Migraine prophylaxis
First line
Per AHS 2021 and 2012, amitriptyline is first-line for migraine prophylaxis. Dose 25–100 mg at bedtime. Efficacy comparable to propranolol and topiramate. Off-label per label (migraine indication not registered).
Tricyclic antidepressants (TCA)
ATC code: N06AA09 (Amitriptyline)
Brand names
Elavil, Endep
Non-selectively inhibits serotonin and norepinephrine reuptake in presynaptic neurons. Pronounced anticholinergic, antihistaminic, and α-adrenergic blockade explain side effects: dry mouth, constipation, urinary retention, orthostatic hypotension, sedation, weight gain. Cardiotoxic in overdose (quinidine-like sodium channel effect). Active metabolite: nortriptyline.
First line
Per AHS 2021 and 2012, amitriptyline is first-line for migraine prophylaxis. Dose 25–100 mg at bedtime. Efficacy comparable to propranolol and topiramate. Off-label per label (migraine indication not registered).
First line
First-line for neuropathic pain per NeuPSIG 2015, alongside gabapentinoids and SNRIs. Dose 25–75 mg at bedtime; start 10–25 mg and titrate. Pain effect emerges in 1–2 weeks at doses below antidepressant levels. Off-label per the Russian label, primary indication is depression. Side-effect profile limits use in elderly.
First line
Amitriptyline 10–50 mg at bedtime is a standard pharmacotherapy for fibromyalgia per 2017. Effects on sleep and pain are comparable to pregabalin and duloxetine. Off-label per Russian label.
Second line
In major depression, amitriptyline is effective, but the unfavorable side-effect profile and cardiotoxicity in overdose make it second-line after SSRIs/SNRIs per 2023 and NG222. Use is justified in patients with depression and concurrent chronic pain, insomnia, or migraine.
The drug is promoted for these uses outside international guidelines. Each entry below is analyzed against AEMPS, FDA, EMA, Cochrane and major RCTs.
Not recommended
Amitriptyline is a tricyclic antidepressant with pronounced anticholinergic and sedative effects. It is prescribed for major depression, neuropathic pain, migraine prophylaxis, fibromyalgia, and some sleep disorders ( NG193, AEMPS Ficha Técnica). For chronic fatigue, amitriptyline is prescribed off-label in people without depression. In people with ordinary chronic fatigue, no clinical studies of efficacy exist. The drug has serious risks: anticholinergic effects (dry mouth, constipation, urinary retention, blurred vision, confusion especially in older adults – AGS Beers Criteria 2023 lists TCAs as potentially inappropriate for older adults), orthostatic hypotension, QT prolongation, cardiotoxicity in overdose, and increased suicide risk in young people ( boxed warning). If amitriptyline was prescribed for fatigue, consider seeking a second opinion.
52 pairs found. Sorted from critical to minor.
Mechanism
Amitriptyline (tricyclic antidepressant) prolongs QT. Dronedarone also prolongs QT. Additive effect raises ventricular arrhythmia risk. Multaq Section 4.3 specifically lists QT-prolonging antidepressants as contraindications.
Symptoms
QT prolongation on ECG. Clinically: dizziness, syncope, palpitations. Severe cases progress to polymorphic ventricular tachycardia (torsades de pointes) with risk of ventricular fibrillation and sudden cardiac death. Risk rises with hypokalaemia and hypomagnesaemia.
Management
The combination is not prescribed. Replace the TCA with sertraline (minimal QT effect, up to 100 mg/day) or agomelatine. If a TCA is required, choose a non-QT antiarrhythmic (beta-blocker).
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Boxed warning
FDA boxed warning: antidepressants increase suicidal ideation/behavior risk in children, adolescents, and adults under 25. Special monitoring in the first months and at dose changes.
Amitriptyline is evaluated for the following indications with varying evidence strength: Migraine prophylaxis (evidence tier A), Neuropathic pain (evidence tier A), Major depressive disorder (evidence tier B). See the full indication matrix with dosing and citations above on this page.
Common side effects of Amitriptyline (≥ 1 in 100): Dry mouth, Sedation, drowsiness, Constipation, Weight gain, Orthostatic hypotension, dizziness, Urinary retention. See the Safety section for uncommon and serious reactions.
