Tramadol is an opioid analgesic used for moderate to severe pain when other painkillers are not enough. It is effective, but can cause dependence, drowsiness, nausea and, in rare cases, seizures or serotonin syndrome.
Also known as: Tramal
Risk of serotonin syndrome. Fluoxetine inhibits CYP2D6, raising Tramadol levels.
The fluoxetine label lists tramadol among the serotonergic drugs whose concomitant use increases the risk of serotonin syndrome, potentially life-threatening, especially at treatment initiation and dose increases; the tramadol label states that concomitant use with CYP2D6 inhibitors (fluoxetine is a potent CYP2D6 inhibitor) has complex effects on tramadol and active metabolite M1 levels, with an increased risk of serious adverse events, including seizures and serotonin syndrome. Whenever possible, avoid the combination or use the lowest effective dose, monitor for serotonin symptoms (agitation, tachycardia, hyperthermia, hyperreflexia) and signs of seizures.
Fluoxetine + tramadol: risk of serotonin syndrome and seizures (SSRI + tramadol, CYP2D6 inhibition). Monitor closely.
Serotonin accumulation: the SSRI effect added to Tramadol's, plus inhibition of its metabolism.
Serotonin signs in the first days.
Agitation, hyperthermia, diarrhoea, tremor, clonus, confusion.
Use an alternative analgesic or monitor signs; avoid combining two serotonergic drugs unless needed.
DailyMed/FDA (NIH/NLM) — approved Fluoxetine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=09fb3100-1e06-4cdc-8016-7e4f5d097490 ; approved Tramadol label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=552955e6-2bb3-8755-e063-6394a90ab21c
Combining ondansetron with tramadol raises the risk of serotonin syndrome.
The ondansetron label states that serotonin syndrome has been reported with 5-HT3 receptor antagonists, mostly with concomitant use of serotonergic drugs such as tramadol, and that ondansetron may increase patient-controlled administration of tramadol, so analgesia should be monitored; the tramadol label includes 5-HT3 receptor antagonists among the serotonergic drugs with a risk of serotonin syndrome. Monitor for serotonin symptoms (agitation, tachycardia, hyperthermia, hyperreflexia) and ensure adequate analgesia; use the lowest effective doses.
Ondansetron + tramadol: risk of serotonin syndrome (5-HT3 antagonist + serotonergic drug) and possible increased tramadol use. Monitor analgesia and serotonin.
Tramadol is serotonergic and ondansetron, although a 5-HT3 antagonist, may contribute to serotonergic excess in susceptible patients.
Monitor agitation, tremor, hyperthermia, myoclonus and diarrhoea.
Serotonin syndrome (hyperthermia, rigidity, confusion).
Monitor serotonergic symptoms; use with caution in polypharmacy patients.
DailyMed (FDA) — approved Ondansetron label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=41366a20-0727-0446-e063-6294a90a957f ; approved Tramadol label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9f0e33bd-65f8-446a-886f-e7e16a142ce5 — additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
Isoniazid with Tramadol raises serotonergic risk and may lower the seizure threshold.
Isoniazid has some monoamine oxidase inhibiting activity (the isoniazid label states it has MAO-inhibiting activity, with interaction with tyramine-rich foods), and tramadol is a weak serotonin and norepinephrine reuptake inhibitor; together, the combination may increase the risk of serotonin syndrome, potentially life-threatening. The tramadol label warns about serotonin syndrome with serotonergic drugs and with drugs that impair the metabolism of serotonin or tramadol (such as MAO inhibitors). Monitor for serotonin symptoms (agitation, tachycardia, hyperthermia, hyperreflexia, myoclonus, rigidity), especially at treatment initiation, and consider alternatives if needed.
Isoniazid + tramadol: risk of serotonin syndrome (isoniazid has MAO-inhibiting activity). Monitor symptoms.
Weak MAO effect of isoniazid and serotonergic and seizure effects of tramadol.
Serotonergic and neurological signs.
Confusion, tremor, seizures, hyperthermia.
Avoid if possible; if used, watch for serotonin signs and seizures.
