Tramadol

Tramadol is a centrally acting analgesic with weak mu-opioid agonist activity and inhibition of serotonin and noradrenaline reuptake. It is used for moderate to moderately severe pain. Its dual mechanism makes seizures, serotonin syndrome, hyponatraemia and hypoglycaemia important risks that are not shared by other weak opioids.

Class. Atypical opioid analgesic (weak mu agonist plus serotonin-noradrenaline reuptake inhibitor).

Mechanism. The parent drug inhibits serotonin and noradrenaline reuptake; the CYP2D6 metabolite O-desmethyltramadol is a stronger mu agonist and provides most opioid effect.

Pharmacokinetics. Oral bioavailability about 70 to 90%. Onset about 1 hour orally, 10 minutes intravenously; peak 2 hours; duration 4 to 6 hours (12 hours for modified release). Half-life about 6 hours (7.5 hours for the active metabolite). Metabolised by CYP2D6 and CYP3A4; renal excretion.

Pharmacogenetics. CYP2D6 poor metabolisers get reduced analgesia. Ultra-rapid metabolisers have a higher risk of respiratory depression.

Indications are moderate to moderately severe acute and chronic pain, neuropathic pain as a second-line option, and postoperative pain.

Adults

• Oral immediate release: 50 to 100 mg every 4 to 6 hours. Maximum 400 mg in 24 hours.
• Modified release: 100 to 200 mg every 12 hours. Maximum 400 mg in 24 hours.
• Intravenous: 50 to 100 mg given slowly over 2 to 3 minutes (or by infusion), repeated every 4 to 6 hours. Maximum 400 mg in 24 hours (some labels allow 600 mg for short-term parenteral use).
• Start chronic use at 25 to 50 mg once or twice daily and increase by 25 to 50 mg every 3 days to limit nausea and dizziness.
• No loading dose.

Age over 75 years. Maximum 300 mg in 24 hours, with longer intervals.

Children. Not advised under 12 years in several regions (contraindicated after tonsillectomy under 18 years). Where licensed from 1 year: 1 to 2 mg/kg every 6 hours, maximum 8 mg/kg in 24 hours and 400 mg.

Conversion. Roughly 10 mg of oral tramadol is equal to 1 to 2 mg of oral morphine (older sources use 5 to 1).

Contraindications. Hypersensitivity; acute intoxication with alcohol, hypnotics, opioids or psychotropic drugs; uncontrolled epilepsy; monoamine oxidase inhibitor within 14 days; severe respiratory depression; children under 12 years or under 18 years after tonsillectomy or adenoidectomy; breastfeeding; severe renal or hepatic impairment (for modified release).

Boxed-warning-level risks. Addiction, abuse and misuse; life-threatening respiratory depression (especially in ultra-rapid metabolisers and children); accidental exposure; neonatal opioid withdrawal syndrome; interactions with CYP2D6 and CYP3A4 inhibitors; concurrent benzodiazepines and other depressants; seizures; serotonin syndrome.

Adverse effects. Common: nausea, vomiting, dizziness, constipation, sweating, drowsiness, dry mouth. Serious: seizures (at therapeutic or high doses, especially above 400 mg a day), serotonin syndrome, hyponatraemia, hypoglycaemia, respiratory depression, and withdrawal with serotonin-noradrenaline features on abrupt cessation.

Interactions. Serotonergic and noradrenergic drugs (SSRIs, SNRIs, tricyclic antidepressants, monoamine oxidase inhibitors, linezolid, triptans, ondansetron) raise seizure and serotonin syndrome risk. Carbamazepine lowers tramadol levels and effect. Ondansetron reduces analgesia. Warfarin: INR may rise. CYP2D6 inhibitors (fluoxetine, paroxetine, quinidine) reduce active metabolite; CYP3A4 inhibitors raise parent drug levels. Naloxone only partly reverses effects and may precipitate seizures.

Common prescribing errors. Exceeding 400 mg daily; combining with an antidepressant without considering serotonin syndrome and seizures; rapid titration causing nausea; prescribing for a person with a seizure disorder; stopping abruptly after prolonged use; assuming it is free of abuse potential.

Special groups

• Pregnancy: avoid; neonatal withdrawal and respiratory depression.
• Breastfeeding: avoid.
• Older adults: lower dose and longer interval; risk of hyponatraemia and delirium.
• Kidney impairment: creatinine clearance under 30 mL/min, give every 12 hours with a maximum of 200 mg in 24 hours; avoid modified release.
• Liver impairment: cirrhosis, 50 mg every 12 hours; avoid modified release.
• Regional: non-prescribed high-dose use is reported in several African countries, so ask about it when seizures or sedation are unexplained.

Formulations. Capsules 50 mg, modified-release tablets 100, 150, 200 mg, oral drops, injection 50 mg/mL, combination tablets with paracetamol.

Administration. Oral doses with or without food. Swallow modified-release tablets whole. Give intravenous doses slowly (rapid injection causes flushing, sweating and tachycardia).

Baseline. Seizure history, concurrent serotonergic medicines, renal and hepatic function, sodium, glucose in patients at risk, and alcohol or substance use.

Monitoring. Pain, nausea, sedation, respiratory rate and mental state. Sodium if prolonged use, especially in older adults. Glucose if unexplained symptoms. Review after 2 to 4 weeks.

Therapeutic drug monitoring. Not used.

Dose reduction and stopping thresholds. Stop for seizures, serotonin syndrome features (agitation, tremor, clonus, hyperthermia), significant hyponatraemia, respiratory depression or no benefit. After more than 1 week of regular use, reduce by 10 to 25% every few days.

Referral and escalation. Seizure, serotonin syndrome or respiratory depression needs emergency care. Treat seizures with a benzodiazepine; naloxone is not a first measure for seizures. Chronic pain needing continued use warrants specialist review.