Tramadol

Mechanism

Tramadol is a weak opioid with additional serotonin–norepinephrine reuptake inhibition. With diazepam, the risk is doubled: additive CNS and respiratory depression plus a lowered seizure threshold (tramadol provokes seizures on its own).

Symptoms

Drowsiness, slowed breathing. Seizures may occur, especially in patients with prior epilepsy or with dose excess. Serotonin syndrome is less common unless other serotonergics are added.

Management

Avoid where possible. If unavoidable, minimal doses of both and a short course. Alternative analgesia: paracetamol with an NSAID; alternative anxiolytics: gabapentinoids or hydroxyzine.

Mechanism

Tramadol is an opioid with serotonin–norepinephrine reuptake inhibition. Linezolid reversibly inhibits MAO. Co-administration causes a sharp rise in synaptic serotonin and risk of serotonin syndrome.

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 tramadol 24–72 hours before starting linezolid. For analgesia, use paracetamol, NSAIDs (if not contraindicated), or pure opioid agonists such as morphine or oxycodone with no serotonergic activity.

Mechanism

Methylene blue (methylthioninium chloride) inhibits monoamine oxidase (MAO). The US Food and Drug Administration (FDA) tramadol 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. Tramadol is an opioid that inhibits noradrenaline reuptake and enhances serotonin release (tramadol SmPC). The FDA methylene blue label warns that use with opioids may cause serious or fatal serotonin syndrome. The FDA tramadol label adds that MAO inhibitor interactions with opioids may also present as opioid toxicity, and that MAO inhibitors raise the risk of seizures on tramadol.

Symptoms

Serotonin syndrome: agitation, hallucinations, coma, tachycardia, labile blood pressure, fever, hyperreflexia, incoordination, muscle rigidity, nausea, vomiting, diarrhoea. Symptoms usually start within several hours to a few days of combined use, but may appear later (US Food and Drug Administration, FDA, tramadol label). Some reported cases with methylene blue were fatal (FDA methylene blue label). Seizures may occur. The interaction can also present as opioid toxicity: respiratory depression up to coma (FDA tramadol label).

Management

The combination is contraindicated: the US Food and Drug Administration (FDA) tramadol label contraindicates tramadol with MAO inhibitors and within 14 days of their use, and the same label classes intravenous methylene blue as an MAO inhibitor. It also says not to start an MAO inhibitor while taking tramadol. The FDA methylene blue label says to avoid it in patients taking opioids, and the European Medicines Agency (EMA) label says to avoid it with drugs that enhance serotonergic transmission. 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 serotonin syndrome is suspected, stop tramadol at once (FDA tramadol label), stop methylene blue and start supportive treatment (methylene blue labels). Start tramadol no earlier than 14 days after the last methylene blue dose (FDA tramadol label).

Mechanism

Moclobemide reversibly inhibits monoamine oxidase (MAO), mainly subtype A, and slows the breakdown of serotonin, noradrenaline and dopamine (moclobemide SmPC). Tramadol is an opioid that inhibits noradrenaline reuptake and enhances serotonin release (tramadol SmPC). Together they can cause life-threatening serotonin syndrome. The tramadol SmPC warns of a second risk: patients who received MAO inhibitors before the opioid pethidine had life-threatening reactions affecting the nervous system, breathing and circulation, and the same reactions cannot be ruled out with tramadol. The US Food and Drug Administration (FDA) tramadol label adds that MAO inhibitors raise the risk of seizures on tramadol.

Symptoms

Serotonin syndrome: agitation, hallucinations, confusion, fever, tachycardia, labile blood pressure, hyperreflexia, myoclonus, muscle rigidity, incoordination, nausea, vomiting, diarrhoea (moclobemide and tramadol labels). Seizures may occur. The interaction of MAO inhibitors with opioids can also present as opioid toxicity: respiratory depression up to coma (FDA tramadol label).

Management

The combination is contraindicated. The moclobemide SmPC prohibits it with tramadol by name. The tramadol SmPC contraindicates tramadol in patients who are taking MAO inhibitors or have taken them within the last 14 days, and the US Food and Drug Administration (FDA) tramadol label sets the same 14-day ban. So tramadol is started no earlier than 14 days after the last moclobemide dose (tramadol labels). The FDA tramadol label also says not to start an MAO inhibitor while taking tramadol. If a patient has received both drugs, watch for signs of serotonin syndrome and stop tramadol at once if it is suspected (FDA tramadol label). Withdrawal of the serotonergic drugs usually brings rapid improvement (tramadol SmPC).