FDA category C. FDA categories were retired in 2015 (historically C). Third-trimester use is associated with neonatal withdrawal syndrome. In pregnant patients with severe depression, continuation is individualized with a psychiatrist — untreated depression risk is significant for mother and fetus.
Transfers into milk in small amounts. Per LactMed, use is acceptable with infant sedation monitoring.
Amitriptyline is contraindicated in: Acute myocardial infarction; AV block, QT-prolonging arrhythmia; Acute intoxication with alcohol or other CNS depressants; Concurrent or recent (14 days) MAOI; Closed-angle glaucoma. Full list in the Safety section.
Mechanism
Amitriptyline, a tricyclic antidepressant, blocks serotonin and norepinephrine reuptake. Linezolid reversibly inhibits MAO. Combined action sharply raises synaptic monoamines, risking serotonin syndrome and hypertensive crisis.
Symptoms
Serotonin syndrome: agitation, confusion, tremor, myoclonus, hyperreflexia, dilated pupils. Autonomic features: profuse sweating, tachycardia, hypertension, fever above 38.5 °C. Severe cases progress to seizures, rhabdomyolysis, disseminated intravascular coagulation, and death. First signs appear within hours of concurrent dosing.
Management
The combination is not prescribed. Stop amitriptyline 1–2 weeks before linezolid. If linezolid is urgently needed, switch the patient to mianserin or agomelatine, which lack a strong serotonergic profile. Alternative antibiotics: vancomycin, daptomycin.
Mechanism
IV methylene blue inhibits MAO-A. Amitriptyline (TCA) raises serotonin and norepinephrine through reuptake blockade. Co-administration sharply increases monoaminergic transmission.
Symptoms
Serotonin syndrome: agitation, confusion, tremor, myoclonus, hyperreflexia, dilated pupils. Autonomic features: profuse sweating, tachycardia, hypertension, fever above 38.5 °C. Severe cases progress to seizures, rhabdomyolysis, disseminated intravascular coagulation, and death. First signs appear within hours of concurrent dosing.
Management
Avoid the combination. Methylene blue is reserved for emergencies with amitriptyline withdrawn 5 days in advance. If unavoidable on a TCA, monitor temperature, pulse, and reflexes in ICU with cyproheptadine available.
Mechanism
Additive CNS depression, sedation, and anticholinergic effect. In older patients: high delirium and fall risk.
Symptoms
Deep sedation, drowsiness, ataxia, confusion (especially in older patients). Dry mouth, constipation, urinary retention (anticholinergic effect).
Management
Avoid the combination in older patients. If needed, use the minimum effective dose of both with a short course. Alternative anxiolytic when a TCA is needed: hydroxyzine or gabapentinoids.
Mechanism
Dual mechanism: both prolong QT, and amitriptyline (TCA) additionally blocks cardiac sodium channels – His-Purkinje conduction is depressed. High risk of torsades de pointes and AV block.
Symptoms
QT prolongation on ECG. Clinically: dizziness, syncope, palpitations. Severe cases progress to polymorphic ventricular tachycardia (torsades de pointes) with risk of ventricular fibrillation and sudden cardiac death. Risk is higher with hypokalaemia, hypomagnesaemia, bradycardia, and ischaemic heart disease.
Management
Avoid the combination. Alternative antidepressants with minimal QT effect: sertraline (up to 100 mg/day) or agomelatine. For neuropathic pain, replace amitriptyline with gabapentin or pregabalin.
Mechanism
Bupropion is a potent CYP2D6 inhibitor, the main amitriptyline metabolic route. TCA plasma levels rise 2- to 5-fold. Both drugs lower the seizure threshold. Plus additive cardiotoxicity.
Symptoms
Seizures (generalised tonic-clonic or focal), agitation, tremor, insomnia. Patients with prior epilepsy or eating disorders are at particular risk.
Management
Avoid the combination. For neuropathic pain, replace amitriptyline with gabapentin or pregabalin. Alternative antidepressants if bupropion is needed: sertraline or escitalopram.
Mechanism
Carbamazepine induces CYP3A4 and CYP2D6; amitriptyline plasma levels fall by 50–60%. Loss of antidepressant and analgesic effect is possible.
Symptoms
Return of depressive symptoms or neuropathic pain. In depression: relapse risk.
