Amitriptyline

Mechanism

Both drugs prolong the QT interval on the electrocardiogram: amiodarone through its main action (amiodarone SmPC), and amitriptyline commonly prolongs QT and widens the QRS complex (amitriptyline SmPC). Together they raise the risk of torsades de pointes. There is a second mechanism: amiodarone inhibits CYP2D6 (amiodarone SmPC), amitriptyline is cleared mainly by CYP2D6 and CYP2C19, and CYP2D6 inhibitors can markedly raise its levels (amitriptyline SmPC). Amiodarone is eliminated very slowly, so the interaction is possible for several months after it is stopped (amiodarone SmPC).

Symptoms

QT prolongation on the electrocardiogram (ECG) causes no symptoms by itself. Palpitations, dizziness or fainting may occur. The dangerous complication is torsades de pointes or other ventricular arrhythmias, sometimes fatal (amiodarone SmPC). Amiodarone can markedly slow the heart rate, especially in older people, and cause atrioventricular block (amiodarone SmPC). The risk of arrhythmia is higher with low potassium or magnesium, marked bradycardia, decompensated heart failure or heart disease (amitriptyline and amiodarone SmPCs).

Management

The combination is contraindicated: one of the Spanish amiodarone SmPCs contraindicates amiodarone with drugs that prolong the QT interval and names amitriptyline (amiodarone SmPC). The SmPC of the original amiodarone (Trangorex) says to avoid it with tricyclic antidepressants (amiodarone SmPC, Trangorex), and the label approved by the US Food and Drug Administration (FDA) says to avoid QT-prolonging drugs and names tricyclic antidepressants among them (amiodarone FDA label). The amitriptyline SmPC contraindicates amitriptyline in any heart block or rhythm disorder and does not recommend it with QT-prolonging drugs (amitriptyline SmPC). Before amiodarone is started, an electrocardiogram (ECG) is recorded and potassium is measured, and the ECG is monitored throughout treatment (amiodarone SmPC); low potassium, magnesium and calcium are corrected before the start (amiodarone FDA label). Amiodarone is eliminated over months, so the interaction is still possible after it is stopped (amiodarone SmPC).

Mechanism

Amitriptyline is a tricyclic antidepressant, and tricyclics are named among QT-prolonging drugs in both SSRI labels. Its own SmPC calls for caution with SSRIs because of serotonin syndrome. The citalopram SmPC lists ongoing treatment with any drug capable of prolonging the QT interval among its contraindications, with no exceptions. The kinetic part is weaker here than with escitalopram: the SmPC calls citalopram a weak CYP2D6 inhibitor and notes that with substrates of that enzyme, amitriptyline included, no clinically meaningful changes were seen. QT and serotonin remain the drivers.

Symptoms

QTc prolongation on ECG, palpitations, dizziness, syncope, with torsade at the far end. Serotonin syndrome is tracked separately: agitation, confusion, tremor, myoclonus, sweating, hyperthermia. Arrhythmia risk is higher with hypokalaemia, hypomagnesaemia and bradycardia.

Management

The pair sits in the citalopram SmPC contraindications, so the question is which drug stays, not how far to cut the dose. Beyond QT there is kinetics: amitriptyline runs through CYP2D6 and CYP2C19, and inhibiting either path raises its levels. For such combinations the amitriptyline label describes plasma level monitoring and dose adjustment.

Mechanism

Amitriptyline (tricyclic antidepressant) prolongs QT. Dronedarone also prolongs QT. Additive effect raises ventricular arrhythmia risk. FDA 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).

Mechanism

The escitalopram SmPC (AEMPS, sections 4.3 and 4.5) lists tricyclic antidepressants among QT-prolonging drugs and contraindicates their concomitant use. The combination has not been studied, and an additive effect on repolarisation cannot be excluded. Two more mechanisms sit on top of QT. Serotonergic: the amitriptyline SmPC calls for caution with SSRIs because of serotonin syndrome. Kinetic: amitriptyline is metabolised mainly through CYP2D6 and CYP2C19, escitalopram inhibits CYP2D6, and tricyclic levels rise. The amitriptyline label does not name escitalopram among potent CYP2D6 inhibitors, but the Lexapro label reports a direct tricyclic experiment: escitalopram 20 mg/day raised desipramine Cmax by 40% and AUC by 100%.

