indication

Indicated in the treatment of moderate to severe pain. Consider for those prone to constipation or respiratory depression. Tramadol is used to treat postoperative, dental, cancer, and acute musculosketetal pain and as an adjuvant to NSAID therapy in patients with osteoarthritis.

pharmacology

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.

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.

toxicity

LD₅₀=350mg/kg (orally in mice)

biotransformation

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.

absorption

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.

half life

23 +/- 10 minutes

route of elimination

Tramadol is eliminated primarily through metabolism by the liver and the metabolites are eliminated primarily by the kidneys. Tramadol and its metabolites are excreted primarily in the urine with observed plasma half-lives of 6.3 and 7.4 hours for tramadol and M1, respectively. Approximately 30% of the dose is excreted in the urine as unchanged drug, whereas 60% of the dose is excreted as metabolites.

drug interactions

Almotriptan: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Aminoglutethimide: Aminoglutethimide may decrease the effect of Tramadol by increasing Tramadol metabolism and clearance.

Amiodarone: Amiodarone may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. Amiodarone may decrease the effect of Tramadol by decreasing active metabolite production.

Amitriptyline: Tramadol increases the risk of serotonin syndrome and seizures.

Amoxapine: Tramadol increases the risk of serotonin syndrome and seizures.

Amprenavir: Amprenavir may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance.

Aprepitant: Aprepitant may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance.

Atazanavir: Atazanavir may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance.

Benzphetamine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Bosentan: Bosentan may decrease the effect of Tramadol by increasing Tramadol metabolism and clearance.

Bromocriptine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Cabergoline: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Carbamazepine: Carbamazepine may decrease the effect of tramadol by increasing Tramadol metabolism and clearance.

Chloroquine: Chloroquine may decrease the effect of Tramadol by decreasing active metabolite production.

Chlorpromazine: Chlorpromazine may decrease the effect of Tramadol by decreasing active metabolite production.

Cimetidine: Cimetidine may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. Cimetidine may decrease the effect of Tramadol by decreasing active metabolite production.

Cinacalcet: Cinacalcet may decrease the effect of Tramadol by decreasing active metabolite production.

Citalopram: The use of two serotonin modulators, such as citalopram and tramadol, may increase the risk of serotonin syndrome. Consider alternate therapy or monitor for serotonin syndrome during concomitant therapy.

Clarithromycin: Clarithromycin may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance.

Clomipramine: Tramadol increases the risk of serotonin syndrome and seizures. Clomipramine may decrease the effect of Tramadol by decreasing active metabolite production.

Clotrimazole: Clotrimazole may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance.

Clozapine: Clozapine may decrease the effect of Tramadol by decreasing active metabolite production.

Cocaine: Cocaine may decrease the effect of Tramadol by decreasing active metabolite production.

Conivaptan: Conivaptan may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance.

Cyclobenzaprine: Increases risk of seizure.

Cyclosporine: Cyclosporine may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance.

Darifenacin: Darifenacin may decrease the effect of Tramadol by decreasing active metabolite production.

Darunavir: Darunavir may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance.

Delavirdine: Delavirdine may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. Delavirdine may decrease the effect of Tramadol by decreasing active metabolite production.

Desipramine: Tramadol increases the risk of serotonin syndrome and seizures. Desipramine may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. Desipramine may decrease the effect of Tramadol by decreasing active metabolite production.

Desvenlafaxine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Dexamethasone: Dexamethasone may decrease the effect of Tramadol by increasing Tramadol metabolism and clearance.

Dextroamphetamine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Dextromethorphan: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Dihydroergotamine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Diltiazem: Diltiazem may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance.

Diphenhydramine: Diphenhydramine may decrease the effect of Tramadol by decreasing active metabolite production.

Doxepin: Tramadol increases the risk of serotonin syndrome and seizures.

Duloxetine: Duloxetine may decrease the effect of Tramadol by decreasing active metabolite production. Increased risk of serotonin syndrome. Monitor for Tramadol efficacy and symptoms of serotonin syndrome.

Efavirenz: Efavirenz may decrease the effect of Tramadol by increasing Tramadol metabolism and clearance.

