anti-CGRP monoclonal antibodies. These are biologic drugs - complex proteins engineered to specifically target either CGRP itself or its receptor in the body, blocking the key molecule that drives migraine.
Four such drugs are currently available: erenumab, fremanezumab, galcanezumab, and eptinezumab. The guidelines report that clinical trials and real-world studies have demonstrated "similar efficacy and tolerability of all these new drugs in chronic and episodic migraine, regardless of the presence of medication overuse and various previous treatment failures."
Their safety profile is described as "very favorable," with reported side effects only slightly more common than in placebo groups. No significant increase in cardiovascular events has been identified.
These are the most migraine-specific preventive treatments ever developed, but they come with a significant caveat: they are considerably more expensive than older preventive options and may not be accessible or covered by insurance for all patients.
Gepants for Prevention Too
Remarkably, one of the gepants - atogepant (60 mg daily) - also earned a strong recommendation with high-quality evidence for preventing episodic and chronic migraine. Rimegepant (75 mg every other day) received a strong recommendation with moderate evidence across migraine types. This means the same class of medication can now be used both to stop attacks and to prevent them - a potentially significant convenience for some patients.
The guidelines note that gepants should be used with caution in people with vascular disease, severe constipation, inflammatory bowel disease, or certain other conditions, because CGRP plays important biological roles in those systems beyond migraine.
Special Situations Worth Knowing About
Migraine and Cardiovascular Disease
Because triptans cause blood vessel constriction, they are traditionally avoided in people with cardiovascular disease or significant risk factors. The guidelines highlight that both lasmiditan and the gepants were specifically studied in patients with cardiovascular risk factors and showed no increased cardiovascular risk - making them valuable options for this population.
Menstrual Migraine
For migraines that occur around the menstrual cycle, the guidelines note that among the triptans, rizatriptan 10 mg showed the best overall evidence for acute treatment. For short-term prevention around the menstrual period, frovatriptan and zolmitriptan have supportive evidence.
Pregnancy
The guidelines are cautious here. Pregnant women were generally excluded from clinical trials of the newer drugs, so gepants and CGRP monoclonal antibodies are not recommended during pregnancy or breastfeeding. Triptans may be considered as a second-line option during pregnancy if paracetamol (acetaminophen) is not effective, with sumatriptan, naratriptan, and rizatriptan having the most safety data available. Any medication use during pregnancy should always be discussed with a healthcare provider.
What the Guidelines Don't Yet Tell Us
Honest guidelines acknowledge their own limitations. The authors note significant gaps that remain in migraine research. Most importantly, there is a "paucity of head-to-head drug comparisons" - meaning most trials compared a drug to placebo, not to other active drugs. This makes it genuinely difficult to say whether one effective medication is better than another effective medication. Long-term outcome studies are also largely lacking.
These gaps mean that choosing between several good options often requires individualized judgment - accounting for a patient's other health conditions, medication tolerability, lifestyle, and access - rather than a single universal answer.
The Bottom Line
Migraine treatment has genuinely transformed over the past decade. Alongside the well-established options (NSAIDs, triptans, beta-blockers, topiramate), people with migraine now have access to a new generation of highly targeted treatments - lasmiditan, gepants, and CGRP monoclonal antibodies - with strong clinical evidence behind them.
For people who have struggled with frequent, severe, or disabling migraines, or for whom older treatments have failed or caused side effects, this guideline confirms that there are now more options than ever - and a growing body of high-quality evidence to guide the choice.
The most important next step is a conversation with your doctor or a headache specialist, who can help you navigate these options in the context of your own health, history, and goals.
Complete Reference: Additional Medications Covered in the Guidelines
The following medications all received formal assessments in the guideline but were not covered in the main sections above. They are grouped below for completeness. Where the guideline recommends against a drug, it means current evidence does not support its use — not necessarily that it is harmful.
Acute Treatment — Additional Options
Preventive Treatment — Additional Options
How to read "weak recommendation against": This does not mean a medication is dangerous or should never be used. It means the current clinical trial evidence is insufficient to support recommending it for migraine prevention. A doctor may still consider these medications in individual cases based on other factors.