Symptoms

Serotonin syndrome: agitation, confusion, tremor, myoclonus, hyperthermia, tachycardia. QT prolongation on ECG up to torsade de pointes. The amitriptyline label singles out marked bradycardia, decompensated heart failure and electrolyte disturbance (hypokalaemia, hyperkalaemia, hypomagnesaemia) as the vulnerable situations. As amitriptyline levels rise, its dose-dependent effects grow stronger: dry mouth, constipation, urinary retention, orthostatic hypotension, confusion in older patients.

Management

The escitalopram label files this combination under contraindications, so ECG monitoring and dose reduction do not settle it, and one of the two drugs goes. Where a tricyclic is already running alongside a CYP2D6 inhibitor, the amitriptyline label describes monitoring tricyclic plasma levels and adjusting the dose. The two regulators diverge. The FDA Lexapro label stops at caution and monitoring, the AEMPS SmPC files the combination under contraindications, and the severity here follows the stricter European document. For neuropathic pain NICE CG173 puts four drugs in the first line – amitriptyline, duloxetine, gabapentin and pregabalin – so dropping amitriptyline leaves three. Duloxetine among them is serotonergic too.

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

Methylene blue (methylthioninium chloride) inhibits monoamine oxidase (MAO). The US Food and Drug Administration (FDA) amitriptyline label classes intravenous methylene blue as an MAO inhibitor, and the FDA methylene blue label cites literature describing it as a potent reversible inhibitor of this enzyme. Amitriptyline inhibits the reuptake of noradrenaline and serotonin (FDA amitriptyline label). Together they can cause severe, sometimes fatal serotonin syndrome (methylene blue labels). All reports that gave the route involved intravenous methylene blue at 1–8 mg/kg. There are no reports with oral tablets, local tissue injection or lower doses (FDA amitriptyline label).

Symptoms

Serotonin syndrome. Mental status changes: agitation, hallucinations, delirium, coma. Autonomic signs: tachycardia, labile blood pressure, dizziness, sweating, flushing, fever. Neuromuscular signs: tremor, rigidity, myoclonus, hyperreflexia, incoordination. Seizures, nausea, vomiting and diarrhoea may occur. Some reported cases were fatal (FDA methylene blue label). With tricyclic antidepressants and MAO inhibitors taken together, the FDA amitriptyline label reports hyperpyretic crises, severe convulsions and deaths.

Management

The combination is contraindicated: the US Food and Drug Administration (FDA) amitriptyline label says it should not be given with MAO inhibitors and should not be started in a patient receiving intravenous methylene blue. The methylene blue labels approved by the European Medicines Agency (EMA) and the FDA say to avoid it in patients taking drugs that enhance serotonergic transmission, antidepressants included. If a patient on amitriptyline needs methylene blue, stop amitriptyline before it is given (FDA amitriptyline label). When methylene blue cannot be avoided, give the lowest possible dose and observe the patient for nervous system effects for 4 hours (methylene blue labels). Monitor the ECG and blood pressure during and after the infusion (EMA methylene blue SmPC). If signs of serotonin syndrome appear, stop methylene blue and amitriptyline and start supportive treatment (FDA labels of both drugs). Restart amitriptyline no earlier than 14 days after the last methylene blue dose, cautiously and with gradual dose increases, as the FDA amitriptyline label requires after an MAO inhibitor.

Mechanism

Selegiline selectively inhibits monoamine oxidase type B (MAO-B), the enzyme mainly responsible for dopamine breakdown in the brain (selegiline SmPC). The US Food and Drug Administration (FDA) label for selegiline in Parkinson's disease adds that this inhibition is irreversible, that selectivity for MAO-B may be incomplete even at the recommended dose, and that it is lost above it (selegiline SmPC: above 10 mg a day). Amitriptyline is a tricyclic antidepressant that blocks the reuptake of noradrenaline and serotonin at nerve endings (amitriptyline SmPC). With breakdown slowed and reuptake blocked, serotonin builds up in the synapse. The selegiline SmPC reports severe central nervous system toxicity, a serotonin syndrome, sometimes with hypertension, hypotension and sweating, in patients on tricyclic antidepressants plus selegiline. On that basis it contraindicates the combination. The FDA amitriptyline label reports hyperpyretic crises, severe convulsions and deaths in patients given a tricyclic antidepressant together with an MAO inhibitor.

