What is an alternative to Selective Serotonin Reuptake Inhibitor (SSRI) for relieving chronic headaches?

Medical Advisory BoardAll articles are reviewed for accuracy by our Medical Advisory Board
Educational purpose only • Exercise caution as content is pending human review
Article Review Status
Submitted
Under Review
Approved

Last updated: April 14, 2025View editorial policy

Personalize

Help us tailor your experience

Which best describes you? Your choice helps us use language that's most understandable for you.

From the Guidelines

Amitriptyline is a recommended alternative to SSRIs for relieving chronic headaches, particularly for patients who experience migraines on ≥2 days per month despite optimized acute treatment. According to the study published in Nature Reviews Neurology in 2021 1, amitriptyline is listed as a second-line medication for the preventive treatment of migraines. The study suggests using beta blockers, topiramate, or candesartan as first-line medications, but amitriptyline is a viable option for patients who may not respond to these treatments.

Some key points to consider when using amitriptyline for chronic headache relief include:

  • Starting with a low dose (10-25mg at bedtime) and gradually increasing as needed to minimize side effects
  • Monitoring for potential side effects, such as drowsiness, dry mouth, and constipation
  • Considering alternative treatments, such as beta blockers (e.g., propranolol), topiramate, or candesartan, if amitriptyline is not effective or tolerated
  • Individualizing treatment based on headache type, medical history, and potential side effects, with regular follow-up to assess effectiveness and adjust as needed.

It's essential to note that the treatment of chronic headaches should be tailored to each patient's specific needs and medical history, and amitriptyline may not be suitable for all patients. However, based on the available evidence, amitriptyline is a recommended alternative to SSRIs for relieving chronic headaches, particularly for patients with migraines 1.

From the FDA Drug Label

Amitriptyline hydrochloride should be used with caution in patients with impaired liver function. The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the caucasian population (about 7 to 10% of Caucasians are so called “poor metabolizers”); While all the selective serotonin reuptake inhibitors (SSRIs), e.g., fluoxetine, sertraline, and paroxetine, inhibit P450 2D6, they may vary in the extent of inhibition.

Amitriptyline is an alternative to an SSRI to relieve chronic headaches, as it is a tricyclic antidepressant that can be used for this purpose.

  • Key considerations:
    • It should be used with caution in patients with impaired liver function.
    • The dose may need to be adjusted based on the patient's clinical response, especially in "poor metabolizers" or when co-administered with other drugs that inhibit cytochrome P450 2D6, such as SSRIs 2.
    • Patients should be monitored for potential side effects, such as anticholinergic effects, and the dose should be adjusted accordingly 2.

From the Research

Alternatives to SSRIs for Relieving Chronic Headaches

  • Tricyclic antidepressants, such as amitriptyline, have been shown to be effective in reducing headache activity and disability in patients with chronic tension-type headaches 3, 4
  • Non-pharmacologic treatments, including stress management therapy, relaxation, cognitive-behavioral therapy, and acupuncture, may also be effective in relieving chronic headaches 3, 5, 6
  • Other alternatives to SSRIs include:
    • Butterbur extract and vitamin B2, which have shown efficacy in preventing chronic headaches 5
    • Anticonvulsant drugs, such as sodium valproate, topiramate, or gabapentin, which may be effective in reducing headache frequency and severity 6
    • Noradrenergic and specific serotonergic antidepressants, such as mirtazapine, which may be used as an alternative to SSRIs 6
  • It's worth noting that the effectiveness of these alternatives may vary depending on the individual patient and the specific type of headache being treated 4, 7

References

Guideline

Guideline Directed Topic Overview

Dr.Oracle Medical Advisory Board & Editors, 2025

Research

Treatment of chronic headache with antidepressants: a meta-analysis.

The American journal of medicine, 2001

Research

Headache (chronic tension-type).

BMJ clinical evidence, 2016

Research

Chronic headaches: pharmacological and non-pharmacological treatment.

Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology, 2006

Professional Medical Disclaimer

This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.

Have a follow-up question?

Our Medical A.I. is used by practicing medical doctors at top research institutions around the world. Ask any follow up question and get world-class guideline-backed answers instantly.