Amitriptyline and Butalbital: Interaction Details
AI-assisted, pharmacist-reviewed · AI content regenerated Jul 11, 2026 · Source data updated Jul 2, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Amitriptyline
Butalbital
No brand names on record
How we grade severity & evidence
Severity levels
- Contraindicated: These should generally not be used together.
- Major: Potentially serious — often needs a change or close monitoring.
- Moderate: Can be significant — usually manageable with monitoring.
- Minor: Usually limited clinical impact.
Evidence grades
- Established: Well documented — supported by controlled studies or strong clinical data.
- Probable: Good supporting evidence, though not definitively proven.
- Suspected: Some evidence suggests this interaction, but it is not well established.
- Possible: Limited or conflicting evidence; the interaction may occur.
- Theoretical: Predicted from the drugs' pharmacology; not yet confirmed in people.
Ratings come from the documented interaction literature and are reviewed by a pharmacist. They describe the documented risk of the combination, not what will necessarily happen to you — your dose, timing, and health picture all matter.
Butalbital is a barbiturate, and it can speed up how your body breaks down amitriptyline (Elavil). Over time, that can lower the amount of amitriptyline in your blood, so it may not work as well for your mood or nerve pain.
At the same time, both drugs can make you very drowsy and slow your breathing, so together they can add up. Amitriptyline can also make seizures a little more likely in some people. The good news is your care team can manage this by watching how you respond and adjusting your treatment. Don't change anything on your own, just talk with your doctor or pharmacist.
Mechanism: Butalbital (barbiturate) induces hepatic microsomal enzymes, increasing metabolism of amitriptyline and lowering TCA serum levels/exposure. Effect is delayed (induction develops over days to weeks). Evidence is probable, based on scattered case reports of reduced TCA concentrations.
- Direction: reduced TCA effect (possible loss of antidepressant/analgesic efficacy).
- Additive risks: CNS and respiratory depression; amitriptyline lowers seizure threshold, potentially worsening seizure control.
- Management: monitor clinical response and for excess sedation/respiratory depression; TCA dose may need individualized adjustment. Consider therapeutic response monitoring and reassess if butalbital is started or stopped.
What happens
Reduced tricyclic antidepressant exposure and possible additive adverse effects
Interaction Deep Dive
Using barbiturates together with tricyclic antidepressants (TCAs) can lead to enhanced metabolism of the TCA. Isolated cases have described patients whose serum TCA concentrations were lowered when a barbiturate was also present123. TCAs may also compromise seizure control because they lower the seizure threshold. Furthermore, the two drug classes produce additive depressant effects on the CNS and respiration4.
Why it happens (mechanism)
Increased tricyclic antidepressant metabolism
How to manage this interaction
Keep taking both medications as prescribed unless your prescriber tells you otherwise. Because butalbital can lower amitriptyline levels over time, your care team may:
- Watch whether your amitriptyline is still working (mood, pain, or sleep control) and adjust and individualize your dose if needed.
- Monitor you more closely for strong drowsiness or slowed breathing, since both drugs can add to those effects.
- Reassess your treatment if butalbital is started or stopped.
Tell your pharmacist or doctor if your symptoms return, or if you feel unusually sedated or short of breath.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
1 report — tap to read
a) The pharmacokinetics of a single oral 100 mg dose of desipramine were examined in eight epilepsy patients receiving long-term PHENobarbital therapy and in eight healthy controls not taking any medication. Every participant was an extensive metabolizer according to the genetically determined CYP2D6-related metabolic polymorphism. Relative to the controls, the epilepsy patients showed reduced peak plasma desipramine levels (74 nmol/L vs. 107 nmol/L), lower desipramine area under the concentration-time curve values (1943 nmol/L/h vs. 3234 nmol/L/h), and shorter desipramine elimination half-lives (15.1 h vs. 20.6 h). It is thought that all barbiturates produce comparable effects resulting in induction of hepatic enzymes, and the 2D6 isozyme is considered important in the metabolism of most or all TCAs. Consequently, comparable effects would be anticipated with any pairing of a TCA and a barbiturate 5.
Common questions
Can I take Amitriptyline and Butalbital together?
Butalbital can speed up the breakdown of amitriptyline, lowering its effect, and both drugs together increase drowsiness and slowed breathing. Keep taking both as prescribed and ask your care team to monitor your response and dose. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Amitriptyline and Butalbital interaction?
It is rated major. Potentially serious — often needs a change or close monitoring.
How quickly could this interaction happen?
The documented onset is "delayed". Effects tend to build up gradually over days to weeks.
How is the Amitriptyline and Butalbital interaction managed?
Keep taking both medications as prescribed unless your prescriber tells you otherwise. Because butalbital can lower amitriptyline levels over time, your care team may: Watch whether your amitriptyline is still working (mood, pain, or sleep control) and adjust and individualize your dose if needed. Monitor you more closely for strong drowsiness or slowed breathing, since both drugs can add to those… Management is individual — always follow your own care team's guidance.
How strong is the evidence for this interaction?
The evidence is graded "probable". Good supporting evidence, though not definitively proven.
From our Q&A
Real reader questions about these medications, each personally answered by our pharmacist:
Questions for your pharmacist
- Does my dose of Amitriptyline or Butalbital need adjusting while I take them together?
- What symptoms should prompt me to call you or my prescriber right away?
- Does the timing of my doses matter for this combination?
- Is there a safer alternative to one of these medications for me?
References (5)
- Moody JP, Whyte SF, MacDonald AJ, et al: Pharmacokinetic aspects of protriptyline plasma levels. Eur J Clin Pharmacol 1977; 11:51-56. PubMed
- Silverman G & Braithwaite R: Interaction of benzodiazepines with tricyclic antidepressants (letter). Br Med J 1972; 4:111. PubMed
- Burrows GD & Davies B: Antidepressants and barbiturates. Br Med J 1971; 4:113. PubMed
- Brodie MJ: Drug interactions in epilepsy. Epilepsia 1992; 33(suppl 1):S13-S22. PubMed
- Spina E, Avenoso A, Campo GM, et al: Phenobarbital induces the 2-hydroxylation of desipramine. Ther Drug Monit 1996; 18:60-64. DOI
Keep reading about Amitriptyline
Keep reading about Butalbital
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