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Identification
Name Tramadol
Accession Number DB00193 (APRD00028)
Type small molecule
Groups approved
Description

A narcotic analgesic proposed for moderate to severe pain. It may be habituating. [PubChem]
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
Tramadol HCl
Tramadol hydrochloride
Tramadolum [INN-Latin]
Tramodol Hcl
Salts Not Available
Brand names
Name Company
Crispin
Ralivia ER
Ralivia Flashtab
Tramadol HCl BP/EP
Tramal
Tridural
Ultram
Ultram ER
Brand mixtures Not Available
Categories
  • Narcotics
  • Analgesics
  • Analgesics, Opioid
CAS number 27203-92-5
Weight Average: 263.3752
Monoisotopic: 263.188529049
Chemical Formula C16H25NO2
InChI Key InChIKey=TVYLLZQTGLZFBW-ZBFHGGJFSA-N
InChI
InChI=1S/C16H25NO2/c1-17(2)12-14-7-4-5-10-16(14,18)13-8-6-9-15(11-13)19-3/h6,8-9,11,14,18H,4-5,7,10,12H2,1-3H3/t14-,16+/m1/s1
Plain Text
IUPAC Name
(1R,2R)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexan-1-ol
SMILES
COC1=CC=CC(=C1)[C@@]1(O)CCCC[C@@H]1CN(C)C
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Phenylpropylamines
Substructures
  • Hydroxy Compounds
  • Benzyl Alcohols and Derivatives
  • Phenols and Derivatives
  • Ethers
  • Benzene and Derivatives
  • Aliphatic and Aryl Amines
  • Alcohols and Polyols
  • Aromatic compounds
  • Anisoles
  • Phenylpropylamines
  • Phenyl Esters
Pharmacology
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.
Pharmacodynamics 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.
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.
Volume of distribution
  • 2.6 L/kg [male 100 mg intravenous dose]
  • 2.9 L/kg [female 100 mg intravenous dose]
Protein binding 20%
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.

Important The metabolism module of DrugBank is currently in beta. Questions or suggestions? Please contact us.