Symptoms

Serotonin syndrome: agitation, confusion, hallucinations, delirium up to coma, tremor, myoclonus, muscle rigidity, hyperreflexia, incoordination, hyperthermia, tachycardia, labile blood pressure, sweating, nausea, vomiting, diarrhoea (amitriptyline and selegiline SmPCs). With tricyclic antidepressants the selegiline SmPC describes severe central nervous system toxicity with hypertension, hypotension and sweating. The US Food and Drug Administration (FDA) amitriptyline label warns of hyperpyretic crises, severe convulsions and deaths when a tricyclic antidepressant and a monoamine oxidase (MAO) inhibitor are taken together.

Management

The combination is contraindicated. The selegiline SmPC bans selegiline with tricyclic antidepressants (sections 4.3 and 4.5). The amitriptyline SmPC bans amitriptyline with monoamine oxidase (MAO) inhibitors and names selegiline (sections 4.3 and 4.5). The US Food and Drug Administration (FDA) amitriptyline label bans MAO inhibitors as a class. The two drugs are not given together at any dose or for any length of time. When switching from selegiline to amitriptyline, allow at least 14 days after the last dose of selegiline (FDA amitriptyline label; FDA label for selegiline in Parkinson's disease). Start amitriptyline cautiously, with gradual dose increases (FDA amitriptyline label). When switching from amitriptyline to selegiline, allow 14 days after stopping amitriptyline (amitriptyline SmPC). If a patient is already taking both, stop both immediately at the first signs of serotonin syndrome and start supportive treatment (FDA amitriptyline label). When the syndrome is suspected, the amitriptyline SmPC asks for a dose reduction or interruption depending on severity. The FDA label for the selegiline patch names only clomipramine and imipramine among tricyclics, but the oral selegiline and amitriptyline documents ban the whole class.

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

Both drugs prolong the QT interval. Azithromycin, like other macrolides, prolongs cardiac repolarisation and the QT interval, which carries a risk of torsades de pointes (azithromycin SmPC). QT prolongation and arrhythmias have been reported with amitriptyline, and its SmPC lists QT-prolonging drugs among combinations that are not recommended: with tricyclic antidepressants they increase the likelihood of ventricular arrhythmias (amitriptyline SmPC).

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

The amitriptyline SmPC lists QT-prolonging drugs among combinations that are not recommended (amitriptyline SmPC). Azithromycin is used with caution in patients who take QT-prolonging drugs and in those with QT prolongation, low potassium or magnesium, clinically relevant bradycardia, arrhythmia, severe heart failure and in older people (azithromycin SmPC). The US Food and Drug Administration (FDA) asks prescribers to weigh the risk of QT prolongation against the benefit of azithromycin in these patients (azithromycin FDA label). Avoid the combination where possible. If it is still needed, keep in mind that with amitriptyline the arrhythmia risk is higher with marked bradycardia, uncompensated heart failure and potassium or magnesium disturbances (amitriptyline SmPC).

Mechanism

The combination works along two lines. Kinetics: bupropion and its metabolite hydroxybupropion inhibit CYP2D6 (bupropion SmPC), an enzyme that clears amitriptyline. The amitriptyline SmPC names bupropion as a potent CYP2D6 inhibitor that can markedly raise tricyclic levels. With another tricyclic, desipramine, bupropion increased peak concentration and AUC 2- to 5-fold, and the enzyme stayed inhibited for at least 7 days after the last bupropion dose (bupropion SmPC). Seizures: bupropion seizure risk is dose-related and rises with drugs that lower the seizure threshold, antidepressants included (bupropion labels).

Symptoms

Seizures: their risk rises when bupropion is combined with antidepressants (bupropion labels). Signs of amitriptyline excess: drowsiness, dry mouth, constipation, urinary retention, dilated pupils, fast heartbeat and dizziness on standing. High amitriptyline levels can cause arrhythmias, QT prolongation and marked hypotension (amitriptyline SmPC). Bupropion itself can cause insomnia and dry mouth (bupropion SmPC).

Management

Use the combination only when it is clinically justified. The bupropion SmPC for smoking cessation says bupropion should not be used in patients taking antidepressants unless there is a justified clinical reason, and then a maximum of 150 mg a day should be considered for the rest of the course. The FDA bupropion label asks for extreme caution, a low starting dose of bupropion and gradual increases, up to 300 mg a day. Assess seizure risk factors in every patient before starting. Bupropion is contraindicated with a current or past seizure disorder, a central nervous system tumour, bulimia or anorexia nervosa. If a seizure occurs, stop bupropion and do not restart it (bupropion labels). When bupropion is added to amitriptyline, consider a lower amitriptyline dose based on response and monitoring of its plasma level (amitriptyline SmPC). Bupropion keeps inhibiting the enzyme for at least 7 days after it is stopped, which matters when doses are changed (bupropion SmPC).

