Continuing Education Activity

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, and postherpetic neuralgia. Nortriptyline has also shown to be useful in patients trying to quit smoking. Nortriptyline is not FDA approved for use in children. This activity covers nortryptyline's indications, mechanism of action, pharmacology, administration, adverse event profiles, eligible patient populations, contraindications, and monitoring, and highlights the role of the interprofessional team in the management of depression and other diseases with nortriptyline therapy.

Objectives:

• Outline the mechanism of action of nortriptyline.
• Review the indications for using nortriptyline.
• Summarize the potential adverse effects associated with nortriptyline therapy.
• Describe the importance of improving care coordination among the interprofessional team to enhance the delivery of care for patients who can benefit from therapy with nortriptyline.

Indications

Nortriptyline is indicated for use in the treatment of depression (FDA-approved). Nortriptyline is not FDA approved for use in children.

Nortriptyline can also be used for the following off-label indications:

• Chronic pain[1] 
• Diabetic neuropathy[2]
• Persistent myofascial pain[3]
• Trigeminal neuralgia[4]
• Postherpetic neuralgia[5]
• Smoking cessation[6]
• Migraine prophylaxis[7]
• Neurogenic cough[8]

Mechanism of Action

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

The proposed mechanism of nortryptyline in neuropathic pain is an increase in noradrenaline levels acting within dorsal root ganglia on β2-adrenoceptors expressed by non-neuronal satellite cells. This stimulation of β2-adrenoreceptors reduces the neuropathy-induced production of TNFα, resulting in the relief of neuropathic pain.[9] Nortriptyline's mechanism in smoking cessation is unclear, but the possible action may involve simulating the noradrenergic actions of nicotine.[10] A recent study suggests that nortriptyline can be used as a new antimicrobial drug against multidrug-resistant Candida Albicans infection by inhibiting biofilm and ability to kill cells in a mature biofilm efficiently; however, more research is needed.[11]

Pharmacokinetics

• Absorption: Peak plasma concentrations are 7 to 8.5 hours after oral administration, although antidepressant action is obtained after a few weeks.[12]
• Distribution: Nortriptyline is distributed to the brain, heart, and liver. Nortriptyline and its metabolite are highly bound to plasma and tissue proteins. Nortriptyline crosses the placenta, and nortriptyline is present in breast milk.[13]
• Metabolism: Nortriptyline, when administered orally, undergoes first-pass metabolism in the liver by CYP2D6.[14]
• Excretion: The primary route of elimination is urinary excretion, approximately one-third of the dose as metabolites within 24 hours, but it is also excreted in feces via the bile.

Administration

Nortriptyline is usually taken orally as a capsule or an oral solution. Capsule form comes in 10 mg, 25 mg, 50 mg, and 75 mg strengths. The oral solution form is usually of the following composition 10 mg/5 mL (473 mL). The usual adult dose is 25 mg three or four times daily; it should begin at a low level and increase as needed. As an alternate regimen, the total daily dosage can be given once daily. When doses higher than 100 mg daily are administered, plasma levels of nortriptyline should be monitored. Doses higher than 150 mg daily are not recommended.

Use in Specific Patient Population

• Patients with Hepatic impairment: No information has been provided in the manufacturer's product labeling. However, caution and dose reduction are advised in patients with hepatic impairment, given the drug's primary metabolism is by liver enzymes.[14]

• Patients with Renal impairment: No information has been provided in the manufacturer's product labeling. 

• Pregnancy Considerations: According to product labeling, preclinical studies during pregnancy have been inconclusive. Safe use of nortriptyline during pregnancy has not been established; therefore, when the drug is administered to pregnant patients or women of childbearing potential, clinicians must weigh the potential benefits against the possible hazard.
• Breastfeeding Considerations: According to product labeling, the safe use of nortriptyline during lactation has not been established. However, nortriptyline's concentration in breastmilk is low. Consequently, amounts ingested by the infant are small. However, the less active metabolites are often detectable in low levels in infant serum. Many reviewers consider nortriptyline preferred TCA during breastfeeding; however, drugs that have a better safety profile during lactation are paroxetine and sertraline.[13]

• Pharmacogenomic considerations:  Advancement in the field of pharmacogenomics can be used to deliver effective patient-centered by individualized drug therapy regimens.[15]
  • In CYP2D6 ultrarapid metabolizer, clinicians should avoid nortriptyline use due to potential lack of efficacy and consider alternative drugs not metabolized by CYP2D6.
  • In patients who are CYP2D6 poor metabolizers avoid nortriptyline use due to the potential for adverse drug reactions. Clinicians can consider alternative drugs not metabolized by CYP2D6. Consider a 50% reduction of the recommended starting dose if a TCA is warranted.[14]

Adverse Effects

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.[16]

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.[17]

The most serious adverse effects include orthostatic hypotension, HTN, syncope, ventricular arrhythmias, AV block, MI, stroke, paralytic ileus, glaucoma, increased IOP, agranulocytosis, leukopenia, thrombocytopenia, hepatitis, angioedema.[18][19]

Neuropsychiatric adverse drug reactions include EPS symptoms, ataxia, tardive dyskinesia, hallucinations, psychosis exacerbation, hypomania/mania, exacerbation of depression, suicidality, serotonin syndrome, SIADH, hyperthermia, and seizures.[20][21][22]

