Can You Take Amitriptyline with Diazepam?
A plain-English look at the major interaction between Amitriptyline (ENTRIP) and Diazepam (Diazepam Elixir) — what it means, why it happens, and what to talk to your doctor or pharmacist about.
Taking Amitriptyline (ENTRIP) with Diazepam (Diazepam Elixir) is a major drug interaction that should be avoided. Life-threatening respiratory depression, overdose, coma, and death. Additive CNS and respiratory depression. Both drug classes suppress breathing through different mechanisms, creating synergistic respiratory depression that can be fatal.
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Key Takeaways
- Interaction severity: Major
- Risk: Life-threatening respiratory depression, overdose, coma, and death.
- Mechanism: Additive CNS and respiratory depression. Both drug classes suppress breathing through different mechanisms, creating synergistic respiratory depression that can be fatal.
- Amitriptyline: S4 in Australia, moderate risk
- Diazepam: S4 in Australia, moderate risk
- Claims action: Flag for immediate prescriber review. Document intervention in claim file.
Amitriptyline vs Diazepam at a Glance
| Property | Amitriptyline | Diazepam |
|---|---|---|
| Brand names | ENTRIP, Amitriptyline Lupin, APX-Amitriptyline | Diazepam Elixir, APX-Diazepam, DIAZEPAM-WGR |
| Drug class | opioid | benzo |
| Risk level | moderate | moderate |
| TGA Schedule (AU) | S4 | S4 |
Why Is This Combination Dangerous?
Additive CNS and respiratory depression. Both drug classes suppress breathing through different mechanisms, creating synergistic respiratory depression that can be fatal.
Regulatory Guidance by Jurisdiction
Australia TGA / SIRA / WorkSafe
The TGA and Australian Medicines Handbook classify this as a major drug interaction requiring immediate intervention.
All Australian state workers compensation schemes (SIRA NSW, WorkSafe VIC, WorkCover QLD) flag concurrent opioid and benzodiazepine prescribing as high-risk. SIRA best practice guidelines explicitly recommend avoiding this combination except in exceptional circumstances with specialist oversight.
United Kingdom NICE / MHRA / FPM
NICE NG193 (Chronic Pain) recommends against initiating opioids for chronic primary pain. The Faculty of Pain Medicine (FPM) Opioids Aware guidelines strongly advise against concurrent opioid and benzodiazepine prescribing. For personal injury claims in the UK, this combination should be flagged for specialist review. Costs for medication review may be recoverable as a disbursement.
United States FDA / CDC / State WC
The FDA requires a Boxed Warning on all opioid and benzodiazepine products about the risks of concurrent use. The CDC Clinical Practice Guideline (2022) recommends clinicians avoid prescribing opioids and benzodiazepines concurrently whenever possible. Most state workers compensation drug formularies flag or restrict this combination.
What Claims Professionals Should Do
- Flag immediately as a high-risk prescribing pattern in the claim file
- Request urgent prescriber review with documented clinical justification for the combination
- Consider an independent medical examination if the prescriber cannot provide adequate justification
- Assess work capacity impact as the combination significantly increases sedation and impairment risk
- Document all interventions for audit trail and compliance purposes
- Check Reasonable and Necessary status for both medications against the compensable injury
Clinical reference
A clinical summary of Amitriptyline and Diazepam drawn from regulator advisories, national guidelines, and authoritative drug references. Read this if you want the deeper clinical picture before talking to your prescriber or pharmacist.
Severity assessment
Moderate. The co-administration of amitriptyline and diazepam can lead to additive central nervous system (CNS) depression, increasing the risk of side effects such as profound sedation, dizziness, confusion, and impaired psychomotor function [1].
Mechanism (plain English)
Both amitriptyline and diazepam affect the central nervous system. Amitriptyline, a tricyclic antidepressant, works by increasing the levels of certain neurotransmitters like serotonin and norepinephrine in the brain, which can also lead to sedative effects. Diazepam, a benzodiazepine, enhances the effect of gamma-aminobutyric acid (GABA), a neurotransmitter that calms brain activity. When taken together, their combined depressant effects on the CNS are additive, meaning they intensify each other, leading to increased drowsiness, reduced alertness, and impaired coordination.
