Continuing Education Activity

Amitriptyline is FDA approved medication to treat depression in adults. The Non-FDA approved indications are anxiety, post-traumatic stress disorder, insomnia, chronic pain (diabetic neuropathy, fibromyalgia), irritable bowel syndrome, interstitial cystitis (bladder pain syndrome), migraine prophylaxis, postherpetic neuralgia, and sialorrhea. This activity reviews the indications, contraindications, activity, adverse events, and other key elements of amitryptiline in the clinical setting as relates to the essential points needed by members of an interprofessional team managing the care of patients that can benefit from amitriptyline therapy.

Objectives:

• Identify the mechanism of action of amitriptyline.
• Describe approved and off-label indications, as well as contraindications for amitriptyline.
• Review the appropriate monitoring of amitriptyline.
• Outline interprofessional team strategies for improving care coordination and communication to advance the use of amitriptyline and improve outcomes.

Indications

Amitriptyline is FDA approved medication to treat depression in adults.[1]

The non-FDA approved indications are anxiety, post-traumatic stress disorder, insomnia, chronic pain (diabetic neuropathy, fibromyalgia), irritable bowel syndrome, interstitial cystitis (bladder pain syndrome), migraine prophylaxis, postherpetic neuralgia, and sialorrhea.[2]

Mechanism of Action

Amitriptyline is in the tricyclic antidepressant (TCA) drug classification and acts by blocking the reuptake of both serotonin and norepinephrine neurotransmitters. The three-ring central structure, along with a side chain, is the basic structure of tricyclic antidepressants. Amitriptyline is a tertiary amine and has strong binding affinities for alpha-adrenergic, histamine (H1), and muscarinic (M1) receptors.[3] It is more sedating and has increased anticholinergic properties compared to other TCAs. 

Like other antidepressants, the onset of therapeutic action typically begins at approximately 2 to 4 weeks. 

Administration

Amitriptyline administration comes in various forms, the most common being oral form. The initial dose recommended for depression is 25 mg/day at bedtime, as it can be sedating. For off-label use such as for chronic pain, therapy can initiate at a much lower dose of 10 to 20 mg/day. It can be increased by 25 mg every 3 to 7 days, with a maximum of 150 to 300 mg/day. If the dose needs to be adjusted, it is preferable to change the dose at bedtime. Once the patient is stable, amitriptyline should be continued for three months or longer to prevent relapse of depression. In cases of therapy cessation, the clinician should gradually taper to avoid withdrawal.

Amitriptyline is not FDA approved for pediatric depression. The recommendation is to start with a lower dosage (around 10 mg/day) in the pediatric and geriatric population.

Its half-life is 10 to 28 hours, and it gets metabolized to nortriptyline. Its metabolism is primarily by CYP3A4 and CYP2C19.[4] 

Amitriptyline administration can also via the intramuscular route (peak concentration occurs within 2 to 12 hours of administration), and an intravenous route is another one.[5] 

Adverse Effects

The most commonly encountered side effects of amitriptyline include weight gain, gastrointestinal symptoms like constipation, xerostomia, dizziness, headache, and somnolence.

The following is a list of other adverse effects including serious side effects of amitriptyline:

1. Secondary to its alpha-adrenergic receptor blockade, it can cause orthostatic hypotension, dizziness, and sedation.  It can also cause heart rate variability, slow intracardiac conduction, induce various arrhythmias, and cause QTc (corrected QT) prolongation.[6]

2. Anticholinergic side effects include blurred vision, dry mouth, urinary retention, tachycardia, acute angle glaucoma, confusion, and delirium.[6]

3. Antihistamine side effects secondary to its H1 receptor binding property include sedation, increased appetite, weight gain, confusion, and delirium. 

4. Amitriptyline can lower the seizure threshold, and it should be used cautiously in patients with a history of seizure disorder.[7] Its seizure threshold reducing effect is dose-dependent, seizure rate is 1 to 4% at doses of 250 to 450 mg/day.

5. It is known to cause abnormalities in liver function tests in 10 to 20% of patients. It is uncommon for the liver function test to be over three times the upper limit of normal. Usually, the effect on the liver is mild, asymptomatic, transient, and reverses with discontinuation. It rarely causes acute liver injury.[8]

6. It can also cause impaired arousal, the risk of bone fracture, tremor, and (rare) bone marrow suppression.[9] 

7. In adolescents and young adults (ages less than 24 years), it can increase the risk of suicidal ideation and behavior (rarely). The risk is very low, but the patient and families require education regarding these risks. 

8. As an antidepressant, amitriptyline can rarely induce mania. Some of the risk factors that can predict amitriptyline inducing mania are a history of bipolar disorder, family history of mania, pharmacologically induced hypomania.

