Tramadol

Identification

Summary

Tramadol is a centrally-acting opioid agonist and SNRI (serotonin/norepinephrine reuptake inhibitor) used for the management of moderate to severe pain in adults.

Brand Names

Conzip, Durela, Qdolo, Ralivia, Ryzolt, Seglentis, Tridural, Ultracet, Ultram, Zytram

Generic Name

Tramadol

DrugBank Accession Number

DB00193

Background

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.^22,37 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

Type

Small Molecule

Groups

Approved, Investigational

Structure

3D

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MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Tramadol (DB00193)

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Weight

Average: 263.381
Monoisotopic: 263.188529049

Chemical Formula

C₁₆H₂₅NO₂

Synonyms

• Tramadol
• Tramadolum

External IDs

• CG 315E
• CG-315E
• E-265
• E265
• ETS-6103
• ETS6103
• U-26255A

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Pharmacology

Indication

Tramadol is approved for the management of moderate to severe pain in adults.^30,37

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

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Used in combination to treat	Acute pain	Combination Product in combination with: Celecoxib (DB00482)	••••••••••••	•••••		••••••
Used in combination to manage	Acute pain	Combination Product in combination with: Acetaminophen (DB00316)	••••••••••••			••••••
Treatment of	Premature ejaculation		••• •••••
Treatment of	Severe pain		••••••••••••	•••••		••••••
Treatment of	Severe pain		••••••••••••	•••••		••••••••• ••••••

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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.³⁰

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.³⁷

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.³⁷

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.³⁷

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.³⁷

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.³⁷

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.³⁷

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.³⁷

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.³⁷

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.³⁷

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.³⁷

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.³⁰

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

Target	Actions	Organism
AMu-type opioid receptor	agonist	Humans
ASodium-dependent noradrenaline transporter	inhibitor	Humans
ASodium-dependent serotonin transporter	inhibitor	Humans
ASodium channel protein type 2 subunit alpha	inhibitor	Humans
ANMDA receptor	inhibitor	Humans
AAdenosine receptor A1	agonist	Humans
AAlpha-2 adrenergic receptors	inducer	Humans
U5-hydroxytryptamine receptor 2C	antagonist	Humans
UKappa-type opioid receptor	agonist	Humans
UDelta-type opioid receptor	agonist	Humans
UNeuronal acetylcholine receptor subunit alpha-7	antagonist	Humans
UMuscarinic acetylcholine receptor M3	antagonist	Humans
UMuscarinic acetylcholine receptor M1	antagonist	Humans
NNeurokinin 1 receptor	inhibitor	Humans
NTransient receptor potential cation channel subfamily V member 1	agonist	Humans

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.³⁷ 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.^12,30

Steady-state plasma concentrations of both tramadol and M1 are achieved within two days of dosing. There is no evidence of self-induction.³⁷ 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.^30,37 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.³⁷

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.^12,30,37

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.^30,37

Hover over products below to view reaction partners

• Tramadol
  • O-Desmethyltramadol
    • N,O-didesmethyltramadol
      • N,N,O-tridesmethyl-tramadol
    • O-Desmethyl-tramado glucuronide
  • N-Desmethyltramadol
    • N,N-didesmethyltramadol
      • N,N,O-tridesmethyl-tramadol
    • N,O-didesmethyltramadol

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.^30,37,6 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.^30,37

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.^30,37

Adverse Effects

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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.^30,37

Pathways

Pathway	Category
Tramadol Action Action Pathway	Drug action
Tramadol Metabolism Pathway	Drug metabolism

