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 related 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 FDA-approved and off-label indications of amitriptyline.
• Review the appropriate adverse drug reactions of amitriptyline.
• Outline interprofessional team strategies for improving patient outcomes.

Indications

Amitriptyline is FDA approved medication to treat major depressive disorder (MDD) 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 with strong binding affinities for alpha-adrenergic, histamine (H1), and muscarinic (M1) receptors.[3] 

Amitriptyline increases noradrenergic or serotonergic neurotransmission by blocking the norepinephrine or serotonin transporter (NET or SERT) at presynaptic terminals. Chronic treatment with amitriptyline desensitizes presynaptic autoreceptors and heteroreceptors, producing long-lasting changes in monoaminergic neurotransmission.[4] 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.

There have been comprehensive studies of brain-derived neurotrophic factor (BDNF), a major neurotrophic factor that plays an essential role in the formation and survival of neurons during development and synaptic plasticity. The neurotrophic hypothesis of depression suggests that stress-related alterations in BDNF levels occur in key limbic structures to contribute to the pathogenic processes in major depressive disorder(MDD). Chronic treatment with antidepressants increases the BDNF levels, which improves the symptoms associated with MDD.[5]

Pharmacokinetics

Amitriptyline has a half-life of 10 to 28 hours, and it gets metabolized to nortriptyline. Its metabolism is primarily by CYP3A4 and CYP2C19.[6] Amitriptyline can be administered by the intramuscular route (peak concentration occurs within 2 to 12 hours of administration) and an intravenous route.[7] Administer amitriptyline at night time, as it can lead to sedation.[8]

Administration

Dosage Formulations: Amitriptyline dosage formulations come in oral tablets of 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, and 150 mg.

Adult Dosing: The initial dose recommended for depression is 25 mg per day at bedtime. For off-label use, such as chronic pain, therapy can initiate a much lower dose of 10 to 20 mg per 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 bedtime dose. In cases of therapy cessation, the clinician should gradually taper to avoid withdrawal.[9]

Maintenance Dose: Amitriptyline maintenance dose is usually 50-100 mg daily, and it can be given in a single dose, preferably at bedtime. When satisfactory improvement is achieved, the dose should be reduced to the lowest amount to maintain relief of symptoms. Once the patient is stable, amitriptyline should be continued for three months or longer to prevent depression. 

Plasma Levels: Because of the wide difference in the absorption and distribution of amitriptyline in body fluids, it is difficult to correlate plasma levels and therapeutic effects directly. However, determining plasma levels might be useful in identifying patients with toxic effects who might have excessively high levels or in whom and/or noncompliance is suspected. Elderly patients have decreased hepatic metabolism and increased intestinal transit time, so plasma levels are usually higher for any given oral dose of amitriptyline than in younger patients. Monitor elderly patients carefully, and obtain quantitative amitriptyline serum levels as clinically indicated. Clinicians should adjust amitriptyline dose according to the patient’s clinical response and not based on plasma levels.[10]

Specific Patient Population

Pregnancy Considerations: Amitriptyline is Pregnancy Category C medicine, and it can cross the placenta. There is no causal relationship, but a few reports of adverse reactions, including limb deformities, developmental delay, and CNS effects in infants whose mothers had used amitriptyline during pregnancy. There is a lack of well-controlled clinical studies on pregnant women. Amitriptyline should be used in pregnancy only if the potential benefit to her than the risk to the mother and fetus. American College of Obstetricians (ACOG) and the American Psychiatry Association (APA) have created treatment algorithms for periconceptional and antenatal management.[11][12]

Breastfeeding Considerations: Amitriptyline can pass into breast milk. Maternal exposure to amitriptyline would usually not cause any adverse reactions in breastfed infants, especially infants older than two months. A safety scoring system finds amitriptyline use possible with caution while breastfeeding.[13] However, rare sedation is reported in neonates. Therefore, other medicines with fewer active metabolites should be preferred when large amitriptyline doses are required or nursing a preterm infant or a newborn.  

Pediatric Patients: Because of the lack of experience using this drug in pediatric patients, it should not be recommended for patients under 12 years.

Adolescent and Geriatric Patients: In general, start at lower dosages for these patients. The recommendation is to start with a lower dosage (around 10 mg/day) in the geriatric population.[14] The maintenance dose can be divided, i.e., 10 mg three times a day with 20 mg at bedtime who do not tolerate higher dosages.

Patients with Renal Impairment: There is no information provided by the manufacturer, and in mild to moderate impairment, no dose adjustments are needed.[15]

Patients with Hepatic Impairment: Amitriptyline hydrochloride should be used with caution in patients with impaired liver function.

Hospitalized Patients: They may require 100 mg a day initially, which can be increased gradually to 200 mg a day if needed.

