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 mechanism allows tramadol to reduce pain perception while potentially causing fewer respiratory side effects than pure opioid analgesics, though it still carries risks of dependence, serotonin syndrome, and seizures at higher doses 1. The weak mu-opioid receptor agonist activity of tramadol contributes to its analgesic effects, while the inhibition of serotonin and norepinephrine reuptake enhances the body's natural pain inhibitory pathways, accounting for approximately 30-40% of tramadol's analgesic properties 1.

Some key points to consider when using tramadol include:

• Tramadol should be used with caution or avoided in patients taking other serotonergic or monoamine oxidase inhibitors (MAOI)-like medications due to the risk of serotonin syndrome 1.
• 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 1.
• Tramadol is less potent than other opioids and is considered to be approximately one-tenth as potent as morphine 1.
• Tramadol may produce more adverse effects, including vomiting, dizziness, and weakness, compared to other opioids such as hydrocodone and codeine 1.

Overall, tramadol's unique mechanism of action makes it an effective option for moderate to moderately severe pain, but its use requires careful consideration of the potential risks and benefits, particularly in certain patient populations 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 involves:

• Binding to μ-opioid receptors: Both the parent compound and its M1 metabolite bind to μ-opioid receptors, with the M1 metabolite having a higher affinity.
• Inhibition of reuptake of norepinephrine and serotonin: Tramadol weakly inhibits the reuptake of norepinephrine and serotonin, which may contribute to its analgesic effects. 2 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.