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Identification
NameTramadol
Accession NumberDB00193  (APRD00028)
TypeSmall Molecule
GroupsApproved, Investigational
Description

A narcotic analgesic proposed for moderate to severe pain. It may be habituating. [PubChem] Tramadol is also prepared as a variable release capsules, marketed under the brand name ConZip. For example, a 150 mg capsule will contain 37.5 mg of the immediate release form and 112.5 mg of the extended release form.

Structure
Thumb
Synonyms
SynonymLanguageCode
(+)-TramadolNot AvailableNot Available
(+)-trans-2-(Dimethylaminomethyl)-1-(m-methoxyphenyl)cyclohexanolNot AvailableNot Available
Salts
Name/CAS Structure Properties
Tramadol Hydrochloride
Thumb
  • InChI Key: PPKXEPBICJTCRU-XMZRARIVSA-N
  • Monoisotopic Mass: 299.165206788
  • Average Mass: 299.836
DBSALT000181
Brand names
NameCompany
ConZipNot Available
DurelaNot Available
RaliviaBiovail
RybixNot Available
RyzoltNot Available
TramalGrünenthal GmbH
TriduralNot Available
UltramJanssen Pharmaceuticals
Zytram XL Not Available
Brand mixtures
Brand NameIngredients
Tramacet Acetaminophen and Tramadol
ULTRACETTramadol + Acetaminophen
CategoriesNot Available
CAS number27203-92-5
WeightAverage: 263.3752
Monoisotopic: 263.188529049
Chemical FormulaC16H25NO2
InChI KeyTVYLLZQTGLZFBW-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
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
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassBenzenoids
ClassBenzene and Substituted Derivatives
SubclassPhenol Ethers
Direct parentAnisoles
Alternative parentsAlkyl Aryl Ethers; Cyclohexanols; Tertiary Alcohols; Tertiary Amines; Cyclic Alcohols and Derivatives; Polyamines
Substituentscyclohexanol; alkyl aryl ether; tertiary alcohol; cyclic alcohol; tertiary amine; ether; polyamine; alcohol; organonitrogen compound; amine
Classification descriptionThis compound belongs to the anisoles. These are organic compounds contaiing a methoxybenzene or a derivative thereof.
Pharmacology
IndicationIndicated 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.
PharmacodynamicsTramadol, 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 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 reuptake 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. 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. Opiate antagonist naloxone only partially antagonized tramadol-induced analgesia.
Mechanism of actionTramadol 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.
AbsorptionRacemic 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 binding20% bound to plasma proteins.
Metabolism

Hepatic. 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. CYP3A4 and CYP2B6 facilitates the biotransformation of tramadol to N-desmethyl-tramadol. CYP2D6 facilitates the biotransformation of tramadol to O-desmethyl-tramadol.