Pharmacogenomic Effects/ADRs

Interacting Gene/Enzyme	Allele name	Genotype(s)	Defining Change(s)	Type(s)	Description	Details
Cytochrome P450 2D6	CYP2D6*3	Not Available	C allele	ADR Inferred Effect	Poor 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 2D6	CYP2D6*4	Not Available	C allele	ADR Inferred Effect	Poor 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 2D6	CYP2D6*5	Not Available	Whole-gene deletion	ADR Inferred Effect	Poor 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 2D6	CYP2D6*6	Not Available	1707delT	ADR Inferred Effect	Poor 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 2D6	CYP2D6*7	Not Available	2935A>C	ADR Inferred Effect	Poor 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 2D6	CYP2D6*8	Not Available	1758G>T	ADR Inferred Effect	Poor 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 2D6	CYP2D6*11	Not Available	883G>C	ADR Inferred Effect	Poor 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 2D6	CYP2D6*12	Not Available	124G>A	ADR Inferred Effect	Poor 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 2D6	CYP2D6*13	Not Available	CYP2D7/2D6 hybrid gene structure	ADR Inferred Effect	Poor 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 2D6	CYP2D6*14A	Not Available	1758G>A	ADR Inferred Effect	Poor 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 2D6	CYP2D6*15	Not Available	137insT, 137_138insT	ADR Inferred Effect	Poor 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 2D6	CYP2D6*19	Not Available	2539_2542delAACT	ADR Inferred Effect	Poor 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 2D6	CYP2D6*20	Not Available	1973_1974insG	ADR Inferred Effect	Poor 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 2D6	CYP2D6*21	Not Available	2573insC	ADR Inferred Effect	Poor 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 2D6	CYP2D6*31	Not Available	-1770G>A / -1584C>G  … show all	ADR Inferred Effect	Poor 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 2D6	CYP2D6*36	Not Available	100C>T / -1426C>T  … show all	ADR Inferred Effect	Poor 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 2D6	CYP2D6*38	Not Available	2587_2590delGACT	ADR Inferred Effect	Poor 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 2D6	CYP2D6*40	Not Available	1863_1864ins(TTT CGC CCC)2	ADR Inferred Effect	Poor 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 2D6	CYP2D6*42	Not Available	3259_3260insGT	ADR Inferred Effect	Poor 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 2D6	CYP2D6*44	Not Available	2950G>C	ADR Inferred Effect	Poor 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 2D6	CYP2D6*47	Not Available	100C>T / -1426C>T  … show all	ADR Inferred Effect	Poor 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 2D6	CYP2D6*51	Not Available	-1584C>G / -1235A>G  … show all	ADR Inferred Effect	Poor 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 2D6	CYP2D6*56	Not Available	3201C>T	ADR Inferred Effect	Poor 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 2D6	CYP2D6*57	Not Available	100C>T / 310G>T  … show all	ADR Inferred Effect	Poor 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 2D6	CYP2D6*62	Not Available	4044C>T	ADR Inferred Effect	Poor 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 2D6	CYP2D6*68A	Not Available	-1426C>T / -1235A>G  … show all	ADR Inferred Effect	Poor 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 2D6	CYP2D6*68B	Not Available	Similar but not identical switch region compared to CYP2D6*68A. Found in tandem arrangement with CYP2D6*4.	ADR Inferred Effect	Poor 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 2D6	CYP2D6*69	Not Available	2988G>A / -1426C>T  … show all	ADR Inferred Effect	Poor 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 2D6	CYP2D6*92	Not Available	1995delC	ADR Inferred Effect	Poor 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 2D6	CYP2D6*100	Not Available	-1426C>T / -1235A>G  … show all	ADR Inferred Effect	Poor 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 2D6	CYP2D6*101	Not Available	-1426C>T / -1235A>G  … show all	ADR Inferred Effect	Poor 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 2D6	CYP2D6*10	Not Available	100C>T (but also appears in other variants)	ADR pgx review	This 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.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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1,2-Benzodiazepine	The risk or severity of CNS depression can be increased when 1,2-Benzodiazepine is combined with Tramadol.
Abacavir	Tramadol may decrease the excretion rate of Abacavir which could result in a higher serum level.
Abametapir	The serum concentration of Tramadol can be increased when it is combined with Abametapir.
Abatacept	The metabolism of Tramadol can be increased when combined with Abatacept.
Abiraterone	The metabolism of Tramadol can be decreased when combined with Abiraterone.

Food Interactions

• Avoid alcohol. Co-administration of alcohol may potentiate the CNS effects of tramadol.
• Take with or without food. Co-administration of food does not affect pharmacokinetics.