Mechanism

Carbamazepine is a potent inducer of CYP3A4 and other phase I and phase II liver enzymes (carbamazepine SmPC). It speeds up the metabolism of tricyclic antidepressants, their plasma levels fall and the antidepressant response weakens (amitriptyline SmPC).

Symptoms

Return of depressive symptoms or neuropathic pain. In depression: relapse risk.

Management

Per the carbamazepine SmPC, adjust the amitriptyline dose to clinical response. After carbamazepine is started or its dose changed, watch for return of depressive symptoms or pain; if they return, increase the amitriptyline dose. The FDA label also allows monitoring amitriptyline plasma levels. When carbamazepine is stopped, induction wears off, so review the amitriptyline dose again.

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

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

Tricyclic antidepressants, amitriptyline included, can counteract centrally acting antihypertensives such as clonidine (amitriptyline SmPC). The clonidine SmPC adds that the blood pressure lowering effect of clonidine may be reduced or lost entirely. The combination can also cause or worsen orthostatic dysregulation, a drop in blood pressure on standing (clonidine SmPC).

Symptoms

Blood pressure drifts above target: home and clinic readings are higher than before, and some patients get headache or dizziness. On standing, orthostatic hypotension can cause dizziness and weakness (clonidine labels).

Management

The combination is not recommended: the Spanish amitriptyline SmPC lists clonidine under combinations that are not recommended and advises reviewing all antihypertensive treatment while a tricyclic antidepressant is used. When reviewing it, keep in mind that clonidine may stop lowering blood pressure and that orthostatic dysregulation may get worse (clonidine SmPC). The FDA clonidine label notes that a higher clonidine dose may be needed with tricyclic antidepressants. If clonidine is to be stopped, do not stop it abruptly: taper the dose over 2–4 days, otherwise blood pressure can rise quickly. In a patient also taking a beta-blocker, withdraw the beta-blocker gradually first and clonidine after it (clonidine SmPC).

Mechanism

Fluconazole moderately inhibits CYP2C9 and CYP3A4 and strongly inhibits CYP2C19 (fluconazole SmPC). The liver breaks down amitriptyline mainly through CYP2D6 and CYP2C19, with CYP3A4 and CYP2C9 also involved (amitriptyline SmPC). Fluconazole raises the levels of amitriptyline and its metabolite nortriptyline and increases their effect (both SmPCs). Each drug can prolong the QT interval on its own. The enzyme effect of fluconazole lasts 4–5 days after it is stopped (fluconazole SmPC).

Symptoms

Stronger amitriptyline side effects: dry mouth, constipation, urinary retention, drowsiness, fast heartbeat. Fainting and torsades de pointes have been reported with this combination (amitriptyline SmPC). The risk of dangerous arrhythmia is higher with low potassium and advanced heart failure (fluconazole SmPC).

Management

The amitriptyline SmPC lists fluconazole among combinations that are not recommended: it raises the levels and toxicity of tricyclic antidepressants. If fluconazole cannot be avoided, measure nortriptyline and amitriptyline levels when co-treatment starts and after one week, and adjust the amitriptyline dose if needed (fluconazole SmPC). Use fluconazole with caution in conditions that predispose to arrhythmia (fluconazole SmPC), and amitriptyline with caution in significant bradycardia, decompensated heart failure and with other QT-prolonging drugs (amitriptyline SmPC). The fluconazole effect lasts 4–5 days after the last dose, so do not stop monitoring as soon as fluconazole is stopped (fluconazole SmPC). Terbinafine is not a substitute: the amitriptyline SmPC names it together with fluconazole, as it also raises tricyclic levels.

Mechanism

The combination works along three lines. Kinetics: fluoxetine strongly inhibits CYP2D6, which clears amitriptyline, so amitriptyline levels can rise markedly (labels of both drugs). The FDA fluoxetine label gives data for imipramine and desipramine: their stable plasma levels rose 2- to 10-fold, and the effect lasted 3 weeks or longer after fluoxetine was stopped. Serotonin: both drugs enhance it and together raise the risk of serotonin syndrome. Heart and seizures: both can prolong the QT interval, and the combination can raise seizure risk (labels of both drugs).

