What is the mechanism of action 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, which help block pain signals 1. Tramadol is metabolized in the liver to O-desmethyltramadol (M1), which has stronger opioid activity than the parent compound. The typical dosage ranges from 50-100 mg every 4-6 hours, with a maximum daily dose of 400 mg (300 mg in elderly patients) 1. Due to its serotonergic effects, tramadol carries a risk of serotonin syndrome when combined with other serotonergic medications and may cause less respiratory depression than traditional opioids but still requires careful monitoring 1.

Key Points

• Tramadol's dual mechanism of action involves weak mu-opioid receptor agonism and inhibition of serotonin and norepinephrine reuptake 1
• The medication is available in immediate-release and extended-release formulations, with a recommended maximum daily dose of 400 mg for adults with normal hepatic and renal function 1
• Tramadol is less potent than other opioids, approximately one-tenth as potent as morphine, and should be used with caution in patients taking other serotonergic or monoamine oxidase inhibitors (MAOI)-like medications due to the risk of serotonin syndrome 1
• The use of tramadol for chronic neuropathic pain carries the risk of addiction and should be avoided whenever possible, opting for other management strategies first 1

Considerations for Use

• Patients with moderate to severe pain may benefit from tramadol, but its use should be carefully considered due to the potential for adverse effects and addiction 1
• Monitoring for signs of serotonin syndrome, respiratory depression, and other adverse effects is crucial when prescribing tramadol, especially in combination with other medications 1
• Genetic differences in the CYP2D6 enzyme can affect the metabolism of tramadol, leading to variability in pain relief among patients 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.

The mechanism of action of tramadol is through two complementary 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 re-uptake of norepinephrine and serotonin: Tramadol also inhibits the re-uptake of norepinephrine and serotonin, which may contribute to its analgesic profile 2.

From the Research

Mechanism of Action of Tramadol

Tramadol is a centrally acting analgesic with a dual mechanism of action, involving both opioid and monoaminergic mechanisms 3, 4, 5, 6, 7. The key aspects of its mechanism include:

• Binding to mu-opioid receptors: Tramadol and its metabolite, (+)-O-desmethyl-tramadol (M1), are agonists of the mu opioid receptor, which contributes to its analgesic activity 3, 5, 6.
• Inhibition of serotonin and norepinephrine reuptake: Tramadol inhibits the reuptake of serotonin and norepinephrine, which enhances inhibitory effects on pain transmission in the spinal cord 3, 5, 6.
• Complementary and synergistic actions: The two enantiomers of tramadol, (+)-tramadol and (-)-tramadol, have different mechanisms of action, with (+)-tramadol inhibiting serotonin reuptake and (-)-tramadol inhibiting norepinephrine reuptake, resulting in a synergistic analgesic effect 3, 5, 6.

Pharmacokinetics and Pharmacodynamics

The pharmacokinetics and pharmacodynamics of tramadol are characterized by:

• Rapid absorption and high bioavailability after oral administration 5, 6.
• Extensive tissue distribution and low plasma protein binding 3, 6.
• Metabolism by cytochrome P450 enzymes, including CYP2D6, CYP2B6, and CYP3A4, to form active metabolites such as M1 5, 6.
• Renal excretion of tramadol and its metabolites 6.
• A mean elimination half-life of approximately 6 hours 6.

Clinical Efficacy and Safety

Tramadol has been shown to be effective in the management of moderate to severe acute and chronic pain, including neuropathic pain, low back pain, osteoarthritis pain, and breakthrough pain 3, 4, 6, 7. Its safety profile is characterized by:

• A lower risk of opioid-type adverse effects, such as nausea, drowsiness, vomiting, dry mouth, and constipation, compared to traditional opioids 3, 4, 6.
• A low potential for abuse and dependence 5, 6.
• A favorable adverse-effect profile, making it a suitable alternative for patients with contraindications to nonsteroidal anti-inflammatory drugs (NSAIDs) or cyclooxygenase-2 (COX-2) inhibitors 4, 7.