Contraindications

Contraindication considerations are one of the most critical aspects while administering a drug to a patient. The following are significant considerations for amitriptyline:

1. Hypersensitivity reactions are an essential consideration. Amitriptyline is contraindicated in patients with hypersensitivity to the drug or any of its dosage form inactive ingredients.

2. Amitriptyline should not be used if there is a history of QTc prolongation, arrhythmias, recent myocardial infarction, or heart failure. 

3. Its use requires caution in patients with angle-closure glaucoma, urinary retention, seizures.[10]

4. Do not use with MAOI (monoamine oxidase inhibitors) and also within 14 days use of MAOIs. 

5. It is essential to keep into account various drug-drug interactions. Considering amitriptyline causes QTc prolongation, the use of other drugs that prolong QTc can lead to cardiac problems, including arrhythmias. The following medications can increase QTc- astemizole, cisapride, disopyramide, ibutilide, indapamide, pentamidine, pimozide, procainamide, quinidine, sotalol, terfenadine.

6. Some drugs, when used along with amitriptyline, may cause an increase in serotonin concentrations, such drugs include isocarboxazid, phenelzine, procarbazine, safinamide, selegiline, tranylcypromine. These drugs can cause serotonin syndrome. 

7. Amitriptyline gets metabolized from CYP3A4. Several drugs alter the activity of CYP3A4, and thus dose should be cautiously regulated, as well as the entire patient medication regimen checked for CYP3A4 inducers and inhibitors. 

8. Lower doses are advisable in renal and hepatic impairment. 

9. Before elective surgery, the recommendation is to discontinue amitriptyline because of its possible interaction with anesthesia and as it may increase the risk of arrhythmia.[11]

Monitoring

In patients with a history of cardiac problems or patients over 50 years of age should have a baseline electrocardiogram. 

Considering the drug's side effect profile, the following parameters require monitoring - BMI, liver function test, thyroid function test, and serum amitriptyline concentrations.[10][11] 

While a patient is on amitriptyline, one should monitor for an increase in suicidality and unusual behavior changes, especially during the first 1 to 2 months of starting medication or during periods of dosage adjustment. 

Toxicity

Amitriptyline toxicity is measurable by a dose of over 5 mg/kg. The clinical features of amitriptyline toxicity include:

1. Neurological symptoms include sedation, seizure, coma.

2. Cardiac symptoms include tachycardia, hypotension, conduction abnormalities include QTc prolongation.

3. Anticholinergic symptoms include dilated pupils, dry mouth, decreased (or absent) bowel sounds, urinary retention.

Amitriptyline toxicity can be serious and even fatal. In treating the toxicity, it is imperative to stabilize the patient, and the patient may need admission to the ICU for monitoring. The most important steps include - protecting the airways, breathing, and stabilizing circulation. Some patients may need tracheal intubation; if required, administer supplemental oxygen. If the patient is hypotensive, an IV bolus of isotonic crystalloid is a therapeutic option. If the patient remains hypotensive despite fluid resuscitation, vasopressors are the next choice. If QRS exceeds 100 msec, intravenous sodium bicarbonate is the appropriate intervention as it is cardioprotective (it increases extracellular sodium concentration) and diminishes the effect of amitriptyline on the cardiac membrane, which results in less blockage of the sodium channel.[12][13]) Activated charcoal can also be given within two hours of amitriptyline oral ingestion to prevent gastrointestinal absorption.[14] Seizures secondary to overdose are treatable with diazepam or lorazepam.

Enhancing Healthcare Team Outcomes

Amitriptyline is a tricyclic antidepressant that is FDA approved to treat depression in adults. It is also used off label to treat chronic pain syndrome, anxiety, and insomnia. It has a considerable side effect profile and is no longer commonly used as a first-line agent to treat depression. It may be useful for patients who have insomnia, severe depression, treatment-resistant depression, and patients with comorbid chronic pain syndromes. Patients on amitriptyline can have anticholinergic, antihistaminic, and alpha-adrenergic blocking effects. It may not be appropriate for patients with cardiac problems. It has many potential drug interactions, which can increase the risk of arrhythmias and serotonin syndrome. Toxicity can be life-threatening, and patients will need to be stabilized and monitored closely. Providers also need to know the increased risk of suicidality in children, adolescents, and young adults, which will require discussion with families.[15]

When a clinician determines to start a patient on amitriptyline, they should consult a pharmacist to verify the absence of drug-drug interactions, which in the case of amitriptyline, can be significant. Nursing can provide medication counseling, evaluate patient adherence, and monitor for side effects on follow-up visits. If the nurse has any concerns, they should be reported to the clinician promptly. While amitriptyline is not a common therapeutic choice any longer, when necessary, it can be effective if the interprofessional team collaborates in therapeutic decisions, the patient can achieve an optimal outcome with minimal adverse events. [Level V]