Substrate Enzymes Product
Tramadol
O-Desmethyltramadol Details
Tramadol
N-Desmethyltramadol Details
Tramadol
    		N,N-didesmethyltramadol Details
    Tramadol
      		N,N,O-tridesmethyl-tramadol Details
      Tramadol
        		N,O-didesmethyltramadol Details
        Tramadol
          		O-Desmethyl-tramado glucuronide Details
          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.
          Half life 23 +/- 10 minutes
          Clearance
          • 5.9 mL/min/Kg [Healthy Adults, 100 mg qid, MD p.o]
          • 8.5 mL/min/Kg [Healthy Adults, 100 mg SD p.o]
          • 6.89 mL/min/Kg [Geriatric, (<75 yr), 50 mg SD p.o.]
          • 4.23 mL/min/Kg [Hepatic Impaired, 50 mg SD p.o.]
          • 4.23 mL/min/Kg [Renal Impaired, Clcr10-3mL/min, 100 mg SD i.v.]
          • 3.73 mL/min/Kg [Renal Impaired, CLcr<5 mL/min, 100 mg SD i.v.]
          • 6.4 mL/min/Kg [Male following a 100 mg IV dose]
          • 5.7 mL/min/Kg [Female following a 100 mg IV dose]
          Toxicity LD50=350mg/kg (orally in mice)
          Affected organisms
          • Humans and other mammals
          Pathways Not Available
          Pharmacoeconomics
          Manufacturers
          • Cipher pharmaceuticals inc
          • Purdue pharma products lp
          • Par pharmaceutical
          • Biovail laboratories international srl
          • Victory pharma inc
          • Actavis elizabeth llc
          • Alphapharm party ltd
          • Amneal pharmaceuticals llc
          • Apotex inc
          • Asta medica inc
          • Caraco pharmaceutical laboratories ltd
          • Ivax pharmaceuticals inc sub teva pharmaceuticals usa
          • Mallinckrodt inc
          • Mutual pharmaceutical co inc
          • Mylan pharmaceuticals inc
          • Northstar healthcare holdings ltd
          • Pliva inc
          • Sandoz inc
          • Teva pharmaceuticals usa inc
          • Watson laboratories
          • Ortho mcneil janssen pharmaceuticals inc
          Packagers
          Dosage forms
          Form Route Strength
          Tablet, extended release Oral
          Prices
          Unit description Cost Unit
          Tramadol hcl powder 29.08 USD g
          Ultram ER 300 mg 24 Hour tablet 10.66 USD tablet
          Ultram er 300 mg tablet 10.25 USD tablet
          Ultram ER 200 mg 24 Hour tablet 7.64 USD tablet
          Ultram er 200 mg tablet 7.35 USD tablet
          TraMADol HCl 200 mg 24 Hour tablet 6.25 USD tablet
          Ultram ER 100 mg 24 Hour tablet 4.62 USD tablet
          Ultram er 100 mg tablet 4.44 USD tablet
          TraMADol HCl 100 mg 24 Hour tablet 3.78 USD tablet
          Ultram 50 mg tablet 1.99 USD tablet
          Tramadol-Acetaminophen 37.5-325 mg tablet 1.07 USD tablet
          Tramadol hcl 50 mg tablet 0.7 USD tablet
          First Prev Next Last
          DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
          Patents
          Country Patent Number Approved Expires (estimated)
          United States 6607748 2000-06-29 2020-06-29
          United States 5464632 1993-03-22 2013-03-22
          Canada 2476201 2009-09-01 2023-02-21
          Canada 2123160 2003-04-29 2014-05-09
          Properties
          State solid
          Experimental Properties
          Property Value Source
          melting point 180-181 °C Not Available
          water solubility Soluble in water. Not Available
          logP 2.4 Not Available
          pKa 9.41 Not Available
          Predicted Properties
          Property Value Source
          water solubility 7.50e-01 g/l ALOGPS
          logP 2.71 ALOGPS
          logP 2.45 ChemAxon
          logS -2.5 ALOGPS
          pKa (strongest acidic) 13.8 ChemAxon
          pKa (strongest basic) 9.23 ChemAxon
          physiological charge 1 ChemAxon
          hydrogen acceptor count 3 ChemAxon
          hydrogen donor count 1 ChemAxon
          polar surface area 32.7 ChemAxon
          rotatable bond count 4 ChemAxon
          refractivity 78.27 ChemAxon
          polarizability 30.45 ChemAxon
          References
          Synthesis Reference Not Available
          General Reference
          1. Dayer P, Desmeules J, Collart L: [Pharmacology of tramadol] Drugs. 1997;53 Suppl 2:18-24. Pubmed
          2. Harati Y, Gooch C, Swenson M, Edelman S, Greene D, Raskin P, Donofrio P, Cornblath D, Sachdeo R, Siu CO, Kamin M: Double-blind randomized trial of tramadol for the treatment of the pain of diabetic neuropathy. Neurology. 1998 Jun;50(6):1842-6. Pubmed
          3. Harati Y, Gooch C, Swenson M, Edelman SV, Greene D, Raskin P, Donofrio P, Cornblath D, Olson WH, Kamin M: Maintenance of the long-term effectiveness of tramadol in treatment of the pain of diabetic neuropathy. J Diabetes Complications. 2000 Mar-Apr;14(2):65-70. Pubmed
          4. Gobel H, Stadler T: [Treatment of post-herpes zoster pain with tramadol. Results of an open pilot study versus clomipramine with or without levomepromazine] Drugs. 1997;53 Suppl 2:34-9. Pubmed
          5. Boureau F, Legallicier P, Kabir-Ahmadi M: Tramadol in post-herpetic neuralgia: a randomized, double-blind, placebo-controlled trial. Pain. 2003 Jul;104(1-2):323-31. Pubmed
          External Links
          Resource Link
          KEGG Compound C07153 Link_out
          PubChem Compound 33741 Link_out
          PubChem Substance 46506256 Link_out
          ChemSpider 31105 Link_out
          BindingDB 50176262 Link_out
          Therapeutic Targets Database DAP000140 Link_out
          PharmGKB PA451735 Link_out
          RxList http://www.rxlist.com/cgi/generic/tramadol.htm Link_out
          Drugs.com http://www.drugs.com/tramadol.html Link_out
          Wikipedia http://en.wikipedia.org/wiki/Tramadol Link_out
          ATC Codes
          • N02AX02
          AHFS Codes
          • 28:08.08
          PDB Entries Not Available
          FDA label show (408 KB)
          MSDS show (74.7 KB)
          Interactions
          Drug Interactions
          Drug Interaction
          Almotriptan Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.
          Alvimopan Increases levels by receptor binding competition. Discontinue opioid administration at least 7 days prior to administrating Alvimopan.
          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.
          Etravirine Tramadol,when used concomitantly with etravirine (a strong CYP3A4 inducer), may experience a decrease in serum concentration and efficacy due to increased tramadol metabolism and clearance.
          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.
          Food Interactions Not Available
          Targets