Management
During carbamazepine therapy, double amitriptyline with clinical efficacy monitoring. Alternative anticonvulsants without induction: levetiracetam, lamotrigine (no CYP3A4 induction).
Mechanism
Additive QT prolongation. Ciprofloxacin additionally blocks CYP1A2 – an amitriptyline metabolic route. Amitriptyline plasma levels rise.
Symptoms
QT prolongation on ECG. Dizziness, syncope, palpitations. Severe cases: polymorphic ventricular tachycardia (torsades de pointes). Risk is higher with hypokalaemia and hypomagnesaemia.
Management
Avoid the combination. Alternative antibiotics without QT effect: a cephalosporin or nitrofurantoin. Alternative for neuropathic pain instead of TCA: gabapentin or pregabalin.
Mechanism
Both drugs prolong QT and are serotonergic. Citalopram weakly blocks CYP2D6, a partial amitriptyline route, so amitriptyline levels rise modestly.
Symptoms
QT prolongation on ECG. Clinically: dizziness, syncope, palpitations. Severe cases progress to polymorphic ventricular tachycardia (torsades de pointes). Risk is higher with hypokalaemia, hypomagnesaemia, bradycardia, and ischaemic heart disease.
Management
Avoid the combination. Alternative antidepressants if citalopram fails: mirtazapine or agomelatine. For neuropathic pain, replace amitriptyline with gabapentin or pregabalin.
Mechanism
Clarithromycin blocks CYP3A4 and prolongs QT itself. Amitriptyline plasma levels rise; additive QT risk.
Symptoms
QT prolongation on ECG. Dizziness, syncope, palpitations. Severe cases: polymorphic ventricular tachycardia (torsades de pointes). Risk is higher with hypokalaemia and hypomagnesaemia.
Management
Avoid the combination. Alternative antibiotics: azithromycin or doxycycline (minimal CYP3A4 and QT effect). Alternative for neuropathic pain instead of TCA: gabapentin or pregabalin.
Mechanism
Amitriptyline (TCA) blocks α2-receptors and antagonises clonidine. Clonidine's antihypertensive effect is fully lost; blood pressure returns to baseline or higher.
Symptoms
Return of hypertension: headache, dizziness, elevated readings on monitoring. In severe hypertension: risk of hypertensive crisis.
Management
The combination is not prescribed. Alternative antidepressants without α2-antagonism: SSRI (sertraline, escitalopram) or agomelatine. Alternative antihypertensives: an ARB or ACE-I with amlodipine (no clonidine).
Mechanism
Duloxetine moderately blocks CYP2D6 (an amitriptyline metabolic route); amitriptyline plasma levels rise. Both drugs are also serotonergic and noradrenergic – serotonin syndrome and cardiotoxicity risk.
Symptoms
Serotonin syndrome: agitation, confusion, tremor, myoclonus, hyperreflexia. Autonomic features: sweating, tachycardia, hypertension, fever. First signs appear within hours of co-administration.
Management
Avoid the combination. For neuropathic pain, choose one: duloxetine (better profile in diabetic neuropathy) or gabapentin/pregabalin. Alternative for anxious depression: mirtazapine.
Mechanism
Both drugs raise serotonergic transmission and prolong QT. Combined action carries serotonin syndrome and torsades de pointes risks. Escitalopram weakly blocks CYP2D6 and amitriptyline levels rise modestly.
Symptoms
Serotonin syndrome (agitation, tremor, tachycardia). QT prolongation on ECG. Amitriptyline anticholinergic effects (dry mouth, constipation, confusion in older patients).
Management
Avoid the combination. Alternative antidepressants if escitalopram fails: mirtazapine or agomelatine. If amitriptyline fails for neuropathic pain: gabapentin or pregabalin.
Mechanism
Dual mechanism. Fluoxetine raises synaptic serotonin and strongly blocks CYP2D6 – the amitriptyline metabolic route. Amitriptyline plasma levels rise 2- to 4-fold while serotonergic activity adds up.
Symptoms
Serotonin syndrome (agitation, tremor, tachycardia, hyperthermia). Amitriptyline anticholinergic effects intensify (dry mouth, constipation, urinary retention, confusion in older patients). QT prolongation.
Management
Avoid the combination. If combined for augmentation, halve amitriptyline and check ECG at 2 weeks. Alternative antidepressant: mirtazapine or agomelatine (no CYP2D6 dependence).