Eletriptan: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Ergoloid mesylate: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Ergonovine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Ergotamine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Erythromycin: Erythromycin may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance.

Escitalopram: Tramadol may increase the risk of serotonin syndrome and seizures.

Fluconazole: Fluconazole may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance.

Fluoxetine: The use of two serotonin modulators, such as fluoxetine and tramadol, may increase the risk of serotonin syndrome. Fluoxetine may decrease the effect of tramadol by decreasing active metabolite production.

Fluvoxamine: Tramadol may increase the risk of serotonin syndrome and seizures.

Fosamprenavir: Fosamprenavir may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance.

Fosphenytoin: Fosphenytoin may decrease the effect of Tramadol by increasing Tramadol metabolism and clearance.

Frovatriptan: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Furazolidone: Tramadol increases the risk of serotonin syndrome and seizure induction by the MAO inhibitor, Furazolidone.

Haloperidol: Haloperidol may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. Haloperidol may decrease the effect of Tramadol by decreasing active metabolite production.

Imatinib: Imatinib may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. Imatinib may decrease the effect of Tramadol by decreasing active metabolite production.

Imipramine: Tramadol increases the risk of serotonin syndrome and seizures. Imipramine may decrease the effect of Tramadol by decreasing active metabolite production.

Indinavir: Indinavir may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance.

Isocarboxazid: Tramadol may increase the risk of serotonin syndrome and seizure induction by the MAO inhibitor, isocarboxazid.

Isoniazid: Isoniazid may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. Isoniazid may decrease the effect of Tramadol by decreasing active metabolite production.

Itraconazole: Itraconazole may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance.

Ketoconazole: Ketoconazole may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. Ketoconazole may decrease the effect of Tramadol by decreasing active metabolite production.

Lapatinib: Lapatinib may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance.

Lidocaine: Lidocaine may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. Lidocaine may decrease the effect of Tramadol by decreasing active metabolite production.

Linezolid: Tramadol increases the risk of serotonin syndrome and seizure induction by the MAO inhibitor, Linezolid.

Lisdexamfetamine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Lopinavir: Lopinavir may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. Lopinavir may decrease the effect of Tramadol by decreasing active metabolite production.

Maprotiline: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Meperidine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Methadone: Methadone may decrease the effect of Tramadol by decreasing active metabolite production.

Methamphetamine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Methotrimeprazine: Additive CNS depressant effects. Decrease dose of tramadol by 50% if initiating methotrimeprazine therapy. Monitor for increased CNS depression and apply further dosage adjustments as required.

Methylergonovine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Metronidazole: Metronidazole may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance.

Miconazole: Miconazole may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. Miconazole may decrease the effect of Tramadol by decreasing active metabolite production.

Mirtazapine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Moclobemide: Tramadol may increase the risk of serotonin syndrome and seizure induction by the MAO inhibitor, moclobemide.

Nafcillin: Nafcillin may decrease the effect of Tramadol by increasing Tramadol metabolism and clearance.

Naratriptan: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Nefazodone: Nefazodone may increase tramadol toxicity by decreasing tramadol metabolism and clearance. Increased risk of serotonin syndrome. Monitor for tramadol toxicity and symptoms of serotonin syndrome.

Nelfinavir: Nelfinavir may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance.

Nevirapine: Nevirapine may decrease the effect of Tramadol by increasing Tramadol metabolism and clearance.

Nicardipine: Nicardipine may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. Nicardipine may decrease the effect of Tramadol by decreasing active metabolite production.

Nilotinib: Nilotinib may decrease the effect of Tramadol by decreasing active metabolite production.

Norfloxacin: Norfloxacin may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance.

Nortriptyline: Tramadol increases the risk of serotonin syndrome and seizures.

Oxcarbazepine: Oxcarbazepine may decrease the effect of Tramadol by increasing Tramadol metabolism and clearance.

Paroxetine: Tramadol may increase the risk of serotonin syndrome and seizures. Paroxetine may decrease the effect of Tramadol by decreasing active metabolite production.

Pentobarbital: Pentobarbital may decrease the effect of Tramadol by increasing Tramadol metabolism and clearance.

