What are the side effects of Amitriptyline (Amitriptyline hydrochloride)?

From the Guidelines

Amitriptyline commonly causes several side effects that patients should be aware of before starting treatment, including somnolence, dry mouth, blurred vision, constipation, weight gain, and prolonged QTc on ECG, as reported in a recent study 1. The most frequent side effects of amitriptyline include:

• Drowsiness
• Dry mouth
• Blurred vision
• Constipation
• Weight gain Many patients experience sedation, which is why it's often taken at bedtime. Amitriptyline can cause urinary retention, increased heart rate, and orthostatic hypotension (drop in blood pressure when standing up). Some patients report sexual dysfunction, including decreased libido or difficulty achieving orgasm. More serious but less common side effects include confusion, hallucinations, irregular heartbeat, and seizures. Amitriptyline carries a risk of serotonin syndrome when combined with other serotonergic medications. It may also cause QT interval prolongation, which can lead to dangerous heart rhythm disturbances. These side effects occur because amitriptyline affects multiple neurotransmitter systems, including serotonin, norepinephrine, and acetylcholine. The anticholinergic effects cause many of the common side effects like dry mouth and constipation. Elderly patients are particularly sensitive to these effects and may require lower doses. Abrupt discontinuation should be avoided as it can cause withdrawal symptoms, so dosage should be tapered gradually when stopping treatment, as suggested by a study on the management of neuropathic corneal pain 1. It's also worth noting that amitriptyline has been compared to other tricyclic antidepressants, such as nortriptyline, in terms of efficacy and side effects, with nortriptyline demonstrating fewer side effects in some cases 1. However, the most recent and highest quality study on the topic, published in 2024, provides the most up-to-date information on the side effects of amitriptyline 1.

From the FDA Drug Label

1. Adverse Reactions Within each category the following adverse reactions are listed in order of decreasing severity. Included in the listing are a few adverse reactions which have not been reported with this specific drug. However, pharmacological similarities among the tricyclic antidepressant drugs require that each of the reactions be considered when amitriptyline is administered Cardiovascular: Myocardial infarction; stroke; nonspecific ECG changes and changes in AV conduction; heart block; arrhythmias; hypotension, particularly orthostatic hypotension; syncope; hypertension; tachycardia; palpitation CNS and Neuromuscular: Coma; seizures; hallucinations; delusions; confusional states; disorientation; incoordination; ataxia; tremors; peripheral neuropathy; numbness, tingling and paresthesias of the extremities; extrapyramidal symptoms including abnormal involuntary movements and tardive dyskinesia; dysarthria; disturbed concentration; excitement; anxiety; insomnia; restlessness; nightmares; drowsiness; dizziness; weakness; fatigue; headache; syndrome of inappropriate ADH (antidiuretic hormone) secretion; tinnitus; alteration in EEG patterns. Anticholinergic: Paralytic ileus, hyperpyrexia; urinary retention, dilatation of the urinary tract; constipation; blurred vision, disturbance of accommodation, increased ocular pressure, mydriasis; dry mouth Allergic: Skin rash; urticaria; photosensitization; edema of face and tongue. Hematologic: Bone marrow depression including agranulocytosis, leukopenia, thrombocytopenia; purpura; eosinophilia. Gastrointestinal: Rarely hepatitis (including altered liver function and jaundice); nausea; epigastric distress; vomiting; anorexia; stomatitis; peculiar taste; diarrhea; parotid swelling; black tongue Endocrine: Testicular swelling and gynecomastia in the male; breast enlargement and galactorrhea in the female; increased or decreased libido; impotence; elevation and lowering of blood sugar levels. Other: Alopecia; edema; weight gain or loss; urinary frequency; increased perspiration Withdrawal Symptoms After prolonged administration, abrupt cessation of treatment may produce nausea, headache, and malaise. Gradual dosage reduction has been reported to produce, within two weeks, transient symptoms including irritability, restlessness, and dream and sleep disturbance. These symptoms are not indicative of addiction Rare instances have been reported of mania or hypomania occurring within 2 to 7 days following cessation of chronic therapy with tricyclic antidepressants Causal Relationship Unknown Other reactions, reported under circumstances where a causal relationship could not be established, are listed to serve as alerting information to physicians: Body as a Whole: Lupus-like syndrome (migratory arthritis, positive ANA and rheumatoid factor). Digestive: Hepatic failure, ageusia Postmarketing Adverse Events A syndrome resembling neuroleptic malignant syndrome (NMS) has been very rarely reported after starting or increasing the dose of amitriptyline hydrochloride, with and without concomitant medications known to cause NMS. Symptoms have included muscle rigidity, fever, mental status changes, diaphoresis, tachycardia, and tremor Very rare cases of serotonin syndrome (SS) have been reported with amitriptyline hydrochloride in combination with other drugs that have a recognized association with SS.