Mechanism
Fluvoxamine blocks CYP1A2 and CYP2C19 – the main amitriptyline demethylation routes. TCA plasma levels rise 2- to 4-fold. Plus serotonin syndrome risk.
Symptoms
Serotonin syndrome: agitation, confusion, tremor, myoclonus, hyperreflexia. Autonomic features: sweating, tachycardia, hypertension, fever. First signs appear within hours of co-administration.
Management
Avoid the combination. Alternative antidepressants if fluvoxamine fails: sertraline or escitalopram (no CYP1A2 effect). For neuropathic pain, replace amitriptyline with gabapentin or pregabalin.
Sources
Mechanism
Additive QT prolongation and anticholinergic effect. Both drugs are sedating. In elderly patients with dementia, severe delirium and arrhythmias have been reported.
Symptoms
Drowsiness, sedation, confusion, delirium (especially in older patients). Dry mouth, constipation, urinary retention. QT prolongation on ECG with torsades de pointes risk.
Management
Avoid the combination, especially in older patients. Alternative antipsychotics with minimal QT effect: olanzapine or aripiprazole. Alternative antidepressants without QT effect: mirtazapine or agomelatine.
Mechanism
Dual risk. Sertraline blocks CYP2D6 – the amitriptyline metabolic route – and amitriptyline plasma levels rise 2- to 4-fold. Both drugs are also serotonergic.
Symptoms
Serotonin syndrome (agitation, tremor, tachycardia). Amitriptyline anticholinergic effects (dry mouth, constipation, confusion in older patients). QT prolongation.
Management
If combined for augmentation, halve amitriptyline and check ECG at 2 weeks. Alternative: mirtazapine or agomelatine (no CYP2D6 dependence).
Sources
Mechanism
Dual risk. Tramadol blocks serotonin and norepinephrine reuptake and lowers seizure threshold. Amitriptyline (TCA) also blocks both reuptakes and itself provokes seizures in overdose. Combined action – serotonin syndrome and seizure risk.
Symptoms
Serotonin syndrome (agitation, tremor, tachycardia, hyperthermia) plus seizure risk. QT prolongation – both drugs contribute. Older patients: ataxia and fall risk.
Management
Avoid the combination. For neuropathic pain on a TCA, choose gabapentin or pregabalin. For analgesia on amitriptyline, use paracetamol, an NSAID, or morphine/oxycodone.
Mechanism
Venlafaxine (SNRI) has serotonin and noradrenergic activity; amitriptyline (TCA) acts the same way. Co-administration: additive serotonin syndrome, hypertension, and cardiotoxicity risk.
Symptoms
Serotonin syndrome: agitation, confusion, tremor, myoclonus, hyperreflexia. Autonomic features: sweating, tachycardia, hypertension, fever. First signs appear within hours of co-administration.
Management
Avoid the combination. For neuropathic pain, choose one: venlafaxine (SNRI) or gabapentin/pregabalin. Alternative for depression: mirtazapine or agomelatine.
Mechanism
Azithromycin weakly prolongs QT, additively with the TCA amitriptyline (a pronounced QT prolonger). Clinically significant arrhythmia is rare in young patients without cardiovascular disease.
Symptoms
QT prolongation on ECG. Dizziness, syncope, palpitations. Rarely: polymorphic ventricular tachycardia (torsades de pointes). Risk is higher with hypokalaemia, hypomagnesaemia, bradycardia, and ischaemic heart disease.
Management
For short azithromycin courses (3–5 days) in young patients, the combination is acceptable. In older patients, cardiac disease, or hypokalaemia: ECG before start, alternative antibiotics (doxycycline, a cephalosporin), or replace amitriptyline with gabapentin/pregabalin for neuropathic pain.
Mechanism
Amitriptyline (TCA) causes orthostatic hypotension via α1-adrenergic blockade. Combined with bisoprolol: dizziness on standing. Anticholinergic effect of amitriptyline may aggravate bradycardia.
Symptoms
Lower blood pressure, postural dizziness, fatigue. Older patients: fall risk. With additional antihypertensives: bradycardia (pulse below 60/min).
Management
The combination is acceptable at low amitriptyline doses (25–50 mg). For neuropathic pain, gabapentin or pregabalin (no α1-blockade) is preferable. Check blood pressure standing and sitting at 1 week after start.