Symptoms

Signs of amitriptyline excess: drowsiness, dry mouth, constipation, urinary retention, dilated pupils, fast heartbeat, dizziness on standing and confusion. High levels can cause arrhythmias, QT prolongation, seizures and marked hypotension (amitriptyline SmPC). Serotonin syndrome as described in the FDA fluoxetine label: agitation, hallucinations, delirium, tremor, rigidity, myoclonus, hyperreflexia, fever, sweating, tachycardia, labile blood pressure, nausea, vomiting, diarrhoea.

Management

The combination is acceptable only with careful dosing. While the patient takes fluoxetine and for 5 weeks after it is stopped, amitriptyline is started or adjusted within the lowest therapeutic range (fluoxetine SmPC). The FDA fluoxetine label warns that the tricyclic dose may need to be reduced and its plasma level monitored for a while, including after fluoxetine was recently stopped. When fluoxetine is added to amitriptyline, consider a lower amitriptyline dose and monitoring of its level (amitriptyline SmPC). Watch for serotonin syndrome at the start of treatment and after each dose increase; if it appears, stop both drugs at once and start supportive treatment (FDA labels of both drugs). In stable heart disease consider an ECG before starting fluoxetine; with risk factors for QT prolongation consider periodic ECGs as well; stop fluoxetine if signs of arrhythmia appear (fluoxetine labels). Low potassium or magnesium raises the risk of arrhythmia, so take it into account when prescribing (labels of both drugs).

Mechanism

Amitriptyline is cleared in the liver by several enzymes, mainly CYP2D6 and CYP2C19, and to a lesser extent CYP1A2 and CYP3A4 (amitriptyline SmPC). Fluvoxamine strongly inhibits CYP1A2 and CYP2C19 (fluvoxamine SmPC). The amitriptyline SmPC states that fluvoxamine raises amitriptyline plasma levels, and the FDA fluvoxamine label reports significantly increased levels of tricyclic antidepressants, amitriptyline included. Both drugs also enhance serotonin activity, so the combination raises the risk of serotonin syndrome (amitriptyline SmPC, FDA fluvoxamine label).

Symptoms

Signs of amitriptyline excess: drowsiness, dry mouth, constipation, urinary retention, dilated pupils, fast heartbeat, dizziness on standing and confusion. High levels can cause arrhythmias, QT prolongation, seizures and marked hypotension (amitriptyline SmPC). Serotonin syndrome: agitation, hallucinations, tremor, muscle rigidity, myoclonus, fever, sweating, tachycardia, labile blood pressure, nausea, vomiting, diarrhoea (FDA fluvoxamine label, amitriptyline SmPC).

Management

Avoid the combination: the Spanish amitriptyline SmPC says so directly. If both drugs are still used, the fluvoxamine SmPC asks to consider lowering the amitriptyline dose when fluvoxamine is started, and the FDA fluvoxamine label advises monitoring tricyclic plasma levels and reducing the tricyclic dose if needed. Watch for serotonin syndrome at the start of treatment and after each dose increase. If it appears, stop amitriptyline and other serotonergic drugs at once and start supportive treatment (FDA amitriptyline label). Use amitriptyline with caution in marked bradycardia, decompensated heart failure and with QT-prolonging drugs; potassium or magnesium disturbances raise the risk of arrhythmia (amitriptyline SmPC).

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

Amitriptyline increases the sedative effect of other central nervous system depressants (amitriptyline SmPC), and morphine combined with such drugs can cause respiratory depression, low blood pressure, deep sedation and coma (morphine SmPC). The second mechanism is the anticholinergic effect of amitriptyline: with morphine it raises the risk of severe constipation, paralytic ileus and urinary retention (morphine SmPC). The third is serotonergic: the US Food and Drug Administration (FDA) warns about serotonin syndrome when opioids are combined with tricyclic antidepressants (morphine FDA label).

Symptoms

Deep sedation, drowsiness, confusion, slow or shallow breathing, low blood pressure. Severe constipation, bloating and abdominal pain, urinary retention. In older people: confusion, delirium, falls. With serotonin syndrome: changes in mental state, swings in blood pressure and pulse, sweating, fever, tremor and muscle twitching, nausea and diarrhoea.