Mechanism

Tramadol inhibits serotonin reuptake (secondary mechanism). Combined with phenelzine causes fatal serotonin syndrome – fatal cases reported. FDA boxed warning on tramadol.

Symptoms

Within 1–6 hours: hyperthermia above 39°C, myoclonus, agitation, seizures. High mortality without tramadol withdrawal.

Management

Combination contraindicated. Alternative analgesic: paracetamol or gabapentin (no serotonergic effect). If opioid is needed, morphine with caution.

Mechanism

Selegiline inhibits monoamine oxidase type B (MAO-B) (selegiline SmPC). The selegiline SmPC warns that above the recommended 10 mg a day it may lose its selectivity for MAO-B, and the US Food and Drug Administration (FDA) selegiline label says that selectivity may be incomplete even at the recommended dose. Tramadol is an opioid that inhibits noradrenaline reuptake and enhances serotonin release (tramadol SmPC). The FDA label for selegiline in Parkinson's disease reports serious, sometimes fatal reactions when opioids, tramadol included, were combined with MAO inhibitors, including selective MAO-B inhibitors. The FDA tramadol label specifies that this interaction presents as serotonin syndrome or opioid toxicity, and that MAO inhibitors raise the risk of seizures on tramadol.

Symptoms

Serotonin syndrome: agitation, hallucinations, confusion, fever, tachycardia, labile blood pressure, hyperreflexia, muscle rigidity, incoordination, nausea, vomiting, diarrhoea (FDA tramadol label). Seizures may occur. The interaction of MAO inhibitors with opioids can also present as opioid toxicity: respiratory depression up to coma (FDA tramadol label).

Management

The combination is contraindicated. The selegiline SmPC prohibits selegiline with opioids, and the US Food and Drug Administration (FDA) selegiline labels name tramadol directly. The Spanish and FDA tramadol labels contraindicate tramadol in patients who are taking MAO inhibitors or have taken them within the last 14 days, and selegiline is an MAO-B inhibitor (selegiline SmPC). So tramadol is started no earlier than 14 days after selegiline is stopped (tramadol labels; FDA label for selegiline in Parkinson's disease). For the reverse switch, the FDA label for transdermal selegiline requires waiting 4 to 5 half-lives of the drug and its active metabolites after the last tramadol dose, about one week. If a patient has received both drugs, watch for signs of serotonin syndrome and stop tramadol at once if it is suspected (FDA tramadol label).

Mechanism

Tranylcypromine irreversibly inhibits MAO. Tramadol inhibits serotonin reuptake. Combination causes fatal serotonin syndrome.

Symptoms

Hyperthermia, myoclonus, agitation, seizures.

Management

Combination contraindicated. Alternative analgesic: paracetamol.

Mechanism

Alprazolam and tramadol depress the central nervous system and respiratory centre. Tramadol additionally lowers the seizure threshold and raises serotonergic activity. Fatal overdoses have been reported.

Symptoms

Drowsiness, sedation, slowed breathing. Seizures may occur (tramadol) and syncope from orthostatic hypotension. Older patients: fall risk.

Management

Avoid the combination. For analgesia on alprazolam, use paracetamol, an NSAID, or morphine/oxycodone (with respiratory depression warning). Alternative anxiolytics: hydroxyzine or gabapentinoids.

Mechanism

Dual mechanism: tramadol weakly prolongs QT (additive with amiodarone) and lowers the seizure threshold. Amiodarone also blocks CYP2D6 – the main tramadol activation route – so analgesia weakens while serotonergic activity persists.

Symptoms

QT prolongation on ECG, palpitations, syncope. Seizures may occur, especially in patients with prior epilepsy. Weakened tramadol analgesic effect.

Management

Avoid the combination. For analgesia in patients on amiodarone, use paracetamol, NSAIDs (with caution in heart failure), or morphine/oxycodone (pure opioids without QT effect).

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

Bupropion blocks CYP2D6 – the route converting tramadol to its active M1 metabolite. Analgesia falls but parent tramadol accumulates, raising seizure risk. Both drugs also lower the seizure threshold.

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 analgesia on bupropion, use paracetamol, an NSAID, or morphine/oxycodone. For neuropathic pain, gabapentin or pregabalin.

Mechanism

Dual risk: both drugs lower the seizure threshold. Ciprofloxacin also blocks CYP1A2 (a minor tramadol activation route) and weakly affects serotonergic activity.