          1. Mu-type opioid receptor

          Pharmacological action: yes
          Actions: agonist

          Inhibits neurotransmitter release by reducing calcium ion currents and increasing potassium ion conductance. Receptor for beta-endorphin

          Organism class: human
          UniProt ID: P35372 Link_out
          Gene: OPRM1 Link_out
          Protein Sequence: FASTA
          Gene Sequence: FASTA
          SNPs: SNPJam Report Link_out

          References:
          1. Gillen C, Haurand M, Kobelt DJ, Wnendt S: Affinity, potency and efficacy of tramadol and its metabolites at the cloned human mu-opioid receptor. Naunyn Schmiedebergs Arch Pharmacol. 2000 Aug;362(2):116-21. Pubmed
          2. Potschka H, Friderichs E, Loscher W: Anticonvulsant and proconvulsant effects of tramadol, its enantiomers and its M1 metabolite in the rat kindling model of epilepsy. Br J Pharmacol. 2000 Sep;131(2):203-12. Pubmed
          3. Raffa RB, Friderichs E, Reimann W, Shank RP, Codd EE, Vaught JL: Opioid and nonopioid components independently contribute to the mechanism of action of tramadol, an ‘atypical’ opioid analgesic. J Pharmacol Exp Ther. 1992 Jan;260(1):275-85. Pubmed
          4. Grond S, Sablotzki A: Clinical pharmacology of tramadol. Clin Pharmacokinet. 2004;43(13):879-923. Pubmed
          5. Ide S, Minami M, Ishihara K, Uhl GR, Sora I, Ikeda K: Mu opioid receptor-dependent and independent components in effects of tramadol. Neuropharmacology. 2006 Sep;51(3):651-8. Epub 2006 Jun 21. Pubmed
          6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
          7. Minami K, Uezono Y, Ueta Y: Pharmacological aspects of the effects of tramadol on G-protein coupled receptors. J Pharmacol Sci. 2007 Mar;103(3):253-60. Pubmed
          8. Frink MC, Hennies HH, Englberger W, Haurand M, Wilffert B: Influence of tramadol on neurotransmitter systems of the rat brain. Arzneimittelforschung. 1996 Nov;46(11):1029-36. Pubmed

          2. Sodium-dependent noradrenaline transporter

          Pharmacological action: yes
          Actions: inhibitor

          Amine transporter. Terminates the action of noradrenaline by its high affinity sodium-dependent reuptake into presynaptic terminals

          Organism class: human
          UniProt ID: P23975 Link_out
          Gene: SLC6A2 Link_out
          Protein Sequence: FASTA
          Gene Sequence: FASTA
          SNPs: SNPJam Report Link_out

          References:
          1. Sagata K, Minami K, Yanagihara N, Shiraishi M, Toyohira Y, Ueno S, Shigematsu A: Tramadol inhibits norepinephrine transporter function at desipramine-binding sites in cultured bovine adrenal medullary cells. Anesth Analg. 2002 Apr;94(4):901-6, table of contents. Pubmed
          2. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
          3. Berrocoso E, Mico JA: Cooperative opioid and serotonergic mechanisms generate superior antidepressant-like effects in a mice model of depression. Int J Neuropsychopharmacol. 2009 Sep;12(8):1033-44. Epub 2009 Apr 3. Pubmed
          4. Frink MC, Hennies HH, Englberger W, Haurand M, Wilffert B: Influence of tramadol on neurotransmitter systems of the rat brain. Arzneimittelforschung. 1996 Nov;46(11):1029-36. Pubmed