Cardiotoxicity is the hallmark adverse drug reaction of tricyclic antidepressants, such as nortriptyline. In the case of TCA toxicity, fast cardiac sodium channels are inhibited, which can lead to cardiac arrhythmias. On electrocardiography. A widened QRS complex is often noted.[23]

A patient can also have withdrawal symptoms such as dizziness, gastrointestinal problems such as nausea and vomiting, anxiety, headaches, and restlessness if the patient discontinues nortriptyline abruptly. Clinicians can avoid these withdrawal symptoms by gradually decreasing the dose of nortriptyline over a period.[24]

Drug Interactions

Clinicians should avoid concurrent usage of cimetidine and tricyclic antidepressants such as nortriptyline as the drug interaction can increase the 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. Significant drug interactions that can inhibit 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 CYP2D6, such as other antidepressants, phenothiazines, and type-1C antiarrhythmics such as propafenone and flecainide.[25][26]

Concurrent usage of nortriptyline with drugs that can inhibit cytochrome CYP2D6 may require lower doses than usually prescribed for either nortriptyline or the other medication.

Many patients 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 discontinuing fluoxetine. Therefore, usage of nortriptyline with SSRIs like fluoxetine can increase the risk for serotonin syndrome. Fluoxetine should be discontinued for up to six weeks before starting another medication that inhibits serotonin reuptake. If serotonin syndrome occurs, clinicians should promptly administer an antidote, i.e., cyproheptadine. Cyproheptadine is a 5-HT1A, 5-HT2A, and H1 receptor antagonist.[27]

Contraindications

Tricyclic antidepressants use along with a monoamine oxidase (MAO) inhibitor, linezolid, and IV methylene blue is contraindicated as they 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.[28] 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, patients with confirmed or suspected Brugada syndrome should avoid nortriptyline as it can result in EKG abnormalities, syncope, and even sudden cardiac death.[29] Nortriptyline can cause pupillary dilation, potentially resulting in an angle-closure attack in an individual with anatomically narrow angles. Finally, nortriptyline is contraindicated during the acute recovery period after myocardial infarction. 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.

Monitoring

As an antidepressant, the therapeutic range for nortriptyline is between 50 to 150 ng/mL (190 to 570 nmol/L). According to APA guidelines, patients using nortriptyline need monitoring for suicidal ideation, especially at the start of therapy and when making dosage changes. Clinicians should frequently monitor cardiac parameters such as heart rate, EKG, and blood pressure in adults who already have existing cardiac disease and elderly patients.[28]

Monitor for improvement/worsening of depression using questionnaires such as PHQ-9 (Patient Health Questionnaire-9), which are patient-reported outcomes[30], and the Montgomery-Asberg Depression Rating Scale (MADRS), which is based on clinical judgment.[31] Integration of clinical decision support tools (CDS tools) in EHR can improve the administration of questionnaires and management of depression.[32]

Toxicity

Like many other TCAs, the toxicity of nortriptyline can be very harmful to the body. During an overdose, there is a blockade of the following receptors: sodium channels (fast) in the heart, muscarinic Ach receptors (central and peripheral), alpha-1 receptors in the periphery, and H1 and GABA-A in the central nervous system. Therefore, the most crucial initial step when assessing a patient with toxicity is ensuring the patient can adequately breathe. Intubation is usually mandatory for airway protection and proper ventilation. In addition, the clinician can administer IV fluids for hypotension.

Additionally, sodium bicarbonate is the recommended treatment for patients with prolonged QRS (greater than 100 milliseconds) or ventricular arrhythmia. The sodium bicarbonate dosage depends on the patient's weight, usually 1 to 2 mEq/kg. Arrhythmias not responding to sodium bicarbonate therapy may need lidocaine, phenytoin, or bretylium. TCAs can also cause seizures. These can have treatment with benzodiazepines such as lorazepam 2 mg or diazepam 5 mg, administered through the intravenous (IV) route. Treatment with activated charcoal for gastrointestinal decontamination is only indicated in patients who present within 2 hours of overdose (1 g/kg). Although there is a strong blockage of muscarinic acetylcholine receptors, physostigmine is contraindicated in the event of TCA toxicity as it can cause adverse cardiac effects such as cardiac arrest.[28] The principles of management of pediatric overdose are similar. However, It is recommended that the clinician contact the local poison control center for specific pediatric treatment.

Enhancing Healthcare Team Outcomes

Interprofessional healthcare team members, including clinicians, psychiatrists, nurse practitioners and physician assistants, nurses, and pharmacists, should be aware that nortriptyline is no longer a first-line choice for its indicated conditions. There are many better and safer antidepressants on the market. The drug has many side effects, which are often not well tolerated.[33] 

However, when a patient is taking nortriptyline, all interprofessional team members should contribute from their individual disciplines to ensure proper dosing, the absence of drug-drug interactions, and participate in patient monitoring and education, to drive optimal outcomes with minimal adverse events. Every team member is responsible for monitoring and counseling the patient and must be alert for signs of therapeutic failure, possible drug interactions, or adverse events, including toxicity. If they note an issue with the patient, they should report these to the other team members and document their observations in the patient's medical record. A randomized controlled trial aimed at the clinical effectiveness of collaborative care in managing patients with moderate to severe depression showed optimistic results. Coordinated care between health care providers had continued promising results up to one year after initiation of the depression treatment and was preferred by patients.[34] [Level 2]