Drug/Small Molecule:
tramadol

last updated 08/10/2011

Dutch Pharmacogenetics Working Group Guideline for tramadol and CYP2D6

Summary

For CYP2D6 poor metabolizers (PM), select an alternative to tramadol (not oxycodone or codeine) and be alert for symptoms of insufficient pain relief. For CYP2D6 intermediate metabolizers (IM), be alert for symptoms of insufficient pain relief, and consider dose increase or select an alternative to tramadol (not oxycodone or codeine). For CYP2D6 ultrarapid metabolizers, use a 30% decreased dose and be alert for ADEs, or use an alternative to tramadol (not oxycodone or codeine).

Annotation

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for tramadol based on CYP2D6 genotypes (PMID:21412232). For PM and IM genotypes, they recommend selecting an alternative drug (not oxycodone or codeine) and/or being extra alert to symptoms of insufficient pain relief. For UM genotypes, they recommend using a 30% decreased dose and being alert for ADEs, or using an alternative drug (not oxycodone or codeine).

Phenotype (Genotype) Therapeutic Dose Recommendation Level of Evidence Clinical Relevance
PM (two inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) alleles) Select alternative drug-not oxycodone or codeine- or be alert to symptoms of insufficient pain relief. Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. Clinical effect (S): short-lived discomfort (< 48 hr) without permanent injury: e.g. reduced decrease in resting heart rate; reduction in exercise tachycardia; decreased pain relief from oxycodone; ADE resulting from increased bioavailability of atomoxetine (decreased appetite, insomnia, sleep disturbance etc); neutropenia > 1.5x109/l; leucopenia > 3.0x109/l; thrombocytopenia > 75x109/l; moderate diarrhea not affecting daily activities; reduced glucose increase following oral glucose tolerance test.
IM (two decreased-activity (*9, *10, *17, *29, *36, *41) alleles or carrying one active (*1, *2, *33, *35) and one inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) allele, or carrying one decreased-activity (*9, *10, *17, *29, *36, *41) allele and one inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) allele) Be alert to decreased efficacy. Consider dose increase. If response is still inadequate, select alternative drug- not oxycodone or codeine-or be alert to symptoms of insufficient pain relief. Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. Clinical effect (S): short-lived discomfort (< 48 hr) without permanent injury: e.g. reduced decrease in resting heart rate; reduction in exercise tachycardia; decreased pain relief from oxycodone; ADE resulting from increased bioavailability of atomoxetine (decreased appetite, insomnia, sleep disturbance etc); neutropenia > 1.5x109/l; leucopenia > 3.0x109/l; thrombocytopenia > 75x109/l; moderate diarrhea not affecting daily activities; reduced glucose increase following oral glucose tolerance test.
UM (a gene duplication in absence of inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) or decreased-activity (*9, *10, *17, *29, *36, *41) alleles) Reduce dose by 30% and be alert to ADEs (e.g., nausea, vomiting, constipation, respiratory depression, confusion, urinary retention) or select alternative drug (e.g., acetaminophen, NSAID, morphine-not oxycodone or codeine). Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. Clinical effect (S): long-standing discomfort (48-168 hr) without permanent injury e.g. failure of therapy with tricyclic antidepressants, atypical antipsychotic drugs; extrapyramidal side effects; parkinsonism; ADE resulting from increased bioavailability of tricyclic antidepressants, metoprolol, propafenone (central effects e.g. dizziness); INR 4.5-6.0; neutropenia 1.0-1.5x109/l; leucopenia 2.0-3.0x109/l; thrombocytopenia 50-75x109/l.
  • *See Methods or PMID: 18253145 for definition of "good" and "moderate" quality.
  • S: statistically significant difference.

PharmGKB gathers information regarding PGx on FDA drug labels from the FDA's "Table of Pharmacogenomic Biomarkers in Drug Labels", and from FDA-approved FDA and EMA-approved (European Medicines Agency) EMA labels brought to our attention. Excerpts from the label and downloadable highlighted label PDFs are manually curated by PharmGKB.

Please note that some drugs may have been removed from or added to the FDA's "Table of Pharmacogenomic Biomarkers in Drug Labels" without our knowledge. We periodically check the table for additions to this table and update PharmGKB accordingly.

There is currently no such list for European drug labels - we are working with the EMA to establish a list of European Public Assessment Reports (EPAR)s that contain PGx information. We are constructing this list by initially searching for drugs for which we have PGx-containing FDA drug labels - of these 44 EMA EPARs were identified and are being curated for pgx information.

We welcome any information regarding drug labels containing PGx information approved by the FDA, EMA or other Medicine Agencies around the world - please contact feedback.


last updated 10/25/2013

FDA Label for acetaminophen, tramadol and CYP2D6

This label is on the FDA Biomarker List
Actionable PGx

Summary

The FDA-approved label contains information regarding metabolism of Tramadol by CYP2D6: CYP2D6 poor metabolizers may have higher tramadol concentrations, and concomitant use of CYP2D6 or CYP3A4 inhibitors may reduce clearance of tramadol and increase a patient's risk for adverse events.