          3. Sodium-dependent serotonin transporter

          Pharmacological action: yes
          Actions: inhibitor

          Terminates the action of serotonine by its high affinity sodium-dependent reuptake into presynaptic terminals

          Organism class: human
          UniProt ID: P31645 Link_out
          Gene: SLC6A4 Link_out
          Protein Sequence: FASTA
          Gene Sequence: FASTA
          SNPs: SNPJam Report Link_out

          References:
          1. Barann M, Urban B, Stamer U, Dorner Z, Bonisch H, Bruss M: Effects of tramadol and O-demethyl-tramadol on human 5-HT reuptake carriers and human 5-HT3A receptors: a possible mechanism for tramadol-induced early emesis. Eur J Pharmacol. 2006 Feb 15;531(1-3):54-8. Epub 2006 Jan 19. Pubmed
          2. Driessen B, Reimann W: Interaction of the central analgesic, tramadol, with the uptake and release of 5-hydroxytryptamine in the rat brain in vitro. Br J Pharmacol. 1992 Jan;105(1):147-51. Pubmed
          3. Frink MC, Hennies HH, Englberger W, Haurand M, Wilffert B: Influence of tramadol on neurotransmitter systems of the rat brain. Arzneimittelforschung. 1996 Nov;46(11):1029-36. Pubmed

          4. 5-hydroxytryptamine 2C receptor

          Pharmacological action: unknown
          Actions: antagonist

          This is one of the several different receptors for 5- hydroxytryptamine (serotonin), a biogenic hormone that functions as a neurotransmitter, a hormone, and a mitogen. This receptor mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system

          Organism class: human
          UniProt ID: P28335 Link_out
          Gene: HTR2C Link_out
          Protein Sequence: FASTA
          Gene Sequence: FASTA
          SNPs: SNPJam Report Link_out

          References:
          1. Ogata J, Minami K, Uezono Y, Okamoto T, Shiraishi M, Shigematsu A, Ueta Y: The inhibitory effects of tramadol on 5-hydroxytryptamine type 2C receptors expressed in Xenopus oocytes. Anesth Analg. 2004 May;98(5):1401-6, table of contents. Pubmed
          2. Horishita T, Minami K, Uezono Y, Shiraishi M, Ogata J, Okamoto T, Shigematsu A: The tramadol metabolite, O-desmethyl tramadol, inhibits 5-hydroxytryptamine type 2C receptors expressed in Xenopus Oocytes. Pharmacology. 2006;77(2):93-9. Epub 2006 May 5. Pubmed

          5. Kappa-type opioid receptor

          Pharmacological action: unknown
          Actions: agonist

          Inhibits neurotransmitter release by reducing calcium ion currents and increasing potassium ion conductance. Receptor for dynorphins. May play a role in arousal and regulation of autonomic and neuroendocrine functions

          Organism class: human
          UniProt ID: P41145 Link_out
          Gene: OPRK1 Link_out
          Protein Sequence: FASTA
          Gene Sequence: FASTA
          SNPs: SNPJam Report Link_out

          References:
          1. Sun HL, Zheng JW, Wang K, Liu RK, Liang JH: Tramadol reduces the 5-HTP-induced head-twitch response in mice via the activation of mu and kappa opioid receptors. Life Sci. 2003 Jan 31;72(11):1221-30. Pubmed

          6. Delta-type opioid receptor

          Pharmacological action: no
          Actions: agonist

          Inhibits neurotransmitter release by reducing calcium ion currents and increasing potassium ion conductance. Highly stereoselective. receptor for enkephalins

          Organism class: human
          UniProt ID: P41143 Link_out
          Gene: OPRD1 Link_out
          Protein Sequence: FASTA
          Gene Sequence: FASTA
          SNPs: SNPJam Report Link_out