Mechanism
Additive orthostatic hypotension via different mechanisms. Captopril (ACE-I) dilates vessels; amitriptyline blocks α1-adrenoceptors and reduces compensatory response.
Symptoms
Postural dizziness, syncope, fatigue. Older patients: fall and fracture risk.
Management
In older patients, check standing and sitting blood pressure 1–2 weeks after starting amitriptyline. For neuropathic pain, alternative: gabapentin or pregabalin.
Mechanism
TCA blocks α1-adrenoceptors — additive orthostatic hypotension with carvedilol (α/β-blocker). Amitriptyline's additive bradycardia and QT effect intensify as heart rate drops with carvedilol.
Symptoms
Postural dizziness, syncope, fatigue. Older patients: fall and fracture risk.
Management
On starting the combination, begin amitriptyline at 10 mg at bedtime. In older patients, do not exceed 25 mg/day. Check standing/sitting BP, heart rate, and ECG at 2 weeks. For neuropathic pain, alternatives: gabapentin or pregabalin. For depression: sertraline or escitalopram (minimal cardiovascular effect).
Mechanism
Additive anticholinergic effect (amitriptyline pronounced, celecoxib mild). In older patients, side-effect severity intensifies.
Symptoms
Dry mouth, constipation, urinary retention, accommodation disturbance, tachycardia. In older patients: delirium and confusion risk.
Management
On the combination, reassess the celecoxib benefit — for osteoarthritis, alternatives: topical NSAIDs or paracetamol up to 2 g/day. Avoid the combination in older patients. If unavoidable, cap amitriptyline at 25 mg/day. For constipation: fibre and adequate fluid intake (1.5 L/day).
Mechanism
Additive anticholinergic effect and sedation. Cetirizine is a second-generation antihistamine with minimal central activity, but the effect adds up with amitriptyline. Older patients: high delirium risk.
Symptoms
Dry mouth, constipation, urinary retention (anticholinergic effect). Drowsiness, ataxia. Older patients: delirium and fall risk.
Management
In older patients, an alternative antihistamine with minimal anticholinergic load: fexofenadine or bilastine. Take cetirizine during the day, not at bedtime. Monitor cognition in prolonged therapy.
Mechanism
Additive CNS depression and sedation. Older patients: delirium and fall risk.
Symptoms
Deep sedation, drowsiness, ataxia, confusion. Older patients: delirium and fall risk.
Management
Avoid the combination in older patients. If an anxiolytic is needed: minimum effective lorazepam or oxazepam dose (short-acting). For neuropathic pain, an alternative to amitriptyline: gabapentin or pregabalin.
Mechanism
Diltiazem weakly inhibits CYP2D6 and CYP3A4; amitriptyline is metabolised by both. TCA levels can rise, amplifying anticholinergic, sedative, and QT effects. Bradycardia is additive.
Symptoms
Dry mouth, constipation, urinary retention, accommodation disturbance, tachycardia. In older patients: delirium and confusion risk. Postural dizziness, syncope, fatigue. Older patients: fall and fracture risk.
Management
On the combination, begin amitriptyline at 10 mg at bedtime. Avoid the combination in older patients — orthostatic hypotension and arrhythmia risk. For neuropathic pain, alternatives: gabapentin or pregabalin. Antihypertensive alternatives: amlodipine or a beta-blocker without CYP effect.
Mechanism
Additive orthostatic hypotension. Enalapril (ACE-I) dilates vessels; amitriptyline blocks α1-adrenoceptors and reduces compensatory response. Older patients: fall and delirium risk.
Symptoms
Postural dizziness, syncope, fatigue. Older patients: fall and fracture risk.
Management
In older patients, check standing and sitting blood pressure 1–2 weeks after starting amitriptyline. For neuropathic pain, alternative: gabapentin or pregabalin (no α1-blockade).
Mechanism
Fluconazole weakly blocks CYP2C19 and CYP3A4 – amitriptyline metabolic routes. TCA plasma levels may rise with prolonged fluconazole courses.
Symptoms
Worsening anticholinergic symptoms (dry mouth, constipation, urinary retention), drowsiness, tachycardia. QT prolongation on ECG at fluconazole doses ≥200 mg.