Annotation

Tramadol and Acetaminophen is a mixture of two analgesic drugs used to treat pain. Tramadol is an opioid and metabolized mainly via CYP2D6. Acetaminophen metabolism involves 3 seperate pathways that include conjugation with glucuronide, conjugation with sulfate and oxidation by CYP-450 enzymes.

Excerpt from the Tramadol and Acetaminophen drug label:

Approximately 7% of the population has reduced activity of the CYP2D6 isoenzyme of cytochrome P450. These individuals are "poor metabolizers" of debrisoquine, dextromethorphan, tricyclic antidepressants, among other drugs. Based on a population PK analysis of Phase 1 studies in healthy subjects, concentrations of tramadol were approximately 20% higher in "poor metabolizers" versus "extensive metabolizers", while M1 concentrations were 40% lower. In vitro drug interaction studies in human liver microsomes indicates that inhibitors of CYP2D6 such as fluoxetine and its metabolite norfluoxetine, amitriptyline and quinidine inhibit the metabolism of tramadol to various degrees. The full pharmacological impact of these alterations in terms of either efficacy or safety is unknown. Concomitant use of SEROTONIN re-uptake INHIBITORS and MAO INHIBITORS may enhance the risk of adverse events, including seizure (see WARNINGS) and serotonin syndrome.

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the Tramadol and Acetaminophen drug label.

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

Full label available at DailyMed

Genes and/or phenotypes found in this label

  • Epidermal Necrolysis, Toxic
    • Warnings section, Adverse reactions section, Precautions section
    • source: PHONT
  • Pain
    • Warnings section, Adverse reactions section, Precautions section
    • source: PHONT
  • Stevens-Johnson Syndrome
    • Warnings section
    • source: PHONT
  • CYP1A2
    • Clinical pharmacology section, Pharmacokinetics section, metabolism/PK
    • source: FDA Label
  • CYP2D6
    • Drug interactions section, Clinical pharmacology section, Pharmacokinetics section, metabolism/PK
    • source: FDA Label
  • CYP2E1
    • Clinical pharmacology section, Pharmacokinetics section, metabolism/PK
    • source: FDA Label
  • CYP3A4
    • Drug interactions section, Clinical pharmacology section, Pharmacokinetics section, metabolism/PK
    • source: FDA Label

Clinical Variants that meet the highest level of criteria, manually curated by PharmGKB, are shown below.

To see more Clinical Variants with lower levels of criteria, click the button at the bottom of the page.

Disclaimer: The PharmGKB's clinical annotations reflect expert consensus based on clinical evidence and peer-reviewed literature available at the time they are written and are intended only to assist clinicians in decision-making and to identify questions for further research. New evidence may have emerged since the time an annotation was submitted to the PharmGKB. The annotations are limited in scope and are not applicable to interventions or diseases that are not specifically identified.

The annotations do not account for individual variations among patients, and cannot be considered inclusive of all proper methods of care or exclusive of other treatments. It remains the responsibility of the health-care provider to determine the best course of treatment for a patient. Adherence to any guideline is voluntary, with the ultimate determination regarding its application to be made solely by the clinician and the patient. PharmGKB assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of the PharmGKB clinical annotations, or for any errors or omissions.

? = Mouse-over for quick help

This is a non-comprehensive list of genetic tests with pharmacogenetics relevance, typically submitted by the manufacturer and manually curated by PharmGKB. The information listed is provided for educational purposes only and does not constitute an endorsement of any listed test or manufacturer.

A more complete listing of genetic tests is found at the Genetic Testing Registry (GTR).

PGx Test Variants Assayed Gene?
GenoChip CYP2D6 (PharmGenomics, GmbH) CYP2D6*5 , rs59421388 , rs28371725 , rs5030867 , rs5030656 , rs35742686 , rs3892097 , rs5030865 , rs5030655 , rs28371706 , rs5030863 , rs1065852 , *xN (gene duplication)

The table below contains information about pharmacogenomic variants on PharmGKB. Please follow the link in the "Variant" column for more information about a particular variant. Each link in the "Variant" column leads to the corresponding PharmGKB Variant Page. The Variant Page contains summary data, including PharmGKB manually curated information about variant-drug pairs based on individual PubMed publications. The PMIDs for these PubMed publications can be found on the Variant Page.

The tags in the first column of the table indicate what type of information can be found on the corresponding Variant Page.

Links in the "Gene" column lead to PharmGKB Gene Pages.

