TRAMADOL HYDROCHLORIDE

12.1 Mechanism of Action Tramadol hydrochloride extended-release tablets contain tramadol, an opioid agonist and an inhibitor of reuptake of norepinephrine and serotonin. Although the mode of action of tramadol is not completely understood, the analgesic effect of tramadol is believed to be due to both binding to μ-opioid receptors and weak inhibition of reuptake of norepinephrine and serotonin. Opioid activity of tramadol is due to both low affinity binding of the parent compound and higher affinity binding of the O-desmethyl metabolite M1 to μ-opioid receptors. In animal models, M1 is up to 6 times more potent than tramadol in producing analgesia and 200 times more potent in μ-opioid binding. Tramadol-induced analgesia is only partially antagonized by the opioid antagonist naloxone in several animal tests. The relative contribution of both tramadol and M1 to human analgesia is dependent upon the plasma concentrations of each compound. Tramadol has been shown to inhibit reuptake of no

Contraindications

• • including paralytic ileus [see Warnings and Precautions (5.15)] Hypersensitivity to tramadol (e.g.
• • anaphylaxis) [see Warnings and Precautions (5.17)
• • including paralytic ileus (4) Hypersensitivity to tramadol (4) Concurrent use of monoamine oxidase inhibitors (MAOIs) or use within the last 14 days (4)