          References:
          1. Wentland MP, Lou R, Lu Q, Bu Y, VanAlstine MA, Cohen DJ, Bidlack JM: Syntheses and opioid receptor binding properties of carboxamido-substituted opioids. Bioorg Med Chem Lett. 2009 Jan 1;19(1):203-8. Epub 2008 Nov 7. Pubmed

          7. Glutamate [NMDA] receptor subunit 3A

          Pharmacological action: unknown
          Actions: antagonist

          NMDA receptor subtype of glutamate-gated ion channels with reduced single-channel conductance, low calcium permeability and low voltage-dependent sensitivity to magnesium. Mediated by glycine. May play a role in the development of dendritic spines. May play a role in PPP2CB-NMDAR mediated signaling mechanism

          Organism class: human
          UniProt ID: Q8TCU5 Link_out
          Gene: GRIN3A Link_out
          Protein Sequence: FASTA
          Gene Sequence: FASTA
          SNPs: SNPJam Report Link_out

          References:
          1. Hara K, Minami K, Sata T: The effects of tramadol and its metabolite on glycine, gamma-aminobutyric acidA, and N-methyl-D-aspartate receptors expressed in Xenopus oocytes. Anesth Analg. 2005 May;100(5):1400-5, table of contents. Pubmed

          8. Alpha-7 nicotinic cholinergic receptor subunit

          Pharmacological action: unknown
          Actions: antagonist
          Organism class: human
          UniProt ID: Q693P7 Link_out
          Gene: CHRFAM7A
          Protein Sequence: FASTA
          Gene Sequence: FASTA
          SNPs: SNPJam Report Link_out

          References:
          1. Shiraishi M, Minami K, Uezono Y, Yanagihara N, Shigematsu A, Shibuya I: Inhibitory effects of tramadol on nicotinic acetylcholine receptors in adrenal chromaffin cells and in Xenopus oocytes expressing alpha 7 receptors. Br J Pharmacol. 2002 May;136(2):207-16. Pubmed

          9. Muscarinic acetylcholine receptor M3

          Pharmacological action: unknown
          Actions: antagonist

          The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the action of G proteins. Primary transducing effect is Pi turnover

          Organism class: human
          UniProt ID: P20309 Link_out
          Gene: CHRM3 Link_out
          Protein Sequence: FASTA
          Gene Sequence: FASTA
          SNPs: SNPJam Report Link_out

          References:
          1. Shiraishi M, Minami K, Uezono Y, Yanagihara N, Shigematsu A: Inhibition by tramadol of muscarinic receptor-induced responses in cultured adrenal medullary cells and in Xenopus laevis oocytes expressing cloned M1 receptors. J Pharmacol Exp Ther. 2001 Oct;299(1):255-60. Pubmed
          2. Shiga Y, Minami K, Shiraishi M, Uezono Y, Murasaki O, Kaibara M, Shigematsu A: The inhibitory effects of tramadol on muscarinic receptor-induced responses in Xenopus oocytes expressing cloned M(3) receptors. Anesth Analg. 2002 Nov;95(5):1269-73, table of contents. Pubmed
          Enzymes

          1. Cytochrome P450 2D6

          Actions: substrate, inhibitor

          Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants

          UniProt ID: P10635 Link_out
          Gene: CYP2D6 Link_out
          Protein Sequence: FASTA
          Gene Sequence: FASTA
          SNPs: SNPJam Report Link_out

          References:
          1. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.
          2. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

          2. Cytochrome P450 3A4

          Actions: substrate, inhibitor

          Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4- hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. The enzyme also hydroxylates etoposide

          UniProt ID: P08684 Link_out
          Gene: CYP3A4
          Protein Sequence: FASTA
          Gene Sequence: FASTA
          SNPs: SNPJam Report Link_out

          References:
          1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

          3. Cytochrome P450 2B6

          Actions: substrate

          Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics

          UniProt ID: P20813 Link_out
          Gene: CYP2B6 Link_out
          Protein Sequence: FASTA
          Gene Sequence: FASTA
          SNPs: SNPJam Report Link_out

          References:
          1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed
          Comments
          Drug created on June 13, 2005 07:24 / Updated on February 08, 2013 16:19