Symptoms

Seizures, especially in patients with prior epilepsy or head injury. Serotonin syndrome may occur with other serotonergics on board (agitation, tremor, hyperthermia).

Management

Avoid the combination in patients with prior epilepsy. Alternative antibiotics: a cephalosporin or nitrofurantoin (no seizure threshold effect). Alternative analgesics: paracetamol, an NSAID, or morphine.

Mechanism

Tramadol inhibits serotonin reuptake, and so does citalopram, so together they raise the risk of serotonin syndrome. Both drugs lower the seizure threshold. Pharmacokinetics play little part: citalopram is only a weak CYP2D6 inhibitor, the enzyme that forms tramadol's active metabolite.

Symptoms

Serotonin syndrome: agitation, confusion, tremor, myoclonus, hyperreflexia, sweating, diarrhoea, tachycardia, and in severe cases hyperthermia and rigidity. Symptoms usually appear within a day of adding the second drug or raising the dose. In patients with cardiac risk factors QTc is tracked separately.

Management

The Spanish citalopram label states that citalopram should not be used with serotonergic drugs, opioids and tramadol included. For pain relief in a patient taking citalopram, choose paracetamol. If tramadol is still needed, warn the patient about serotonin syndrome and watch for agitation, tremor, myoclonus, sweating and fever during the first days and after each dose increase. Stop both drugs if serotonin syndrome is suspected. Keep tramadol at or below 400 mg a day per the label, and use it in patients with epilepsy only when the circumstances require it.

Mechanism

Tramadol and clozapine both depress the central nervous system, and together they raise the risk of profound sedation, respiratory depression, coma and death (tramadol label). Both lower the seizure threshold: tramadol can cause seizures even at recommended doses and adds to the seizure potential of antipsychotics, while the seizure risk of clozapine rises with the dose (tramadol and clozapine labels). Clozapine slows gut motility through its potent anticholinergic effect and tramadol also reduces motility, so together they increase the risk of severe constipation and bowel obstruction (US clozapine and tramadol labels). The liver enzyme CYP2D6 converts tramadol to its active metabolite. The US clozapine label says clozapine can raise levels of drugs broken down by CYP2D6, while the Spanish clozapine label reports no clinically relevant interactions with such drugs. Clozapine is not on the serotonergic drug lists in the tramadol labels, and no document describes serotonin syndrome for this pair.

Symptoms

Central nervous system depression shows as unusual drowsiness, confusion, pinpoint pupils, slow and shallow breathing, and coma in severe cases (tramadol label). Seizures present as sudden loss of consciousness with convulsions and are more likely at higher doses of either drug. Constipation, abdominal distension or pain, nausea and vomiting point to slowed gut motility that can progress to obstruction (US clozapine label). Both drugs can lower blood pressure, causing dizziness or fainting on standing up (clozapine and tramadol labels).

Management

Under the US tramadol label (FDA), combine tramadol with antipsychotics only when other pain treatment options are inadequate. Use the lowest effective tramadol dose and the shortest duration of combined use (Spanish tramadol label). When adding tramadol for a patient who already takes clozapine, start tramadol at a lower dose than usual and titrate to response (US tramadol and clozapine labels). Keep tramadol at or below 400 mg a day, since the seizure risk rises above that dose (tramadol label). Uncontrolled epilepsy contraindicates both tramadol and clozapine (both labels). If seizures occur, reduce the clozapine dose and start anticonvulsant treatment if needed (clozapine label). Warn the patient and carers about drowsiness and signs of respiratory depression, and advise against driving or operating machinery (clozapine and tramadol labels). Check bowel function often, treat constipation promptly and consider preventive laxatives in high-risk patients (US clozapine label).

Mechanism

Additive QT risk. Tramadol weakly prolongs QT and blocks serotonin/norepinephrine reuptake. Dronedarone is a potent QT prolonger. Tramadol also lowers seizure threshold.

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. For analgesia on dronedarone, use paracetamol, an NSAID, or morphine/oxycodone (no QT effect).

Mechanism

Dual mechanism. Fluoxetine (SSRI) raises synaptic serotonin; tramadol weakly inhibits serotonin reuptake – combined serotonergic activity adds up. Fluoxetine also blocks CYP2D6 – the route activating tramadol to O-desmethyltramadol – so analgesia weakens.

Symptoms

Serotonin syndrome: agitation, confusion, tremor, myoclonus, hyperreflexia, dilated pupils. Autonomic features: sweating, tachycardia, hypertension, fever. First signs appear within hours of co-administration.

