Oral Neuropathic pain, Prophylaxis of chronic tension-type headache, Prophylaxis of migraine
Adult: Initially, 10-25 mg daily, preferably in the evening. May increase gradually in increments of 10-25 mg every 3-7 days as tolerated. Recommended doses: 25-75 mg daily, preferably in the evening. Use the lowest effective dose for the shortest duration needed to treat symptoms.
Oral Major depressive disorder
Adult: Initially, 25 mg bid; may gradually increase by 25 mg every other day up to 150 mg daily in 2 divided doses if necessary. Alternatively, may initiate at 75 mg daily in divided doses, or 50-100 mg at bedtime and then may be increased by 25 mg or 50 mg at bedtime, as necessary, to a total of 150 mg daily. For hospitalised patients: Initially, 100 mg daily, may be increased gradually to 200 mg daily as necessary, up to 300 mg daily. Use the lowest effective maintenance dose. Duration of treatment: Up to 6 months. Elderly: Initially, 10-25 mg daily, may increase gradually to 100 mg daily according to patient tolerability and response. Doses above 100 mg must be used with caution. Use the lowest effective maintenance dose.
Oral Nocturnal enuresis
Child: In patients whom organic pathology has been excluded and has no response to all other non-drug and drug treatments: 6-10 years 10-20 mg; ≥11 years 25-50 mg. All doses to be taken 1-1.5 hours before bedtime. Max duration of treatment: 3 months. If repeated courses are necessary, conduct a medical review every 3 months. Treatment recommendations may vary among countries and individual products (refer to specific product guidelines).
Special Patient Group
Major depressive disorder:
Patient with CV disease: Initially, 10-25 mg daily, may increase gradually to 100 mg daily according to patient tolerability and response. Doses above 100 mg must be used with caution. Use the lowest effective maintenance dose.
Pharmacogenomics:
Amitriptyline, a tertiary amine, is primarily metabolised by CYP2C19 isoenzyme via demethylation into the secondary amine, nortriptyline (active metabolite); both amitriptyline and nortriptyline are metabolised by CYP2D6 isoenzyme into less active hydroxy metabolites. CYP2C19 and CYP2D6 genes are highly polymorphic. Genetic variation in CYP2C19 altering the ratio of parent drug to metabolites or in CYP2D6 altering drug clearance may predispose patients to treatment failure or adverse effects.
Genetic testing may be considered to identify patients who are at an increased risk of experiencing amitriptyline adverse effects or therapeutic failure. Gene-based dosing recommendations for situations in which higher initial doses are required (e.g. treatment for depression) are indicated below.
Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines as of December 2016:
CYP2C19
Phenotype and Genotype
Implications
Recommendations
CYP2C19 ultrarapid metaboliser
Patients carrying 2 increased function alleles e.g. *17/*17
Increased metabolism of tertiary amines as compared to normal metabolisers. Increased conversion of amitriptyline to nortriptyline may affect response or adverse effects.
Avoid amitriptyline use and consider an alternative drug not metabolised by CYP2C19 (e.g. nortriptyline, desipramine). If use is warranted, therapeutic drug monitoring is recommended to guide dose adjustments.
CYP2C19 rapid metaboliser
Patients carrying 1 normal functional allele and 1 increased function allele e.g. *1/*17
Increased metabolism of tertiary amines as compared to normal metabolisers. Increased conversion of amitriptyline to nortriptyline may affect response or adverse effects.
Avoid amitriptyline use and consider an alternative drug not metabolised by CYP2C19 (e.g. nortriptyline, desipramine). If use is warranted, therapeutic drug monitoring is recommended to guide dose adjustments.
CYP2C19 intermediate metaboliser
Patients carrying 1 normal functional allele and 1 non-functional allele, or 1 non-functional allele and 1 increased function allele e.g. *1/*2, *1/*3, *2/*17
Reduced metabolism of amitriptyline as compared to normal metabolisers.
Initiate treatment with the recommended initial dose.