Management

The morphine SmPCs require reduced doses and the greatest caution in patients who take tricyclic antidepressants (morphine SmPCs). The oral morphine SmPC lists antidepressants among central nervous system depressants and requires limiting the dose and duration of concomitant use (oral morphine SmPC). Morphine is not recommended with drugs that have anticholinergic action unless strictly necessary; if they are combined, reduce the dose of the other drug and monitor the patient closely (injectable morphine SmPC). Watch the patient for respiratory depression and excessive sedation, urinary retention and slowed bowel movement (morphine SmPCs). The US Food and Drug Administration (FDA) asks for frequent evaluation of the patient, especially at the start of treatment and after dose changes, and for stopping morphine if serotonin syndrome is suspected (morphine FDA label).

Mechanism

Both drugs prolong the QT interval. The amitriptyline SmPC lists QT-prolonging drugs, including some antipsychotics, among combinations that are not recommended because of the risk of ventricular arrhythmias (amitriptyline SmPC), and QT prolongation has been reported with quetiapine at therapeutic doses (quetiapine SmPC). A second mechanism is the combined anticholinergic effect: in quetiapine it comes from its metabolite norquetiapine (quetiapine SmPC), and amitriptyline has its own (amitriptyline label of the US Food and Drug Administration, FDA). Tricyclic antidepressants and neuroleptics inhibit each other's metabolism, which can lower the seizure threshold (amitriptyline SmPC). The quetiapine SmPC also warns about serotonin syndrome with tricyclic antidepressants.

Symptoms

Palpitations, dizziness, fainting; QT prolongation on the electrocardiogram (ECG) and, in severe cases, torsades de pointes. Dry mouth, constipation, urinary retention, blurred vision, fast heart rate; in older people, confusion, slowed thinking, delirium and falls. Drowsiness and dizziness on standing. Raised body temperature has been reported when amitriptyline is combined with anticholinergic or neuroleptic drugs, especially in hot weather.

Management

The amitriptyline SmPC lists QT-prolonging drugs among combinations that are not recommended (amitriptyline SmPC), and the US Food and Drug Administration (FDA) says quetiapine should be avoided with other drugs known to prolong the QT interval (quetiapine FDA label). Avoid the combination where possible. If it is still needed, take into account the situations in which the quetiapine SmPC asks for particular caution: older age, congenital long QT, heart failure, cardiac hypertrophy, low potassium or magnesium (quetiapine SmPC). In older patients, start amitriptyline at low doses and observe them closely (amitriptyline FDA label). Because of the combined anticholinergic effect, use quetiapine with caution in patients with urinary retention, enlarged prostate, bowel obstruction, raised intraocular pressure or narrow-angle glaucoma (quetiapine SmPC). The dose of either drug may need adjustment because each inhibits the metabolism of the other (amitriptyline SmPC).

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).

Mechanism

Amitriptyline has marked anticholinergic properties (amitriptyline label). Solifenacin blocks muscarinic receptors and also causes anticholinergic adverse effects (solifenacin label). These effects add up. According to the amitriptyline label, tricyclic antidepressants can potentiate the action of anticholinergic drugs on the eye, brain, bowel and bladder, which raises the risk of paralytic ileus and hyperpyrexia. The second pathway is cardiac. QT interval prolongation is a common adverse reaction to amitriptyline (amitriptyline label). QT prolongation and torsade de pointes have occurred with solifenacin in patients with risk factors (solifenacin label). The labels describe no pharmacokinetic interaction. Solifenacin does not inhibit the cytochrome P450 (CYP) enzymes that break down amitriptyline and is unlikely to change its clearance. The labels say nothing about the effect of amitriptyline on solifenacin.

Symptoms

Peripheral anticholinergic effects include dry mouth, constipation, urinary retention, blurred vision, a fast heartbeat and, in people with a narrow anterior chamber angle, an attack of angle-closure glaucoma (both labels). The most serious complications are paralytic ileus and overheating with high fever, especially in hot weather, because sweating decreases (amitriptyline and solifenacin labels). Central effects include confusion, hallucinations, drowsiness and delirium (both labels). Older people have a higher risk of falls (amitriptyline label, US Food and Drug Administration, FDA). An arrhythmia due to QT interval prolongation shows as palpitations or fainting, and the electrocardiogram shows a long QT interval.