SubstrateEnzymesProduct
Tramadol
O-DesmethyltramadolDetails
Tramadol
N-DesmethyltramadolDetails
O-Desmethyltramadol
O-Desmethyl-tramado glucuronideDetails
O-Desmethyltramadol
N,O-didesmethyltramadolDetails
N-Desmethyltramadol
N,O-didesmethyltramadolDetails
N-Desmethyltramadol
N,N-didesmethyltramadolDetails
N,O-didesmethyltramadol
Not Available
N,N,O-tridesmethyl-tramadolDetails
N,N-didesmethyltramadol
Not Available
N,N,O-tridesmethyl-tramadolDetails
Route of eliminationTramadol is eliminated primarily through metabolism by the liver and the metabolites are excreted primarily by the kidneys. Approximately 30% of the dose is excreted in the urine as unchanged drug, whereas 60% of the dose is excreted as metabolites.
Half lifeTramadol 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.
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]
ToxicityLD50=350mg/kg (orally in mice)
Affected organisms
  • Humans and other mammals
Pathways
PathwayCategorySMPDB ID
Tramadol Metabolism PathwayDrug metabolismSMP00637
Tramadol Action Action PathwayDrug actionSMP00671
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 0.9924
Blood Brain Barrier + 0.9382
Caco-2 permeable + 0.8866
P-glycoprotein substrate Substrate 0.6283
P-glycoprotein inhibitor I Inhibitor 0.7807
P-glycoprotein inhibitor II Inhibitor 0.9589
Renal organic cation transporter Non-inhibitor 0.6398
CYP450 2C9 substrate Non-substrate 0.7678
CYP450 2D6 substrate Substrate 0.8919
CYP450 3A4 substrate Substrate 0.7726
CYP450 1A2 substrate Non-inhibitor 0.7136
CYP450 2C9 substrate Non-inhibitor 0.704
CYP450 2D6 substrate Inhibitor 0.6566
CYP450 2C19 substrate Non-inhibitor 0.6841
CYP450 3A4 substrate Non-inhibitor 0.6256
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.7832
Ames test Non AMES toxic 0.7899
Carcinogenicity Non-carcinogens 0.6663
Biodegradation Not ready biodegradable 0.9975
Rat acute toxicity 3.0316 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.6136
hERG inhibition (predictor II) Inhibitor 0.7098
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
FormRouteStrength
CapsuleOral100 mg, 150 mg, 200 mg, 300 mg
TabletOral50 mg
Tablet, extended releaseOral100 mg, 200 mg, 300 mg
Tablet, orally disintegratingOral50 mg
Prices
Unit descriptionCostUnit
Tramadol hcl powder29.08USDg
Ultram ER 300 mg 24 Hour tablet10.66USDtablet
Ultram er 300 mg tablet10.25USDtablet
Ultram ER 200 mg 24 Hour tablet7.64USDtablet
Ultram er 200 mg tablet7.35USDtablet
TraMADol HCl 200 mg 24 Hour tablet6.25USDtablet
Ultram ER 100 mg 24 Hour tablet4.62USDtablet
Ultram er 100 mg tablet4.44USDtablet
TraMADol HCl 100 mg 24 Hour tablet3.78USDtablet
Ultram 50 mg tablet1.99USDtablet
Tramadol-Acetaminophen 37.5-325 mg tablet1.07USDtablet
Tramadol hcl 50 mg tablet0.7USDtablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
CountryPatent NumberApprovedExpires (estimated)
United States66077482000-06-292020-06-29
United States54646321993-03-222013-03-22
Canada24762012009-09-012023-02-21
Canada21231602003-04-292014-05-09
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point180-181 °CNot Available
water solubilitySoluble Not Available
logP2.4FDA label
pKa9.41FDA label
Predicted Properties
PropertyValueSource
Water Solubility0.75ALOGPS
logP2.71ALOGPS
logP2.45ChemAxon
logS-2.5ALOGPS
pKa (Strongest Acidic)13.8ChemAxon
pKa (Strongest Basic)9.23ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area32.7 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity78.27 m3·mol-1ChemAxon
Polarizability30.45 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleNoChemAxon
Spectra
Spectra
References
Synthesis Reference

Wolfgang Reimann, “Combination preparation containing tramadol and a calcium channel antagonist.” U.S. Patent US5929122, issued March, 1993.

