What is the metabolism of tramadol (tramadol hydrochloride)?

From the Guidelines

Tramadol is primarily metabolized in the liver through two main pathways, involving O-demethylation by CYP2D6 and N-demethylation by CYP3A4 and CYP2B6 enzymes, with the former producing the active metabolite O-desmethyltramadol (M1) responsible for most of tramadol's analgesic effects. The metabolism of tramadol is crucial in understanding its efficacy and potential side effects. According to the most recent and highest quality study available 1, tramadol's metabolism involves the conversion of tramadol to its active metabolite O-desmethyltramadol (M1) by the cytochrome P450 enzyme CYP2D6. This metabolite has a significantly higher affinity for μ-opioid receptors than the parent compound and is responsible for much of tramadol's analgesic effects.

Some key points to consider in the metabolism of tramadol include:

• Genetic variations in CYP2D6 activity can significantly impact tramadol's effectiveness, with poor metabolizers experiencing reduced pain relief and ultra-rapid metabolizers potentially experiencing increased side effects or toxicity.
• Approximately 5-10% of Caucasians are poor CYP2D6 metabolizers, which can affect the efficacy of tramadol.
• Tramadol and its metabolites are primarily excreted through the kidneys, with about 30% of the dose excreted unchanged in urine and the remainder as metabolites.
• This metabolism profile explains why tramadol's effects can vary between individuals and why dose adjustments are necessary in patients with liver or kidney impairment or those taking medications that inhibit or induce these enzyme systems, as noted in studies such as 1 and 1.

In terms of clinical implications, understanding the metabolism of tramadol is essential for optimizing its use in pain management, particularly in patients with cancer pain, as discussed in guidelines such as 1. The NCCN panel recommends a maximum daily dose of 400 mg for immediate-release formulations and 300 mg/day for extended-release formulations, with lower doses recommended for older adults and those with hepatic and/or renal dysfunction. By considering the metabolism of tramadol and adjusting doses accordingly, healthcare providers can minimize the risk of adverse effects and maximize the efficacy of this medication in managing pain.

From the FDA Drug Label

Tramadol is extensively metabolized after oral administration by a number of pathways, including CYP2D6 and CYP3A4, as well as by conjugation of parent and metabolites. Approximately 30% of the dose is excreted in the urine as unchanged drug, whereas 60% of the dose is excreted as metabolites. The major metabolic pathways appear to be N- and O-demethylation and glucuronidation or sulfation in the liver. One metabolite (O-desmethyltramadol, denoted M1) is pharmacologically active in animal models.

The metabolism of tramadol involves several pathways, including:

• CYP2D6: responsible for the formation of the active metabolite M1
• CYP3A4: involved in the metabolism of tramadol
• Conjugation: of parent and metabolites The major metabolic pathways are:
• N- and O-demethylation
• Glucuronidation or sulfation in the liver Approximately 30% of the dose is excreted unchanged, while 60% is excreted as metabolites 2.

From the Research

Metabolism of Tramadol

• Tramadol is mainly metabolized by O- and N-demethylation and by conjugation reactions forming glucuronides and sulfates 3
• The O-demethylation of tramadol to M1, the main analgesic effective metabolite, is catalysed by cytochrome P450 (CYP) 2D6, whereas N-demethylation to M2 is catalysed by CYP2B6 and CYP3A4 3
• Tramadol's major active metabolite, O-desmethyltramadol (ODT), shows higher affinity for the mu-opioid receptor and has twice the analgesic potency of the parent drug 4
• The opioid analgesic potency of a given dose of tramadol is influenced by an individual's CYP genetics, with poor metabolizers experiencing little conversion to the active M1 opioid metabolite and individuals with a high metabolic profile, or ultra-metabolizers, experiencing the greatest opioid analgesic effects 5

Factors Affecting Metabolism

• The pharmacokinetics of tramadol are dependent on multiple factors, such as the route of administration, genetic variability in pharmacokinetic components and concurrent consumption of other drugs 6
• CYP inhibition can significantly depress tramadol steady-state (+)-M1, reduce its adverse events, and lead to insignificant analgesia comparable with placebo 7
• Desmetramadol, an investigational analgesic consisting of (+) and (-) enantiomers of the tramadol metabolite O-desmethyltramadol (M1), has the safety and analgesic profile of tramadol without its metabolic liabilities 7

Metabolic Liabilities

• Tramadol labeling indicates cytochrome P450 (CYP) isozyme 2D6 ultrarapid metabolizer can produce dangerous (+)-M1 levels, and CYP2D6 poor metabolizers insufficient (+)-M1 for analgesia 7
• The wide variability in the pharmacokinetic properties of tramadol can partly be ascribed to CYP polymorphism 3
• O- and N-demethylation of tramadol as well as renal elimination are stereoselective 3