Amitriptyline × Methylthioninium chloride (methylene blue)

Methylene blue (methylthioninium chloride) inhibits monoamine oxidase (MAO). The US Food and Drug Administration (FDA) amitriptyline 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. Amitriptyline inhibits the reuptake of noradrenaline and serotonin (FDA amitriptyline label). Together they can cause severe, sometimes fatal serotonin syndrome (methylene blue labels). All reports that gave the route involved intravenous methylene blue at 1–8 mg/kg. There are no reports with oral tablets, local tissue injection or lower doses (FDA amitriptyline label).

Serotonin syndrome. Mental status changes: agitation, hallucinations, delirium, coma. Autonomic signs: tachycardia, labile blood pressure, dizziness, sweating, flushing, fever. Neuromuscular signs: tremor, rigidity, myoclonus, hyperreflexia, incoordination. Seizures, nausea, vomiting and diarrhoea may occur. Some reported cases were fatal (FDA methylene blue label). With tricyclic antidepressants and MAO inhibitors taken together, the FDA amitriptyline label reports hyperpyretic crises, severe convulsions and deaths.

The combination is contraindicated: the US Food and Drug Administration (FDA) amitriptyline label says it should not be given with MAO inhibitors and should not be started in a patient receiving intravenous methylene blue. The methylene blue labels approved by the European Medicines Agency (EMA) and the FDA say to avoid it in patients taking drugs that enhance serotonergic transmission, antidepressants included. If a patient on amitriptyline needs methylene blue, stop amitriptyline before it is given (FDA amitriptyline label). 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 signs of serotonin syndrome appear, stop methylene blue and amitriptyline and start supportive treatment (FDA labels of both drugs). Restart amitriptyline no earlier than 14 days after the last methylene blue dose, cautiously and with gradual dose increases, as the FDA amitriptyline label requires after an MAO inhibitor.