Management
For short fluconazole courses (up to 7 days), no special adjustment. For prolonged systemic therapy (>14 days), reduce amitriptyline by 25% temporarily. Alternative antifungals: terbinafine for dermatophytosis or echinocandins.
Mechanism
Additive orthostatic hypotension. Amitriptyline blocks α1-adrenoceptors and reduces the compensatory vascular response to hypovolaemia (from the diuretic).
Symptoms
Postural dizziness, syncope, fatigue. Older patients: fall and fracture risk.
Management
In older patients, check standing and sitting blood pressure 1–2 weeks after starting amitriptyline. Advise slow rising. For neuropathic pain, alternative: gabapentin or pregabalin (no α1-blockade).
Mechanism
Additive CNS depression via different mechanisms. Sedation, dizziness, and fall risk amplify, especially in older patients.
Symptoms
Sedation, fatigue, slowed reactions, impaired coordination. In older patients: fall and fracture risk. Driving and operating machinery: accident risk.
Management
For neuropathic pain (diabetic neuropathy, post-herpetic neuralgia), start both at minimum doses: amitriptyline 10 mg at bedtime, gabapentin 100 mg three times daily. Up-titrate every 1–2 weeks as tolerated. Avoid in older patients — fall risk. Alternatives: duloxetine with topicals (capsaicin, lidocaine patch).
Mechanism
TCAs may mask hypoglycaemia symptoms (tremor, tachycardia) via anticholinergic effect. No direct pharmacokinetic interaction.
Symptoms
Sudden confusion, weakness, ataxia without preceding tachycardia or sweating. Older patients: risk of severe hypoglycaemia without warning symptoms.
Management
Warn the patient that the TCA masks hypoglycaemia warning signs. Check glucose more often (4 times daily in the first week, then by self-monitoring). In older patients, prefer gliclazide (less hypoglycaemia) or metformin/DPP-4 inhibitor over glibenclamide.
Mechanism
Additive orthostatic hypotension. Older patients: fall and delirium risk with thiazide-induced hypovolaemia.
Symptoms
Postural dizziness, syncope, fatigue. Older patients: fall and fracture risk.
Management
In older patients, check standing and sitting blood pressure and assess fluid and electrolyte balance. For neuropathic pain, alternative: gabapentin or pregabalin.
Mechanism
Additive orthostatic hypotension and hypokalaemia risk. Older patients: delirium risk with thiazide-like diuretic hypovolaemia.
Symptoms
Postural dizziness, syncope, fatigue. Older patients: fall and fracture risk.
Management
In older patients, check standing and sitting blood pressure, assess potassium and sodium. For neuropathic pain, alternative: gabapentin or pregabalin.
Mechanism
Ketoconazole blocks CYP3A4 (one of the amitriptyline metabolic routes). TCA plasma levels may rise.
Symptoms
Worsening anticholinergic symptoms, drowsiness, tachycardia. Older patients: delirium and fall risk.
Management
For short ketoconazole courses, reduce amitriptyline by 25% temporarily. Alternative antifungals without CYP3A4 effect: terbinafine for dermatophytosis or echinocandins for systemic mycoses.
Mechanism
Additive orthostatic hypotension. Losartan (ARB) dilates vessels; amitriptyline blocks α1-adrenoceptors. Older patients: fall risk.
Symptoms
Postural dizziness, syncope, fatigue. Older patients: fall and fracture risk.
Management
In older patients, check standing and sitting blood pressure 1–2 weeks after starting amitriptyline. For neuropathic pain, alternative: gabapentin or pregabalin.
Mechanism
Amitriptyline is a CYP2D6 substrate, as is metoprolol. Enzyme competition raises both drug levels. Plus additive anticholinergic effect on the heart (bradycardia, PR prolongation).
Symptoms
Bradycardia (heart rate below 50/min), dizziness, syncope. ECG: PR prolongation. Older patients: delirium and fall risk.
Management
In older patients, check pulse and ECG 1–2 weeks after starting amitriptyline. Alternative beta-blocker without CYP2D6 dependence: bisoprolol or carvedilol. For neuropathic pain, alternative: gabapentin or pregabalin.
Mechanism
Additive sedation, anticholinergic effect, and weight gain. Mirtazapine's serotonergic effect (via α2-blockade) is not pronounced on a TCA.
