From the Guidelines
Tramadol is not a partial mu-opioid receptor agonist but rather a weak mu-opioid receptor agonist with additional mechanisms of action. It binds to mu-opioid receptors with relatively low affinity compared to traditional opioids like morphine, producing about 1/10th the analgesic potency through this mechanism 1. What makes tramadol unique is its dual mechanism of action - it also inhibits the reuptake of serotonin and norepinephrine in the central nervous system, similar to some antidepressants. This combined activity contributes to its pain-relieving effects.
Some key points to consider when using tramadol include:
- It is available as immediate-release and extended-release formulations 1
- The maximum daily dose is recommended to be 400 mg for adults with normal hepatic and renal function 1
- Lower doses are 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
Additionally, tramadol is a prodrug that gets metabolized in the liver to O-desmethyltramadol (M1), which has significantly stronger mu-opioid receptor binding than the parent compound. This metabolic activation explains why tramadol's effects can vary between individuals based on their CYP2D6 enzyme activity, with poor metabolizers experiencing less analgesia and fewer opioid-related side effects. Understanding tramadol's pharmacology helps explain why it has a different side effect profile and lower abuse potential than pure mu-opioid agonists, though it still carries risks of dependence and withdrawal.
It's also worth noting that the use of tramadol has been compared to other opioids in several studies, with mixed results. For example, one study found that tramadol produced more adverse effects than hydrocodone and codeine 1, while another study found that tramadol was effective in decreasing pain intensity and improving quality of life in patients with cancer pain 1. However, the evidence is not strong enough to support the routine use of tramadol in cancer patients with mild to moderate cancer pain 1.
From the FDA Drug Label
Tramadol has mu-opioid agonist activity. 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-induced analgesia is only partially antagonized by the opiate antagonist naloxone in several animal tests.
Tramadol is a mu-opioid receptor agonist, but the fact that its analgesia is only partially antagonized by naloxone suggests that it may not be a full agonist at this receptor. Therefore, tramadol can be considered a partial opioid (mu-opioid receptor) agonist 2.
From the Research
Tramadol Mechanism of Action
- Tramadol is a centrally acting analgesic with a low affinity for opioid receptors, specifically mu receptors 3.
- The M1 metabolite of tramadol, produced by liver O-demethylation, shows a higher affinity for opioid receptors than the parent drug 3.
- Tramadol's analgesic action is only partially inhibited by the opioid antagonist naloxone, suggesting the existence of another mechanism of action 3, 4.
- Tramadol also inhibits the reuptake of noradrenaline and serotonin, making a significant contribution to its analgesic action 3, 5, 6.
Tramadol as a Partial Opioid Agonist
- Tramadol is considered a mixed-mechanism opioid drug, exerting its effects via binding to mu receptors and blocking the reuptake of monoamines 7.
- The (+)-tramadol and the metabolite (+)-O-desmethyl-tramadol (M1) are agonists of the mu opioid receptor 5.
- Tramadol's analgesia is only partially mediated by a mu opioid agonist effect, with non-opioid effects (monoaminergic system) also playing a role 4.
- Tramadol is a weak agonist of opioid receptors, with a lower affinity compared to other opioids like morphine 3, 6.
Clinical Implications
- Tramadol's unique mechanism of action and lower affinity for opioid receptors may contribute to its relatively safer profile compared to other opioids 3, 5, 6.
- However, tramadol can still cause adverse effects, including nausea, vomiting, and constipation, and its use should be carefully considered and monitored 3, 5, 6.