Management

If a patient taking fluoxetine needs tramadol, start at the lowest dose and keep it at the low end of the therapeutic range. The fluoxetine SmPC requires this for all drugs metabolised by CYP2D6, including for 5 weeks after fluoxetine is stopped. Fluoxetine reduces formation of tramadol's active metabolite, so analgesia may be weaker while the risk of seizures and serotonin syndrome is higher (FDA tramadol label). At the start and after each dose increase, watch for signs of serotonin syndrome and stop tramadol if it is suspected. Paracetamol is a suitable analgesic. NSAIDs taken with SSRIs increase bleeding risk (fluoxetine SmPC).

Mechanism

SSRI (fluvoxamine) + tramadol – serotonin syndrome. Tramadol also lowers seizure threshold.

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 analgesia on fluvoxamine, use paracetamol, an NSAID, or morphine/oxycodone. For neuropathic pain, gabapentin or pregabalin.

Mechanism

Additive CNS depression. Gabapentin does not lower the seizure threshold, but opioid-gabapentinoid combinations are associated with respiratory depression risk, especially in older patients.

Symptoms

Drowsiness, slowed breathing (rate below 12/min), cyanosis of lips. Severe cases include respiratory arrest. Older patients: fall risk.

Management

The combination is possible in neuropathic pain. Keep doses minimal, start low. Warn the patient about drowsiness and ataxia. Older patients: enhanced fall monitoring.

Mechanism

Tramadol lowers seizure threshold and prolongs QT. Haloperidol is a strong QT prolonger, especially parenterally. Additive seizure and torsades de pointes 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. For analgesia on haloperidol, use paracetamol, an NSAID, or morphine/oxycodone. Alternative antipsychotics: olanzapine or aripiprazole.

Mechanism

Tramadol is a serotonergic opioid; mirtazapine raises serotonergic transmission via α2-blockade. Additive serotonin syndrome risk.

Symptoms

Serotonin syndrome: agitation, confusion, tremor, myoclonus, hyperreflexia. Autonomic features: sweating, tachycardia, fever.

Management

If a patient taking mirtazapine needs tramadol, start with a low dose and keep the course short. Mirtazapine increases the sedative effect of opioids (mirtazapine SmPC), and the tramadol SmPC requires the lowest effective dose and shortest duration with CNS depressants. At the start and after each dose increase, watch for signs of serotonin syndrome and excessive drowsiness. Stop tramadol if serotonin syndrome is suspected. Both drugs lower the seizure threshold. In epilepsy, use tramadol only when it cannot be avoided; it is contraindicated in uncontrolled epilepsy (tramadol SmPC).

Mechanism

Additive CNS and respiratory centre depression. Tramadol is also serotonergic and lowers seizure threshold.

Symptoms

Drowsiness, slowed breathing (rate below 12/min), cyanosis of lips. Severe cases include respiratory arrest. Older patients: fall risk.

Management

Avoid the combination. To strengthen opioid analgesia on tramadol, switch to a pure opioid agonist (morphine, oxycodone) and stop tramadol. Dual opioid therapy is only used in palliative care with careful respiratory monitoring.

Mechanism

Tramadol and oxycodone are both opioid agonists, and their depressant effects on the central nervous system (CNS) and breathing add up. The SmPCs of both drugs list 'other opioids' among CNS depressants whose concomitant use raises the risk of sedation, respiratory depression, coma and death (tramadol SmPC, AEMPS, section 4.5; oxycodone SmPC, AEMPS, section 4.5). Tramadol has a second mechanism: it inhibits serotonin and noradrenaline reuptake. The FDA label of oxycodone lists tramadol among serotonergic drugs whose combination with opioids has resulted in serotonin syndrome (FDA label of oxycodone, section 7). Tramadol also lowers the seizure threshold, and other opioids increase that risk (FDA label of tramadol, section 5.10). CYP3A4 and CYP2D6 metabolise both drugs, but the labels describe no effect of one on the other's blood levels.

Symptoms

Somnolence, slowed thinking, confusion, slow shallow breathing, pinpoint pupils, a drop in blood pressure; in severe cases deep sedation, coma and death (tramadol SmPC, AEMPS, sections 4.4 and 4.5; FDA label of oxycodone, section 5.3). The risk is highest at the start of concomitant use and after a dose increase, and in elderly or debilitated patients and those with chronic lung disease (FDA label of oxycodone, sections 5.2 and 5.8). Signs of serotonin syndrome: agitation, hallucinations, tachycardia, labile blood pressure, fever, hyperreflexia, incoordination, muscle rigidity, nausea, vomiting, diarrhoea, usually within hours to a few days of concomitant use (FDA label of tramadol, section 5.9). Tramadol can cause seizures even at recommended doses, and other opioids raise that risk (FDA label of tramadol, section 5.10).