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 adverse drug reactions of amitriptyline:

• Amitriptyline, due to its alpha-adrenergic receptor blockade, 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.
• Anticholinergic side effects include blurred vision, dry mouth, urinary retention, tachycardia, acute angle glaucoma, confusion, and delirium.[16]
• Antihistamine side effects secondary to its histamine(H1) receptor binding property include sedation, increased appetite, weight gain, confusion, and delirium.[17]
• Amitriptyline can decrease the seizure threshold in a dose-dependent manner; therefore, caution is required in patients with a seizure disorder. Seizure rate is 1 to 4% at 250 to 450 mg/day doses.[18] 
• Abnormalities in liver function tests. Usually, the effect on the liver is mild, asymptomatic, transient, and reverses with discontinuation. Liver function tests are usually under three times the upper limit of normal It rarely causes acute liver injury.[19]       
• It can increase the risk of bone fracture and (rare) bone marrow suppression.[20] 
• Amitriptyline gets metabolized through CYP3A4. Several drugs alter the activity of CYP3A4, and thus dose should be cautiously regulated, and the entire patient medication regimen should be checked for CYP3A4 inducers and inhibitors. 
• Black box warning - The FDA has issued a black box warning regarding the use of amitriptyline in adolescents and young adults (ages less than 24 years). It can increase the risk of suicidal ideation and behavior.[21]
• As an antidepressant, amitriptyline can rarely induce mania. Risk factors are a history of bipolar disorder, family history of mania, pharmacologically induced hypomania.[22]

Contraindications

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

• Hypersensitivity reactions: Amitriptyline is contraindicated in patients with hypersensitivity to the drug or inactive ingredients of the dosage form per FDA product labeling. 
• Amitriptyline should not be used if there is a history of QTc prolongation, arrhythmias, recent myocardial infarction, or heart failure, as per the FDA product labeling. Amitriptyline toxicity may cause acute myocardial infarction.[23]
• Its use requires caution in patients with angle-closure glaucoma, urinary retention, seizures.[24]
• Do not use monoamine oxidase inhibitors(MAOI) within 14 days of use of MAOIs.[25]
• Avoid using amitryptiline with the drugs that can increase QTc, such as astemizole, cisapride, disopyramide, ibutilide, indapamide, pentamidine, pimozide, procainamide, quinidine, sotalol, terfenadine which can lead to cardiac problems, including arrhythmias[26]
• When used along with amitriptyline, some drugs may cause an increase in serotonin concentrations; such drugs include isocarboxazid, phenelzine, procarbazine, safinamide, selegiline, tranylcypromine, sertraline. These drugs can cause serotonin syndrome.[27][28]
• Lower doses are advisable for renal and hepatic impairment.[29]
• Discontinue amitriptyline before elective surgery, considering possible interaction with anesthetic agents and increased risk of arrhythmia.[30]

Monitoring

Patients with a history of cardiac problems or over 50 years of age should have a baseline electrocardiogram to get the value of baseline QTc.[31] 

Considering the drug's side effect profile, the following parameters require monitoring - Body Mass Index, liver function test, thyroid function test, and serum amitriptyline concentrations.[24] 

While a patient is on amitriptyline, one should monitor for increased suicidality and unusual behavior changes, especially during the first 1 to 2 months of starting medication or during periods of dosage adjustment.[32]

Toxicity

Amitriptyline toxicity is measurable by a dose of over 5 mg/kg. The clinical symptoms of amitriptyline toxicity include neurological, cardiac, and anticholinergic adverse reactions. Neurological symptoms include sedation, seizure, and coma. Cardiac symptoms include tachycardia, hypotension, and conduction abnormalities, including QTc prolongation. Anticholinergic symptoms include dilated pupils, dry mouth, decreased (or absent) bowel sounds, and 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. All patients suspected of tricyclic antidepressant overdose should receive gastrointestinal decontamination. This should include large volume gastric lavage followed by activated charcoal.[33] Seizures secondary to overdose are treatable with diazepam or lorazepam.[34] If the patient is hypotensive, an IV bolus of isotonic crystalloid is a therapeutic option. Vasopressors are the next choice if the patient remains hypotensive despite fluid resuscitation. If QRS exceeds 100 msec, intravenous sodium bicarbonate is the appropriate intervention. 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.[35][36]

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 co-morbid chronic pain syndromes. Patients on amitriptyline can have anticholinergic, antihistaminic, and alpha-adrenergic blocking adverse effects. It may not be appropriate for patients with cardiac problems. It has many potential drug interactions, increasing the risk of arrhythmias and serotonin syndrome. Toxicity can be life-threatening, and patients will need to be stabilized and monitored closely. Health care providers also need to know the increased risk of suicidality in children, adolescents, and young adults, which will require discussion with families.[32]

When a clinician (MDs, DOs, NPs, PAs) determines to start a patient on amitriptyline, they should counsel the patient about the risks associated with amitriptyline therapy. It is always prudent to obtain a psychiatry consultation when prescribing amitriptyline for major depressive disorder. There are significant drug-drug interactions of other medicines with amitriptyline; therefore, pharmacists should report back to the clinician if there is any concern. Pharmacists should also perform medication reconciliation and ensure appropriate dosage.

Specially trained nurses can provide medication counseling, evaluate patient adherence, and monitor for side effects on follow-up visits. The nurse should report to clinicians in the case of concern regarding therapy. In an acute overdose of amitriptyline, emergency medicine physicians and triage nurses should rapidly stabilize the patient. Critical care physician supervision is necessary if the patient remains in the ICU. In severe overdose, clinicians should obtain a medical toxicologist consultation and contact the poison control center. In case of intentional overdose, the clinician should obtain a psychiatrist consultation. As depicted above, there needs to be excellent communication between multiple healthcare providers involved in taking care of the patient receiving amitriptyline. Each provider should understand their responsibility and work collaboratively. When the interprofessional team collaborates in therapeutic decisions, amitriptyline can effectively treat depression, and patients can achieve optimal outcomes with minimal adverse events. [Level 5]