CYP2C19 poor metaboliser
Patients carrying 2 non-functional alleles e.g. *2/*2, *2/*3, *3/*3
Greatly reduced metabolism of tertiary amines as compared to normal metabolisers. Reduced conversion of amitriptyline to nortriptyline may affect response or adverse effects.
Avoid amitriptyline use and consider an alternative drug not metabolised by CYP2C19 (e.g. nortriptyline, desipramine). If amitriptyline use is warranted, consider a 50% reduction of the recommended initial dose. Therapeutic drug monitoring is recommended to guide dose adjustments.
CYP2D6
CYP2D6 isoenzyme activity is reduced in a subset of Caucasians and approx 7-10% of this population are classified as CYP2D6 poor metabolisers. Reliable estimates of the prevalence of reduced CYP2D6 isoenzyme activity among Asians, Africans, and other populations are not yet available.
Phenotype and Genotype
Implications
Recommendations
CYP2D6 ultrarapid metaboliser (activity score of >2)
Patients carrying duplications of functional alleles e.g. (*1/*1)xN, (*1/*2)xN, (*2/*2)xN (where xN represents the number of CYP2D6 gene copies)
Increased metabolism of TCAs to less active metabolites as compared to normal metabolisers. Lower plasma concentrations of the active metabolite may increase the possibility of pharmacotherapy failure.
Avoid TCA use and consider an alternative drug not metabolised by CYP2D6. If TCA use is warranted, consider titrating to a higher target dose (compared to that of normal metabolisers). Therapeutic drug monitoring is strongly recommended to guide dose adjustments.
CYP2D6 intermediate metaboliser (activity score of 0.5 and 1)
Patients carrying 1 decreased function and 1 non-functional allele e.g. *4/*41, *5/*9, *4/*10
CPIC update as of October 2019: Phenotype assignment for activity scores of 1 has been changed from CYP2D6 normal metaboliser to CYP2D6 intermediate metaboliser.
Reduced metabolism of TCAs to less active metabolites as compared to normal metabolisers. Higher plasma concentrations of the active metabolite may increase the risk of adverse effects.
Consider a 25% reduction of the recommended initial dose. Titrate dose to observed clinical response with symptom improvement and lesser adverse effects. Therapeutic drug monitoring is strongly recommended to guide dose adjustments.
CYP2D6 poor metaboliser (activity score of 0)
Patients carrying non-functional alleles only e.g. *4/*4, (*4/*4)xN, *3/*4, *5/*5, *5/*6
Greatly reduced metabolism of TCAs to less active metabolites as compared to normal metabolisers. Higher plasma concentrations of the active metabolite may increase the risk of adverse effects.
Avoid TCA use and consider an alternative drug not metabolised by CYP2D6. If TCA use is warranted, consider a 50% reduction of the recommended initial dose. Therapeutic drug monitoring is strongly recommended to guide dose adjustments.
Additionally, patients taking strong CYP2D6 inhibitors are suggested to be treated similarly to CYP2D6 poor metabolisers. Consider drug-drug interactions along with patient characteristics in addition to gene-based dosing recommendations indicated above.
The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group (DPWG) Guideline (as of August 2019) recommends using 70% of the standard dose for CYP2D6 poor metabolisers. Monitoring of effect and adverse effects or plasma concentrations of amitriptyline or nortriptyline to adjust the maintenance dose is also recommended.
Dosage recommendations may vary among countries or clinical guidelines. Refer to local treatment guidelines.
Hepatic Impairment
Severe: Contraindicated.
Administration
May be taken with or without food.
Contraindications
Recent MI, any degree of heart block or cardiac rhythm disorders. Severe hepatic impairment. Children <6 years. Concomitant use with MAOIs or within 14 days of discontinuing non-selective, irreversible MAOIs. Concomitant use with cisapride.