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Product Ingredients

Ingredient	UNII	CAS	InChI Key
Tramadol hydrochloride	9N7R477WCK	36282-47-0	PPKXEPBICJTCRU-UHFFFAOYSA-N

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International/Other Brands

Rybix (Shionogi Inc.) / Tramal (Grünenthal GmbH)

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
ConZip	Capsule, extended release	300 mg/1	Oral	Vertical Pharmaceuticals, LLC	2011-09-20	Not applicable
ConZip	Capsule, extended release	100 mg/1	Oral	Vertical Pharmaceuticals, Inc.	2011-08-31	2017-02-28
ConZip	Capsule, extended release	300 mg/1	Oral	Vertical Pharmaceuticals, Inc.	2011-08-31	2016-04-30
ConZip	Capsule, extended release	200 mg/1	Oral	Vertical Pharmaceuticals, LLC	2011-09-20	Not applicable
ConZip	Capsule, extended release	100 mg/1	Oral	Vertical Pharmaceuticals, LLC	2011-09-20	Not applicable

Generic Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Apo-tramadol	Tablet	50 mg	Oral	Apotex Corporation	2014-06-23	Not applicable
Auro-tramadol	Tablet	50 mg	Oral	Auro Pharma Inc	2019-04-11	Not applicable
Jamp Tramadol	Tablet	50 mg	Oral	Jamp Pharma Corporation	2021-04-21	Not applicable
Jamp Tramadol HCl	Tablet	50 mg	Oral	Jamp Pharma Corporation	2023-02-08	Not applicable
Mar-tramadol	Tablet	50 mg	Oral	Marcan Pharmaceuticals Inc	2019-07-18	Not applicable

Mixture Products

Name	Ingredients	Dosage	Route	Labeller	Marketing Start	Marketing End	Region	Image
Act Tramadol/acet	Tramadol hydrochloride (37.5 mg) + Acetaminophen (325 mg)	Tablet	Oral	Actavis Pharma Company	2012-05-01	2018-06-18
ACUVICTA®	Tramadol hydrochloride (37.5 mg) + Acetaminophen (325 mg)	Tablet, coated	Oral	MEGA LIFESCIENCES COLOMBIA S.A.S	2018-11-30	Not applicable
ADORLAN® FORTE	Tramadol hydrochloride (50 mg) + Diclofenac sodium (50 mg)	Tablet	Oral	Grünenthal Colombiana S.A.	2018-08-02	Not applicable
ADORLAN® TABLETAS	Tramadol hydrochloride (25 mg) + Diclofenac sodium (25 mg)	Tablet	Oral	Grünenthal Colombiana S.A.	2010-05-12	Not applicable
Ag-acet-tramadol	Tramadol hydrochloride (37.5 mg) + Acetaminophen (325 mg)	Tablet	Oral	Angita Pharma Inc.	Not applicable	Not applicable

Unapproved/Other Products

Name	Ingredients	Dosage	Route	Labeller	Marketing Start	Marketing End	Region	Image
Synapryn	Tramadol hydrochloride (5.8 g/5.8g)	Kit	Oral	California Pharmaceuticals, Llc	2017-05-01	Not applicable
Synapryn	Tramadol hydrochloride (5 g/5g)	Kit	Oral	Fusion Pharmaceuticals LLC	2009-09-14	2010-07-20
Theratramadol-60	Tramadol hydrochloride (50 mg/1) + gamma-Aminobutyric acid (100 mg/1)	Kit	Oral	Physician Therapeutics Llc	2011-05-20	Not applicable
Theratramadol-90	Tramadol hydrochloride (50 mg/1) + gamma-Aminobutyric acid (100 mg/1)	Kit	Oral	Physician Therapeutics Llc	2011-02-04	Not applicable
Topical Pain	Tramadol (0.1 g/100mL) + Diazepam (0.1 g/100mL) + Hydrocodone (0.1 g/100mL) + Ibuprofen (0.1 g/100mL)	Cream	Topical	Dr Marc's Manufacturing And Sales	2016-02-23	2018-04-17

Categories

ATC Codes

N02AJ16 — Tramadol and celecoxib

• N02AJ — Opioids in combination with non-opioid analgesics
• N02A — OPIOIDS
• N02 — ANALGESICS
• N — NERVOUS SYSTEM

