Identification

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Name
Tramadol
Accession Number
DB00193  (APRD00028)
Type
Small Molecule
Groups
Approved, Investigational
Description

Tramadol is a centrally acting synthetic opioid analgesic and SNRI (serotonin/norepinephrine reuptake-inhibitor) that is structurally related to codeine and morphine. Due to its good tolerability profile and multimodal mechanism of action, tramadol is generally considered a lower-risk opioid option for the treatment of moderate to severe pain. It is considered a Step 2 option on the World Health Organization's pain ladder and has about 1/10th of the potency of morphine.

Tramadol differs from other traditional opioid medications in that it doesn't just act as a μ-opioid agonist, but also affects monoamines by modulating the effects of neurotransmitters involved in the modulation of pain such as serotonin and norepinpehrine which activate descending pain inhibitory pathways.13 Tramadol's effects on serotonin and norepinephrine mimic the effects of other SNRI antidepressants such as duloxetine and venlafaxine.

Tramadol exists as a racemic mixture consisting of two pharmacologically active enantiomers that both contribute to its analgesic property through different mechanisms and are also themselves metabolized into active metabolites: (+)-tramadol and its primary metabolite (+)-O-desmethyl-tramadol (M1) are agonists of the μ opioid receptor while (+)-tramadol inhibits serotonin reuptake and (-)-tramadol inhibits norepinephrine reuptake. These pathways are complementary and synergistic, improving tramadol's ability to modulate the perception of and response to pain.12,25

Tramadol has also been shown to affect a number of other pain modulators within the central nervous system as well as non-neuronal inflammatory markers and immune mediators.17,18,20,26,16 Due to the broad spectrum of targets involved in pain and inflammation, it's not surprising that the evidence has shown that tramadol is effective for a number of pain types including neuropathic pain, post-operative pain, lower back pain, as well as pain associated with labour, osteoarthritis, fibromyalgia, and cancer. Due to its SNRI activity, tramadol also has anxiolytic, antidepressant, and anti-shivering effects which are all frequently found as comorbidities with pain.16

Similar to other opioid medications, tramadol poses a risk for development of tolerance, dependence and abuse. If used in higher doses, or with other opioids, there is a dose-related risk of overdose, respiratory depression, and death.22,30 However, unlike other opioid medications, tramadol use also carries a risk of seizure and serotonin syndrome, particularly if used with other serotonergic medications.23,24

Structure
Thumb
Synonyms
  • Tramadol
  • Tramadolum
External IDs
ETS-6103 / ETS6103
Product Ingredients
IngredientUNIICASInChI Key
Tramadol hydrochloride9N7R477WCK36282-47-0PPKXEPBICJTCRU-XMZRARIVSA-N
Product Images
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
ConZipCapsule, extended release300 mg/1OralVertical Pharmaceuticals, Inc.2011-08-312016-04-30Us
ConZipCapsule, extended release300 mg/1OralVertical Pharmaceuticals, LLC2011-08-31Not applicableUs
ConZipCapsule, extended release200 mg/1OralVertical Pharmaceuticals, Inc.2011-08-312017-03-31Us
ConZipCapsule, extended release200 mg/1OralVertical Pharmaceuticals, LLC2011-08-31Not applicableUs
ConZipCapsule, extended release100 mg/1OralVertical Pharmaceuticals, Inc.2011-08-312017-02-28Us
ConZipCapsule, extended release100 mg/1OralVertical Pharmaceuticals, LLC2011-08-31Not applicableUs
DurelaCapsule, extended releaseOralCipher Pharmaceuticals Inc.2012-03-19Not applicableCanada
DurelaCapsule, extended releaseOralCipher Pharmaceuticals Inc.2012-03-19Not applicableCanada
DurelaCapsule, extended releaseOralCipher Pharmaceuticals Inc.2012-03-19Not applicableCanada
RaliviaTablet, extended releaseOralValeant Canada Lp Valeant Canada S.E.C.2007-10-25Not applicableCanada
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Apo-tramadolTabletOralApotex Corporation2014-06-23Not applicableCanada
Auro-tramadolTabletOralAuro Pharma Inc2019-04-11Not applicableCanada
Mar-tramadolTabletOralMarcan Pharmaceuticals Inc2019-07-18Not applicableCanada
RyzoltTablet, delayed release200 mg/1OralPd Rx Pharmaceuticals, Inc.2010-01-012014-10-13Us
Taro-tramadol ERTablet, extended releaseOralTaro Pharmaceuticals, Inc.2016-05-27Not applicableCanada
Taro-tramadol ERTablet, extended releaseOralTaro Pharmaceuticals, Inc.2016-05-27Not applicableCanada
Taro-tramadol ERTablet, extended releaseOralTaro Pharmaceuticals, Inc.2016-03-07Not applicableCanada
TramadolTablet50 mg/1OralAccord Healthcare Limited2017-10-232017-10-23Us
Tramadol ERTablet, extended release200 mg/1OralStat Rx USA2009-10-27Not applicableUs49884 0822 11 nlmimage10 b9125cd2
Tramadol HClTablet, film coated50 mg/1OralNorthwind Pharmaceuticals2017-10-03Not applicableUs
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

    Learn more
  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
Act Tramadol/acetTramadol hydrochloride (37.5 mg) + Acetaminophen (325 mg)TabletOralActavis Pharma Company2012-05-012018-06-18Canada
Ag-acet-tramadolTramadol hydrochloride (37.5 mg) + Acetaminophen (325 mg)TabletOralAngita Pharma Inc.Not applicableNot applicableCanada
Apo-tramadol/acetTramadol hydrochloride (37.5 mg) + Acetaminophen (325 mg)TabletOralApotex Corporation2009-11-09Not applicableCanada
Auro-tramadol/acetaminophenTramadol hydrochloride (37.5 mg) + Acetaminophen (325 mg)TabletOralAuro Pharma Inc2015-04-08Not applicableCanada
Bio-tramadol/acetTramadol hydrochloride (37.5 mg) + Acetaminophen (325 mg)TabletOralBiomed PharmaNot applicableNot applicableCanada
Ipg-tramadol/acetTramadol hydrochloride (37.5 mg) + Acetaminophen (325 mg)TabletOralMarcan Pharmaceuticals IncNot applicableNot applicableCanada
Jamp-acet-tramadolTramadol hydrochloride (37.5 mg) + Acetaminophen (325 mg)TabletOralJamp Pharma Corporation2012-09-05Not applicableCanada
Lupin-tramadol/acetTramadol hydrochloride (37.50 mg) + Acetaminophen (325.00 mg)TabletOralLupin PharmaNot applicableNot applicableCanada
Mar-tramadol/acetTramadol hydrochloride (37.5 mg) + Acetaminophen (325 mg)TabletOralMarcan Pharmaceuticals Inc2012-09-04Not applicableCanada
Mint-tramadol/acetTramadol hydrochloride (37.5 mg) + Acetaminophen (325 mg)TabletOralMint Pharmaceuticals Inc2012-09-18Not applicableCanada
Unapproved/Other Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
SynaprynTramadol hydrochloride (5 g/5g)KitOralFusion Pharmaceuticals LLC2009-09-142010-07-20Us
SynaprynTramadol hydrochloride (5.8 g/5.8g)KitOralCalifornia Pharmaceuticals, Llc2017-05-01Not applicableUs
Theratramadol-60Tramadol hydrochloride (50 mg/1) + gamma-Aminobutyric acid (100 mg/1)KitOralPhysician Therapeutics Llc2011-05-20Not applicableUs
Theratramadol-90Tramadol hydrochloride (50 mg/1) + gamma-Aminobutyric acid (100 mg/1)KitOralPhysician Therapeutics Llc2011-02-04Not applicableUs
Topical PainTramadol (0.1 g/100mL) + Diazepam (0.1 g/100mL) + Hydrocodone (0.1 g/100mL) + Ibuprofen (0.1 g/100mL)CreamTopicalDr Marc's Manufacturing And Sales2016-02-232018-04-18Us
TramapapTramadol hydrochloride (1 g/1g) + Acetaminophen (1 g/1g)KitOralLiving Well Pharmacy, Inc.2010-04-07Not applicableUs
International/Other Brands
Rybix (Shionogi Inc.) / Tramal (Grünenthal GmbH)
Categories
UNII
0NG5TTM63P
CAS number
27203-92-5
Weight
Average: 263.3752
Monoisotopic: 263.188529049
Chemical Formula
C16H25NO2
InChI Key
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
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

Pharmacology

Indication

Tramadol is approved for the management of moderate to severe pain in adults.29,30

Tramadol is also used off-label in the treatment of premature ejaculation.8

Associated Conditions
Pharmacodynamics

Tramadol modulates the descending pain pathways within the central nervous system through the binding of parent and M1 metabolite to μ-opioid receptors and the weak inhibition of the reuptake of norepinephrine and serotonin.7,6

Apart from analgesia, tramadol may produce a constellation of symptoms (including dizziness, somnolence, nausea, constipation, sweating and pruritus) similar to that of other opioids.

Central Nervous System

In contrast to morphine, tramadol has not been shown to cause histamine release. At therapeutic doses, tramadol has no effect on heart rate, left-ventricular function or cardiac index. Orthostatic hypotension has been observed.29

Tramadol produces respiratory depression by direct action on brain stem respiratory centres. The respiratory depression involves both a reduction in the responsiveness of the brain stem centres to increases in CO2 tension and to electrical stimulation.

Tramadol depresses the cough reflex by a direct effect on the cough centre in the medulla. Antitussive effects may occur with doses lower than those usually required for analgesia.