Special Precautions
Patient with CV disease (e.g. stroke, significant bradycardia, uncompensated heart failure, tachycardia, conduction abnormalities), electrolyte disturbances (e.g. hypokalaemia, hyperkalaemia, hypomagnesaemia); history of suicide-related events or exhibiting a significant degree of suicidal ideation; bipolar disorder, seizure disorder or at risk of seizures (e.g. history of seizures, head trauma, brain damage, alcoholism), diabetes mellitus, myasthenia gravis, angle-closure glaucoma, increased IOP, urinary retention, prostatic hypertrophy, paranoid symptomatology, pyloric stenosis, paralytic ileus, hyperthyroidism, phaeochromocytoma. Concomitant electroconvulsive therapy. Patients undergoing surgery; discontinue treatment before surgery if possible. CYP2C19 ultrarapid, rapid, and poor metabolisers. CYP2D6 ultrarapid, intermediate, and poor metabolisers. Avoid abrupt withdrawal. Renal and mild to moderate hepatic impairment. Children and elderly. Pregnancy and lactation.
Adverse Reactions
Significant: Suicidal thoughts and behaviour (particularly in children and young adults); may precipitate mania or hypomania (particularly in patients with known manic-depressive illness), may aggravate psychotic symptoms (in schizophrenic patients); cardiac arrhythmias, QT interval prolongation, AV conduction disturbance; withdrawal symptoms (upon abrupt discontinuation after chronic treatment), bone fractures, hyponatraemia, acute angle-closure glaucoma, orthostatic hypotension. Cardiac disorders: Tachycardia, palpitations. Eye disorders: Accommodation disorder, mydriasis. Gastrointestinal disorders: Nausea, constipation, dry mouth, dysgeusia. General disorders and administration site conditions: Fatigue, feeling thirsty. Investigations: Increased weight, abnormal ECG (most commonly prolonged QRS complex). Nervous system disorders: Headache, dizziness, somnolence, tremor, speech disorder (dysarthria), paraesthesia, ataxia, disturbance in attention. Psychiatric disorders: Aggression, agitation, confusional state. Renal and urinary disorders: Micturition disorders. Reproductive system and breast disorders: Decreased libido, erectile dysfunction. Respiratory, thoracic and mediastinal disorders: Congested nose. Skin and subcutaneous tissue disorders: Hyperhidrosis.
This drug may cause drowsiness, dizziness, and impairment in general attention and concentration; if affected, do not drive or operate machinery.
Monitoring Parameters
Screen patients for family history of bipolar disorder, suicide, and depression before treatment. Closely monitor for clinical worsening, suicidal behaviour or thoughts, and unusual changes in behaviour. Obtain blood glucose, heart rate, blood pressure, weight, BMI, ECG (in elderly and patients with pre-existing cardiac disease), and electrolyte levels (as indicated). When used for nocturnal enuresis: Perform ECG before initiating treatment to exclude long QT syndrome.
Overdosage
Symptoms: CNS depression, respiratory depression, cardiac arrhythmias or conduction defects, heart failure, cardiogenic shock, metabolic acidosis, hypokalaemia, hyponatraemia, convulsions, mydriasis, tachycardia, urinary retention, dry mucous membranes, reduced bowel motility, fever, severe hypotension, disturbed concentration, hypothermia, coma, hyperreflexia with extensor plantar reflexes, Brugada syndrome unmasking and Brugada ECG patterns. Confusion, agitation, hallucinations, and ataxia may occur upon awakening. Management: Symptomatic and supportive treatment. Ensure adequate airway and IV access. Perform gastric lavage and administer activated charcoal within 1 hour of ingestion. If the patient is unconscious, secure the airway before initiating lavage. Obtain ECG and initiate cardiac monitoring. Administer IV Na bicarbonate to maintain a serum pH between 7.45-7.55; hyperventilation may also be used if pH response is inadequate. Lidocaine, bretylium tosilate, or phenytoin may be used in patients with dysrhythmias unresponsive to Na bicarbonate or hyperventilation. Early intubation is advised in patients with CNS depression. Administer benzodiazepines or other anticonvulsants (e.g. phenobarbital, phenytoin) to control seizures. In patients who are unconscious for a considerable time, monitor for rhabdomyolysis.