Gene ? Variant?
(138)
Alternate Names / Tag SNPs ? Drugs ? Alleles ?
(+ chr strand)
Function ? Amino Acid?
Translation
VIP CA VA CYP2D6 *1 N/A N/A N/A
No VIP available CA VA CYP2D6 *1XN N/A N/A N/A
VIP CA VA CYP2D6 *2 N/A N/A N/A
VIP CA VA CYP2D6 *3 N/A N/A N/A
VIP CA VA CYP2D6 *4 N/A N/A N/A
No VIP available CA VA CYP2D6 *5 N/A N/A N/A
VIP CA VA CYP2D6 *6 N/A N/A N/A
VIP No VIP available No VIP available CYP2D6 *9 N/A N/A N/A
VIP CA VA CYP2D6 *10 N/A N/A N/A
VIP No VIP available VA CYP2D6 *17 N/A N/A N/A
VIP No VIP available No VIP available CYP2D6 *29 N/A N/A N/A
VIP No VIP available No VIP available CYP2D6 *41 N/A N/A N/A
rs1065852 100C>T, 21917263G>A, 42526694G>A, 5190C>T, CYP2D6:100C>T, Pro34Ser, part of CYP2D6*4 and CYP2D6*10
G > A
Missense
Pro34Ser
rs12208357 160543148C>T, 181C>T, 64712605C>T, Arg61Cys, R61C, SLC22A1: R61C, SLC22A1:148C>T
C > T
Missense
Arg61Cys
VIP No Clinical Annotations available No Variant Annotations available
rs16947 21914512A>G, 42523943A>G, 733C>C, 7941C>C, 886C>C, Arg245=, Arg296=, CYP2D6:2850C>T
A > G
Not Available
No VIP available No Clinical Annotations available VA
rs1799971 -11+28644A>G, 118A>G, 154360797A>G, 34162A>G, 397A>G, 47+29103A>G, 58530254A>G, Asn133Asp, Asn40Asp, OPRM1: A118G
A > G
Missense
Asn40Asp
rs28371706 21916341G>A, 320C>T, 42525772G>A, 6112C>T, CYP2D6:1023 C>T, Thr107Ile
G > A
Missense
Thr107Ile
rs28371725 21914374C>T, 42523805C>T, 8079G>A, 832+39G>A, 985+39G>A, CYP2D6*41, CYP2D6:2988G>A, part of CYP2D6*41
C > T
Intronic
rs34130495 1201G>A, 160560824G>A, 64730281G>A, Gly401Ser, SLC22A1: G401S
G > A
Missense
Gly401Ser
No VIP available CA VA
rs35167514 1258delA, 160560881delA, 64730338delA, Met420Terfs, part of SLC22A1:M420del
A > -
Frameshift
Met420null
rs35742686 21914813delT, 42524244delT, 622delA, 7640delA, 775delA, Arg208Glyfs, Arg259Glyfs
A > T
A > -
Frameshift
Arg208Gly
rs3892097 21915516C>T, 353-1G>A, 42524947C>T, 506-1G>A, 6937G>A, CYP2D6*4, CYP2D6:1846G>A, part of CYP2D6*4
C > T
Acceptor
No VIP available No Clinical Annotations available VA
rs4680 1-5G>A, 19951271G>A, 27009G>A, 3103421G>A, 322G>A, 472G>A, COMP: Val158Met, COMT:Val108Met, Val108Met, Val158Met
G > A
5' Flanking
Val158Met
rs5030655 21915655delA, 353-140delT, 42525086delA, 454delT, 6798delT, CYP2D6*6, CYP2D6:1707 del T, Trp152Glyfs, part of CYP2D6*6
T > A
T > -
Intronic
Trp152Gly
rs5030656 21914745_21914747delCTT, 42524176_42524178delCTT, 688_690delAAG, 7706_7708delAAG, 841_843delAAG, Lys230del, Lys281del
CTT > -
CTT > TTC
Non-synonymous
rs59421388 1012G>A, 21914179C>T, 3271G>A, 42523610C>T, 8274G>A, 859G>A, CYP2D6: 3183G>A, Val287Met, Val338Met
G > T
G > C
Missense
Val287Met
VIP No Clinical Annotations available No Variant Annotations available
rs61736512 1747G>A, 21915703C>T, 353-188G>A, 406G>A, 42525134C>T, 6750G>A, CYP2D6: 1659G>A, Val136Met
G > T
G > C
Intronic
Val136Met
VIP No Clinical Annotations available No Variant Annotations available
rs72552763 1260_1262delGAT, 160560883_160560885delGAT, 64730340_64730342delGAT, Met420_Ile421delinsIle
GAT > -
Non-synonymous
Alleles, Functions, and Amino Acid Translations are all sourced from dbSNP 138
2D structure from PubChem
provided by PubChem

Overview

Generic Names
  • Tramadol HCl
  • Tramadol hydrochloride
  • Tramadolum [INN-Latin]
  • Tramodol Hcl
  • tramadol
Trade Names
  • Crispin
  • Ralivia ER
  • Ralivia Flashtab
  • Tramadol HCl BP/EP
  • Tramal
  • Tridural
  • Ultram
  • Ultram ER
  • Zydol
Brand Mixture Names

PharmGKB Accession Id:
PA451735

Description

A narcotic analgesic proposed for moderate to severe pain. It may be habituating.