Tramadol causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origin may produce similar findings). Marked mydriasis rather than miosis may be seen with hypoxia in the setting of oxycodone overdose.30

Seizures have been reported in patients receiving tramadol within the recommended dosage range. Spontaneous post-marketing reports indicate that seizure risk is increased with doses of tramadol above the recommended range. Risk of convulsions may also increase in patients with epilepsy, those with a history of seizures or in patients with a recognized risk for seizure (such as head trauma, metabolic disorders, alcohol and drug withdrawal, CNS infections), or with concomitant use of other drugs known to reduce the seizure threshold.30

Tramadol can cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs (e.g., anti-depressants, migraine medications). Treatment with the serotoninergic drug should be discontinued if such events (characterized by clusters of symptoms such as hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes including confusion, irritability, extreme agitation progressing to delirium and coma) occur and supportive symptomatic treatment should be initiated. Tramadol should not be used in combination with MAO inhibitors or serotonin-precursors (such as L-tryptophan, oxitriptan) and should be used with caution in combination with other serotonergic drugs (triptans, certain tricyclic antidepressants, lithium, St. John’s Wort) due to the risk of serotonin syndrome.30

Gastrointestinal Tract and Other Smooth Muscle

Tramadol causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm resulting in constipation. Other opioid-induced effects may include a reduction in gastric, biliary and pancreatic secretions, spasm of the sphincter of Oddi, and transient elevations in serum amylase.30

Endocrine System

Opioids may influence the hypothalamic-pituitary-adrenal or -gonadal axes. Some changes that can be seen include an increase in serum prolactin and decreases in plasma cortisol and testosterone. Clinical signs and symptoms may be manifest from these hormonal changes.30

Hyponatremia has been reported very rarely with the use of tramadol, usually in patients with predisposing risk factors, such as elderly patients and/or patients using concomitant medications that may cause hyponatremia (e.g., antidepressants, benzodiazepines, diuretics). In some reports, hyponatremia appeared to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and resolved with discontinuation of tramadol and appropriate treatment (e.g., fluid restriction). During tramadol treatment, monitoring for signs and symptoms of hyponatremia is recommended for patients with predisposing risk factors.30

Cardiovascular

Tramadol administration may result in severe hypotension in patients whose ability to maintain adequate blood pressure is compromised by reduced blood volume, or concurrent administration of drugs such as phenothiazines and other tranquillizers, sedative/hypnotics, tricyclic antidepressants or general anesthetics. These patients should be monitored for signs of hypotension after initiating or titrating the dose of tramadol.30

QTc-Interval Prolongation

The maximum placebo-adjusted mean change from baseline in the QTcF interval was 5.5 ms in the 400 mg/day treatment arm and 6.5 ms in the 600 mg/day mg treatment arm, both occurring at the 8h time point. Both treatment groups were within the 10 ms threshold for QT prolongation. Post-marketing experience with the use of tramadol containing products included rare reports of QT prolongation reported with an overdose. Particular care should be exercised when administering tramadol to patients who are suspected to be at an increased risk of experiencing torsade de pointes during treatment with a QTc-prolonging drug.30

Abuse and Misuse

Like all opioids, tramadol has the potential for abuse and misuse, which can lead to overdose and death. Therefore, tramadol should be prescribed and handled with caution.30

Dependence/Tolerance

Physical dependence and tolerance reflect the neuroadaptation of the opioid receptors to chronic exposure to an opioid and are separate and distinct from abuse and addiction. Tolerance, as well as physical dependence, may develop upon repeated administration of opioids, and are not by themselves evidence of an addictive disorder or abuse. Patients on prolonged therapy should be tapered gradually from the drug if it is no longer required for pain control. Withdrawal symptoms may occur following abrupt discontinuation of therapy or upon administration of an opioid antagonist. Some of the symptoms that may be associated with abrupt withdrawal of an opioid analgesic include body aches, diarrhea, gooseflesh, loss of appetite, nausea, nervousness or restlessness, anxiety, runny nose, sneezing, tremors or shivering, stomach cramps, tachycardia, trouble with sleeping, unusual increase in sweating, palpitations, unexplained fever, weakness and yawning.30

Mechanism of action

Tramadol is a centrally acting μ-opioid receptor agonist and SNRI (serotonin/norepinephrine reuptake-inhibitor) that is structurally related to codeine and morphine. Tramadol binds weakly to κ- and δ-opioid receptors and to the μ-opioid receptor with 6000-fold less affinity than morphine.16

Tramadol exists as a racemic mixture consisting of two pharmacologically active enantiomers that both contribute to its analgesic property through different mechanisms: (+)-tramadol and its primary metabolite (+)-O-desmethyl-tramadol (M1) are agonists of the μ opioid receptor while (+)-tramadol inhibits serotonin reuptake and (-)-tramadol inhibits norepinephrine reuptake. These pathways are complementary and synergistic, improving tramadol's ability to modulate the perception of and response to pain.12

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.29

Tramadol has also been shown to affect a number of pain modulators including alpha2-adrenoreceptors, neurokinin 1 receptors, the voltage-gated sodium channel type II alpha subunit17, transient receptor potential cation channel subfamily V member 1 (TRPV1 - also known as the capsaicin receptor)18, muscarinic receptors (M1 and M3), N-methyl-D-aspartate receptor (also known as the NMDA receptor or glutamate receptor)19, Adenosine A1 receptors20, and nicotinic acetylcholine receptor.26

In addition to the above neuronal targets, tramadol has a number of effects on inflammatory and immune mediators involved in the pain response. This includes inhibitory effects on cytokines, prostaglandin E2 (PGE2), nuclear factor-κB, and glial cells as well as a change in the polarization state of M1 macrophages.16

TargetActionsOrganism
AMu-type opioid receptor
agonist
Humans
ASodium-dependent noradrenaline transporter
inhibitor
Humans
ASodium-dependent serotonin transporter
inhibitor
Humans
U5-hydroxytryptamine receptor 2C
antagonist
Humans
UKappa-type opioid receptor
agonist
Humans
UDelta-type opioid receptor
agonist
Humans
UAlpha-7 nicotinic cholinergic receptor subunit
antagonist
Humans
UMuscarinic acetylcholine receptor M3
antagonist
Humans
UMuscarinic acetylcholine receptor M1
antagonist
Humans
NNeurokinin 1 receptor
inhibitor
Humans
ASodium channel protein type 2 subunit alpha
inhibitor
Humans
NTransient receptor potential cation channel subfamily V member 1
agonist
Humans
ANMDA receptor
inhibitor
Humans
AAdenosine receptor A1
stimulator
Humans
AAlpha-2 adrenergic receptors
stimulator
Humans
Additional Data Available
Adverse Effects

Comprehensive structured data on known drug adverse effects with statistical prevalence. MedDRA and ICD10 ids are provided for adverse effect conditions and symptoms.

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Additional Data Available
Contraindications

Structured data covering drug contraindications. Each contraindication describes a scenario in which the drug is not to be used. Includes restrictions on co-administration, contraindicated populations, and more.

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Additional Data Available
Blackbox Warnings

Structured data representing warnings from the black box section of drug labels. These warnings cover important and dangerous risks, contraindications, or adverse effects.

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Absorption

Oral Administration

Tramadol is administered as a racemate, with both the [-] and [+] forms of both tramadol and the M1 metabolite detected in circulation. Following administration, racemic tramadol is rapidly and almost completely absorbed, with a bioavailability of 75%. This difference in absorption and bioavailability can be attributed to the 20-30% first-pass metabolism. Peak plasma concentrations of tramadol and the primary metabolite M1 occur at two and three hours, respectively.30 Following a single oral dose of 100mg of tramadol, the Cmax was found to be approximately 300μg/L with a Tmax of 1.6-1.9 hours, while metabolite M1 was found to have a Cmax of 55μg/L with a Tmax of 3 hours.12,29

Steady-state plasma concentrations of both tramadol and M1 are achieved within two days of dosing. There is no evidence of self-induction.30 Following multiple oral doses, Cmax is 16% higher and AUC is 36% higher than after a single dose, demonstrating a potential role of saturable first-pass hepatic metabolism in increasing bioavailability.12

Intramuscular Administration

Tramadol is rapidly and almost completely absorbed following intramuscular administration. Following injection of 50mg of tramadol, Cmax of 166μg/L was found with a Tmax of 0.75 hours.12

Rectal Administration

Following rectal administration with suppositories containing 100mg of tramadol, Cmax of 294μg/L was found with a Tmax of 3.3 hours. The absolute bioavailability was found to be higher than oral administration (77% vs 75%), likely due to reduced first-pass metabolism with rectal administration compared to oral administration.12

Volume of distribution

The volume of distribution of tramadol is reported to be in the range of 2.6-2.9 L/kg.29,30 Tramadol has high tissue affinity; the total volume of distribution after oral administration was 306L and 203L after parenteral administration.16 Tramadol crosses the blood-brain barrier with peak brain concentrations occurring 10 minutes following oral administration. It also crosses the placental barrier with umbilical concentrations being found to be ~80% of maternal concentrations.12

Protein binding

About 20% of the administered dose is found to bind to plasma proteins. Protein binding appears to be independent of concentrations up to 10μg/mL. Saturation only occurs at concentrations outside of the clinical range.30

Metabolism

Tramadol undergoes extensive first-pass metabolism in the liver by N- and O- demethylation and conjugation. From the extensive metabolism, there have been identified at least 23 metabolites. There are two main metabolic pathways: the O-demethylation of tramadol to produce O-desmethyl-tramadol (M1) catalyzed by CYP2D6 and the N-demethylation to N-desmethyl-tramadol (M2) catalyzed by CYP3A4 and CYP2B6.12,29,30

The wide variability in the pharmacokinetic properties between patients can partly be ascribed to polymorphisms within the gene for CYP2D6 that determine its enzymatic activity. CYP2D6*1 is considered the wild-type allele associated with normal enzyme activity and the "extensive metabolizer" phenotype; 90-95% of Caucasians are considered "extensive metabolizers" (with normal CYP2D6 function) while the remaining 5-10% are considered "poor metabolizers" with reduced or non-functioning enzyme.14 CYP2D6 alleles associated with non-functioning enzyme include *3, *4, *5, and *6 while alleles associated with reduced activity include *9, *10, *17, and *41.21

