Brands, Medical Use, Clinical Data
Brands / Synonyms
Crispin; Ralivia ER; Ralivia Flashtab; Ryzolt; Tramadol; Tramadol and Acetaminophen; Tramadol HCl; Tramadol HCl BP/EP; Tramadol hydrochloride; Tramadolum [Inn-Latin]; Tramal; Tramodol Hcl; Ultracet; Ultram; Ultram ER; Zydol
Indicated in the treatment of moderate to severe pain.
Tramadol, a centrally-acting analgesic, exists as a racemic mixture of the trans isomer, with important differences in binding, activity, and metabolism associated with the two enantiomers. Although Tramadol is a synthetic analog of codeine, it has a significantly lower affinity for opioid receptors than codeine. Tramadol is used to treat postoperative, dental, cancer, and acute musculosketetal pain and as an adjuvant to NSAID therapy in patients with osteoarthritis.
Mechanism of Action
Tramadol and its O-desmethyl metabolite (M1) are selective, weak OP3-receptor agonists. Opiate receptors are coupled with G-protein receptors and function as both positive and negative regulators of synaptic transmission via G-proteins that activate effector proteins. As the effector system is adenylate cyclase and cAMP located at the inner surface of the plasma membrane, opioids decrease intracellular cAMP by inhibiting adenylate cyclase. Subsequently, the release of nociceptive neurotransmitters such as substance P, GABA, dopamine, acetylcholine and noradrenaline is inhibited. The analgesic properties of Tramadol can be attributed to norepinephrine and serotonin reuptake blockade in the CNS, which inhibits pain transmission in the spinal cord. The (+) enantiomer has higher affinity for the OP3 receptor and preferentially inhibits serotonin uptake and enhances serotonin release. The (-) enantiomer preferentially inhibits norepinephrine reuptake by stimulating alpha(2)-adrenergic receptors.
Racemic tramadol is rapidly and almost completely absorbed after oral administration. The mean absolute bioavailability of a 100 mg oral dose is approximately 75%.The mean peak plasma concentration of racemic tramadol and M1 occurs at two and three hours, respectively, after administration in healthy adults.
LD50=350mg/kg (orally in mice)
Biotrnasformation / Drug Metabolism
The major metabolic pathways appear to be N- and O- demethylation and glucuronidation or sulfation in the liver. One metabolite (O-desmethyltramadol, denoted M1) is pharmacologically active in animal models.
ULTRAM should not be administered to patients who have previously demonstrated hypersensitivity to tramadol, any
other component of this product or opioids. ULTRAM is contraindicated in any situation where opioids are
contraindicated, including acute intoxication with any of the following: alcohol, hypnotics, narcotics, centrally
acting analgesics, opioids or psychotropic drugs. ULTRAM may worsen central nervous system and respiratory depression
in these patients.
In vitro studies indicate that tramadol is unlikely to inhibit the CYP3A4-mediated metabolism of other drugs when
tramadol is administered concomitantly at therapeutic doses. Tramadol does not appear to induce its own metabolism in
humans, since observed maximal plasma concentrations after multiple oral doses are higher than expected based on
single-dose data. Tramadol is a mild inducer of selected drug metabolism pathways measured in animals.
Use With Carbamazepine
Patients taking carbamazepine may have a significantly reduced analgesic effect of ULTRAM. Because
carbamazepine increases tramadol metabolism and because of the seizure risk associated with tramadol, concomitant
administration of ULTRAM and carbamazepine is not recommended.
Use With Quinidine
Tramadol is metabolized to M1 by CYP2D6. Quinidine is a selective inhibitor of that isoenzyme, so that
concomitant administration of quinidine and ULTRAM results in increased concentrations of tramadol and reduced
concentrations of M1.The clinical consequences of these findings are unknown. In vitro drug interaction studies in
human liver microsomes indicate that tramadol has no effect on quinidine metabolism.
Use With Inhibitors of CYP2D6
In vitro drug interaction studies in human liver microsomes indicate that concomitant administration with
inhibitors of CYP2D6 such as fluoxetine, paroxetine, and amitriptyline could result in some inhibition of the
metabolism of tramadol.
Use With Cimetidine
Concomitant administration of ULTRAM with cimetidine does not result in clinically significant changes in
tramadol pharmacokinetics. Therefore, no alteration of the ULTRAM dosage regimen is recommended.
Use With MAO Inhibitors
Interactions with MAO Inhibitors, due to interference with detoxification mechanisms, have been reported
for some centrally acting drugs.
Use With Digoxin and Warfarin
Post-marketing surveillance has revealed rare reports of digoxin toxicity and alteration of warfarin effect,
including elevation of prothrombin times.