Tramadol is metabolised by the cytochrome P450 isoenzymes, CYP 3A4 and CYP 2D6, but it is not an inducer or an inhibitor of the enzymes. Probably low PXR-affinity of the parent substance. Physiological effects on PXR/CAR-activation by serotonergic action is probably without relevance to acute porphyria. There are 12 reports (per February 2010) of safe use in carriers of acute porphyria.

(±)-trans-2-Dimethylaminomethyl-1-(3-methoxyphenyl)cyclohexanol hydrochloride. M=300. Terminal tertiary amine function.

Tramadol is used for moderate to severe pain. It is a non-selective, complete agonist of µ-, δ- and κ opioid receptors with a higher affinity for µ-receptors. Other mechanisms contributing to the analgesic effect are the inhibition of the neural noradrenalin reuptake and an enhanced release of serotonine. Common confounding side-effects are nausea, vomiting, obstipation. Overdosage may give cardiovascular collapse or respiratory arrest.

Probably significant.

In humans the cytochrome P450 isoenzymes, CYP 3A4 and CYP 2D6 are involved in the metabolism of tramadol. It is a substrate of these enzymes (Rendic 2002 ; Martindale 2009)and clinical interaction studies give evidence of absence of significant capacity for CYP-induction or inhibition. Tramadol is mainly metabolised by means of N- and O-demethylation and conjugation of the O-demethylation products with glucuronic acid. Only O-desmethyltramadol is pharmacologically active (The electronic Medicines Compendium (eMC),UK). On oral administration it has relatively low first-pass effect, maximum of 30 per cent. High tissue affinity Vdb= around 203 l. After N-demethylation via CYP 3A4, the principal pharmacodynamically active O-demethylated metabolite is generated by CYP 2D6, which exhibits genetic polymorphism (Martindale 2009). The N-methylated parent drug is water soluble and thus probably of relatively low PXR-affinity.

Observed to give rise to porphyrin accumulation in chicken embryo system, (Lambrecht,1999).

S.Thunell 2004, patient inquiry: tolerated (n=1).

No observations of clinical porphyrogenicity published.

Uneventful use reported in 15 patients with acute porphyria.