Poor metabolizers have reduced activity of the CYP2D6 enzyme and therefore less production of tramadol metabolites M1 and M2, which ultimately results in a reduced analgesic effect as tramadol interacts with the μ-opioid receptor primarily via M1.12

There are also large differences in the frequency of these alleles between different ethnicities: *3, *4, *5, *6, and *41 are more common among Caucasians while *17 is more common in Africans for example.21 Compared to 5-10% of Caucasians, only ~1% of Asians are considered poor metabolizers, however Asian populations carry a much higher frequency (51%) of the CYP2D6*10 allele, which is relatively rare in Caucasian populations and results in higher exposure to tramadol.14

Some individuals are considered "ultra-rapid metabolizers", such as those carrying CYP2D6 gene duplications (CYP2D6*DUP) or multiplications. These individuals are at risk of intoxication or exaggerated effects of tramadol due to higher concentrations of its active metabolite (M1).15 The occurrence of this phenotype is seen in approximately 1% to 2% of East Asians (Chinese, Japanese, Korean), 1% to 10% of Caucasians, 3% to 4% of African-Americans, and may be >10% in certain racial/ethnic groups (ie, Oceanian, Northern African, Middle Eastern, Ashkenazi Jews, Puerto Rican). The FDA label recommends avoiding the use of tramadol in these individuals.29,30

Route of elimination

Tramadol is eliminated primarily through metabolism by the liver and the metabolites are excreted primarily by the kidneys, accounting for 90% of the excretion while the remaining 10% is excreted through feces.29,30,6 Approximately 30% of the dose is excreted in the urine as unchanged drug, whereas 60% of the dose is excreted as metabolites.11

The mean terminal plasma elimination half-lives of racemic tramadol and racemic M1 are 6.3 ± 1.4 and 7.4 ± 1.4 hours, respectively. The plasma elimination half-life of racemic tramadol increased from approximately six hours to seven hours upon multiple dosing.29,30

Half life

Tramadol reported a half-life of 5-6 hours while the M1 metabolite presents a half-life of 8 hours.6

Clearance

In clinical trials, the clearance rate of tramadol ranged from 3.73 ml/min/kg in renal impairment patients to 8.50 ml/min/kg in healthy adults.29,30

Toxicity

The reported LD50 for tramadol, when administered orally in mice, is 350 mg/kg.11

In carcinogenic studies, there are reports of murine tumors which cannot be concluded to be carcinogenic in humans. On the other hand, tramadol showed no evidence to be mutagenic in different assays and does not have effects on fertility. However, there are clear reports of embryotoxicity and fetotoxicity.29,30

Affected organisms
  • Humans and other mammals
Pathways
PathwayCategory
Tramadol Action Action PathwayDrug action
Tramadol Metabolism PathwayDrug metabolism
Pharmacogenomic Effects/ADRs
Interacting Gene/EnzymeAllele nameGenotype(s)Defining Change(s)Type(s)DescriptionDetails
Cytochrome P450 2D6CYP2D6*3Not AvailableC alleleADR Inferred EffectPoor drug metabolizer. This results in reduced analgesic efficacy and decreased risk of opioid toxicity as well as increased risk of seizures and serotonin syndrome. Consider alternative therapies.Details
Cytochrome P450 2D6CYP2D6*4Not AvailableC alleleADR Inferred EffectPoor drug metabolizer. This results in reduced analgesic efficacy and decreased risk of opioid toxicity as well as increased risk of seizures and serotonin syndrome. Consider alternative therapies.Details
Cytochrome P450 2D6CYP2D6*5Not AvailableWhole-gene deletionADR Inferred EffectPoor drug metabolizer. This results in reduced analgesic efficacy and decreased risk of opioid toxicity as well as increased risk of seizures and serotonin syndrome. Consider alternative therapies.Details
Cytochrome P450 2D6CYP2D6*6Not Available1707delTADR Inferred EffectPoor drug metabolizer. This results in reduced analgesic efficacy and decreased risk of opioid toxicity as well as increased risk of seizures and serotonin syndrome. Consider alternative therapies.Details
Cytochrome P450 2D6CYP2D6*7Not Available2935A>CADR Inferred EffectPoor drug metabolizer. This results in reduced analgesic efficacy and decreased risk of opioid toxicity as well as increased risk of seizures and serotonin syndrome. Consider alternative therapies.Details
Cytochrome P450 2D6CYP2D6*8Not Available1758G>TADR Inferred EffectPoor drug metabolizer. This results in reduced analgesic efficacy and decreased risk of opioid toxicity as well as increased risk of seizures and serotonin syndrome. Consider alternative therapies.Details
Cytochrome P450 2D6CYP2D6*11Not Available883G>CADR Inferred EffectPoor drug metabolizer. This results in reduced analgesic efficacy and decreased risk of opioid toxicity as well as increased risk of seizures and serotonin syndrome. Consider alternative therapies.Details
Cytochrome P450 2D6CYP2D6*12Not Available124G>AADR Inferred EffectPoor drug metabolizer. This results in reduced analgesic efficacy and decreased risk of opioid toxicity as well as increased risk of seizures and serotonin syndrome. Consider alternative therapies.Details
Cytochrome P450 2D6CYP2D6*13Not AvailableCYP2D7/2D6 hybrid gene structureADR Inferred EffectPoor drug metabolizer. This results in reduced analgesic efficacy and decreased risk of opioid toxicity as well as increased risk of seizures and serotonin syndrome. Consider alternative therapies.Details
Cytochrome P450 2D6CYP2D6*14ANot Available1758G>AADR Inferred EffectPoor drug metabolizer. This results in reduced analgesic efficacy and decreased risk of opioid toxicity as well as increased risk of seizures and serotonin syndrome. Consider alternative therapies.Details
Cytochrome P450 2D6CYP2D6*15Not Available137insT, 137_138insTADR Inferred EffectPoor drug metabolizer. This results in reduced analgesic efficacy and decreased risk of opioid toxicity as well as increased risk of seizures and serotonin syndrome. Consider alternative therapies.Details
Cytochrome P450 2D6CYP2D6*19Not Available2539_2542delAACTADR Inferred EffectPoor drug metabolizer. This results in reduced analgesic efficacy and decreased risk of opioid toxicity as well as increased risk of seizures and serotonin syndrome. Consider alternative therapies.Details
Cytochrome P450 2D6CYP2D6*20Not Available1973_1974insGADR Inferred EffectPoor drug metabolizer. This results in reduced analgesic efficacy and decreased risk of opioid toxicity as well as increased risk of seizures and serotonin syndrome. Consider alternative therapies.Details
Cytochrome P450 2D6CYP2D6*21Not Available2573insCADR Inferred EffectPoor drug metabolizer. This results in reduced analgesic efficacy and decreased risk of opioid toxicity as well as increased risk of seizures and serotonin syndrome. Consider alternative therapies.Details
Cytochrome P450 2D6CYP2D6*31Not Available-1770G>A / -1584C>G  … show all ADR Inferred EffectPoor drug metabolizer. This results in reduced analgesic efficacy and decreased risk of opioid toxicity as well as increased risk of seizures and serotonin syndrome. Consider alternative therapies.Details
Cytochrome P450 2D6CYP2D6*36Not Available100C>T / -1426C>T  … show all ADR Inferred EffectPoor drug metabolizer. This results in reduced analgesic efficacy and decreased risk of opioid toxicity as well as increased risk of seizures and serotonin syndrome. Consider alternative therapies.Details
Cytochrome P450 2D6CYP2D6*38Not Available2587_2590delGACTADR Inferred EffectPoor drug metabolizer. This results in reduced analgesic efficacy and decreased risk of opioid toxicity as well as increased risk of seizures and serotonin syndrome. Consider alternative therapies.Details
Cytochrome P450 2D6CYP2D6*40Not Available1863_1864ins(TTT CGC CCC)2ADR Inferred EffectPoor drug metabolizer. This results in reduced analgesic efficacy and decreased risk of opioid toxicity as well as increased risk of seizures and serotonin syndrome. Consider alternative therapies.Details
Cytochrome P450 2D6CYP2D6*42Not Available3259_3260insGTADR Inferred EffectPoor drug metabolizer. This results in reduced analgesic efficacy and decreased risk of opioid toxicity as well as increased risk of seizures and serotonin syndrome. Consider alternative therapies.Details
Cytochrome P450 2D6CYP2D6*44Not Available2950G>CADR Inferred EffectPoor drug metabolizer. This results in reduced analgesic efficacy and decreased risk of opioid toxicity as well as increased risk of seizures and serotonin syndrome. Consider alternative therapies.Details
Cytochrome P450 2D6CYP2D6*47Not Available100C>T / -1426C>T  … show all ADR Inferred EffectPoor drug metabolizer. This results in reduced analgesic efficacy and decreased risk of opioid toxicity as well as increased risk of seizures and serotonin syndrome. Consider alternative therapies.Details
Cytochrome P450 2D6CYP2D6*51Not Available-1584C>G / -1235A>G  … show all ADR Inferred EffectPoor drug metabolizer. This results in reduced analgesic efficacy and decreased risk of opioid toxicity as well as increased risk of seizures and serotonin syndrome. Consider alternative therapies.Details
Cytochrome P450 2D6CYP2D6*56Not Available3201C>TADR Inferred EffectPoor drug metabolizer. This results in reduced analgesic efficacy and decreased risk of opioid toxicity as well as increased risk of seizures and serotonin syndrome. Consider alternative therapies.Details
Cytochrome P450 2D6CYP2D6*57Not Available100C>T / 310G>T  … show all ADR Inferred EffectPoor drug metabolizer. This results in reduced analgesic efficacy and decreased risk of opioid toxicity as well as increased risk of seizures and serotonin syndrome. Consider alternative therapies.Details
Cytochrome P450 2D6CYP2D6*62Not Available4044C>TADR Inferred EffectPoor drug metabolizer. This results in reduced analgesic efficacy and decreased risk of opioid toxicity as well as increased risk of seizures and serotonin syndrome. Consider alternative therapies.Details
Cytochrome P450 2D6CYP2D6*68ANot Available-1426C>T / -1235A>G  … show all ADR Inferred EffectPoor drug metabolizer. This results in reduced analgesic efficacy and decreased risk of opioid toxicity as well as increased risk of seizures and serotonin syndrome. Consider alternative therapies.Details
Cytochrome P450 2D6CYP2D6*68BNot AvailableSimilar but not identical switch region compared to CYP2D6*68A. Found in tandem arrangement with CYP2D6*4.ADR Inferred EffectPoor drug metabolizer. This results in reduced analgesic efficacy and decreased risk of opioid toxicity as well as increased risk of seizures and serotonin syndrome. Consider alternative therapies.Details
Cytochrome P450 2D6CYP2D6*69Not Available2988G>A / -1426C>T  … show all ADR Inferred EffectPoor drug metabolizer. This results in reduced analgesic efficacy and decreased risk of opioid toxicity as well as increased risk of seizures and serotonin syndrome. Consider alternative therapies.Details
Cytochrome P450 2D6CYP2D6*92Not Available1995delCADR Inferred EffectPoor drug metabolizer. This results in reduced analgesic efficacy and decreased risk of opioid toxicity as well as increased risk of seizures and serotonin syndrome. Consider alternative therapies.Details
Cytochrome P450 2D6CYP2D6*100Not Available-1426C>T / -1235A>G  … show all ADR Inferred EffectPoor drug metabolizer. This results in reduced analgesic efficacy and decreased risk of opioid toxicity as well as increased risk of seizures and serotonin syndrome. Consider alternative therapies.Details
Cytochrome P450 2D6CYP2D6*101Not Available-1426C>T / -1235A>G  … show all ADR Inferred EffectPoor drug metabolizer. This results in reduced analgesic efficacy and decreased risk of opioid toxicity as well as increased risk of seizures and serotonin syndrome. Consider alternative therapies.Details
Cytochrome P450 2D6CYP2D6*10Not Available100C>T (but also appears in other variants)ADR pgx reviewThis mutation leads to an unstable CYP2D6 enzyme with lower metabolic activity.Details