Management

Prescribe two opioids together only when other treatment options are inadequate, at the lowest effective dose and for the shortest time (tramadol SmPC, AEMPS, sections 4.4 and 4.5; oxycodone SmPC, AEMPS, sections 4.4 and 4.5; FDA label of oxycodone, section 7). The prolonged-release oxycodone SmPC allows an immediate-release opioid as rescue medication; if the patient needs rescue medication more than twice a day, increase the prolonged-release oxycodone dose (oxycodone SmPC, AEMPS, section 4.2). When starting oxycodone in a patient already on tramadol, begin with one-third to one-half of the usual starting dose (FDA label of oxycodone, section 2.6). Keep tramadol at or below 400 mg per day, because above that limit the seizure risk rises (tramadol SmPC, AEMPS, sections 4.2 and 4.4). Watch the patient for respiratory depression and sedation, especially in the first days and after a dose increase, and warn the patient and carers about these signs (tramadol SmPC, AEMPS, section 4.4; oxycodone SmPC, AEMPS, section 4.4). The FDA advises discussing an opioid overdose reversal agent, naloxone or nalmefene, with the patient (FDA label of oxycodone, section 5.3). On suspicion of serotonin syndrome, stop tramadol immediately and stop oxycodone as well (FDA label of tramadol, section 7; FDA label of oxycodone, section 7).

Mechanism

Similar to tramadol + gabapentin: additive CNS depression, seizure risk (tramadol lowers threshold). FDA issued a 2019 warning about respiratory depression with opioid-gabapentinoid combinations.

Symptoms

Drowsiness, sedation, slowed breathing. Seizures (tramadol) and syncope from orthostatic hypotension are possible. Older patients: fall risk.

Management

The combination is possible in neuropathic pain. Keep doses minimal, start low. Warn the patient about drowsiness and ataxia. Older patients: enhanced fall monitoring. Alternative opioid for neuropathic pain: pure opioid agonist (morphine, oxycodone) without serotonergic activity.

Mechanism

Additive CNS depression plus seizure threshold reduction (tramadol lowers it, quetiapine at high doses).

Symptoms

Deep sedation, drowsiness, ataxia. Seizures (especially with prior epilepsy) are possible. Older patients: fall risk.

Management

Avoid the combination with quetiapine above 300 mg. For analgesia on quetiapine, use paracetamol, an NSAID, or morphine/oxycodone (without serotonergic activity).

Mechanism

Sertraline (SSRI) raises synaptic serotonin; tramadol blocks serotonin and norepinephrine reuptake. Combined action amplifies serotonergic transmission. Sertraline also blocks CYP2D6 (less than fluoxetine) – the tramadol activation route.

Symptoms

Serotonin syndrome: agitation, confusion, tremor, myoclonus, hyperreflexia, dilated pupils. Autonomic features: sweating, tachycardia, hypertension, fever. First signs appear within hours of co-administration.

Management

Avoid the combination. For analgesia on sertraline, use paracetamol, an NSAID, or morphine/oxycodone. For chronic analgesic needs, gabapentin or pregabalin for neuropathic pain.

Mechanism

Venlafaxine (SNRI) + tramadol – serotonin syndrome plus additive seizure risk. Tramadol itself is a weak serotonin-norepinephrine reuptake inhibitor with proconvulsant effect.

Symptoms

Serotonin syndrome: agitation, confusion, tremor, myoclonus, hyperreflexia. Autonomic features: sweating, tachycardia, fever.

Management

Avoid the combination. For analgesia on venlafaxine, use paracetamol, an NSAID, or morphine/oxycodone (without serotonergic activity). For neuropathic pain: gabapentin or pregabalin.

Mechanism

Additive QT prolongation (tramadol weakly prolongs QT). Weak serotonergic risk (tramadol inhibits serotonin reuptake).

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 patients without cardiovascular disease, the combination is acceptable. In epilepsy: watch tramadol-related seizure threshold reduction. Alternative analgesic: paracetamol or morphine/oxycodone (no QT effect).