Symptoms
Deep sedation, drowsiness, dry mouth, constipation, weight gain. Older patients: delirium and fall risk.
Management
Avoid the combination, especially in older patients. For resistant depression augmentation: mirtazapine + SSRI (sertraline, escitalopram) instead of a TCA. For neuropathic pain: gabapentin or pregabalin.
Mechanism
Additive CNS depression, sedation, and anticholinergic effect (constipation, urinary retention). Older patients: delirium and fall risk.
Symptoms
Deep sedation, drowsiness, confusion. Constipation and urinary retention (amitriptyline anticholinergic effect amplified by opioid constipation). Older patients: delirium risk.
Management
The combination is common in cancer pain with depression or neuropathic pain. In older patients and palliative care: constipation prophylaxis (lactulose, polyethylene glycol) and urine output monitoring. Alternative antidepressant without anticholinergic effect: mirtazapine or agomelatine.
Mechanism
Additive orthostatic hypotension with sublingual nitroglycerin. Amitriptyline blocks α1-adrenoceptors and reduces compensatory response.
Symptoms
Postural dizziness, syncope, fatigue. Older patients: fall and fracture risk.
Management
The patient takes the first nitroglycerin dose sitting or lying down. Older patients: enhanced fall monitoring. Alternative antidepressants without α1-blockade: sertraline or agomelatine.
Mechanism
Similar to amitriptyline plus gabapentin — additive CNS depression. The combination is widely used in neuropathic pain, especially when monotherapy is insufficient.
Symptoms
Sedation, fatigue, slowed reactions, impaired coordination. In older patients: fall and fracture risk. Driving and operating machinery: accident risk.
Management
For neuropathic pain, start both at minimum doses: amitriptyline 10 mg at bedtime, pregabalin 75 mg twice daily. Up-titrate every 1–2 weeks as tolerated. Avoid in older patients — fall risk. Alternatives: duloxetine with topicals.
Mechanism
Additive bradycardia and orthostatic hypotension. Propranolol is non-selective (blocks β1 and β2); bradycardia risk is higher than with bisoprolol. Plus additive cardiac anticholinergic effect.
Symptoms
Bradycardia (heart rate below 50/min), dizziness, syncope. In asthma or COPD: bronchospasm risk. Older patients: delirium and fall risk.
Management
In older patients, check pulse and blood pressure 1–2 weeks after starting amitriptyline. In asthma or COPD, a selective beta-blocker (bisoprolol, metoprolol) is preferable.
Mechanism
Additive anticholinergic and QT effects. Both are sedating and orthostatically active. In older patients, cumulative anticholinergic burden raises delirium risk.
Symptoms
Dry mouth, constipation, urinary retention, accommodation disturbance, tachycardia. In older patients: delirium and confusion risk. Postural dizziness, syncope, fatigue. Older patients: fall and fracture risk. Pronounced morning sedation possible.
Management
Avoid in older patients — delirium and fall risk. In bipolar disorder with chronic pain, alternatives: lamotrigine (a non-sedating mood stabiliser) with gabapentin or pregabalin. If unavoidable (severe insomnia, migraine), begin both at minimum doses and check ECG at 2 weeks.
Mechanism
Ritonavir is a strong CYP2D6 and CYP3A4 inhibitor. Amitriptyline is metabolised by both. TCA AUC rises 2–3-fold, amplifying anticholinergic effects and QT prolongation.
Symptoms
Dry mouth, constipation, urinary retention, accommodation disturbance, tachycardia. In older patients: delirium and confusion risk. QT prolongation with torsades risk.
Management
Avoid in HIV-therapy patients. For neuropathic pain, alternatives: gabapentin or pregabalin. For depression: sertraline or escitalopram. If unavoidable, begin amitriptyline at 5 mg at bedtime and do not exceed 25 mg/day; check ECG at 1 and 2 weeks.
Mechanism
Tacrolimus prolongs QT; the TCA does the same independently via a quinidine-like effect on cardiomyocyte Na/K channels. Additive ventricular arrhythmia risk.
Symptoms
QT prolongation on ECG. Dizziness, syncope, palpitations. Maximum risk in older transplant patients with electrolyte disturbances.