Source: Drug Bank

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.

Source: Drug Bank

Other Vocabularies

Information pulled from DrugBank has not been reviewed by PharmGKB.

Pharmacology, Interactions, and Contraindications

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.

Source: Drug Bank

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.

Source: Drug Bank

Absorption, Distribution, Metabolism, Elimination & Toxicity

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.

Source: Drug Bank

Protein Binding

20%

Source: Drug Bank

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.

Source: Drug Bank

Half-Life

23 +/- 10 minutes

Source: Drug Bank

Toxicity

LD 50=350mg/kg (orally in mice)

Source: Drug Bank

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.

Source: Drug Bank

Volume of Distribution

Chemical Properties

Chemical Formula

C16H25NO2

Source: Drug Bank

Isomeric SMILES

CN(C)C[C@H]1CCCC[C@@]1(c2cccc(c2)OC)O

Source: OpenEye

Canonical SMILES

COC1=CC=CC(=C1)[C@@]1(O)CCCC[C@@H]

Source: Drug Bank

Average Molecular Weight

263.3752

Source: Drug Bank

Monoisotopic Molecular Weight

263.188529049

Source: Drug Bank

PharmGKB Curated Pathways

Pathways created internally by PharmGKB based primarily on literature evidence.

External Pathways

Links to non-PharmGKB pathways.

PharmGKB contains no links to external pathways for this drug. To report a pathway, click here.

Genes that are associated with this drug in PharmGKB's database based on (1) variant annotations, (2) literature review, (3) pathways or (4) information automatically retrieved from DrugBank, depending on the "evidence" and "source" listed below.

Curated Information ?

Drug Targets

Gene Description
CHRM3 (source: Drug Bank)
GRIN3A (source: Drug Bank)
HTR2C (source: Drug Bank)
OPRD1 (source: Drug Bank)
OPRK1 (source: Drug Bank)
OPRM1 (source: Drug Bank)
SLC6A2 (source: Drug Bank)
SLC6A4 (source: Drug Bank)