Pergolide: Pergolide may decrease the effect of Tramadol by decreasing active metabolite production. Increased risk of serotonin syndrome. Monitor for Tramadol efficacy and symptoms of serotonin syndrome.

Phendimetrazine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Phenelzine: Tramadol may increase the risk of serotonin syndrome and seizure induction by the MAO inhibitor, phenelzine.

Phenobarbital: Phenobarbital may decrease the effect of Tramadol by increasing Tramadol metabolism and clearance.

Phentermine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Phenytoin: Phenytoin may decrease the effect of Tramadol by increasing Tramadol metabolism and clearance.

Pioglitazone: Pioglitazone may decrease the effect of Tramadol by decreasing active metabolite production.

Posaconazole: Posaconazole may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance.

Primidone: Primidone may decrease the effect of Tramadol by increasing Tramadol metabolism and clearance.

Procarbazine: Tramadol increases the risk of serotonin syndrome and seizure induction by the MAO inhibitor, Procarbazine.

Promethazine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Protriptyline: Tramadol increases the risk of serotonin syndrome and seizures.

Pyrimethamine: Pyrimethamine may decrease the effect of Tramadol by decreasing active metabolite production.

Quinidine: Quinidine may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. Quinidine may decrease the effect of Tramadol by decreasing active metabolite production.

Quinine: Quinine may decrease the effect of Tramadol by decreasing active metabolite production.

Ranolazine: Ranolazine may decrease the effect of Tramadol by decreasing active metabolite production.

Rasagiline: Tramadol may increase the risk of serotonin syndrome and seizure induction by the MAO inhibitor, rasagiline.

Rifabutin: Rifabutin may decrease the effect of Tramadol by increasing Tramadol metabolism and clearance.

Rifampin: Rifampin may decrease the effect of Tramadol by increasing Tramadol metabolism and clearance.

Rifapentine: Rifapentine may decrease the effect of Tramadol by increasing Tramadol metabolism and clearance.

Ritonavir: Ritonavir may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. Ritonavir may decrease the effect of Tramadol by decreasing active metabolite production.

Rizatriptan: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

S-Adenosylmethionine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Saquinavir: Saquinavir may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance.

Selegiline: Tramadol increases the risk of serotonin syndrome and seizure induction by the MAO inhibitor, Selegiline.

Sertraline: Tramadol increases the risk of serotonin syndrome and seizures. Sertraline may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. Sertraline may decrease the effect of Tramadol by decreasing active metabolite production.

Sibutramine: Sibutramine may incrase the serotonergic effect of the Tramadol. Concomitant therapy should be avoided.

Sitaxentan: Sitaxsentan may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance.

St. John's Wort: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Sumatriptan: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Telithromycin: Telithromycin may decrease the metabolism and clearance of tramadol. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of tramadol if telithromycin is initiated, discontinued or dose changed.

Terbinafine: Terbinafine may decrease the effect of Tramadol by decreasing active metabolite production.

Tetracycline: Tetracycline may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance.

Thioridazine: Thioridazine may decrease the effect of Tramadol by decreasing active metabolite production.

Ticlopidine: Ticlopidine may decrease the effect of Tramadol by decreasing active metabolite production.

Tranylcypromine: Tramadol may increase the risk of serotonin syndrome and seizure induction by the MAO inhibitor, tranylcypromine. Tranylcypromine may decrease the effect of tramadol by decreasing active metabolite production.

Trazodone: The use of two serotonin modulators, such as trazodone and tramadol, may increase the risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Trimipramine: Tramadol may increase the risk of serotonin syndrome and seizures.

Triprolidine: The CNS depressants, Triprolidine and Tramadol, may increase adverse/toxic effects due to additivity. Monitor for increased CNS depressant effects during concomitant therapy.

Venlafaxine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Verapamil: Verapamil may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance.

Voriconazole: Voriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of tramadol by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of tramadol if voriconazole is initiated, discontinued or dose changed.

Zolmitriptan: The use of two serotonin modulators, such as zolmitriptan and tramadol, may increase the risk of serotonin syndrome. Consider alternate therapy or monitor for serotonin syndrome during concomitant therapy.