Nortriptyline is indicated for use in the treatment of depression (FDA-approved). It can also be used off-label for conditions such as chronic pain, diabetic neuropathy, myofascial pain, orofacial pain, postherpetic neuralgia. Nortriptyline has also shown to be useful in patients trying to quit smoking. Nortriptyline is not FDA approved for use in children.[1][2][3][4]

Nortriptyline is an antidepressant that falls under the pharmacological category of tricyclics (secondary amine), more commonly known as TCAs.

It is the consensus that nortriptyline inhibits the reuptake of serotonin and norepinephrine by the presynaptic neuronal membrane, thereby increasing the concentration of those neurotransmitters in the synapse. Additionally, nortriptyline inhibits the activity of histamine, 5-hydroxytryptamine, and acetylcholine. Nortriptyline increases the pressor effect of norepinephrine but hinders the pressor response of phenethylamine. However, research has found additional receptor effects, including desensitization of adenylyl cyclase, down-regulation of beta-adrenergic receptors, and downregulation of serotonin receptors.

Nortriptyline is usually taken orally as a capsule or an oral solution. Capsule form comes in the following dosages 10 mg, 25 mg, 50 mg, 75 mg. The oral solution form is usually of the following composition 10 mg/5 mL (473 mL).

Nortriptyline has a black box warning for increased risk of suicide in adolescents, children, and young adults with major depressive disorder and multiple other psychiatric disorders.[5][6][7][8]

The most common adverse effects of nortriptyline include downiness, xerostomia, dizziness, constipation, blurred visions, palpitations, tachycardia, impaired coordination, increased appetite, nausea/vomiting, diaphoresis, weakness, disorientation, confusion, restlessness, insomnia, anxiety/agitation, urinary retention, urinary frequency, rash, urticaria, pruritus, weight gain, libido changes, impotence, gynecomastia, galactorrhea, tremor, hypo/hyperglycemia, paraesthesia, and photosensitivity.

The most serious adverse effects include orthostatic hypotension, HTN, syncope, ventricular arrhythmias, AV block, MI, stroke, seizures, EPS symptoms, ataxia, tardive dyskinesia paralytic ileus, glaucoma, increased IOP, agranulocytosis, leukopenia, thrombocytopenia, hallucinations, psychosis exacerbation, hypomania/mania, depression exacerbation, suicidality, serotonin syndrome, SIADH, hepatitis, angioedema, anticholinergic psychosis, hyperthermia, and heatstroke.

The hallmark side effect of tricyclic antidepressants, such as nortriptyline, is cardiotoxicity. In the case of TCA toxicity, fast cardiac sodium channels are inhibited, which can lead to cardiac arrhythmias. A widened QRS complex is often noted on electrocardiography.

A patient can also have withdrawal symptoms such as dizziness, gastrointestinal (GI) problems such as nausea and vomiting, anxiety, headaches, and restlessness if the patient discontinues nortriptyline abruptly. These withdrawal symptoms can be avoided by gradually decreasing the dose of nortriptyline over a period.

Drug Interactions

Concurrent usage of cimetidine and tricyclic antidepressants such as nortriptyline results in increased concentration of TCAs. Using nortriptyline, along with alcohol, can increase the effects of alcohol on patients. Cytochrome P450 2D6 metabolizes nortriptyline. All pharmacological drugs that inhibit 2D6 can produce an adverse reaction. Examples of major drug interactions that can result in inhibition of cytochrome P450 2D6 include quinidine and cimetidine.  Cimetidine increases bioavailability and decreases the clearance of this drug due to its inhibition of metabolic pathways of both demethylation and hydroxylation, as well as its ability to reduce hepatic extraction of nortriptyline. Other drugs are substrates for P450 2D6, such as other antidepressants, phenothiazines, and type-1C antiarrhythmics such as propafenone and flecainide.

Concurrent usage of nortriptyline with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either nortriptyline or the other medication.

Many patients who are prescribed nortriptyline may already be taking SSRIs such as fluoxetine. If the benefit of switching from fluoxetine to nortriptyline is higher than the risk, the clinician should consider that fluoxetine has an active metabolite, norfluoxetine, with a long half-life. The risk of adverse effects and interactions may be high for several weeks after discontinuation of fluoxetine. Therefore, usage of nortriptyline with SSRIs like fluoxetine can result in an increased risk for serotonin syndrome. Fluoxetine should be discontinued for up to six weeks before starting another medication that inhibits serotonin reuptake.[9] If serotonin syndrome were to occur, the antidote of cyproheptadine should be administered. Cyproheptadine is a 5-HT1A, 5-HT2A, and H1 receptor antagonist.

Tricyclic antidepressants use along with a monoamine oxidase (MAO) inhibitor, linezolid, and IV methylene blue is contraindicated as it can lead to an increased risk of developing serotonin syndrome. Serotonin syndrome can be life-threatening as it can cause a change in mental status, autonomic instability, neuromuscular changes, seizures, and gastrointestinal symptoms. More importantly, concurrent use of both medications can cause convulsions, hyper-pyretic crises, and death. The patient must discontinue MAO inhibitors for at least 14 days before starting nortriptyline.

If nortriptyline must be used alongside serotonergic drugs such as triptans, other TCAs, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John’s Wort, the benefits must outweigh the risks.

Postmarketing reports have shown a possible association between nortriptyline and the unmasking of Brugada syndrome. For this reason, the patient’s with Brugada syndrome or suspected for it should generally avoid nortriptyline as it can result in ECG abnormalities, syncope, and even sudden cardiac death.

Nortriptyline can cause pupillary dilation, which can result in an angle-closure attack in an individual with anatomically narrow angles.

The use of nortriptyline is also contraindicated in patients with hypersensitivity to nortriptyline or its components. Cross-sensitivity between nortriptyline hydrochloride and other dibenzazepines is a possibility.

Finally, nortriptyline is contraindicated during the acute recovery period after myocardial infarction.