Oxycodone × Tramadol

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.

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).

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).