Amitriptyline and Triptans: Safety and Management
Amitriptyline and triptans can be safely used together in patients with chronic migraine and comorbid depression, as the theoretical risk of serotonin syndrome is not supported by clinical evidence, though vigilance for symptoms remains prudent. 1, 2
Understanding the Serotonin Syndrome Concern
The FDA issued a warning in 2006 about potential serotonin syndrome when combining triptans with serotonergic antidepressants (including tricyclic antidepressants like amitriptyline). However, this warning has been challenged by subsequent evidence:
Of 29 cases cited in the FDA alert, only 10 actually met validated diagnostic criteria (Sternbach Criteria) for serotonin syndrome, and zero cases met the more stringent Hunter Criteria. 2
The available evidence is limited to Class IV level only, which is insufficient to determine actual risk or support limiting the use of triptans with serotonergic antidepressants. 2
Approximately 700,000 patients annually use SSRIs/SNRIs with triptans, and millions have used this combination safely over the past decade. 3
Evidence Supporting Combined Use
The combination of amitriptyline with acute triptan therapy is not only safe but often necessary for optimal migraine management:
Amitriptyline is classified as a "drug of second choice for migraine prophylaxis" with evidence from small open-label trials in transformed migraine. 4
A study specifically examining amitriptyline combined with citalopram (an SSRI) in patients with comorbid depression, migraine, and tension-type headache found substantial improvement without producing major side effects related to serotonin syndrome. 5
Triptans should be limited to fewer than 10 days per month to prevent medication overuse headache, regardless of whether they are combined with prophylactic medications. 4
Practical Management Algorithm
For Acute Migraine Treatment:
Prescribe triptans (sumatriptan 50-100 mg, rizatriptan 10 mg, or alternatives) for moderate to severe attacks while maintaining amitriptyline prophylaxis. 4, 6
Limit triptan use to no more than 2 days per week (10 days per month) to prevent medication overuse headache. 4
For mild to moderate attacks, use NSAIDs (naproxen 500-825 mg, ibuprofen 400-800 mg) as first-line therapy. 7
For Prophylactic Treatment:
Initiate amitriptyline at 50-100 mg at bedtime, increasing by 25-50 mg as necessary to a total of 150 mg per day for outpatients. 8
Common adverse effects include dry mouth, sedation, weight gain, and constipation; serious effects include cardiac dysrhythmias. 4
Monitor for therapeutic effect, which may take up to 30 days to develop. 8
Critical Contraindications and Precautions
Absolute Contraindications for Triptans:
Do NOT use triptans within 24 hours of ergot-containing medications (ergotamine, dihydroergotamine, methysergide) due to additive vasospastic effects. 1
Do NOT use triptans in patients with coronary artery disease, ischemic vascular disease, uncontrolled hypertension, or hemiplegic/basilar migraine. 4, 6
Do NOT use triptans within 24 hours of other 5-HT1 agonists (other triptans). 1
Monitoring for Serotonin Syndrome:
While the risk is extremely low, clinicians should remain vigilant for symptoms:
Monitor for agitation, confusion, tachycardia, hypertension, dilated pupils, tremor, hyperreflexia, diaphoresis, and hyperthermia. 1, 2
If serotonin syndrome is suspected, discontinue all serotonergic agents immediately and provide supportive care. 2
Alternative Treatment Options
If Concerns Persist About Combination Therapy:
Consider topiramate (Level A evidence for chronic migraine) as an alternative prophylactic agent, starting at low doses and titrating to 100-200 mg daily. 4
Consider beta-blockers (propranolol 80-240 mg/day, metoprolol) for prophylaxis, though these may exacerbate depression. 4
For acute treatment in patients where triptans are contraindicated, use dihydroergotamine (DHE) intranasal spray or parenteral formulations. 9
For Patients with Treatment-Resistant Migraine:
If one triptan fails after 2-3 episodes, try a different triptan, as failure of one does not predict failure of others. 6
Consider newer CGRP antagonists (ubrogepant, rimegepant) when triptans are contraindicated or ineffective. 7, 6
Common Clinical Pitfalls to Avoid
Do NOT withhold necessary triptan therapy due to unfounded fears of serotonin syndrome when combined with amitriptyline. 2, 3
Do NOT allow patients to use acute medications (triptans or analgesics) more than twice weekly, as this creates medication overuse headache. 4
Do NOT prescribe opioids or butalbital-containing compounds for migraine, as they lead to dependency, rebound headaches, and loss of efficacy. 7, 6
Do NOT use triptans and ergot medications within 24 hours of each other due to additive vasoconstrictive effects. 1