DailyMed/FDA (NIH/NLM) — approved Isoniazid label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=93252cc8-c8d4-401b-bde5-ca8a3b57651e ; approved Tramadol label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=552955e6-2bb3-8755-e063-6394a90ab21c
Combining dextromethorphan with tramadol increases the risk of serotonin syndrome and seizures.
Both dextromethorphan and tramadol have serotonergic action (serotonin reuptake inhibition), and the combination adds up the risk of serotonin syndrome, potentially life-threatening, with symptoms such as agitation, hallucinations, tachycardia, hyperthermia, hyperreflexia, myoclonus and rigidity. The tramadol label warns about serotonin syndrome with concomitant use of serotonergic drugs, and the combination of an antitussive with an opioid should be avoided whenever possible. If unavoidable, use the lowest doses, monitor for serotonin symptoms and consider alternatives (e.g., a non-serotonergic antitussive).
Dextromethorphan + tramadol: risk of serotonin syndrome (two serotonergic drugs). Avoid or monitor closely.
Both drugs raise serotonin; tramadol also lowers the seizure threshold.
Monitor serotonergic and neurological symptoms.
Serotonin syndrome, seizures.
Avoid the combination; if unavoidable, monitor closely and use the lowest effective dose.
DailyMed (FDA) — approved Dextromethorphan label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0d99237c-0b52-0af6-e063-6394a90aba14 ; approved Tramadol label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9f0e33bd-65f8-446a-886f-e7e16a142ce5 — additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
Sedating antihistamine + tramadol: additive sedation and seizure risk.
Diphenhydramine (first-generation antihistamine) and tramadol (opioid) both depress the central nervous system; the diphenhydramine label warns that antihistamines are most likely to cause dizziness, sedation and hypotension in elderly patients, and the combination adds this effect to that of the opioid, with a risk of excessive sedation, drowsiness, confusion and falls. Avoid the combination whenever possible (especially in the elderly), use the lowest effective doses, monitor sedation and advise the patient not to drive or operate machinery during the combination.
Diphenhydramine + tramadol: additive sedation and CNS depression risk. Avoid in the elderly or monitor closely.
Additive CNS depressant effect; tramadol lowers the seizure threshold.
Level of consciousness and neurological symptoms.
Seizures, excessive drowsiness, confusion.
Avoid in elderly/frail patients; watch for sedation and neurological symptoms.
DailyMed (FDA) — approved Diphenhydramine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d8944f3c-acef-4ebe-9633-7d641ae95edf ; approved Tramadol label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9f0e33bd-65f8-446a-886f-e7e16a142ce5 — additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
High risk of serotonin syndrome and seizures with Linezolid and Tramadol.
Tramadol increases synaptic serotonin (reuptake blockade) and lowers the seizure threshold; linezolid inhibits monoamine oxidase. The combination can precipitate serotonin syndrome and seizures, both potentially severe; the approved tramadol label contraindicates use with MAO inhibitors (linezolid acts as one). Avoid the combination whenever possible; if clinically indispensable, use the lowest effective dose, monitor serotonergic and neurological symptoms and discontinue at any warning sign.
Linezolid (MAO inhibitor) + tramadol: risk of serotonin syndrome and seizures. Avoid the combination; monitor serotonergic and neurological symptoms.
MAO inhibition (linezolid) plus tramadol serotonergic action and low seizure threshold.
Serotonergic and neurological signs.
Seizures, confusion, hyperthermia, myoclonus.
Avoid; choose an alternative analgesic (e.g. paracetamol or a non-serotonergic opioid).
DailyMed/FDA (NIH/NLM) — approved Linezolid label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=374af2a7-d994-40bd-a86a-cd9038d0b72c ; approved Tramadol label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=552955e6-2bb3-8755-e063-6394a90ab21c
Risk of serotonin syndrome and a lowered seizure threshold when Sertraline is combined with Tramadol.
The sertraline label lists tramadol among the serotonergic drugs whose concomitant use increases the risk of serotonin syndrome, and the tramadol label states that concomitant use with CYP2D6 inhibitors (sertraline inhibits CYP2D6) can raise tramadol levels and lower the active metabolite M1, with an increased risk of serious adverse events, including seizures and serotonin syndrome. The combination should be avoided whenever possible; if unavoidable, use the lowest effective dose, monitor for serotonin symptoms (agitation, tachycardia, hyperthermia, hyperreflexia) and signs of seizures, and reassess the need for the opioid.