The side effects of Amitriptyline include:

• Cardiovascular side effects: myocardial infarction, stroke, arrhythmias, hypotension, syncope, hypertension, tachycardia, palpitation
• CNS and Neuromuscular side effects: coma, seizures, hallucinations, delusions, confusional states, disorientation, incoordination, ataxia, tremors, peripheral neuropathy, numbness, tingling, paresthesias, extrapyramidal symptoms, dysarthria, disturbed concentration, excitement, anxiety, insomnia, restlessness, nightmares, drowsiness, dizziness, weakness, fatigue, headache
• Anticholinergic side effects: paralytic ileus, hyperpyrexia, urinary retention, constipation, blurred vision, dry mouth
• Allergic side effects: skin rash, urticaria, photosensitization, edema of face and tongue
• Hematologic side effects: bone marrow depression, agranulocytosis, leukopenia, thrombocytopenia, purpura, eosinophilia
• Gastrointestinal side effects: hepatitis, nausea, epigastric distress, vomiting, anorexia, stomatitis, peculiar taste, diarrhea, parotid swelling, black tongue
• Endocrine side effects: testicular swelling, gynecomastia, breast enlargement, galactorrhea, increased or decreased libido, impotence, elevation and lowering of blood sugar levels
• Other side effects: alopecia, edema, weight gain or loss, urinary frequency, increased perspiration
• Withdrawal symptoms: nausea, headache, malaise, irritability, restlessness, dream and sleep disturbance
• Postmarketing adverse events: neuroleptic malignant syndrome, serotonin syndrome 2

From the Research

Side Effects of Amitriptyline

The side effects of Amitriptyline can be categorized into various types, including:

• Mild symptoms such as constipation and dry mouth 3
• Severe adverse events such as seizures and coma 3
• Hypertension, as evidenced by a case study where a patient's blood pressure normalized after stopping Amitriptyline but became elevated when reintroduced 3
• Pro-suicidal effects, particularly in patients with hints of suicidality or suicidal behavior, due to its hypothetic asynchronous cognitive-psychomotor pharmacodynamic action 4
• Extrapyramidal side effects, which can occur along with consecutive psychological side effects 4
• Somatic-metabolic side effects, which can be more pronounced in new antipsychotics compared to classic ones 4
• Increased risk of adverse events, such as dysphoria, anxiety, impulsiveness, and agitation 4

Specific Side Effects

Some specific side effects of Amitriptyline include:

• Cardiovascular effects, such as first-degree atrioventricular block, prolonged QTc interval, and orthostatic hypotension 5
• Neurological side effects, such as seizures and coma 3
• Psychological side effects, such as suicidal behavior and dysphoria 4
• Gastrointestinal side effects, such as constipation 3
• Metabolic side effects, such as weight gain or loss 6

Comparison with Other Medications

Amitriptyline has been compared with other medications, including:

• Selective serotonin reuptake inhibitors (SSRIs), which may have a more favorable tolerability/efficacy profile 7
• Other tricyclic antidepressants, which may have similar efficacy and tolerability profiles 7
• Placebo, which may have a lower risk of adverse events 6