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
1-(2-Phenylethyl)-4-phenyl-4-acetoxypiperidineThe metabolism of Tramadol can be decreased when combined with 1-(2-Phenylethyl)-4-phenyl-4-acetoxypiperidine.
1,10-PhenanthrolineThe therapeutic efficacy of Tramadol can be decreased when used in combination with 1,10-Phenanthroline.
2,5-Dimethoxy-4-ethylamphetamine2,5-Dimethoxy-4-ethylamphetamine may increase the analgesic activities of Tramadol.
2,5-Dimethoxy-4-ethylthioamphetamine2,5-Dimethoxy-4-ethylthioamphetamine may increase the analgesic activities of Tramadol.
4-Bromo-2,5-dimethoxyamphetamine4-Bromo-2,5-dimethoxyamphetamine may increase the analgesic activities of Tramadol.
4-Methoxyamphetamine4-Methoxyamphetamine may increase the central nervous system depressant (CNS depressant) activities of Tramadol.
5-methoxy-N,N-dimethyltryptamineThe risk or severity of adverse effects can be increased when Tramadol is combined with 5-methoxy-N,N-dimethyltryptamine.
7-Nitroindazole7-Nitroindazole may increase the central nervous system depressant (CNS depressant) activities of Tramadol.
7,8-Dichloro-1,2,3,4-tetrahydroisoquinolineThe risk or severity of serotonin syndrome and seizure can be increased when 7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline is combined with Tramadol.
AbacavirTramadol may decrease the excretion rate of Abacavir which could result in a higher serum level.
Additional Data Available
  • Extended Description
    Extended Description

    Extended description of the mechanism of action and particular properties of each drug interaction.

    Learn more
  • Severity
    Severity

    A severity rating for each drug interaction, from minor to major.

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  • Evidence Level
    Evidence Level

    A rating for the strength of the evidence supporting each drug interaction.

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  • Action
    Action

    An effect category for each drug interaction. Know how this interaction affects the subject drug.

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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.