Mechanism

Duloxetine is a serotonin and noradrenaline reuptake inhibitor (SNRI). Tramadol also inhibits serotonin and noradrenaline reuptake, so together they add up serotonergic effects and raise the risk of serotonin syndrome. Tramadol lowers the seizure threshold, and SNRIs increase this risk (tramadol SmPC). There is a kinetic part too: duloxetine is a moderate CYP2D6 inhibitor (duloxetine SmPC), and tramadol needs CYP2D6 to form the metabolite that gives most of its analgesia. Less active metabolite is formed and more tramadol itself stays in the blood (FDA tramadol label).

Symptoms

Serotonin syndrome: agitation, confusion, tremor, myoclonus, hyperreflexia. Autonomic features: sweating, tachycardia, labile blood pressure, fever. Gastrointestinal: nausea, vomiting, diarrhoea. Seizures can occur on this combination. When less active tramadol metabolite is formed, pain relief is weaker than expected.

Management

Use the combination when it is clinically warranted (both SmPCs). In a patient with depression, the FDA tramadol label advises considering a non-opioid analgesic first. Keep tramadol at or below 400 mg a day, because seizure risk rises above it. Tramadol is contraindicated in epilepsy that is not controlled; in controlled epilepsy it is used only when the circumstances require it (tramadol SmPC). Watch for signs of serotonin syndrome at the start of co-treatment and after each dose increase. If they appear, stop tramadol and duloxetine at once and start symptomatic treatment (FDA labels of both drugs). Measure blood pressure before starting duloxetine and periodically during treatment, and do not start duloxetine in uncontrolled hypertension (duloxetine labels). If duloxetine is stopped and tramadol continues, more active metabolite is formed: consider lowering the tramadol dose and watch for sedation and slowed breathing (FDA tramadol label).

Mechanism

This pair meets at three points. Tramadol inhibits serotonin reuptake, so with escitalopram the risk of serotonin syndrome rises. Both drugs lower the seizure threshold (both SmPCs). The third point is kinetic: most of the analgesia comes from a tramadol metabolite formed via CYP2D6, and escitalopram inhibits this enzyme (escitalopram SmPC). Less active metabolite is formed and more tramadol itself stays in the blood (FDA tramadol label).

Symptoms

Serotonin syndrome: agitation, confusion, tremor, myoclonus, hyperreflexia, sweating, diarrhoea, tachycardia, and in severe cases hyperthermia and rigidity. Seizures can occur on this combination, including without serotonin syndrome. When less active tramadol metabolite is formed, pain relief is weaker than expected.

Management

The combination is allowed but needs monitoring. In a patient with depression, the FDA tramadol label advises considering a non-opioid analgesic first. If tramadol is still needed, keep the daily dose at or below 400 mg, because seizure risk rises above it (tramadol SmPC). Tramadol is contraindicated in epilepsy that is not controlled; in controlled epilepsy it is used only when the circumstances require it, with close observation (both SmPCs). Watch for signs of serotonin syndrome at the start of co-treatment and after each dose increase. If they appear, stop both drugs at once and start symptomatic treatment (escitalopram SmPC). If escitalopram is being started, correct potassium and magnesium first, and in stable heart disease consider an ECG before the first dose. Escitalopram is contraindicated with a prolonged QT interval. If signs of arrhythmia appear, such as palpitations, skipped beats or fainting, stop escitalopram and do an ECG (escitalopram SmPC).

Mechanism

Both lower the seizure threshold. Additive risk, especially in theophylline overdose or in patients with epilepsy and prior head trauma.

Symptoms

Tremor, jitters, anxiety; severe cases: seizures. Symptoms appear with theophylline or tramadol dose escalation.

Management

Avoid the combination in epilepsy or prior head trauma. At usual therapeutic theophylline doses and short tramadol courses (3–5 days), the combination is acceptable in young patients. Keep theophylline levels in the lower half of normal range (10–15 mcg/mL). Analgesic alternatives: paracetamol with codeine, or gabapentin for neuropathic pain.

Mechanism

Tramadol indirectly affects CYP2C9-mediated warfarin metabolism via CYP2D6. INR increases of 1–2 points have been reported, especially in older patients.

Symptoms

Gum bleeding, epistaxis, bruising without trauma, black or tarry stools, haematuria. Higher risk in older patients, prior peptic ulcer disease, and chronic kidney disease.

Management

On tramadol start, check INR at 5–7 days. For pronounced pain, alternatives: paracetamol up to 2 g/day or a short tramadol course at 50 mg at night. High-dose opioids and NSAIDs are less preferred.