Tramadol Overdose

Tramadol overdose causes opioid effects, seizures, serotonin toxicity and, in large doses, cardiovascular toxicity. Seizures are the leading serious complication and are only partly opioid mediated, so naloxone may precipitate them.

Tramadol is widely prescribed and misused, and in some regions it is a major cause of poisoning. Seizures occur in about 5 to 15% of overdoses, mostly above 500 mg (or 7 mg/kg) in adults, and doses above 1 to 2 g can be fatal.

Risk factors for harm. Co-ingestion with serotonergic drugs (SSRIs, SNRIs, MAOIs), epilepsy, renal impairment, modified release preparations, and chronic use.

Course. Onset in 1 to 2 hours (4 to 12 hours for modified release); effects last 12 to 24 hours or more, with seizures usually within 24 hours.

Pathophysiology.

Tramadol and its active metabolite (O-desmethyltramadol) act on mu opioid receptors, while also inhibiting serotonin and noradrenaline reuptake.

Lowering of the seizure threshold is mediated by monoamine effects and GABA antagonism.

• Drowsiness, nausea, vomiting, agitation, tachycardia, miosis (not always) and respiratory depression.
• Seizures, often generalised and sometimes recurrent or status epilepticus.
• Serotonin toxicity: clonus, hyperreflexia, diaphoresis and hyperthermia.
• QRS or QT prolongation, hypotension and coma in severe cases.

Red flags.

• Seizures, status epilepticus or coma.
• Respiratory rate under 10 breaths/minute.
• Temperature over 38.5 degrees Celsius with clonus.

• History of dose, formulation and co-ingestants; paracetamol and salicylate levels.
• ECG (QRS, QTc), glucose, electrolytes, renal and liver function, creatine kinase and venous gas.
• Clinical assessment for serotonin toxicity (inducible clonus, hyperreflexia).
• Routine urine opiate screens do not detect tramadol.

Differential diagnosis. Other opioid overdose, SSRI or SNRI overdose, bupropion overdose, epilepsy, alcohol withdrawal and sympathomimetic toxicity.

• Airway protection, oxygen and ventilation as needed.
• Activated charcoal 50 g orally once (1 g/kg, maximum 50 g, in children) within 1 hour (2 hours for modified release) if the airway is protected. Monitor the airway for aspiration. Avoid with reduced consciousness without a protected airway, ileus or gastrointestinal obstruction; no renal or hepatic adjustment; acceptable in pregnancy.
• Seizures: lorazepam 0.1 mg/kg intravenously (maximum 4 mg for each dose) over 2 minutes, repeated once after 5 to 10 minutes if seizures continue. Maximum 8 mg in total. Monitor breathing, oxygen saturation, blood pressure and sedation. Use lower doses in older adults, respiratory disease and hepatic impairment; no renal adjustment; use only when needed in pregnancy.
• Refractory seizures: intubation and propofol 1 to 2 mg/kg intravenously, then 1 to 4 mg/kg/hour infusion. Maximum 4 mg/kg/hour. Monitor blood pressure, triglycerides, lactate and propofol infusion syndrome.
• Respiratory depression: naloxone 0.4 mg intravenously, repeated every 2 to 3 minutes up to 2 mg for each dose, titrated to breathing only (not to consciousness). Maximum 10 mg before reviewing the diagnosis. Monitor for seizures (naloxone can provoke them), respiratory rate and withdrawal; use the smallest effective dose and give ventilation first if possible. No renal or hepatic adjustment; acceptable in pregnancy.
• Serotonin toxicity: diazepam 5 to 10 mg intravenously, repeated every 5 to 10 minutes as needed. Maximum 30 mg in the first hour without specialist review. Monitor breathing, oxygen saturation and blood pressure. Cyproheptadine 12 mg orally or via nasogastric tube once, then 2 mg every 2 hours until symptoms settle, then 8 mg every 6 hours (maximum 32 mg daily; monitor sedation; avoid in glaucoma and urinary retention).
• Hyperthermia over 41.1 degrees Celsius: sedation, intubation and rocuronium 1 mg/kg intravenously once (avoid suxamethonium).
• Observe for at least 12 hours (24 hours for modified release or large ingestions).
• Psychiatric assessment in intentional ingestion.

Monitoring. Conscious level, respiratory rate, ECG, temperature and creatine kinase; neurological observation for seizures.

Referral and escalation. Poisons information centre; intensive care for status epilepticus, coma or hyperthermia.

Special groups. Epilepsy patients: lower threshold for admission. Renal impairment: prolonged effect.