Management
Avoid in prior QT prolongation or electrolyte disturbance. For neuropathic pain, alternatives: gabapentin or pregabalin (minimal QT effect). For depression: sertraline (minimal QT effect). If unavoidable: ECG before starting amitriptyline and at 1 and 4 weeks. Keep potassium and magnesium in the upper half of normal range.
Mechanism
Additive orthostatic hypotension. Both block α1-adrenoceptors: tamsulosin selectively (for the prostate), amitriptyline systemically. Effects add up.
Symptoms
Postural dizziness, syncope, fatigue. Older patients: fall and fracture risk.
Management
On the combination, begin amitriptyline at 10 mg at bedtime. In older patients, do not exceed 25 mg/day. Take tamsulosin in the evening. Check standing/sitting BP at 1–2 weeks. For neuropathic pain, alternatives: gabapentin or pregabalin.
Mechanism
Additive hypotension, especially orthostatic. Amitriptyline blocks α1-adrenoceptors; telmisartan is an ARB. Effects add up.
Symptoms
Postural dizziness, syncope, fatigue. Older patients: fall and fracture risk.
Management
On starting the combination, begin amitriptyline at 10 mg at bedtime. In older patients, do not exceed 25 mg/day. Check standing/sitting BP at 1–2 weeks. For neuropathic pain, alternatives: gabapentin or pregabalin.
Mechanism
Valproate weakly blocks hepatic amitriptyline metabolism; TCA plasma levels may rise. Plus additive sedation.
Symptoms
Worsening anticholinergic symptoms, drowsiness, sedation. Older patients: delirium and fall risk.
Management
Reduce amitriptyline by 25% if needed when combined. In older patients, monitor cognition and fall risk. For neuropathic pain, alternative: gabapentin or pregabalin.
Mechanism
Verapamil blocks CYP3A4 (one of the amitriptyline metabolic routes). TCA plasma levels may rise slightly. Plus additive bradycardia and PR prolongation.
Symptoms
Bradycardia, postural dizziness, syncope. ECG: PR prolongation. Older patients: delirium risk.
Management
In older patients, check pulse and ECG 1–2 weeks after starting amitriptyline. Alternative calcium channel blocker without CYP effect: amlodipine (with amitriptyline's α1-blockade – see the related pair). For neuropathic pain, alternative: gabapentin or pregabalin.
Mechanism
Amitriptyline is metabolised via CYP2C9 (a minor route) – weak competition with warfarin is possible. Mild INR rises have been reported when adding a TCA.
Symptoms
Mostly no changes. In some patients: a 10–15% INR rise 2–4 weeks after starting amitriptyline.
Management
After starting amitriptyline, check INR at 2 and 4 weeks, then resume routine monitoring. If INR rises above target, reduce warfarin by 5–10%. Alternative antidepressants without CYP2C9 dependence: sertraline or agomelatine.
Sources
Mechanism
Levetiracetam is not metabolised by the CYP system; no pharmacokinetic interaction with amitriptyline. Mild additive CNS depression is possible.
Symptoms
Possible mild sedation and fatigue at the start; usually resolve within 1–2 weeks.
Management
No dose adjustment needed. In epilepsy with depression or neuropathic pain, the combination is reasonable. Amitriptyline lowers seizure threshold at high doses, so begin with minimal doses (10 mg at bedtime) and monitor seizure frequency.
Mechanism
No direct interaction. Additive orthostatic hypotension possible in older patients during hypovolaemia: spironolactone via diuresis, amitriptyline via α1-blockade.
Symptoms
Possible postural dizziness, fatigue. In older patients: fall risk.
Management
Begin amitriptyline at 10 mg at bedtime. In older patients, do not exceed 25 mg/day. Check standing/sitting BP at 1–2 weeks. With pronounced orthostatic hypotension, consider neuropathic-pain alternatives: gabapentin or pregabalin.
FDA categories were retired in 2015 (historically C). Third-trimester use is associated with neonatal withdrawal syndrome. In pregnant patients with severe depression, continuation is individualized with a psychiatrist — untreated depression risk is significant for mother and fetus.
Transfers into milk in small amounts. Per LactMed, use is acceptable with infant sedation monitoring.
Reference information, not a clinical decision. Discuss feeding pauses or changes with your physician or an IBCLC.
FDA boxed warning: antidepressants increase suicidal ideation/behavior risk in children, adolescents, and adults under 25. Special monitoring in the first months and at dose changes.