References

Synthesis Reference

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

US5929122
General References
  1. Dayer P, Desmeules J, Collart L: [Pharmacology of tramadol]. Drugs. 1997;53 Suppl 2:18-24. [PubMed:9190321]
  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:9633738]
  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:10959067]
  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:9190323]
  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:12855342]
  6. Beakley BD, Kaye AM, Kaye AD: Tramadol, Pharmacology, Side Effects, and Serotonin Syndrome: A Review. Pain Physician. 2015 Jul-Aug;18(4):395-400. [PubMed:26218943]
  7. Shin HW, Ju BJ, Jang YK, You HS, Kang H, Park JY: Effect of tramadol as an adjuvant to local anesthetics for brachial plexus block: A systematic review and meta-analysis. PLoS One. 2017 Sep 27;12(9):e0184649. doi: 10.1371/journal.pone.0184649. eCollection 2017. [PubMed:28953949]
  8. Martyn-St James M, Cooper K, Kaltenthaler E, Dickinson K, Cantrell A, Wylie K, Frodsham L, Hood C: Tramadol for premature ejaculation: a systematic review and meta-analysis. BMC Urol. 2015 Jan 30;15:6. doi: 10.1186/1471-2490-15-6. [PubMed:25636495]
  9. Monteiro BP, Klinck MP, Moreau M, Guillot M, Steagall PV, Pelletier JP, Martel-Pelletier J, Gauvin D, Del Castillo JR, Troncy E: Analgesic efficacy of tramadol in cats with naturally occurring osteoarthritis. PLoS One. 2017 Apr 12;12(4):e0175565. doi: 10.1371/journal.pone.0175565. eCollection 2017. [PubMed:28403198]
  10. Stoops WW, Lofwall MR, Nuzzo PA, Craig LB, Siegel AJ, Walsh SL: Pharmacodynamic profile of tramadol in humans: influence of naltrexone pretreatment. Psychopharmacology (Berl). 2012 Oct;223(4):427-38. doi: 10.1007/s00213-012-2739-4. Epub 2012 May 24. [PubMed:22623016]
  11. Vazzana M, Andreani T, Fangueiro J, Faggio C, Silva C, Santini A, Garcia ML, Silva AM, Souto EB: Tramadol hydrochloride: pharmacokinetics, pharmacodynamics, adverse side effects, co-administration of drugs and new drug delivery systems. Biomed Pharmacother. 2015 Mar;70:234-8. doi: 10.1016/j.biopha.2015.01.022. Epub 2015 Feb 7. [PubMed:25776506]
  12. Grond S, Sablotzki A: Clinical pharmacology of tramadol. Clin Pharmacokinet. 2004;43(13):879-923. [PubMed:15509185]
  13. Wiffen PJ, Derry S, Moore RA: Tramadol with or without paracetamol (acetaminophen) for cancer pain. Cochrane Database Syst Rev. 2017 May 16;5:CD012508. doi: 10.1002/14651858.CD012508.pub2. [PubMed:28510996]
  14. Xu J, Zhang XC, Lv XQ, Xu YY, Wang GX, Jiang B, Cai L, Cai XJ: Effect of the cytochrome P450 2D6*10 genotype on the pharmacokinetics of tramadol in post-operative patients. Pharmazie. 2014 Feb;69(2):138-41. [PubMed:24640604]
  15. Arafa MH, Atteia HH: Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6) are associated with long term tramadol treatment-induced oxidative damage and hepatotoxicity. Toxicol Appl Pharmacol. 2018 May 1;346:37-44. doi: 10.1016/j.taap.2018.03.019. Epub 2018 Mar 16. [PubMed:29555325]
  16. Barakat A: Revisiting Tramadol: A Multi-Modal Agent for Pain Management. CNS Drugs. 2019 May;33(5):481-501. doi: 10.1007/s40263-019-00623-5. [PubMed:31004280]
  17. Haeseler G, Foadi N, Ahrens J, Dengler R, Hecker H, Leuwer M: Tramadol, fentanyl and sufentanil but not morphine block voltage-operated sodium channels. Pain. 2006 Dec 15;126(1-3):234-44. doi: 10.1016/j.pain.2006.07.003. Epub 2006 Sep 1. [PubMed:16949748]
  18. Marincsak R, Toth BI, Czifra G, Szabo T, Kovacs L, Biro T: The analgesic drug, tramadol, acts as an agonist of the transient receptor potential vanilloid-1. Anesth Analg. 2008 Jun;106(6):1890-6. doi: 10.1213/ane.0b013e318172fefc. [PubMed:18499628]
  19. 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:15845694]
  20. Sawynok J, Reid AR, Liu J: Spinal and peripheral adenosine A(1) receptors contribute to antinociception by tramadol in the formalin test in mice. Eur J Pharmacol. 2013 Aug 15;714(1-3):373-8. doi: 10.1016/j.ejphar.2013.07.012. Epub 2013 Jul 16. [PubMed:23872384]
  21. Dean L: Tramadol Therapy and CYP2D6 Genotype . [PubMed:28520365]
  22. Epstein DH, Preston KL, Jasinski DR: Abuse liability, behavioral pharmacology, and physical-dependence potential of opioids in humans and laboratory animals: lessons from tramadol. Biol Psychol. 2006 Jul;73(1):90-9. doi: 10.1016/j.biopsycho.2006.01.010. Epub 2006 Feb 23. [PubMed:16497429]
  23. Murray BP, Carpenter JE, Dunkley CA, Moran TP, Alfaifi M, Alsukaiti WS, Kazzi Z: Seizures in tramadol overdoses reported in the ToxIC registry: predisposing factors and the role of naloxone. Clin Toxicol (Phila). 2019 Aug;57(8):692-696. doi: 10.1080/15563650.2018.1547826. Epub 2019 Jan 24. [PubMed:30676832]
  24. Hassamal S, Miotto K, Dale W, Danovitch I: Tramadol: Understanding the Risk of Serotonin Syndrome and Seizures. Am J Med. 2018 Nov;131(11):1382.e1-1382.e6. doi: 10.1016/j.amjmed.2018.04.025. Epub 2018 May 10. [PubMed:29752906]
  25. Raffa RB, Friderichs E, Reimann W, Shank RP, Codd EE, Vaught JL, Jacoby HI, Selve N: Complementary and synergistic antinociceptive interaction between the enantiomers of tramadol. J Pharmacol Exp Ther. 1993 Oct;267(1):331-40. [PubMed:8229760]
  26. 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:12010769]
  27. FDA approvals [Link]
  28. WHO reports [Link]
  29. FDA Label - Tramadol [File]
  30. Health Canada Monograph - Tramadol [File]
External Links
Human Metabolome Database
HMDB0014339
KEGG Drug
D08623
KEGG Compound
C07153
PubChem Compound
33741
PubChem Substance
46506256
ChemSpider
31105
BindingDB
50176259
ChEBI
75725
ChEMBL
CHEMBL1066
Therapeutic Targets Database
DAP000140
PharmGKB
PA451735
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Tramadol
ATC Codes
N02AJ13 — Tramadol and paracetamolN02AJ14 — Tramadol and dexketoprofenN02AX02 — Tramadol
AHFS Codes
  • 28:08.08 — Opiate Agonists
FDA label
Download (408 KB)
MSDS
Download (74.7 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedNot AvailableBack Pain Lower Back1
1CompletedNot AvailableHealthy Volunteers4
1CompletedNot AvailablePain1
1CompletedNot AvailableTo Determine Bioequivalence Under Fasting Conditions1
1CompletedBasic ScienceAging / Pain1
1CompletedBasic ScienceHealthy Volunteers1
1CompletedBasic SciencePharmacokinetics1
1CompletedDiagnosticOsteoarthritis (OA)1
1CompletedOtherOsteoarthritis Thumbs1
1CompletedOtherTo Determine Bioequivalence Under Fed Conditions1
1CompletedSupportive CareHealthy Volunteers1
1CompletedTreatmentBioavailability / Healthy Volunteers / Pharmacokinetics1
1CompletedTreatmentHealthy Volunteers4
1CompletedTreatmentPain6
1CompletedTreatmentPharmacokinetics1
1RecruitingTreatmentHealthy Volunteers1
1, 2CompletedBasic ScienceOpioid Induced Motor Disturbances1
1, 2CompletedTreatmentOpioid Abuse / Opioid Addiction / Stimulant Abuse / Stimulant Addiction1
1, 2CompletedTreatmentOpioid Addiction / Opioid Dependence / Opioid Related Disorders1
1, 2CompletedTreatmentOpioid-Related Disorders1
1, 2CompletedTreatmentPain Management / Pulpitis dental1
1, 2Unknown StatusTreatmentChoroidal Melanoma / Eye Neoplasms / Melanoma1
2CompletedBasic ScienceBreast Cancer1
2CompletedPreventionOpioid Analgesic Adverse Reaction / Traumas1
2CompletedSupportive CarePain2
2CompletedTreatmentAcute Low Back Pain1
2CompletedTreatmentAmbulatory Surgery1
2CompletedTreatmentBack Pain Lower Back / Osteoarthritis (OA)1
2CompletedTreatmentFibromyalgia / Human Growth Hormone Deficiency1
2CompletedTreatmentGeriatric Hip Fracture Pain Management1
2CompletedTreatmentMajor Depressive Disorder (MDD)1
2CompletedTreatmentOpioid-Related Disorders1
2CompletedTreatmentOsteoarthritis (OA)1
2CompletedTreatmentPain1
2CompletedTreatmentPain, Acute1
2CompletedTreatmentRotator Cuff Injury / Shoulder Arthritis / Shoulder Dislocation / Shoulder Fractures1
2Not Yet RecruitingPreventionPost Anaesthetic Shivering1
2Not Yet RecruitingTreatmentKnee Osteoarthritis (Knee OA)1
2Not Yet RecruitingTreatmentTramadol for Labor Analgesia1
2RecruitingPreventionPain, Neuropathic1
2Unknown StatusTreatmentNausea / Pain / Pruritus / Vertigo1
2, 3Active Not RecruitingDiagnosticBreast Cancer1
2, 3CompletedTreatmentSubstance Withdrawal Syndrome1
2, 3Not Yet RecruitingTreatmentAnterior Cruciate Ligament Rupture / Muscle Weakness1
2, 3RecruitingTreatmentAnalgesics, Opioid / Buprenorphine / Rotator Cuff Injury / Rotator Cuff Syndrome1
3Active Not RecruitingOtherPain Management1
3Active Not RecruitingTreatmentPain Management1
3CompletedTreatmentAcute Low Back Pain1
3CompletedTreatmentAcute Post-surgical Pain1
3CompletedTreatmentAcute Toothache Patients Above Moderate Pain After Teeth Extraction Surgery1
3CompletedTreatmentAnaesthesia therapy1
3CompletedTreatmentAnalgesia / Neonatal Infections / Pain1
3CompletedTreatmentBack Pain Lower Back3
3CompletedTreatmentDiabetic Neuropathies1
3CompletedTreatmentDisease (or Disorder); Intervertebral Disc, With Myelopathy (Manifestation)1
3CompletedTreatmentFibromyalgia1
3CompletedTreatmentAdjunct to general anesthesia therapy / Indwelling Urinary Catheter / Male Patients1
3CompletedTreatmentKnee Osteoarthritis (Knee OA)1
3CompletedTreatmentKnee Osteoarthritis (Knee OA) / Pain3
3CompletedTreatmentOpioids Use / Pain, Chronic1
3CompletedTreatmentOsteoarthritis (OA) / Pain1
3CompletedTreatmentPain2
3CompletedTreatmentPain During Labour1
3CompletedTreatmentPain, Acute5
3CompletedTreatmentPain, Chronic6
3CompletedTreatmentPain / Postoperative pain1
3CompletedTreatmentPostoperative pain1
3Not Yet RecruitingPreventionPain, Procedure1
3RecruitingPreventionHysteroscopy2
3RecruitingPreventionHysteroscopy / Pain1
3RecruitingPreventionPain1
3RecruitingPreventionPain, Post Procedural / Procedural Pain1
3RecruitingTreatmentAbdominal Pain1
3RecruitingTreatmentAmitriptyline / Hansen's Disease / Leprosy Neuropathy / Pain, Neuropathic1
3RecruitingTreatmentOpioids Use / Shoulder Pain1
3RecruitingTreatmentPain Management1
3TerminatedNot AvailablePremature Ejaculation1
3TerminatedTreatmentPain, Chronic1
3Unknown StatusTreatmentHip Arthroplasty / Knee Replacement Surgery / Spinal Anaesthesia1
3WithdrawnTreatmentChronic Pain Due to Trauma / Spinal Cord Injuries (SCI)1
3WithdrawnTreatmentOpiate withdrawal symptoms / Opioid-Related Disorders1
4Active Not RecruitingTreatmentPain, Acute1
4CompletedNot AvailablePain, Chronic1
4CompletedNot AvailableRheumatic Diseases1
4CompletedHealth Services ResearchAnkylosing Spondylitis (AS)1
4CompletedOtherHealthy Volunteers1
4CompletedOtherPolyps, Nasal1
4CompletedPreventionCaesarean Sections1
4CompletedPreventionDisease, Chronic1
4CompletedPreventionPostoperative pain1
4CompletedSupportive CareOsteoarthritis (OA)1
4CompletedSupportive CarePost-Operative Nausea and Vomiting (PONV) / Postoperative pain1
4CompletedTreatmentAnalgesia, Postoperative / Heart Surgery Via Sternotomy1
4CompletedTreatmentArthroplasty1
4CompletedTreatmentBack Pain Lower Back / Neck Pain / Shoulder Pain1
4CompletedTreatmentBack Pain, Unspecified1
4CompletedTreatmentChildren / Inguinal Hernias1
4CompletedTreatmentChildren / Postoperative pain / Recovery of Function1
4CompletedTreatmentDiabetic Neuropathies1
4CompletedTreatmentFibromyalgia / Pain1
4CompletedTreatmentFracture Bone / Pain1
4CompletedTreatmentGall Stone Disease1
4CompletedTreatmentHeadache / Migraine1
4CompletedTreatmentHealthy Volunteers1
4CompletedTreatmentHernia1
4CompletedTreatmentHysterectomy / Postoperative pain1
4CompletedTreatmentInadequate or Impaired Respiratory Function / Pain1
4CompletedTreatmentInfertilities / Pain1
4CompletedTreatmentInguinal Hernias / Postoperative pain1
4CompletedTreatmentKidney Stones1
4CompletedTreatmentMalignancies1
4CompletedTreatmentOsteoarthritis (OA)3
4CompletedTreatmentOsteoarthritis (OA) / Pain1
4CompletedTreatmentPain3
4CompletedTreatmentPain, Acute1
4CompletedTreatmentPain, Neuropathic / Type 1 Insulin-Dependent Diabetes Mellitus / Type 2 Diabetes Mellitus1
4CompletedTreatmentPain / Tonsillitis1
4CompletedTreatmentOr Peripheral Nerve Injury (PNI) / Peripheral Neuropathic Pain (PNP) Due to Postherpetic Neuralgia (PHN)1
4CompletedTreatmentPostoperative pain / Postoperative Pain Following Cesarean Section1
4CompletedTreatmentPostoperative pain5
4CompletedTreatmentPostoperative pain / Spinal Stenosis1
4CompletedTreatmentPostoperative pain / Surgery, Oral1
4CompletedTreatmentRheumatoid Arthritis1
4CompletedTreatmentRotator Cuff Syndrome1
4CompletedTreatmentSymptomatic Irreversible Pulpitis1
4Enrolling by InvitationTreatmentNonspecific Pain Post Traumatic Injury1
4Not Yet RecruitingHealth Services ResearchIUD Insertion Complication1
4Not Yet RecruitingSupportive CareHysteroscopy1
4Not Yet RecruitingTreatmentChild, Only / Postoperative pain / Sleep Disorder; Breathing-Related1
4Not Yet RecruitingTreatmentFertility1
4Not Yet RecruitingTreatmentMenstrual Cramps1
4Not Yet RecruitingTreatmentPerineal Pain1
4RecruitingPreventionNeoplasms, Brain1
4RecruitingPreventionPain1
4RecruitingSupportive CareColon Diverticulosis / Colonic Neoplasms / Constipation / Constipation Drug Induced / Diverticulitis, Colonic / Ileus / Ileus paralytic / Ileus; Mechanical / Malignant Neoplasm of Colon / Postoperative pain / Rectum Cancer / Rectum Neoplasm1
4RecruitingSupportive CareNeoplasms, Thyroid / Parathyroid Adenomas / Parathyroid Diseases / Parathyroid Hyperplasia / Thyroid Cancers / Thyroid Diseases / Thyroid Goitre / Thyroid Nodules1
4RecruitingTreatmentAnalgesia, Postoperative1
4RecruitingTreatmentHealthy Volunteers / Osteoarthritis of Multiple Joints of Ankle or Foot1
4RecruitingTreatmentPain1
4RecruitingTreatmentPost-Cesarean Section / Postoperative pain1
4RecruitingTreatmentSleep Apnea1
4RecruitingTreatmentTendon Injuries1
4TerminatedTreatmentAnkylosing Spondylitis (AS) / Pain1
4TerminatedTreatmentBack Pain Lower Back / Back Pain, Unspecified1
4TerminatedTreatmentPain1
4Unknown StatusTreatmentDepression / Pain1
4Unknown StatusTreatmentLaparoscopic Nissen Fundoplication1
4Unknown StatusTreatmentPain1
4Unknown StatusTreatmentPost Operative Pain1
4Unknown StatusTreatmentPost Traumatic Stress Disorder (PTSD)1
4WithdrawnTreatmentDiabetic Polyneuropathy / Postherpetic Neuralgia1
Not AvailableActive Not RecruitingTreatmentPain, Acute1
Not AvailableCompletedNot AvailablePost-operative Patients Treated by Tramadol1
Not AvailableCompletedNot AvailablePostoperative pain1
Not AvailableCompletedNot AvailablePostoperative pain / Pregnancy1
Not AvailableCompletedBasic ScienceExercise / Opioids Use1
Not AvailableCompletedBasic ScienceHealthy Volunteers1
Not AvailableCompletedDiagnosticLumbar Disc Disease1
Not AvailableCompletedOtherPostoperative pain1
Not AvailableCompletedOtherTramadol - Anesthetics- Child - Circumcision1
Not AvailableCompletedSupportive CarePain, Acute1
Not AvailableCompletedSupportive CarePostoperative pain1
Not AvailableCompletedTreatmentCataracts1
Not AvailableCompletedTreatmentCesarean Section / Pain1
Not AvailableCompletedTreatmentCaudal epidural block therapy / Cholecystectomy / Postoperative pain1
Not AvailableCompletedTreatmentFlail Chest / General Surgery / Rib Fractures / Traumas1
Not AvailableCompletedTreatmentKnee Osteoarthritis (Knee OA)1
Not AvailableCompletedTreatmentPain1
Not AvailableCompletedTreatmentPain After Knee Arthroscop1
Not AvailableCompletedTreatmentCaudal epidural block therapy / Pain Management / Ultrasound1
Not AvailableCompletedTreatmentPeriapical Abscess1
Not AvailableCompletedTreatmentPost Cesarean Pain Management1
Not AvailableCompletedTreatmentPost-Operative Nausea and Vomiting (PONV)1
Not AvailableCompletedTreatmentPostoperative Sedation, Abdominal Surgery1
Not AvailableCompletedTreatmentPostoperative pain2
Not AvailableCompletedTreatmentPregnancy Termination1
Not AvailableCompletedTreatmentSpinal Stenosis of Lumbar Region1
Not AvailableCompletedTreatmentCaudal epidural block therapy1
Not AvailableEnrolling by InvitationSupportive CareBreast Cancer / Radical Mastectomy Surgery1
Not AvailableNot Yet RecruitingPreventionCervical Biopsy1
Not AvailableNot Yet RecruitingTreatmentCatheter Site Discomfort1
Not AvailableNot Yet RecruitingTreatmentOsteoarthritis (OA)1
Not AvailableRecruitingNot AvailableAbdominal Surgeries / Liver Dysfunction / Multiorgan Failure / Renal Failure / Respiratory Failure1
Not AvailableRecruitingTreatmentBack Pain Lower Back1
Not AvailableRecruitingTreatmentGeneral Surgery / Pain / Rib Fractures / Traumas1
Not AvailableRecruitingTreatmentParathyroid Diseases / Thyroid Diseases1
Not AvailableRecruitingTreatmentPost-Mastectomy Chronic Pain Syndrome1
Not AvailableRecruitingTreatmentPostoperative Sedation,Gastrectomy, Enhanced Recovery After Surgery1
Not AvailableRecruitingTreatmentSecond Degree Burns1
Not AvailableRecruitingTreatmentSleep Deprivation1
Not AvailableTerminatedNot AvailablePain, Chronic1
Not AvailableTerminatedScreeningCytochrome P450 Phenotype and Genotype Metrics1
Not AvailableUnknown StatusTreatmentPain Relief1
Not AvailableUnknown StatusTreatmentPeritonsillar Abscess1
Not AvailableUnknown StatusTreatmentPostoperative pain1
Not AvailableWithdrawnTreatmentPostoperative pain1

