What triptans (serotonin receptor agonists) have the least side effects and are most effective for treating migraine headaches?

Most Effective Triptans with Fewest Side Effects

Rizatriptan 10mg and eletriptan 80mg are the most effective triptans for acute migraine treatment, with rizatriptan offering the best balance of superior efficacy, rapid onset, and tolerability. 1, 2, 3

Efficacy Rankings

Highest Efficacy Triptans

• Rizatriptan 10mg demonstrates the highest clinical effectiveness rating (4 out of 4) and provides faster pain relief with higher rates of pain-free status at 2 hours compared to other triptans 1, 4
• Eletriptan 80mg shows superior efficacy to sumatriptan 100mg for most endpoints, with 68% headache response at 2 hours and 38% pain-free at 2 hours 2, 5
• Almotriptan 12.5mg provides similar 2-hour efficacy to sumatriptan 100mg but with better sustained pain-free response and consistency 2, 3

Moderate Efficacy Triptans

• Sumatriptan 100mg (the reference standard) achieves 59% headache response at 2 hours and 29% pain-free at 2 hours 2, 3
• Zolmitriptan 2.5-5mg and eletriptan 40mg show very similar results to sumatriptan 100mg 2, 3

Lower Efficacy Triptans

• Naratriptan 2.5mg has the longest half-life but lower efficacy, though this may reduce headache recurrence 4, 2
• Frovatriptan demonstrates substantially lower efficacy compared to other triptans 4, 2

Side Effect Profiles

Best Tolerability

• Almotriptan 12.5mg offers the best overall tolerability profile while maintaining good efficacy, with fewer adverse events than sumatriptan 100mg 2, 3
• Naratriptan 2.5mg has better tolerability than sumatriptan but at the cost of reduced efficacy 2, 3
• Frovatriptan is generally well tolerated with common side effects including dizziness (8%), fatigue (5%), flushing (4%), paresthesia (4%), and hot/cold sensation (3%) 6

Moderate Tolerability

• Rizatriptan 10mg shows similar tolerability to sumatriptan 100mg despite superior efficacy 2, 3
• Sumatriptan 100mg causes adverse events in 13% more patients than placebo (placebo-subtracted), with common effects including nausea, warmth, chest pressure/heaviness, neck/throat/jaw pain, vertigo, and malaise 7, 8, 2

Lower Tolerability

• Eletriptan 80mg demonstrates lower tolerability than sumatriptan 100mg, though it remains generally well tolerated 2, 3

Practical Selection Algorithm

Step 1: First Triptan Trial

• Start with rizatriptan 10mg for optimal balance of efficacy and tolerability, reaching peak concentration in 60-90 minutes 4, 1, 2
• For patients with significant nausea/vomiting, use rizatriptan orally disintegrating wafers (Maxalt MLT) 4, 1
• Dose: 5-20mg orally every 2 hours, maximum 30mg per 24 hours 1

Step 2: If Rizatriptan Fails or Is Contraindicated

• Try almotriptan 12.5mg for better tolerability with maintained efficacy 4, 2
• Consider eletriptan 80mg if maximum efficacy is prioritized over tolerability 9, 10, 5

Step 3: Special Situations

• Rapid onset needed: Subcutaneous sumatriptan 6mg reaches peak concentration in 15 minutes with 70-82% effectiveness 4
• Recurrent headaches: Consider naratriptan 2.5mg for its longer half-life, though efficacy is lower 4, 2
• Cannot tolerate oral medications: Sumatriptan intranasal or subcutaneous formulations 4

Step 4: Combination Therapy

• If monotherapy inadequate: Combine triptan (sumatriptan or rizatriptan) with naproxen sodium or ibuprofen for greater net benefit 4
• This combination provides 300 more pain-free events per 1000 patients at 2 hours compared to acetaminophen alone 4

Critical Contraindications (All Triptans)

Absolute contraindications include: 1, 8

• Coronary artery disease or vasospasm
• Wolff-Parkinson-White syndrome or other cardiac accessory pathways
• History of stroke, TIA, hemiplegic or basilar migraine
• Peripheral vascular disease or ischemic bowel disease
• Uncontrolled hypertension
• Recent use (within 24 hours) of another triptan or ergotamine
• Recent use (within 2 weeks) of MAO-A inhibitors
• Severe hepatic impairment

Specific to rizatriptan: Contraindicated with propranolol, SSRIs, and cimetidine 1

Common Pitfalls and How to Avoid Them

Medication Overuse Headache

• Critical threshold: Using triptans more than 2 days per week causes medication overuse headache 4, 11
• Prevention: If treating ≥3 attacks per month, initiate preventive therapy with propranolol, amitriptyline, or divalproex 11

Timing of Administration

• Take triptans early when headache is still mild for maximum effectiveness 4
• Do NOT take during aura phase - no evidence supports this and it may reduce efficacy 4

Inadequate Trial Period

• Try each triptan for 2-3 separate headache episodes before concluding it is ineffective 4
• If one triptan fails, try a different one - individual response varies significantly 4

Recurrence Management

• Recurrence occurs in 8-12 hours after initial response 4
• Can repeat dose separated by at least 2 hours, but this increases medication overuse headache risk 4, 8
• Better strategy: Combine triptan with fast-acting NSAID (naproxen sodium, ibuprofen lysine, or diclofenac potassium) 4