Sertraline + tramadol: risk of serotonin syndrome and seizures (tramadol + SSRI). Monitor closely; consider alternatives.
Sertraline raises central serotonin and Tramadol does as well, further lowering the seizure threshold.
Watch for serotonin signs and seizures in the first days of association.
Agitation, tremor, hyperthermia, clonus, seizures, confusion.
Avoid the combination if possible; if unavoidable, use the lowest dose and monitor signs.
DailyMed/FDA (NIH/NLM) — approved Sertraline label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=91e24d17-ff0a-449c-9472-b9df74c98456 ; approved Tramadol label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=552955e6-2bb3-8755-e063-6394a90ab21c
Alcohol potentiates the central nervous system depression of tramadol, with a risk of excessive sedation and respiratory depression.
Avoid alcohol intake during treatment.
DailyMed/FDA (NIH/NLM) — approved Tramadol label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9f0e33bd-65f8-446a-886f-e7e16a142ce5
Tramadol can be administered with or without food; taking it with food may reduce nausea.
Take at the same time every day, with or without food.
DailyMed/FDA (NIH/NLM) — approved Tramadol label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9f0e33bd-65f8-446a-886f-e7e16a142ce5
Tramadol lowers the seizure threshold and increases the risk of seizures, especially at high doses or with serotonergic drugs.
Use with caution in patients with epilepsy and avoid high doses.
DailyMed/FDA (NIH/NLM) — approved Tramadol label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9f0e33bd-65f8-446a-886f-e7e16a142ce5
Tramadol depresses the respiratory centre; the risk is higher in patients with severe respiratory disease or at high doses.
Use with caution and monitor respiration, especially at treatment start.
DailyMed/FDA (NIH/NLM) — approved Tramadol label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9f0e33bd-65f8-446a-886f-e7e16a142ce5
Prolonged opioid use in pregnancy causes dependence and neonatal withdrawal syndrome; use at delivery can depress the newborn respiration.
Avoid chronic use; use the lowest dose for the shortest possible time.
Present in breast milk; avoid breastfeeding during use (risk of sedation in the infant).
Use effective contraception if treatment is chronic.
DailyMed/FDA (NIH/NLM) — approved Tramadol label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9f0e33bd-65f8-446a-886f-e7e16a142ce5
Clinical and educational support tool. The information does not replace a medical prescription or the opinion of a qualified healthcare professional.
Opioid analgesic with inhibition of norepinephrine and serotonin reuptake. Analgesia begins about one hour after administration and peaks in 2 to 3 hours. No significant effect on QTcF at 600 mg/day (1.5-fold the maximum immediate-release daily dose). Causes respiratory depression by direct action on the brain stem respiratory centres.
μ-opioid receptor agonist (low-affinity binding of the parent compound and higher-affinity binding of the M1 metabolite, O-desmethyltramadol) and weak inhibition of norepinephrine and serotonin reuptake. In animal models, M1 is up to 6 times more potent in analgesia and 200 times more potent in μ-opioid binding.
Mean absolute oral bioavailability of about 75% (100 mg); peak plasma concentrations of tramadol about 2 hours and of M1 about 3 hours; steady state within 2 days with four times daily dosing. Food does not significantly affect the rate or extent of absorption.
Extensively metabolised after oral administration (CYP2D6 to active M1 — subject to inhibition by fluoxetine, paroxetine, quinidine — and CYP3A4, with conjugation). About 30% of the dose is excreted unchanged in the urine and 60% as metabolites. In severe hepatic impairment, the half-life increases to 13 hours (tramadol) and 19 hours (M1).
Terminal elimination half-lives of 6.3 ± 1.4 hours (racemic tramadol) and 7.4 ± 1.4 hours (M1); volume of distribution of 2.6 to 2.9 L/kg and plasma protein binding of about 20%. Regimen adjustment is recommended in renal impairment (CLcr <30 mL/min).
Medicines from the same therapeutic group (ATC classification) or the same pharmacological class.