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
  • 4uOrtho LLC
  • Able Laboratories Inc.
  • Advanced Pharmaceutical Services Inc.
  • Alphapharm Party Ltd.
  • Altura Pharmaceuticals Inc.
  • Amerisource Health Services Corp.
  • Amneal Pharmaceuticals
  • Apotex Inc.
  • Apotheca Inc.
  • A-S Medication Solutions LLC
  • Atlantic Biologicals Corporation
  • BC Vision Inc.
  • Biovail Pharmaceuticals
  • Blenheim Pharmacal
  • Bryant Ranch Prepack
  • Caraco Pharmaceutical Labs
  • Cardinal Health
  • Concern Stirol
  • Confab Laboratories Inc.
  • Corepharma LLC
  • Coupler Enterprises Inc.
  • D.M. Graham Laboratories Inc.
  • Deca Pharmaceuticals LLC
  • DHHS Program Support Center Supply Service Center
  • Direct Dispensing Inc.
  • DispenseXpress Inc.
  • Dispensing Solutions
  • Diversified Healthcare Services Inc.
  • Eon Labs
  • Fusion Pharmaceuticals LLC
  • H.J. Harkins Co. Inc.
  • Heartland Repack Services LLC
  • Innoviant Pharmacy Inc.
  • Ivax Pharmaceuticals
  • Janssen-Ortho Inc.
  • Kali Laboratories Inc.
  • Keltman Pharmaceuticals Inc.
  • Labopharm Inc.
  • Lake Erie Medical and Surgical Supply
  • Liberty Pharmaceuticals
  • Major Pharmaceuticals
  • Mallinckrodt Inc.
  • McNeil Laboratories
  • Medisca Inc.
  • Medvantx Inc.
  • Murfreesboro Pharmaceutical Nursing Supply
  • Mutual Pharmaceutical Co.
  • Mylan
  • Novopharm Ltd.
  • Nucare Pharmaceuticals Inc.
  • Ortho Mcneil Janssen Pharmaceutical Inc.
  • Ortho-McNeil-Janssen Pharmaceuticals Inc.
  • Palmetto Pharmaceuticals Inc.
  • Par Pharmaceuticals
  • Patriot Pharmaceuticals
  • PD-Rx Pharmaceuticals Inc.
  • Physicians Total Care Inc.
  • Piramal Healthcare
  • Pliva Inc.
  • Preferred Pharmaceuticals Inc.
  • Prepackage Specialists
  • Prepak Systems Inc.
  • Prescription Dispensing Service Inc.
  • Purdue Pharma LP
  • Rebel Distributors Corp.
  • Redpharm Drug
  • Remedy Repack
  • Resource Optimization and Innovation LLC
  • Ropack Inc.
  • Sandhills Packaging Inc.
  • Southwood Pharmaceuticals
  • St Mary's Medical Park Pharmacy
  • Stat Rx Usa
  • Teva Pharmaceutical Industries Ltd.
  • Torpharm Inc.
  • Trinity Laboratories Inc.
  • UDL Laboratories
  • United Research Laboratories Inc.
  • Va Cmop Dallas
  • Vangard Labs Inc.
  • Watson Pharmaceuticals
Dosage forms
FormRouteStrength
TabletOral
Capsule, extended releaseOral100 mg/1
Capsule, extended releaseOral200 mg/1
Capsule, extended releaseOral300 mg/1
Capsule, extended releaseOral
Tablet, delayed releaseOral200 mg/1
KitOral5 g/5g
KitOral5.8 g/5.8g
CreamTopical
TabletOral50 mg/1
CapsuleOral150 mg/1
Capsule, coated, extended releaseOral150 mg/1
Capsule, extended releaseOral150 mg/1
TabletOral50 mg/50mg
Tablet, coatedOral100 mg/1
Tablet, coatedOral200 mg/1
Tablet, film coatedOral50 1/1
Tablet, film coatedOral50 mg/1
Tablet, film coatedOral
Capsule, extended releaseNot applicable150 mg/1
CapsuleOral100 mg/1
CapsuleOral200 mg/1
CapsuleOral300 mg/1
Tablet, film coated, extended releaseOral100 mg/1
Tablet, film coated, extended releaseOral200 mg/1
Tablet, film coated, extended releaseOral300 mg/1
KitOral
TabletOral
Tablet, coatedOral
TabletOral50 mg
Tablet, coatedOral50 mg/1
Tablet, coatedOral50 mg/201
Tablet, orally disintegratingOral50 mg/1
TabletOral100 mg/1
Tablet, extended releaseOral100 mg/1
Tablet, extended releaseOral200 mg/1
Tablet, extended releaseOral300 mg/1
Tablet, extended releaseOral
Prices
Unit descriptionCostUnit
Tramadol hcl powder29.08USD g
Ultram ER 300 mg 24 Hour tablet10.66USD tablet
Ultram er 300 mg tablet10.25USD tablet
Ultram ER 200 mg 24 Hour tablet7.64USD tablet
Ultram er 200 mg tablet7.35USD tablet
TraMADol HCl 200 mg 24 Hour tablet6.25USD tablet
Ultram ER 100 mg 24 Hour tablet4.62USD tablet
Ultram er 100 mg tablet4.44USD tablet
TraMADol HCl 100 mg 24 Hour tablet3.78USD tablet
Ultram 50 mg tablet1.99USD tablet
Tramadol-Acetaminophen 37.5-325 mg tablet1.07USD tablet
Tramadol hcl 50 mg tablet0.7USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US5464632No1995-11-072013-03-22Us
CA2476201No2009-09-012023-02-21Canada
CA2123160No2003-04-292014-05-09Canada
US6339105Yes2002-01-152020-04-12Us
US6106861No2000-08-222017-12-05Us
US6607748No2003-08-192020-06-29Us
US7988998No2011-08-022023-10-27Us
US7858118No2010-12-282022-04-11Us
Additional Data Available
  • Filed On
    Filed On

