What is the mechanism of action (MOA) of tramadol?

From the Guidelines

Tramadol works through a dual mechanism of action in the body, primarily functioning as a weak mu-opioid receptor agonist and inhibiting the reuptake of serotonin and norepinephrine in the central nervous system. This dual action enhances pain relief by both activating opioid pathways and increasing levels of these neurotransmitters that help regulate pain signals. According to the most recent and highest quality study 1, tramadol is a weak opioid receptor agonist with some norepinephrine and serotonin reuptake inhibition used for mild to moderate pain. The study also notes that tramadol should be avoided in patients receiving selective serotonin reuptake inhibitors (SSRIs) or tricyclic antidepressants due to the risk of serotonin syndrome.

Some key points to consider when using tramadol include:

• Tramadol is metabolized in the liver to O-desmethyltramadol (M1), which has a stronger affinity for mu-opioid receptors than the parent compound.
• The metabolism of tramadol varies between individuals due to genetic differences in the CYP2D6 enzyme system, explaining why some patients experience better pain relief than others at similar doses.
• The combination of these mechanisms provides analgesia while potentially causing fewer respiratory depression effects than traditional opioids, though tramadol still carries risks of dependence, serotonin syndrome, and seizures at higher doses.
• The maximum daily dose of tramadol is recommended to be 400 mg for adults with normal hepatic and renal function, with lower doses recommended for older adults and those with hepatic and/or renal dysfunction to reduce the risk of seizures, as noted in 1.

Overall, tramadol's unique mechanism of action and potential benefits and risks should be carefully considered when prescribing it for pain management, taking into account the latest clinical guidelines and evidence, such as those provided in 1 and 1.

From the FDA Drug Label

Although its mode of action is not completely understood, from animal tests, at least two complementary mechanisms appear applicable: binding of parent and M1 metabolite to μ-opioid receptors and weak inhibition of re-uptake of norepinephrine and serotonin Opioid activity is due to both low affinity binding of the parent compound and higher affinity binding of the O-demethylated metabolite M1 to μ-opioid receptors. Tramadol has been shown to inhibit reuptake of norepinephrine and serotonin in vitro, as have some other opioid analgesics.

The mechanism of action (MOA) of tramadol is through two main mechanisms:

• Binding to μ-opioid receptors: Tramadol and its metabolite M1 bind to μ-opioid receptors, with M1 being up to 6 times more potent than tramadol in producing analgesia.
• Inhibition of reuptake of norepinephrine and serotonin: Tramadol also inhibits the reuptake of norepinephrine and serotonin, which may contribute to its analgesic effects 2.

From the Research

Mechanism of Action of Tramadol

• Tramadol is a centrally acting analgesic with a dual mechanism of action, binding to mu-opioid receptors and weakly inhibiting the neuronal reuptake of norepinephrine and serotonin 3, 4, 5, 6, 7.
• The (+) enantiomer of tramadol and its metabolite (+)-O-desmethyl-tramadol (M1) are agonists of the mu opioid receptor, while the (-) enantiomer inhibits norepinephrine reuptake 3, 5, 6.
• The complementary and synergistic actions of the two enantiomers improve the analgesic efficacy and tolerability profile of the racemate 3, 6.
• Tramadol's analgesic action is only partially inhibited by the opioid antagonist naloxone, suggesting the existence of another mechanism of action, which is the monoaminergic activity that inhibits noradrenaline and serotonin reuptake 5.

Pharmacokinetics and Pharmacodynamics

• Tramadol is rapidly and almost completely absorbed after oral administration, with a bioavailability of 68-95% 5, 6.
• The elimination kinetics of tramadol can be described as 2-compartmental, with a half-life of 5-6 hours for tramadol and 9 hours for the M1 derivative 5, 6.
• Tramadol is mainly metabolised by O- and N-demethylation and by conjugation reactions forming glucuronides and sulfates, with the O-demethylation of tramadol to M1 catalysed by cytochrome P450 (CYP) 2D6 6.

Clinical Efficacy and Safety

• Tramadol is effective in managing moderate to moderately severe chronic pain, including neuropathic pain, low back pain, osteoarthritis pain, and breakthrough pain 3, 4, 7.
• Tramadol has a lower potential for abuse and dependence compared to other opioids, and is generally well-tolerated, with common adverse effects including dizziness, nausea, dry mouth, and sedation 3, 4, 7.