What anti-migraine medication has the least side effects?

Anti-Migraine Medications with the Least Side Effects

For acute migraine treatment, NSAIDs (particularly naproxen) have the most favorable side effect profile, with adverse event rates not significantly higher than placebo, while triptans as a class are generally well tolerated despite more frequent minor adverse events. 1

NSAIDs: Best Overall Tolerability Profile

NSAIDs represent the safest first-line option for mild to moderate migraine attacks. 1

• Naproxen sodium specifically showed side effect rates not significantly higher than placebo in controlled trials, making it the optimal choice when tolerability is the primary concern 1
• The most commonly reported adverse events with NSAIDs were gastrointestinal symptoms (nausea, vomiting, gastritis, blood in stool), occurring in 3% to 45% of participants, but these rates were comparable to other migraine treatments 1
• Aspirin, ibuprofen, and combination medications containing acetaminophen, aspirin, and caffeine also demonstrate favorable tolerability profiles 2

Triptans: Well Tolerated Despite Higher Adverse Event Rates

Among triptans, naratriptan has the longest half-life and may offer advantages in tolerability, though all triptans as a class are generally well tolerated 1

• Newer oral triptans (frovatriptan, almotriptan, eletriptan) reportedly have fewer adverse reactions than sumatriptan 1
• The 25 mg dose of oral sumatriptan showed no statistically significant difference in adverse events compared to placebo (risk difference not significant), while the 100 mg dose had a number-needed-to-harm of 7.1 3
• Common triptan adverse events include neck/throat/jaw pain, dizziness, paresthesia, asthenia, somnolence, warm/cold sensation, nausea, and dry mouth, with clear dose-response relationships 4
• Adverse events with triptans are typically transient and mild, lasting only briefly after administration 1, 5

Comparative Side Effect Profiles by Dose and Route

Lower doses consistently produce fewer side effects across all medication classes:

• Oral sumatriptan 25 mg has similar efficacy to 50 mg but with better tolerability than 100 mg 3, 5
• Subcutaneous sumatriptan 6 mg, while most effective (59% pain-free at 2 hours), has the highest adverse event rate with injection site reactions in approximately 30% and chest symptoms in 3-5% 6, 7
• Intranasal and oral routes show intermediate tolerability profiles between subcutaneous and lower-dose oral formulations 7

Medications to Avoid for Side Effect Concerns

Ergotamine derivatives have significantly worse side effect profiles and should be avoided when tolerability is a priority 1:

• Ergotamine causes increased incidence of migraines, daily headaches, ergot poisoning, tachycardia, bradycardia, arterial spasm, localized edema, numbness and tingling in extremities, nausea, vomiting, and diarrhea 1
• These medications have more limited use due to potential for medication-overuse headaches and negative effects on prophylactic medications 1

Preventive Medications: Side Effect Considerations

For patients requiring preventive therapy, beta-blockers (propranolol, timolol) show the best balance of efficacy and tolerability 1:

• Adverse effects with beta-blockers (fatigue, depression, nausea, dizziness, insomnia) are fairly well tolerated and seldom cause premature withdrawal from trials 1
• Anticonvulsants (divalproex sodium, sodium valproate) have more concerning side effects including weight gain, hair loss, tremor, and teratogenic potential 1
• Amitriptyline causes drowsiness, weight gain, and anticholinergic symptoms frequently 1

Critical Pitfall to Avoid

Medication-overuse headache develops from using acute medications more than twice weekly, regardless of which medication is chosen, leading to increasing headache frequency and potentially daily headaches 1, 2, 8. This risk applies to all acute migraine treatments and should guide frequency of use rather than medication selection.