    The date on which a patent was filed with the relevant government.

    Learn more

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)178-181 °C'MSDS'
boiling point (°C)406.6 ºCChemical Book
water solubilitySoluble 'MSDS'
logP1.34'MSDS'
pKa9.41'FDA label'
Predicted Properties
PropertyValueSource
Water Solubility0.75 mg/mLALOGPS
logP2.71ALOGPS
logP2.45ChemAxon
logS-2.6ALOGPS
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
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9924
Blood Brain Barrier+0.9382
Caco-2 permeable+0.8866
P-glycoprotein substrateSubstrate0.6283
P-glycoprotein inhibitor IInhibitor0.7807
P-glycoprotein inhibitor IIInhibitor0.9589
Renal organic cation transporterNon-inhibitor0.6398
CYP450 2C9 substrateNon-substrate0.7678
CYP450 2D6 substrateSubstrate0.8919
CYP450 3A4 substrateSubstrate0.7726
CYP450 1A2 substrateNon-inhibitor0.7136
CYP450 2C9 inhibitorNon-inhibitor0.704
CYP450 2D6 inhibitorInhibitor0.6566
CYP450 2C19 inhibitorNon-inhibitor0.6841
CYP450 3A4 inhibitorNon-inhibitor0.6256
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.7832
Ames testNon AMES toxic0.7899
CarcinogenicityNon-carcinogens0.6663
BiodegradationNot ready biodegradable0.9975
Rat acute toxicity3.0316 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.6136
hERG inhibition (predictor II)Inhibitor0.7098
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Mass Spectrum (Electron Ionization)MSsplash10-0a4i-9010000000-ffea37e400f0860f2e7f
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-QTOF , positiveLC-MS/MSsplash10-03di-0090000000-7850be0ba78033f1f677
LC-MS/MS Spectrum - LC-ESI-QTOF , positiveLC-MS/MSsplash10-03di-0090000000-62a3c5cb6717bff20e2c
LC-MS/MS Spectrum - LC-ESI-QTOF , positiveLC-MS/MSsplash10-05fs-0930000000-b8297a71c45e9630f6c0
LC-MS/MS Spectrum - LC-ESI-QTOF , positiveLC-MS/MSsplash10-05fr-0900000000-f650c49b70db20869d0f
LC-MS/MS Spectrum - LC-ESI-QTOF , positiveLC-MS/MSsplash10-0adl-0900000000-b17dfc32e2eb57efaf42
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-0002-0090000000-c35bec467cfec28511fb
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-03di-1090000000-9ca08dcdc5a2027bcb03
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-0a4i-9030000000-469467d2583e7202d89f
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-0a4i-9000000000-89f055b497c88cdc5e79
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-0a4i-9000000000-1922068301c6d3b4f457
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-0a4i-9000000000-1922068301c6d3b4f457
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-0a4i-9000000000-5a9396f20ce15b9c08ba
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-03di-1090000000-e040861e9fa18a8f44a5
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-0a4i-9030000000-fa1522b6a491e6da41c9
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-0a4i-9000000000-8ab0ebc3ceff7c5e5ce5
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-0a4i-9000000000-7645dc9b29d8b2867495
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-0a4i-9000000000-70cad0a31ff2d57bab81
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-0a4i-9000000000-bf1b2c15c6511355c9e1
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-0002-0090000000-02e5642feacadbc07dba
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-0abi-0900000000-5e83a9ee1a223ef36905
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-00di-0900000000-56f60436c6df4aeb6515
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-0002-0090000000-1336e1f66542750cc1de
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-0002-0090000000-0f15435bd2e7f629a898
MS/MS Spectrum - , positiveLC-MS/MSsplash10-03di-0090000000-1550dc2447717d7d8728

Taxonomy

Description
This compound belongs to the class of organic compounds known as anisoles. These are organic compounds containing a methoxybenzene or a derivative thereof.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Phenol ethers
Sub Class
Anisoles
Direct Parent
Anisoles
Alternative Parents
Phenoxy compounds / Methoxybenzenes / Cyclohexanols / Aralkylamines / Alkyl aryl ethers / Tertiary alcohols / Trialkylamines / Cyclic alcohols and derivatives / Organopnictogen compounds / Hydrocarbon derivatives
Substituents
Phenoxy compound / Anisole / Methoxybenzene / Alkyl aryl ether / Cyclohexanol / Aralkylamine / Monocyclic benzene moiety / Tertiary alcohol / Cyclic alcohol / Tertiary aliphatic amine
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol (CHEBI:75725)