US5929122
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
  6. FDA label
External Links
ResourceLink
KEGG DrugD08623
KEGG CompoundC07153
PubChem Compound33741
PubChem Substance46506256
ChemSpider31105
BindingDB50176262
Therapeutic Targets DatabaseDAP000140
PharmGKBPA451735
RxListhttp://www.rxlist.com/cgi/generic/tramadol.htm
Drugs.comhttp://www.drugs.com/tramadol.html
WikipediaTramadol
ATC CodesN02AX02
AHFS Codes
  • 28:08.08
PDB EntriesNot Available
FDA labelshow(408 KB)
MSDSshow(74.7 KB)
Interactions
Drug Interactions
Drug
AlmotriptanIncreased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.
AlvimopanIncreases levels by receptor binding competition. Discontinue opioid administration at least 7 days prior to administrating Alvimopan.
AminoglutethimideAminoglutethimide may decrease the effect of Tramadol by increasing Tramadol metabolism and clearance.
AmiodaroneAmiodarone may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. Amiodarone may decrease the effect of Tramadol by decreasing active metabolite production.
AmitriptylineTramadol increases the risk of serotonin syndrome and seizures.
AmoxapineTramadol increases the risk of serotonin syndrome and seizures.
AmprenavirAmprenavir may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance.
AprepitantAprepitant may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance.
AtazanavirAtazanavir may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance.
BenzphetamineIncreased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.
BosentanBosentan may decrease the effect of Tramadol by increasing Tramadol metabolism and clearance.
BromocriptineIncreased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.
CabergolineIncreased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.
CarbamazepineCarbamazepine may decrease the effect of tramadol by increasing Tramadol metabolism and clearance.
ChloroquineChloroquine may decrease the effect of Tramadol by decreasing active metabolite production.
ChlorpromazineChlorpromazine may decrease the effect of Tramadol by decreasing active metabolite production.
CimetidineCimetidine may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. Cimetidine may decrease the effect of Tramadol by decreasing active metabolite production.
CinacalcetCinacalcet may decrease the effect of Tramadol by decreasing active metabolite production.
CitalopramThe 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.
ClarithromycinClarithromycin may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance.
ClomipramineTramadol increases the risk of serotonin syndrome and seizures. Clomipramine may decrease the effect of Tramadol by decreasing active metabolite production.
ClotrimazoleClotrimazole may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance.
ClozapineClozapine may decrease the effect of Tramadol by decreasing active metabolite production.
CocaineCocaine may decrease the effect of Tramadol by decreasing active metabolite production.
ConivaptanConivaptan may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance.
CyclobenzaprineIncreases risk of seizure.
CyclosporineCyclosporine may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance.
DarifenacinDarifenacin may decrease the effect of Tramadol by decreasing active metabolite production.
DarunavirDarunavir may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance.
DelavirdineDelavirdine may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. Delavirdine may decrease the effect of Tramadol by decreasing active metabolite production.
DesipramineTramadol 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.
DesvenlafaxineIncreased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.
DexamethasoneDexamethasone may decrease the effect of Tramadol by increasing Tramadol metabolism and clearance.
DextroamphetamineIncreased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.
DextromethorphanIncreased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.
DihydroergotamineIncreased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.
DiltiazemDiltiazem may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance.
DiphenhydramineDiphenhydramine may decrease the effect of Tramadol by decreasing active metabolite production.
DoxepinTramadol increases the risk of serotonin syndrome and seizures.
DuloxetineDuloxetine 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.
EfavirenzEfavirenz may decrease the effect of Tramadol by increasing Tramadol metabolism and clearance.
EletriptanIncreased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.
Ergoloid mesylateIncreased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.
ErgonovineIncreased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.
ErgotamineIncreased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.
ErythromycinErythromycin may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance.
EscitalopramTramadol may increase the risk of serotonin syndrome and seizures.
EtravirineTramadol,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.
FluconazoleFluconazole may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance.
FluoxetineThe 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.
FluvoxamineTramadol may increase the risk of serotonin syndrome and seizures.
FosamprenavirFosamprenavir may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance.
FosphenytoinFosphenytoin may decrease the effect of Tramadol by increasing Tramadol metabolism and clearance.
FrovatriptanIncreased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.
FurazolidoneTramadol increases the risk of serotonin syndrome and seizure induction by the MAO inhibitor, Furazolidone.
HaloperidolHaloperidol may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. Haloperidol may decrease the effect of Tramadol by decreasing active metabolite production.
ImatinibImatinib may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. Imatinib may decrease the effect of Tramadol by decreasing active metabolite production.
ImipramineTramadol increases the risk of serotonin syndrome and seizures. Imipramine may decrease the effect of Tramadol by decreasing active metabolite production.
IndinavirIndinavir may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance.
IsocarboxazidTramadol may increase the risk of serotonin syndrome and seizure induction by the MAO inhibitor, isocarboxazid.
IsoniazidIsoniazid may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. Isoniazid may decrease the effect of Tramadol by decreasing active metabolite production.
ItraconazoleItraconazole may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance.
KetoconazoleKetoconazole may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. Ketoconazole may decrease the effect of Tramadol by decreasing active metabolite production.
LapatinibLapatinib may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance.
LidocaineLidocaine may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. Lidocaine may decrease the effect of Tramadol by decreasing active metabolite production.
LinezolidTramadol increases the risk of serotonin syndrome and seizure induction by the MAO inhibitor, Linezolid.
LisdexamfetamineIncreased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.
LopinavirLopinavir may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. Lopinavir may decrease the effect of Tramadol by decreasing active metabolite production.
MaprotilineIncreased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.
MethadoneMethadone may decrease the effect of Tramadol by decreasing active metabolite production.
MethamphetamineIncreased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.
MethotrimeprazineAdditive 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.
MethylergometrineIncreased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.
MetronidazoleMetronidazole may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance.
MiconazoleMiconazole may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. Miconazole may decrease the effect of Tramadol by decreasing active metabolite production.
MirtazapineIncreased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.