Management

The combination is not recommended. The amitriptyline label says to avoid it with anticholinergic drugs because of the risk of paralytic ileus and hyperpyrexia (Spanish Agency of Medicines and Medical Devices, AEMPS, section 4.5). The solifenacin label of the US Food and Drug Administration (FDA) does not recommend solifenacin in patients who take drugs known to prolong the QT interval. Amitriptyline is one of these drugs (amitriptyline label, 4.4 and 4.8). For nocturnal enuresis in children, amitriptyline must not be combined with any anticholinergic drug (amitriptyline label, 4.4). Solifenacin tablets are not for children (solifenacin label, 4.2). If both drugs are still prescribed, supervise closely and adjust doses carefully. In older patients, start amitriptyline at low doses (US amitriptyline label, FDA). Before starting, rule out the solifenacin contraindications: urinary retention, severe gastrointestinal disorders, angle-closure glaucoma or a risk of these conditions (solifenacin label, 4.3). For the heart, take into account the risk factors named in both labels: marked bradycardia, decompensated heart failure, low or high potassium, low magnesium and known QT prolongation. If confusion, hallucinations or drowsiness appear, consider lowering the solifenacin dose or stopping it (US solifenacin label, FDA). Ask the patient to report constipation lasting 3 days or more or abdominal pain, and to avoid overheating in hot weather (US solifenacin label; amitriptyline label). When solifenacin is stopped to switch to another drug with anticholinergic action, wait about one week (solifenacin label, 4.5).

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

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

The combination works along two lines. Kinetics: duloxetine is a moderate inhibitor of CYP2D6, an enzyme that clears amitriptyline (labels of both drugs). With another tricyclic, desipramine, duloxetine tripled AUC (duloxetine SmPC). Serotonin: both drugs block the reuptake of serotonin and noradrenaline, and the combination raises the risk of serotonin syndrome (labels of both drugs).

Symptoms

Serotonin syndrome: agitation, hallucinations, coma, tachycardia, labile blood pressure, fever, hyperreflexia, incoordination, nausea, vomiting, diarrhoea. In its most severe form it resembles neuroleptic malignant syndrome, with fever and muscle rigidity (duloxetine SmPC). Signs of amitriptyline excess: drowsiness, dry mouth, constipation, urinary retention, fast heartbeat, dizziness on standing, and at high levels arrhythmias and QT prolongation (amitriptyline SmPC).

Management

Use the combination with caution (labels of both drugs). Watch for serotonin syndrome at the start of treatment and after each dose increase. The FDA labels of both drugs require stopping both drugs at once and starting supportive treatment if it appears. The amitriptyline plasma level may need monitoring and its dose may need reducing (FDA duloxetine label). Measure blood pressure before starting duloxetine and periodically during treatment, and do not start duloxetine in uncontrolled hypertension (duloxetine labels). Use amitriptyline with caution in marked bradycardia, decompensated heart failure and with QT-prolonging drugs; potassium or magnesium disturbances raise the risk of arrhythmia (amitriptyline SmPC).

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

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 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

Ritonavir strongly inhibits CYP3A4, and at full antiretroviral doses it probably inhibits CYP2D6 as well (ritonavir SmPC). The liver breaks down amitriptyline mainly through CYP2D6 and CYP2C19, and to a lesser degree through CYP3A4 (amitriptyline SmPC). The ritonavir SmPC expects higher amitriptyline levels, and the amitriptyline SmPC expects a clinically relevant interaction with strong CYP3A4 inhibitors, naming ritonavir. Neither document gives the size of the rise.

Symptoms

Dry mouth, constipation, urinary retention, accommodation disturbance, tachycardia. In older patients: delirium and confusion risk. QT prolongation with torsades risk.

Management

The combination is allowed but needs monitoring. With ritonavir at full antiretroviral doses, watch the therapeutic and adverse effects of amitriptyline closely (ritonavir SmPC). The amitriptyline dose may need to be lowered (US Food and Drug Administration (FDA) ritonavir label). When a tricyclic antidepressant is combined with a strong CYP2D6 inhibitor, the amitriptyline SmPC advises considering plasma level monitoring and adjusting the dose if needed. Use amitriptyline with caution in significant bradycardia, decompensated heart failure and with other drugs that prolong the QT interval (amitriptyline SmPC). After ritonavir is stopped, amitriptyline levels may fall and a higher antidepressant dose may be needed (FDA amitriptyline label).

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.

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.