Drug Interactions

Drug Description
tramadol Reduces the efficacy of tramadol (source: Drug Bank)
tramadol Reduces the efficacy of tramadol (source: Drug Bank)
tramadol Increased risk of serotonin syndrome (source: Drug Bank)
tramadol Increased risk of serotonin syndrome (source: Drug Bank)
tramadol Increased risk of serotonin syndrome (source: Drug Bank)
tramadol Increased risk of serotonin syndrome (source: Drug Bank)
tramadol Increased risk of serotonin syndrome (source: Drug Bank)
tramadol Increased risk of serotonin syndrome (source: Drug Bank)
tramadol Increased risk of serotonin syndrome (source: Drug Bank)
tramadol Increased risk of serotonin syndrome (source: Drug Bank)
tramadol Increased risk of seizures and serotonin syndrome (source: Drug Bank)
tramadol Increased risk of seizures and serotonin syndrome (source: Drug Bank)
tramadol Increased risk of seizures and serotonin syndrome (source: Drug Bank)
tramadol Increased risk of seizures and serotonin syndrome (source: Drug Bank)
tramadol Increased risk of seizures and serotonin syndrome (source: Drug Bank)
tramadol Increased risk of serotonin syndrome (source: Drug Bank)
tramadol Increased risk of serotonin syndrome (source: Drug Bank)
tramadol Risk of serotoninergic syndrome (source: Drug Bank)
tramadol Risk of serotoninergic syndrome (source: Drug Bank)
tramadol Increased risk of seizures and serotonin syndrome (source: Drug Bank)
tramadol Increased risk of seizures and serotonin syndrome (source: Drug Bank)
tramadol Increased risk of seizures and serotonin syndrome (source: Drug Bank)
tramadol Telithromycin may reduce 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. (source: Drug Bank)
almotriptan Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome. (source: Drug Bank)
aminoglutethimide Aminoglutethimide may decrease the effect of Tramadol by increasing Tramadol metabolism and clearance. (source: Drug Bank)
amiodarone Amiodarone may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. Amiodarone may decrease the effect of Tramadol by decreasing active metabolite production. (source: Drug Bank)
amitriptyline Tramadol increases the risk of serotonin syndrome and seizures. (source: Drug Bank)
amoxapine Tramadol increases the risk of serotonin syndrome and seizures. (source: Drug Bank)
amprenavir Amprenavir may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. (source: Drug Bank)
aprepitant Aprepitant may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. (source: Drug Bank)
atazanavir Atazanavir may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. (source: Drug Bank)
benzphetamine Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome. (source: Drug Bank)
bosentan Bosentan may decrease the effect of Tramadol by increasing Tramadol metabolism and clearance. (source: Drug Bank)
bromocriptine Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome. (source: Drug Bank)
cabergoline Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome. (source: Drug Bank)
carbamazepine Carbamazepine may decrease the effect of Tramadol by increasing Tramadol metabolism and clearance. (source: Drug Bank)
chloroquine Chloroquine may decrease the effect of Tramadol by decreasing active metabolite production. (source: Drug Bank)
chlorpromazine Chlorpromazine may decrease the effect of Tramadol by decreasing active metabolite production. (source: Drug Bank)
cimetidine Cimetidine may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. Cimetidine may decrease the effect of Tramadol by decreasing active metabolite production. (source: Drug Bank)
cinacalcet Cinacalcet may decrease the effect of Tramadol by decreasing active metabolite production. (source: Drug Bank)
citalopram Tramadol increases the risk of serotonin syndrome and seizures. (source: Drug Bank)
clarithromycin Clarithromycin may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. (source: Drug Bank)
clomipramine Tramadol increases the risk of serotonin syndrome and seizures. Clomipramine may decrease the effect of Tramadol by decreasing active metabolite production. (source: Drug Bank)
clotrimazole Clotrimazole may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. (source: Drug Bank)
clozapine Clozapine may decrease the effect of Tramadol by decreasing active metabolite production. (source: Drug Bank)
cocaine Cocaine may decrease the effect of Tramadol by decreasing active metabolite production. (source: Drug Bank)
conivaptan Conivaptan may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. (source: Drug Bank)
cyclobenzaprine Increases risk of seizure. (source: Drug Bank)
cyclosporine Cyclosporine may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. (source: Drug Bank)
darifenacin Darifenacin may decrease the effect of Tramadol by decreasing active metabolite production. (source: Drug Bank)
darunavir Darunavir may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. (source: Drug Bank)
delavirdine Delavirdine may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. Delavirdine may decrease the effect of Tramadol by decreasing active metabolite production. (source: Drug Bank)
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. (source: Drug Bank)
dexamethasone Dexamethasone may decrease the effect of Tramadol by increasing Tramadol metabolism and clearance. (source: Drug Bank)
dextroamphetamine Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome. (source: Drug Bank)
dextromethorphan Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome. (source: Drug Bank)
dihydroergotamine Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome. (source: Drug Bank)
diltiazem Diltiazem may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. (source: Drug Bank)
diphenhydramine Diphenhydramine may decrease the effect of Tramadol by decreasing active metabolite production. (source: Drug Bank)
doxepin Tramadol increases the risk of serotonin syndrome and seizures. (source: Drug Bank)
