Nortriptyline is a tricyclic antidepressant (TCA) used to treat symptoms of depression and, off-label, for conditions like neuropathic pain [1.2.5, 1.5.3]. It works by affecting the balance of neurotransmitters in the brain, primarily norepinephrine and serotonin [1.4.5]. Due to its mechanism of action, nortriptyline can interact with numerous other medications, leading to potentially severe health consequences. Before starting this medication, it is vital to disclose all current medications, including over-the-counter drugs and herbal supplements, to your healthcare provider [1.2.1].
Critical Drug Interactions: The 'Do Not Take' List
Certain medications are strictly contraindicated with nortriptyline due to the high risk of severe, life-threatening reactions. It is essential to be aware of these combinations.
Monoamine Oxidase Inhibitors (MAOIs)
The most dangerous interaction is between nortriptyline and Monoamine Oxidase Inhibitors (MAOIs) [1.3.2]. Combining these can lead to hyperpyretic crises (extremely high body temperature), severe convulsions, dangerously high blood pressure, and even death [1.3.1, 1.3.2].
There must be a mandatory washout period when switching between these medications. At least 14 days should pass between stopping an MAOI and starting nortriptyline, and vice versa [1.3.5]. Examples of MAOIs include:
- Isocarboxazid (Marplan) [1.3.6]
- Phenelzine (Nardil) [1.3.6]
- Tranylcypromine (Parnate) [1.3.6]
- Linezolid (Zyvox), an antibiotic with MAOI properties [1.3.5]
- Methylene Blue (intravenous) [1.3.5]
Serotonergic Drugs (SSRIs, SNRIs, and others)
Taking nortriptyline with other drugs that increase serotonin levels can lead to a potentially fatal condition called serotonin syndrome [1.3.6]. This condition results from an excess of serotonin in the brain [1.4.3]. Symptoms include agitation, hallucinations, fever, sweating, shivering, rapid heart rate, muscle stiffness, and loss of coordination [1.3.6].
Drugs that increase this risk include:
- Selective Serotonin Reuptake Inhibitors (SSRIs): fluoxetine, sertraline, citalopram [1.2.5]. Some SSRIs also inhibit the enzyme (CYP2D6) that metabolizes nortriptyline, increasing its levels in the blood and elevating toxicity risk [1.4.2, 1.4.5].
- Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs): duloxetine, venlafaxine [1.3.4].
- Triptans (migraine medications): sumatriptan, rizatriptan [1.2.2].
- Opioid Pain Relievers: tramadol, fentanyl [1.3.1].
- Herbal Supplements: St. John's Wort [1.2.3].
QT Prolonging Drugs
Nortriptyline itself can affect heart rhythms by prolonging the QT interval, which can lead to a dangerous arrhythmia called Torsades de Pointes [1.7.1, 1.7.2]. Combining it with other drugs that have the same effect significantly increases this risk. Examples of such drugs include:
- Certain antiarrhythmics (quinidine, sotalol) [1.2.2]
- Some antipsychotics (thioridazine, ziprasidone) [1.2.2, 1.6.3]
- Specific antibiotics (grepafloxacin) [1.2.1]
- Dronedarone [1.2.2]
Anticholinergic Medications
Nortriptyline has strong anticholinergic properties [1.6.1]. When taken with other anticholinergic drugs, these effects become additive and can cause severe discomfort or complications, especially in older adults [1.6.2, 1.6.6]. Symptoms include severe dry mouth, blurred vision, constipation, urinary retention, confusion, and delirium [1.4.3, 1.6.1].
Common anticholinergics to be cautious with include:
- Over-the-counter antihistamines like diphenhydramine (Benadryl) [1.2.1]
- Medications for overactive bladder (oxybutynin, tolterodine) [1.2.2]
- Certain medications for Parkinson's disease (benztropine) [1.2.2]
Comparison Table of Major Interactions
| Drug Class | Mechanism of Interaction | Potential Outcome |
|---|---|---|
| MAOIs | Extreme increase in norepinephrine and serotonin | Hypertensive crisis, serotonin syndrome, convulsions, death [1.3.1, 1.3.2] |
| SSRIs/SNRIs | Additive serotonergic effects; metabolic inhibition | Serotonin syndrome, increased nortriptyline toxicity [1.4.2, 1.4.5] |
| QT Prolonging Agents | Additive effect on heart's electrical cycle | Increased risk of severe cardiac arrhythmias (Torsades de Pointes) [1.7.1] |
| Anticholinergics | Cumulative blockage of acetylcholine | Severe dry mouth, constipation, urinary retention, confusion, delirium [1.6.1, 1.6.2] |
| CNS Depressants | Additive sedative effects | Extreme drowsiness, respiratory depression, impaired coordination [1.2.1, 1.8.2] |
Medications Requiring Caution and Dose Adjustment
Some medications don't require an absolute stop but necessitate close monitoring and potential dose changes by a doctor.
- Central Nervous System (CNS) Depressants: This includes alcohol, benzodiazepines (e.g., Xanax), sleeping pills, and opioids. Combining them with nortriptyline can lead to excessive drowsiness, impaired coordination, and respiratory depression [1.2.1, 1.8.1]. Alcohol should be avoided [1.8.4].
- Blood Pressure Medications: Nortriptyline can counteract the effects of certain antihypertensives like clonidine and guanethidine [1.9.2]. It can also have additive blood pressure-lowering effects with other agents like lisinopril or amlodipine, causing dizziness and fainting [1.9.1, 1.9.3].
- Cimetidine (Tagamet): This medication for stomach ulcers can inhibit the metabolism of nortriptyline, leading to increased levels and a higher risk of side effects [1.2.3].
Conclusion
Navigating the drug interactions of nortriptyline is critical for safety and treatment success. The absolute contraindication with MAOIs is the most serious warning, requiring a strict 14-day separation [1.3.5]. Significant risks also exist with a wide range of serotonergic drugs, QT-prolonging agents, and medications with anticholinergic or CNS depressant effects. Always maintain open communication with your healthcare provider about every medication and supplement you are taking to prevent harmful interactions and ensure your treatment plan is both safe and effective.
Authoritative Link: For more detailed information, you can visit the Nortriptyline page on MedlinePlus, a service of the National Library of Medicine.
