Methylthioninium chloride (methylene blue) × Tramadol

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.

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).

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).