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. (source: Drug Bank)
efavirenz Efavirenz may decrease the effect of Tramadol by increasing Tramadol metabolism and clearance. (source: Drug Bank)
eletriptan Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome. (source: Drug Bank)
ergonovine Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome. (source: Drug Bank)
ergotamine Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome. (source: Drug Bank)
erythromycin Erythromycin may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. (source: Drug Bank)
escitalopram Tramadol increases the risk of serotonin syndrome and seizures. (source: Drug Bank)
fluconazole Fluconazole may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. (source: Drug Bank)
fluoxetine Tramadol increases the risk of serotonin syndrome and seizures. Fluoxetine may decrease the effect of Tramadol by decreasing active metabolite production. (source: Drug Bank)
fluvoxamine Tramadol increases the risk of serotonin syndrome and seizures. (source: Drug Bank)
fosamprenavir Fosamprenavir may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. (source: Drug Bank)
fosphenytoin Fosphenytoin may decrease the effect of Tramadol by increasing Tramadol metabolism and clearance. (source: Drug Bank)
frovatriptan Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome. (source: Drug Bank)
furazolidone Tramadol increases the risk of serotonin syndrome and seizure induction by the MAO inhibitor, Furazolidone. (source: Drug Bank)
haloperidol Haloperidol may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. Haloperidol may decrease the effect of Tramadol by decreasing active metabolite production. (source: Drug Bank)
imatinib Imatinib may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. Imatinib may decrease the effect of Tramadol by decreasing active metabolite production. (source: Drug Bank)
imipramine Tramadol increases the risk of serotonin syndrome and seizures. Imipramine may decrease the effect of Tramadol by decreasing active metabolite production. (source: Drug Bank)
indinavir Indinavir may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. (source: Drug Bank)
isocarboxazid Tramadol increases the risk of serotonin syndrome and seizure induction by the MAO inhibitor, Isocarboxazid. (source: Drug Bank)
isoniazid Isoniazid may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. Isoniazid may decrease the effect of Tramadol by decreasing active metabolite production. (source: Drug Bank)
itraconazole Itraconazole may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. (source: Drug Bank)
ketoconazole Ketoconazole may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. Ketoconazole may decrease the effect of Tramadol by decreasing active metabolite production. (source: Drug Bank)
lapatinib Lapatinib may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. (source: Drug Bank)
lidocaine Lidocaine may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. Lidocaine may decrease the effect of Tramadol by decreasing active metabolite production. (source: Drug Bank)
linezolid Tramadol increases the risk of serotonin syndrome and seizure induction by the MAO inhibitor, Linezolid. (source: Drug Bank)
lisdexamfetamine Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome. (source: Drug Bank)
lopinavir Lopinavir may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. Lopinavir may decrease the effect of Tramadol by decreasing active metabolite production. (source: Drug Bank)
maprotiline Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome. (source: Drug Bank)
meperidine Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome. (source: Drug Bank)
methadone Methadone may decrease the effect of Tramadol by decreasing active metabolite production. (source: Drug Bank)
methamphetamine Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome. (source: Drug Bank)
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. (source: Drug Bank)
methylergonovine Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome. (source: Drug Bank)
metronidazole Metronidazole may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. (source: Drug Bank)
miconazole Miconazole may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. Miconazole may decrease the effect of Tramadol by decreasing active metabolite production. (source: Drug Bank)
mirtazapine Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome. (source: Drug Bank)
moclobemide Tramadol increases the risk of serotonin syndrome and seizure induction by the MAO inhibitor, Moclobemide. (source: Drug Bank)
nafcillin Nafcillin may decrease the effect of Tramadol by increasing Tramadol metabolism and clearance. (source: Drug Bank)
naratriptan Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome. (source: Drug Bank)
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. (source: Drug Bank)
nelfinavir Nelfinavir may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. (source: Drug Bank)
nevirapine Nevirapine may decrease the effect of Tramadol by increasing Tramadol metabolism and clearance. (source: Drug Bank)
nicardipine Nicardipine may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. Nicardipine may decrease the effect of Tramadol by decreasing active metabolite production. (source: Drug Bank)
nilotinib Nilotinib may decrease the effect of Tramadol by decreasing active metabolite production. (source: Drug Bank)
norfloxacin Norfloxacin may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. (source: Drug Bank)
nortriptyline Tramadol increases the risk of serotonin syndrome and seizures. (source: Drug Bank)
oxcarbazepine Oxcarbazepine may decrease the effect of Tramadol by increasing Tramadol metabolism and clearance. (source: Drug Bank)
paroxetine Tramadol increases the risk of serotonin syndrome and seizures. Paroxetine may decrease the effect of Tramadol by decreasing active metabolite production. (source: Drug Bank)