Evidence level
Regulator-flagged. The FDA labels for both diazepam and amitriptyline warn about concomitant use with other CNS depressants, highlighting the risk of additive effects [2] [3].
Top regulator advisories (cite verbatim or close paraphrase)
- TGA (Australia): No pair-specific public advisory found. However, product information for both drug classes generally advises caution with concomitant CNS depressants.
- MHRA / NICE (UK): No specific guidance for this exact pair found in initial searches. General guidance for benzodiazepines and tricyclic antidepressants would advise caution due to additive sedative effects.
- FDA / CDC (US): The FDA label for Diazepam (Valium) includes a warning regarding concomitant use with other CNS depressants, stating: "Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death." While amitriptyline is not an opioid, it is a CNS depressant, and the principle of additive effects applies [2]. The FDA label for Amitriptyline Hydrochloride also warns about CNS depressant effects and advises caution when used with other CNS depressants [3].
- EMA (Europe): No specific guidance for this exact pair found in initial searches. General European product information for both drug classes would recommend caution due to potential for additive CNS depression.
Clinical risk factors that elevate the danger
- Elderly patients: Increased sensitivity to CNS depressant effects, leading to a higher risk of falls, confusion, and cognitive impairment [1].
- Patients with respiratory conditions: Increased risk of respiratory depression due to additive CNS depressant effects.
- Patients with liver impairment: Reduced metabolism of both drugs can lead to higher drug levels and increased side effects.
- Concomitant use of other CNS depressants: Alcohol, opioids, antihistamines, or other sedatives will further enhance CNS depression.
- High doses of either medication: Higher doses increase the likelihood and severity of adverse effects.
- Rapid dose escalation: Not allowing the body to adjust to the medications can increase risk.
What a patient should be told
- Risk: Taking amitriptyline and diazepam together can make you very drowsy, dizzy, and confused, and can impair your ability to think clearly or react quickly. This can increase your risk of falls or accidents.
- Don't stop suddenly: Do not stop taking either medication suddenly without talking to your doctor or pharmacist, as this can lead to withdrawal symptoms or worsening of your condition.
- Warning signs: Be aware of signs of excessive sedation, such as extreme drowsiness, difficulty waking up, slow or shallow breathing, or unusual confusion. If you experience these, seek medical attention immediately.
- Safer alternatives: Discuss with your doctor or pharmacist if there are alternative treatments or ways to manage your conditions that might reduce the risk of this interaction.
- Urgent care: If you experience severe dizziness, extreme drowsiness, difficulty breathing, or feel like you might pass out, seek urgent medical care.
Top 3 sources (with full citation)
- Drugs.com. Amitriptyline + Diazepam: Can You Take Them Together? https://www.drugs.com/drug-interactions/amitriptyline-with-diazepam-168-0-862-0.html
- DailyMed. DIAZEPAM injection, solution. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c8e95ff5-c177-1ec3-e053-2995a90a6d78
- DailyMed. AMITRIPTYLINE HYDROCHLORIDE tablet, film coated. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1e6d2c80-fbc8-444e-bdd3-6a91fe1b95bd
Notes for the reviewing pharmacist
This interaction is primarily pharmacodynamic, involving additive CNS depression. While pharmacokinetic interactions between amitriptyline and diazepam are not prominently flagged in the reviewed sources, both drugs are metabolized by cytochrome P450 enzymes, suggesting a theoretical potential for altered metabolism if other interacting drugs are present or in individuals with genetic polymorphisms affecting these enzymes. However, the most immediate and clinically significant concern remains the additive CNS depressant effects. It is crucial to emphasize to patients the importance of avoiding alcohol and other sedatives while on this combination. Monitoring for excessive sedation and respiratory depression is paramount, especially in vulnerable populations like the elderly. The brief emphasizes consumer-relevant language and actionable advice, which should be reviewed for clarity and accuracy for the target audience.
Source metadata JSON
Sources used in this brief (3)
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Related Resources
Important: This page is general health information, not personal medical advice. If you have questions about your medication — including starting it, stopping it, changing the dose, or combining it with something else — speak with your doctor or pharmacist. For an emergency or suspected overdose, call your local emergency number or poison information service immediately. Information is drawn from regulator and clinical guideline sources (TGA, FDA, MHRA, NICE, PBS, CDC); see our methodology for details.