MoclobemideTramadol may increase the risk of serotonin syndrome and seizure induction by the MAO inhibitor, moclobemide.
NafcillinNafcillin may decrease the effect of Tramadol by increasing Tramadol metabolism and clearance.
NaratriptanIncreased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.
NefazodoneNefazodone may increase tramadol toxicity by decreasing tramadol metabolism and clearance. Increased risk of serotonin syndrome. Monitor for tramadol toxicity and symptoms of serotonin syndrome.
NelfinavirNelfinavir may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance.
NevirapineNevirapine may decrease the effect of Tramadol by increasing Tramadol metabolism and clearance.
NicardipineNicardipine may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. Nicardipine may decrease the effect of Tramadol by decreasing active metabolite production.
NilotinibNilotinib may decrease the effect of Tramadol by decreasing active metabolite production.
NorfloxacinNorfloxacin may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance.
NortriptylineTramadol increases the risk of serotonin syndrome and seizures.
OxcarbazepineOxcarbazepine may decrease the effect of Tramadol by increasing Tramadol metabolism and clearance.
ParoxetineTramadol may increase the risk of serotonin syndrome and seizures. Paroxetine may decrease the effect of Tramadol by decreasing active metabolite production.
PentobarbitalPentobarbital may decrease the effect of Tramadol by increasing Tramadol metabolism and clearance.
PergolidePergolide 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.
PethidineIncreased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.
PhendimetrazineIncreased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.
PhenelzineTramadol may increase the risk of serotonin syndrome and seizure induction by the MAO inhibitor, phenelzine.
PhenobarbitalPhenobarbital may decrease the effect of Tramadol by increasing Tramadol metabolism and clearance.
PhentermineIncreased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.
PhenytoinPhenytoin may decrease the effect of Tramadol by increasing Tramadol metabolism and clearance.
PioglitazonePioglitazone may decrease the effect of Tramadol by decreasing active metabolite production.
PosaconazolePosaconazole may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance.
PrimidonePrimidone may decrease the effect of Tramadol by increasing Tramadol metabolism and clearance.
ProcarbazineTramadol increases the risk of serotonin syndrome and seizure induction by the MAO inhibitor, Procarbazine.
PromethazineIncreased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.
ProtriptylineTramadol increases the risk of serotonin syndrome and seizures.
PyrimethaminePyrimethamine may decrease the effect of Tramadol by decreasing active metabolite production.
QuinidineQuinidine may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. Quinidine may decrease the effect of Tramadol by decreasing active metabolite production.
QuinineQuinine may decrease the effect of Tramadol by decreasing active metabolite production.
RanolazineRanolazine may decrease the effect of Tramadol by decreasing active metabolite production.
RasagilineTramadol may increase the risk of serotonin syndrome and seizure induction by the MAO inhibitor, rasagiline.
RifabutinRifabutin may decrease the effect of Tramadol by increasing Tramadol metabolism and clearance.
RifampicinRifampin may decrease the effect of Tramadol by increasing Tramadol metabolism and clearance.
RifapentineRifapentine may decrease the effect of Tramadol by increasing Tramadol metabolism and clearance.
RitonavirRitonavir may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. Ritonavir may decrease the effect of Tramadol by decreasing active metabolite production.
RizatriptanIncreased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.
S-AdenosylmethionineIncreased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.
SaquinavirSaquinavir may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance.
SelegilineTramadol increases the risk of serotonin syndrome and seizure induction by the MAO inhibitor, Selegiline.
SertralineTramadol 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.
SibutramineSibutramine may incrase the serotonergic effect of the Tramadol. Concomitant therapy should be avoided.
SitaxentanSitaxsentan may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance.
St. John's WortIncreased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.
SumatriptanIncreased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.
TelithromycinTelithromycin 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.
TerbinafineTerbinafine may decrease the effect of Tramadol by decreasing active metabolite production.
TetracyclineTetracycline may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance.
ThioridazineThioridazine may decrease the effect of Tramadol by decreasing active metabolite production.
TiclopidineTiclopidine may decrease the effect of Tramadol by decreasing active metabolite production.
TranylcypromineTramadol 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.
TrazodoneThe use of two serotonin modulators, such as trazodone and tramadol, may increase the risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.
TrimipramineTramadol may increase the risk of serotonin syndrome and seizures.
TriprolidineThe CNS depressants, Triprolidine and Tramadol, may increase adverse/toxic effects due to additivity. Monitor for increased CNS depressant effects during concomitant therapy.
VenlafaxineIncreased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.
VerapamilVerapamil may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance.
VoriconazoleVoriconazole, 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.
ZolmitriptanThe 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
  • Oral administration of tramadol hydrochloride with food does not significantly affect its rate or extent of absorption, therefore, tramadol hydrochloride can be administered without regard to food.

Targets

1. Mu-type opioid receptor

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: agonist

Components

Name UniProt ID Details
Mu-type opioid receptor P35372 Details

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

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Sodium-dependent noradrenaline transporter P23975 Details

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

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Sodium-dependent serotonin transporter P31645 Details

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 receptor 2C

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: antagonist

Components

Name UniProt ID Details
5-hydroxytryptamine receptor 2C P28335 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: agonist

Components

Name UniProt ID Details
Kappa-type opioid receptor P41145 Details

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

Kind: protein

Organism: Human

Pharmacological action: no

Actions: agonist

Components

Name UniProt ID Details
Delta-type opioid receptor P41143 Details

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 receptor ionotropic, NMDA 3A

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: antagonist

Components

Name UniProt ID Details
Glutamate receptor ionotropic, NMDA 3A Q8TCU5 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: antagonist

Components

Name UniProt ID Details
Alpha-7 nicotinic cholinergic receptor subunit Q693P7 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: antagonist

Components

Name UniProt ID Details
Muscarinic acetylcholine receptor M3 P20309 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2D6 P10635 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inhibitor

Components

Name UniProt ID Details
Cytochrome P450 3A4 P08684 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 2B6 P20813 Details

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

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Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:08