pentobarbital Pentobarbital may decrease the effect of Tramadol by increasing Tramadol metabolism and clearance. (source: Drug Bank)
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. (source: Drug Bank)
phendimetrazine Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome. (source: Drug Bank)
phenelzine Tramadol increases the risk of serotonin syndrome and seizure induction by the MAO inhibitor, Phenelzine. (source: Drug Bank)
phenobarbital Phenobarbital may decrease the effect of Tramadol by increasing Tramadol metabolism and clearance. (source: Drug Bank)
phentermine Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome. (source: Drug Bank)
phenytoin Phenytoin may decrease the effect of Tramadol by increasing Tramadol metabolism and clearance. (source: Drug Bank)
pioglitazone Pioglitazone may decrease the effect of Tramadol by decreasing active metabolite production. (source: Drug Bank)
posaconazole Posaconazole may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. (source: Drug Bank)
primidone Primidone may decrease the effect of Tramadol by increasing Tramadol metabolism and clearance. (source: Drug Bank)
procarbazine Tramadol increases the risk of serotonin syndrome and seizure induction by the MAO inhibitor, Procarbazine. (source: Drug Bank)
promethazine Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome. (source: Drug Bank)
protriptyline Tramadol increases the risk of serotonin syndrome and seizures. (source: Drug Bank)
pyrimethamine Pyrimethamine may decrease the effect of Tramadol by decreasing active metabolite production. (source: Drug Bank)
quinidine Quinidine may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. Quinidine may decrease the effect of Tramadol by decreasing active metabolite production. (source: Drug Bank)
quinine Quinine may decrease the effect of Tramadol by decreasing active metabolite production. (source: Drug Bank)
ranolazine Ranolazine may decrease the effect of Tramadol by decreasing active metabolite production. (source: Drug Bank)
rasagiline Tramadol increases the risk of serotonin syndrome and seizure induction by the MAO inhibitor, Rasagiline. (source: Drug Bank)
rifabutin Rifabutin may decrease the effect of Tramadol by increasing Tramadol metabolism and clearance. (source: Drug Bank)
rifampin Rifampin may decrease the effect of Tramadol by increasing Tramadol metabolism and clearance. (source: Drug Bank)
rifapentine Rifapentine may decrease the effect of Tramadol by increasing Tramadol metabolism and clearance. (source: Drug Bank)
ritonavir Ritonavir may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. Ritonavir may decrease the effect of Tramadol by decreasing active metabolite production. (source: Drug Bank)
rizatriptan Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome. (source: Drug Bank)
s-adenosylmethionine Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome. (source: Drug Bank)
saquinavir Saquinavir may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. (source: Drug Bank)
selegiline Tramadol increases the risk of serotonin syndrome and seizure induction by the MAO inhibitor, Selegiline. (source: Drug Bank)
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. (source: Drug Bank)
sibutramine Sibutramine may incrase the serotonergic effect of the Tramadol. Concomitant therapy should be avoided. (source: Drug Bank)
sumatriptan Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome. (source: Drug Bank)
telithromycin Telithromycin may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. (source: Drug Bank)
terbinafine Terbinafine may decrease the effect of Tramadol by decreasing active metabolite production. (source: Drug Bank)
tetracycline Tetracycline may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. (source: Drug Bank)
thioridazine Thioridazine may decrease the effect of Tramadol by decreasing active metabolite production. (source: Drug Bank)
ticlopidine Ticlopidine may decrease the effect of Tramadol by decreasing active metabolite production. (source: Drug Bank)
tranylcypromine Tramadol increases 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. (source: Drug Bank)
trazodone Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome. (source: Drug Bank)
trimipramine Tramadol increases the risk of serotonin syndrome and seizures. (source: Drug Bank)
venlafaxine Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome. (source: Drug Bank)
verapamil Verapamil may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. (source: Drug Bank)
voriconazole Voriconzole may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. (source: Drug Bank)
zolmitriptan Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome. (source: Drug Bank)
tramadol Increased risk of serotonin syndrome. Use caution during concomitant therapy and monitor for symptoms of serotonin syndrome. (source: Drug Bank)
tramadol Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome. (source: Drug Bank)
tramadol Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome. (source: Drug Bank)
tramadol Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome. (source: Drug Bank)
tramadol The CNS depressants, Triprolidine and Tramadol, may increase adverse/toxic effects due to additivity. Monitor for increased CNS depressant effects during concomitant therapy. (source: Drug Bank)
tramadol The CNS depressants, Triprolidine and Tramadol, may increase adverse/toxic effects due to additivity. Monitor for increased CNS depressant effects during concomitant therapy. (source: Drug Bank)
tramadol Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome. (source: Drug Bank)
tramadol 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. (source: Drug Bank)
tramadol Use of two serotonin modulators, such as zolmitriptan and tramadol, increases the risk of serotonin syndrome. Consider alternate therapy or monitor for serotonin syndrome during concomitant therapy. (source: Drug Bank)