Drug Interactions
May increase the risk of serotonin syndrome with opioids (e.g. buprenorphine, tramadol). May increase the risk of arrhythmias and hypotension with anaesthetics. Concomitant use with anticholinergics or neuroleptics, particularly in hot weather, may cause hyperpyrexia. May potentiate the CV effects of sympathomimetic agents (e.g. epinephrine, ephedrine, isoprenaline, norepinephrine, phenylephrine, phenylpropanolamine). May enhance the sedative effects of barbiturates and other CNS depressants. May reduce the antihypertensive effects of adrenergic neurone blockers (e.g. guanethidine, betanidine, reserpine, clonidine, methyldopa). May increase the risk of ventricular arrhythmias with antiarrhythmics (e.g. quinidine, amiodarone), certain antihistamines (e.g. astemizole, terfenadine), certain antipsychotics (e.g. pimozide, sertindole, thioridazine), halofantrine, and sotalol. Potential additive effects on QT interval and increased risk of serious CV effects when used with methadone. Concomitant use with diuretics (e.g. furosemide) may increase the risk of hypokalaemia. May increase serum concentrations with fluconazole, fluvoxamine, Na valproate, valpromide, topiramate, CYP2D6 inhibitors (e.g. duloxetine, terbinafine, bupropion, fluoxetine, paroxetine, quinidine), and other CYP450 inhibitors (e.g. cimetidine, diltiazem, verapamil). May reduce plasma concentrations with CYP450 inducers (e.g. oral contraceptives, rifampicin, phenytoin, barbiturates, carbamazepine). Risk of delirium with disulfiram. Increased anticholinergic adverse effects with nefopam. May increase the risk of bleeding with antiplatelets and anticoagulants. May increase the risk of bone fractures with SSRIs. Potentially Fatal: Increased risk of serotonin syndrome with MAOIs (e.g. selegiline, moclobemide). Increased risk of QT interval prolongation and cardiac arrhythmia with cisapride.
Food Interaction
May enhance the sedative effect of alcohol. May reduce plasma concentrations with St. John's wort.
Action
Description: Mechanism of Action: Amitriptyline is a dibenzocycloheptadiene tricyclic antidepressant. It inhibits the neuronal membrane pump mechanism responsible for the reuptake of serotonin (5-HT) and/or norepinephrine, hence prolonging and potentiating their action in the brain. In the maintenance of neuropathic pain and prophylaxis of chronic tension-type headache and migraine, the known mechanism of action involved also includes ion-channel blocking effects on Na, K, and NMDA channels at both central and spinal cord levels. It also has an affinity for muscarinic and histamine (H1) receptors to varying degrees. Onset: Antidepressant effect: 1-2 weeks. Pharmacokinetics: Absorption: Readily and completely absorbed from the gastrointestinal tract. Bioavailability: Approx 43-46%. Time to peak plasma concentration: Approx 2-5 hours. Distribution: Widely distributed throughout the body. Crosses the placenta; enters breast milk (small amounts). Volume of distribution: Approx 18-22 L/kg. Plasma protein binding: >90%. Metabolism: Metabolised in the liver by CYP3A4 and CYP2C19 via demethylation and by CYP2D6 via hydroxylation, followed by conjugation with glucuronic acid to form metabolites, nortriptyline (primary active metabolite), hydroxy and conjugated derivatives. Undergoes extensive first-pass metabolism. Excretion: Via urine (mainly as glucuronide or sulfate conjugate metabolites with small amounts of unchanged drug); faeces (small amounts). Elimination half-life: Approx 13-36 hours.
Chemical Structure
Amitriptyline Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 2160, Amitriptyline. https://pubchem.ncbi.nlm.nih.gov/compound/Amitriptyline. Accessed Apr. 28, 2023.
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