Major Contraindicated Medications
Certain drugs are strictly contraindicated for use with amitriptyline due to the high risk of severe and life-threatening reactions. These combinations must be completely avoided.
Monoamine Oxidase Inhibitors (MAOIs)
Combining amitriptyline with Monoamine Oxidase Inhibitors (MAOIs) is considered one of the most dangerous drug interactions. MAOIs are a class of antidepressants that include phenelzine (Nardil), tranylcypromine (Parnate), and isocarboxazid (Marplan). Using them together can cause serotonin syndrome, a condition characterized by high fever, extreme agitation, increased blood pressure, severe muscle rigidity, and even death. To switch between an MAOI and amitriptyline, a mandatory washout period of at least 14 days is required.
Sympathomimetic Agents (e.g., Epinephrine)
Amitriptyline can significantly potentiate the cardiovascular effects of direct-acting sympathomimetic agents like epinephrine (adrenaline). This can result in a hypertensive crisis, causing a severe increase in blood pressure, heart rate irregularities, and chest pain. Unless in an emergency setting with careful monitoring, this combination should be avoided.
Potentially Dangerous Drug Combinations
These combinations are not as strictly contraindicated as MAOIs, but they carry a high risk of adverse reactions and should generally be avoided or managed with extreme caution under a doctor's supervision.
Central Nervous System (CNS) Depressants
Amitriptyline itself is a CNS depressant, causing drowsiness and sedation. Combining it with other CNS depressants exponentially increases this effect, leading to excessive fatigue, impaired coordination, slowed breathing, memory blackouts, and potentially overdose. Common CNS depressants to avoid include:
- Alcohol: Significantly amplifies the sedative and impairment effects.
- Opioids: Pain medications like tramadol, hydrocodone, and oxycodone can increase sedation and the risk of respiratory depression.
- Benzodiazepines: Anti-anxiety medications like alprazolam (Xanax) and diazepam (Valium) have a compounding sedative effect.
- Sleep Medications: Prescription sleep aids such as zolpidem (Ambien) should be avoided due to severe drowsiness.
- Antihistamines: First-generation antihistamines like diphenhydramine (Benadryl) can add to the sedative and anticholinergic effects.
Other Serotonergic Drugs
Co-administering amitriptyline with other drugs that increase serotonin levels can increase the risk of serotonin syndrome. This is particularly relevant when combining with other antidepressants. For example, some SSRIs and SNRIs, like sertraline (Zoloft) and fluoxetine (Prozac), can significantly increase the concentration of amitriptyline in the body due to enzymatic inhibition. Other serotonergic drugs include triptans for migraines, lithium, and the herbal supplement St. John's wort.
Drugs Affecting Heart Rhythm (QT Prolongation)
Amitriptyline can prolong the QT interval on an electrocardiogram (ECG), which can lead to dangerous and chaotic heart rhythms. This risk is amplified when combined with other drugs known to affect heart rhythm. Examples include quinidine, pimozide, and certain antiarrhythmic drugs.
Medications That Affect Amitriptyline Metabolism
Amitriptyline is processed by liver enzymes, primarily CYP2D6 and CYP2C19. Some medications can interfere with this process, altering the level of amitriptyline in your bloodstream.
- Enzyme Inhibitors: Drugs that block these enzymes, such as certain SSRIs (e.g., fluoxetine, paroxetine) and cimetidine (Tagamet), can cause amitriptyline levels to rise, increasing the risk of side effects or toxicity.
- Enzyme Inducers: Conversely, medications that speed up these enzymes, like carbamazepine or St. John's Wort, can cause amitriptyline levels to drop, reducing its effectiveness.
Comparison Table of Common Amitriptyline Interactions
| Drug/Drug Class | Interaction Type | Primary Risk | Management & Comments |
|---|---|---|---|
| MAOIs (e.g., phenelzine, selegiline) | Potentially Fatal | Serotonin Syndrome | Contraindicated. Requires a 14-day washout period between medications. |
| CNS Depressants (e.g., alcohol, opioids, benzodiazepines) | Pharmacodynamic | Excessive Sedation, Respiratory Depression | Avoid combination; severe drowsiness and impaired coordination. |
| Other Serotonergic Drugs (e.g., SSRIs, SNRIs, Tramadol) | Pharmacodynamic | Serotonin Syndrome | Use with extreme caution; may require close monitoring or dose adjustment. |
| Drugs with QT Prolongation Risk (e.g., quinidine, pimozide) | Pharmacodynamic | Dangerous Arrhythmias | Avoid combination due to increased risk of heart rhythm problems. |
| Anticholinergic Drugs (e.g., diphenhydramine, certain antipsychotics) | Pharmacodynamic | Additive Side Effects (Dry mouth, urinary retention, confusion) | Use with caution, especially in older adults; worsens side effects. |
| CYP450 Inhibitors (e.g., fluoxetine, cimetidine) | Pharmacokinetic | Increased Amitriptyline Levels & Side Effects | May require a lower amitriptyline dose and close monitoring. |
| Bupropion (Wellbutrin) | Pharmacodynamic | Increased Seizure Risk | Use with caution, especially at higher doses. |
| Grapefruit Juice | Pharmacokinetic | Increased Amitriptyline Levels & Side Effects | Avoid consumption of grapefruit and its juice while taking amitriptyline. |
Anticholinergic and Other Important Interactions
Beyond the primary risk groups, several other interactions are crucial to be aware of.
Anticholinergic Effects
Amitriptyline has significant anticholinergic effects, causing side effects like dry mouth, constipation, and blurred vision. Combining it with other medications that also have these properties, such as certain antihistamines, antipsychotics, and medications for Parkinson's disease, can worsen these effects. This is a particular concern for older adults, who are more susceptible to the cognitive side effects of anticholinergic drugs, such as confusion and memory impairment.
Alcohol
As both a CNS depressant and a substance metabolized by the liver, alcohol consumption with amitriptyline can increase the risk of extreme sedation, impaired motor coordination, and a severe reaction affecting the heart. It can also interfere with amitriptyline's effectiveness in treating depression or pain. Healthcare professionals strongly advise avoiding alcohol entirely while taking amitriptyline.
Bupropion
Bupropion (Wellbutrin) is an antidepressant sometimes prescribed alongside other medications. However, it can lower the seizure threshold. Taking it with amitriptyline, which also carries a seizure risk at high doses, should be done cautiously, as it increases the overall risk of seizures.
Conclusion
Understanding what medications should not be taken with amitriptyline is essential for your health and safety. The list of potentially harmful interactions is extensive, ranging from other antidepressants like MAOIs and SSRIs to common substances like alcohol and certain over-the-counter medications. Always provide your healthcare provider and pharmacist with a complete list of all medications, supplements, and herbal products you use. Never adjust your dosage or stop taking a medication without professional guidance, as improper changes can lead to withdrawal symptoms or other severe consequences. Being proactive about potential drug interactions is the best way to ensure the safe and effective use of your treatment plan.