Curated Information ?

Relationships from National Drug File - Reference Terminology (NDF-RT)

May Treat
Contraindicated With

Publications related to tramadol: 38

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Challenges in pharmacogenetics. European journal of clinical pharmacology. 2013. Cascorbi Ingolf, et al. PubMed
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Cytochrome P450-mediated drug metabolism in the brain. Journal of psychiatry & neuroscience : JPN. 2012. Miksys Sharon, et al. PubMed
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Mutations in monoamine oxidase (MAO) genes in mice lead to hypersensitivity to serotonin-enhancing drugs: implications for drug side effects in humans. The pharmacogenomics journal. 2012. Fox M A, et al. PubMed
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Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer. European journal of clinical pharmacology. 2011. Elkalioubie Ahmed, et al. PubMed
Genetically Polymorphic OCT1: Another Piece in the Puzzle of the Variable Pharmacokinetics and Pharmacodynamics of the Opioidergic Drug Tramadol. Clinical pharmacology and therapeutics. 2011. Tzvetkov M V, et al. PubMed
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Uniform assessment and ranking of opioid μ receptor binding constants for selected opioid drugs. Regulatory toxicology and pharmacology : RTP. 2011. Volpe Donna A, et al. PubMed
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Pharmacogenetics: From Bench to Byte- An Update of Guidelines. Clinical pharmacology and therapeutics. 2011. Swen J J, et al. PubMed
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Developmental pharmacology of tramadol during infancy: ontogeny, pharmacogenetics and elimination clearance. Paediatric anaesthesia. 2011. Allegaert Karel, et al. PubMed
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Absorption, distribution, metabolism and excretion pharmacogenomics of drugs of abuse. Pharmacogenomics. 2011. Meyer Markus R, et al. PubMed
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Systematic review of pharmacoeconomic studies of pharmacogenomic tests. Pharmacogenomics. 2010. Beaulieu Mathieu, et al. PubMed
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Adverse events in analgesic treatment with tramadol associated with CYP2D6 extensive-metaboliser and OPRM1 high-expression variants. Annals of the rheumatic diseases. 2010. Kim Eunjin, et al. PubMed
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Personalized therapy in pain management: where do we stand?. Pharmacogenomics. 2010. Stamer Ulrike M, et al. PubMed
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Relationship of CYP2D6 genetic polymorphisms and the pharmacokinetics of tramadol in Chinese volunteers. Journal of clinical pharmacy and therapeutics. 2010. Li Q, et al. PubMed
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Warfarin interactions with substances listed in drug information compendia and in the FDA-approved label for warfarin sodium. Clinical pharmacology and therapeutics. 2009. Anthony M, et al. PubMed
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Cytochrome P450 2D6. Pharmacogenetics and genomics. 2009. Owen Ryan P, et al. PubMed
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Utilization of pharmacogenomics and therapeutic drug monitoring for opioid pain management. Pharmacogenomics. 2009. Jannetto Paul J, et al. PubMed
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Cross-sectional analysis of the influence of currently known pharmacogenetic modulators on opioid therapy in outpatient pain centers. Pharmacogenetics and genomics. 2009. Lötsch Jörn, et al. PubMed
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Escitalopram is a weak inhibitor of the CYP2D6-catalyzed O-demethylation of (+)-tramadol but does not reduce the hypoalgesic effect in experimental pain. Clinical pharmacology and therapeutics. 2009. Noehr-Jensen L, et al. PubMed
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The hypoalgesic effect of oxycodone in human experimental pain models in relation to the CYP2D6 oxidation polymorphism. Basic & clinical pharmacology & toxicology. 2009. Zwisler Stine T, et al. PubMed
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Functional pharmacogenetics/genomics of human cytochromes P450 involved in drug biotransformation. Analytical and bioanalytical chemistry. 2008. Zanger Ulrich M, et al. PubMed
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Respiratory depression with tramadol in a patient with renal impairment and CYP2D6 gene duplication. Anesthesia and analgesia. 2008. Stamer Ulrike M, et al. PubMed
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Pharmacogenetics of analgesics: toward the individualization of prescription. Pharmacogenomics. 2008. Rollason Victoria, et al. PubMed
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Effects of the CYP2D6 gene duplication on the pharmacokinetics and pharmacodynamics of tramadol. Journal of clinical psychopharmacology. 2008. Kirchheiner Julia, et al. PubMed
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Stevens-Johnson syndrome and toxic epidermal necrolysis: assessment of medication risks with emphasis on recently marketed drugs. The EuroSCAR-study. The Journal of investigative dermatology. 2008. Mockenhaupt Maja, et al. PubMed
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Pharmacologic management of neuropathic pain: evidence-based recommendations. Pain. 2007. Dworkin Robert H, et al. PubMed
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Comparative metabolic capabilities and inhibitory profiles of CYP2D6.1, CYP2D6.10, and CYP2D6.17. Drug metabolism and disposition: the biological fate of chemicals. 2007. Shen Hongwu, et al. PubMed
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Concentrations of tramadol and O-desmethyltramadol enantiomers in different CYP2D6 genotypes. Clinical pharmacology and therapeutics. 2007. Stamer U M, et al. PubMed
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Effect of the CYP2D6*10 C188T polymorphism on postoperative tramadol analgesia in a Chinese population. European journal of clinical pharmacology. 2006. Wang GuoXiang, et al. PubMed
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Response to hydrocodone, codeine and oxycodone in a CYP2D6 poor metabolizer. Progress in neuro-psychopharmacology & biological psychiatry. 2006. Susce Margaret T, et al. PubMed
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The analgesic effect of tramadol after intravenous injection in healthy volunteers in relation to CYP2D6. Anesthesia and analgesia. 2006. Enggaard Thomas P, et al. PubMed
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CYP2D6 polymorphism, tramadol pharmacokinetics and pupillary response. European journal of clinical pharmacology. 2006. Slanar Ondrej, et al. PubMed
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Tramadol as a new probe for cytochrome P450 2D6 phenotyping: a population study. Clinical pharmacology and therapeutics. 2005. Pedersen Rasmus Steen, et al. PubMed
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A rapid and simple CYP2D6 genotyping assay--case study with the analgetic tramadol. Metabolism: clinical and experimental. 2003. Borlak Jürgen, et al. PubMed
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Impact of CYP2D6 genotype on postoperative tramadol analgesia. Pain. 2003. Stamer Ulrike M, et al. PubMed
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Post-mortem SNP analysis of CYP2D6 gene reveals correlation between genotype and opioid drug (tramadol) metabolite ratios in blood. Forensic science international. 2003. Levo Antti, et al. PubMed
The hypoalgesic effect of tramadol in relation to CYP2D6. Clinical pharmacology and therapeutics. 1996. Poulsen L, et al. PubMed
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[Pharmacology of tramadol]. Drugs. 1997. Dayer P, et al. PubMed
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Polymorphic CYP2D6 mediates O-demethylation of the opioid analgesic tramadol. European journal of clinical pharmacology. 1997. Paar W D, et al. PubMed

LinkOuts

Web Resource:
Wikipedia
National Drug Code Directory:
0045-0659-60
DrugBank:
DB00193
KEGG Compound:
C07153
PubChem Compound:
33741
PubChem Substance:
175579
46506256
BindingDB:
50176262
ChemSpider:
31105
Therapeutic Targets Database:
DAP000140
FDA Drug Label at DailyMed:
c0938808-fe14-4b8d-98c4-d04dcc5c9642

Clinical Trials

These are trials that mention tramadol and are related to either pharmacogenetics or pharmacogenomics.

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Sources for PharmGKB drug information: DrugBank, Open Eye Scientific Software.