Targets

Details
1. Mu-type opioid receptor
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
Curator comments
Peripheral and central.
General Function
Voltage-gated calcium channel activity
Specific Function
Receptor for endogenous opioids such as beta-endorphin and endomorphin. Receptor for natural and synthetic opioids including morphine, heroin, DAMGO, fentanyl, etorphine, buprenorphin and methadone...
Gene Name
OPRM1
Uniprot ID
P35372
Uniprot Name
Mu-type opioid receptor
Molecular Weight
44778.855 Da
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:10961373]
  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:10991912]
  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:1309873]
  4. Grond S, Sablotzki A: Clinical pharmacology of tramadol. Clin Pharmacokinet. 2004;43(13):879-923. [PubMed:15509185]
  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:16793069]
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
  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:17380034]
  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:8955860]
  9. Barakat A: Revisiting Tramadol: A Multi-Modal Agent for Pain Management. CNS Drugs. 2019 May;33(5):481-501. doi: 10.1007/s40263-019-00623-5. [PubMed:31004280]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Norepinephrine:sodium symporter activity
Specific Function
Amine transporter. Terminates the action of noradrenaline by its high affinity sodium-dependent reuptake into presynaptic terminals.
Gene Name
SLC6A2
Uniprot ID
P23975
Uniprot Name
Sodium-dependent noradrenaline transporter
Molecular Weight
69331.42 Da
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:11916794]
  2. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
  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. doi: 10.1017/S1461145709000236. Epub 2009 Apr 3. [PubMed:19341511]
  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:8955860]
  5. Barakat A: Revisiting Tramadol: A Multi-Modal Agent for Pain Management. CNS Drugs. 2019 May;33(5):481-501. doi: 10.1007/s40263-019-00623-5. [PubMed:31004280]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Serotonin:sodium symporter activity
Specific Function
Serotonin transporter whose primary function in the central nervous system involves the regulation of serotonergic signaling via transport of serotonin molecules from the synaptic cleft back into t...
Gene Name
SLC6A4
Uniprot ID
P31645
Uniprot Name
Sodium-dependent serotonin transporter
Molecular Weight
70324.165 Da
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:16427041]
  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:1596676]
  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:8955860]
  4. Barakat A: Revisiting Tramadol: A Multi-Modal Agent for Pain Management. CNS Drugs. 2019 May;33(5):481-501. doi: 10.1007/s40263-019-00623-5. [PubMed:31004280]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Antagonist
General Function
Serotonin receptor activity
Specific Function
G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for various drugs and psychoactive substances, including ergot alkaloid derivatives, 1-2,5,-dimethoxy-4-...
Gene Name
HTR2C
Uniprot ID
P28335
Uniprot Name
5-hydroxytryptamine receptor 2C
Molecular Weight
51820.705 Da
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:15105221]
  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:16679816]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Agonist
General Function
Opioid receptor activity
Specific Function
G-protein coupled opioid receptor that functions as receptor for endogenous alpha-neoendorphins and dynorphins, but has low affinity for beta-endorphins. Also functions as receptor for various synt...
Gene Name
OPRK1
Uniprot ID
P41145
Uniprot Name
Kappa-type opioid receptor
Molecular Weight
42644.665 Da
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:12570923]
  2. Barakat A: Revisiting Tramadol: A Multi-Modal Agent for Pain Management. CNS Drugs. 2019 May;33(5):481-501. doi: 10.1007/s40263-019-00623-5. [PubMed:31004280]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Agonist
General Function
Opioid receptor activity
Specific Function
G-protein coupled receptor that functions as receptor for endogenous enkephalins and for a subset of other opioids. Ligand binding causes a conformation change that triggers signaling via guanine n...
Gene Name
OPRD1
Uniprot ID
P41143
Uniprot Name
Delta-type opioid receptor
Molecular Weight
40368.235 Da
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. doi: 10.1016/j.bmcl.2008.10.134. Epub 2008 Nov 7. [PubMed:19027293]
  2. Barakat A: Revisiting Tramadol: A Multi-Modal Agent for Pain Management. CNS Drugs. 2019 May;33(5):481-501. doi: 10.1007/s40263-019-00623-5. [PubMed:31004280]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Antagonist
General Function
Not Available
Specific Function
Not Available
Gene Name
CHRNA7
Uniprot ID
Q693P7
Uniprot Name
Alpha-7 nicotinic cholinergic receptor subunit
Molecular Weight
2987.635 Da
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:12010769]
  2. Barakat A: Revisiting Tramadol: A Multi-Modal Agent for Pain Management. CNS Drugs. 2019 May;33(5):481-501. doi: 10.1007/s40263-019-00623-5. [PubMed:31004280]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Antagonist
General Function
Receptor activity
Specific Function
The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the...
Gene Name
CHRM3
Uniprot ID
P20309
Uniprot Name
Muscarinic acetylcholine receptor M3
Molecular Weight
66127.445 Da
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:11561087]
  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:12401609]
  3. Barakat A: Revisiting Tramadol: A Multi-Modal Agent for Pain Management. CNS Drugs. 2019 May;33(5):481-501. doi: 10.1007/s40263-019-00623-5. [PubMed:31004280]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Antagonist
General Function
Phosphatidylinositol phospholipase c activity
Specific Function
The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the...
Gene Name
CHRM1
Uniprot ID
P11229
Uniprot Name
Muscarinic acetylcholine receptor M1
Molecular Weight
51420.375 Da
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:11561087]
  2. Barakat A: Revisiting Tramadol: A Multi-Modal Agent for Pain Management. CNS Drugs. 2019 May;33(5):481-501. doi: 10.1007/s40263-019-00623-5. [PubMed:31004280]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
General Function
Tachykinin receptor activity
Specific Function
This is a receptor for the tachykinin neuropeptide substance P. It is probably associated with G proteins that activate a phosphatidylinositol-calcium second messenger system. The rank order of aff...
Gene Name
TACR1
Uniprot ID
P25103
Uniprot Name
Substance-P receptor
Molecular Weight
46250.5 Da
References
  1. Barakat A: Revisiting Tramadol: A Multi-Modal Agent for Pain Management. CNS Drugs. 2019 May;33(5):481-501. doi: 10.1007/s40263-019-00623-5. [PubMed:31004280]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
Curator comments
Peripheral and central.
General Function
Voltage-gated sodium channel activity
Specific Function
Mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a...
Gene Name
SCN2A
Uniprot ID
Q99250
Uniprot Name
Sodium channel protein type 2 subunit alpha
Molecular Weight
227972.64 Da
References
  1. Haeseler G, Foadi N, Ahrens J, Dengler R, Hecker H, Leuwer M: Tramadol, fentanyl and sufentanil but not morphine block voltage-operated sodium channels. Pain. 2006 Dec 15;126(1-3):234-44. doi: 10.1016/j.pain.2006.07.003. Epub 2006 Sep 1. [PubMed:16949748]
  2. Barakat A: Revisiting Tramadol: A Multi-Modal Agent for Pain Management. CNS Drugs. 2019 May;33(5):481-501. doi: 10.1007/s40263-019-00623-5. [PubMed:31004280]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Agonist
Curator comments
Initially stimulates then inhibits.
General Function
Transmembrane signaling receptor activity
Specific Function
Ligand-activated non-selective calcium permeant cation channel involved in detection of noxious chemical and thermal stimuli. Seems to mediate proton influx and may be involved in intracellular aci...
Gene Name
TRPV1
Uniprot ID
Q8NER1
Uniprot Name
Transient receptor potential cation channel subfamily V member 1
Molecular Weight
94955.33 Da
References
  1. Marincsak R, Toth BI, Czifra G, Szabo T, Kovacs L, Biro T: The analgesic drug, tramadol, acts as an agonist of the transient receptor potential vanilloid-1. Anesth Analg. 2008 Jun;106(6):1890-6. doi: 10.1213/ane.0b013e318172fefc. [PubMed:18499628]
  2. Barakat A: Revisiting Tramadol: A Multi-Modal Agent for Pain Management. CNS Drugs. 2019 May;33(5):481-501. doi: 10.1007/s40263-019-00623-5. [PubMed:31004280]
Kind
Protein group
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
Curator comments
Inhibits and dephosphorylates.
General Function
Voltage-gated cation channel activity
Specific Function
NMDA receptor subtype of glutamate-gated ion channels with high calcium permeability and voltage-dependent sensitivity to magnesium. Mediated by glycine. This protein plays a key role in synaptic p...

Components:
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:15845694]
  2. Barakat A: Revisiting Tramadol: A Multi-Modal Agent for Pain Management. CNS Drugs. 2019 May;33(5):481-501. doi: 10.1007/s40263-019-00623-5. [PubMed:31004280]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Stimulator
General Function
Purine nucleoside binding
Specific Function
Receptor for adenosine. The activity of this receptor is mediated by G proteins which inhibit adenylyl cyclase.
Gene Name
ADORA1
Uniprot ID
P30542
Uniprot Name
Adenosine receptor A1
Molecular Weight
36511.325 Da
References
  1. Sawynok J, Reid AR, Liu J: Spinal and peripheral adenosine A(1) receptors contribute to antinociception by tramadol in the formalin test in mice. Eur J Pharmacol. 2013 Aug 15;714(1-3):373-8. doi: 10.1016/j.ejphar.2013.07.012. Epub 2013 Jul 16. [PubMed:23872384]
  2. Barakat A: Revisiting Tramadol: A Multi-Modal Agent for Pain Management. CNS Drugs. 2019 May;33(5):481-501. doi: 10.1007/s40263-019-00623-5. [PubMed:31004280]
Kind
Protein group
Organism
Humans
Pharmacological action
Yes
Actions
Stimulator
General Function
Thioesterase binding
Specific Function
Alpha-2 adrenergic receptors mediate the catecholamine-induced inhibition of adenylate cyclase through the action of G proteins. The rank order of potency for agonists of this receptor is oxymetazo...

Components:
References
  1. Barakat A: Revisiting Tramadol: A Multi-Modal Agent for Pain Management. CNS Drugs. 2019 May;33(5):481-501. doi: 10.1007/s40263-019-00623-5. [PubMed:31004280]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
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...
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da
References
  1. Grond S, Sablotzki A: Clinical pharmacology of tramadol. Clin Pharmacokinet. 2004;43(13):879-923. [PubMed:15509185]
  2. Flockhart Table of Drug Interactions [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
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 react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Subrahmanyam V, Renwick AB, Walters DG, Young PJ, Price RJ, Tonelli AP, Lake BG: Identification of cytochrome P-450 isoforms responsible for cis-tramadol metabolism in human liver microsomes. Drug Metab Dispos. 2001 Aug;29(8):1146-55. [PubMed:11454734]
  2. Grond S, Sablotzki A: Clinical pharmacology of tramadol. Clin Pharmacokinet. 2004;43(13):879-923. [PubMed:15509185]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
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 un...
Gene Name
CYP2B6
Uniprot ID
P20813
Uniprot Name
Cytochrome P450 2B6
Molecular Weight
56277.81 Da
References
  1. Subrahmanyam V, Renwick AB, Walters DG, Young PJ, Price RJ, Tonelli AP, Lake BG: Identification of cytochrome P-450 isoforms responsible for cis-tramadol metabolism in human liver microsomes. Drug Metab Dispos. 2001 Aug;29(8):1146-55. [PubMed:11454734]
  2. Grond S, Sablotzki A: Clinical pharmacology of tramadol. Clin Pharmacokinet. 2004;43(13):879-923. [PubMed:15509185]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Steroid binding
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform glucuronidates bilirubin IX-alpha to form both the...
Gene Name
UGT1A1
Uniprot ID
P22309
Uniprot Name
UDP-glucuronosyltransferase 1-1
Molecular Weight
59590.91 Da
References
  1. Williams JA, Hyland R, Jones BC, Smith DA, Hurst S, Goosen TC, Peterkin V, Koup JR, Ball SE: Drug-drug interactions for UDP-glucuronosyltransferase substrates: a pharmacokinetic explanation for typically observed low exposure (AUCi/AUC) ratios. Drug Metab Dispos. 2004 Nov;32(11):1201-8. doi: 10.1124/dmd.104.000794. Epub 2004 Aug 10. [PubMed:15304429]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
References
  1. Vazzana M, Andreani T, Fangueiro J, Faggio C, Silva C, Santini A, Garcia ML, Silva AM, Souto EB: Tramadol hydrochloride: pharmacokinetics, pharmacodynamics, adverse side effects, co-administration of drugs and new drug delivery systems. Biomed Pharmacother. 2015 Mar;70:234-8. doi: 10.1016/j.biopha.2015.01.022. Epub 2015 Feb 7. [PubMed:25776506]

Drug created on June 13, 2005 07:24 / Updated on November 19, 2019 12:32