N02AJ13 — Tramadol and paracetamol

• N02AJ — Opioids in combination with non-opioid analgesics
• N02A — OPIOIDS
• N02 — ANALGESICS
• N — NERVOUS SYSTEM

N02AJ14 — Tramadol and dexketoprofen

• N02AJ — Opioids in combination with non-opioid analgesics
• N02A — OPIOIDS
• N02 — ANALGESICS
• N — NERVOUS SYSTEM

N02AX02 — Tramadol

• N02AX — Other opioids
• N02A — OPIOIDS
• N02 — ANALGESICS
• N — NERVOUS SYSTEM

Drug Categories

• Agents producing tachycardia
• Agents that reduce seizure threshold
• Alcohols
• Amines
• Analgesics
• Anticholinergic Agents
• Antidepressive Agents
• Central Nervous System Agents
• Central Nervous System Depressants
• Combined Inhibitors of Serotonin/Norepinephrine Reuptake
• Cyclohexanes
• Cyclohexanols
• Cycloparaffins
• Cytochrome P-450 CYP2B6 Substrates
• Cytochrome P-450 CYP2D6 Substrates
• Cytochrome P-450 CYP3A Substrates
• Cytochrome P-450 CYP3A4 Substrates
• Cytochrome P-450 Substrates
• Dimethylamines
• Drugs that are Mainly Renally Excreted
• Muscarinic Antagonists
• Narcotics
• Nervous System
• NMDA Receptor Antagonists
• Opiate Agonists
• Opioid Agonist
• Opioids
• Peripheral Nervous System Agents
• Sensory System Agents
• Serotonergic Drugs Shown to Increase Risk of Serotonin Syndrome
• Serotonin 5-HT2 Receptor Antagonists
• Serotonin 5-HT2C Receptor Antagonists
• Serotonin Agents
• Serotonin Modulators
• Serotonin Receptor Antagonists
• UGT1A1 Substrates

Classification

Not classified

Affected organisms

• Humans and other mammals

Chemical Identifiers

UNII

39J1LGJ30J

CAS number

27203-92-5

InChI Key

TVYLLZQTGLZFBW-UHFFFAOYSA-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

IUPAC Name

2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexan-1-ol

SMILES

COC1=CC=CC(=C1)C1(O)CCCCC1CN(C)C

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. [Article]
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. [Article]
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. [Article]
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. [Article]
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. [Article]
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. [Article]
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. [Article]
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. [Article]
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. [Article]
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. [Article]
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. [Article]
12. Grond S, Sablotzki A: Clinical pharmacology of tramadol. Clin Pharmacokinet. 2004;43(13):879-923. [Article]
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. [Article]
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. [Article]
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. [Article]
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. [Article]
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. [Article]
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. [Article]
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. [Article]
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. [Article]
21. Dean L: Tramadol Therapy and CYP2D6 Genotype . [Article]
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. [Article]
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. [Article]
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. [Article]
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. [Article]
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. [Article]
27. Khan AH, Rasaily D: Tramadol use in premature ejaculation: daily versus sporadic treatment. Indian J Psychol Med. 2013 Jul;35(3):256-9. doi: 10.4103/0253-7176.119477. [Article]
28. FDA approvals [Link]
29. WHO reports [Link]
30. FDA Approved Drug Products: Ultram (tramadol hydrochloride) oral tablets [Link]
31. FDA Approved Drug Products: QDOLO (tramadol hydrochloride) oral solution C-IV [Link]
32. FDA Approved Drug Products: SEGLENTIS (celecoxib and tramadol hydrochloride) tablets, for oral use, C-IV [Link]
33. DailyMed: Tramadol and Acetaminophen Oral Tablet [Link]
34. DailyMed: Tramadol Oral Capsule, Extended Release [Link]
35. DailyMed: Tramadol Oral Tablet, Extended Release [Link]
36. Health Canada Approved Drug Proucts: APO-TRAMADOL (Tramadol) tablet for oral use [Link]
37. Health Canada Monograph - Tramadol [File]

External Links

Human Metabolome Database

HMDB0259401

KEGG Drug

D08623

KEGG Compound

C07153

PubChem Compound

33741

PubChem Substance

46506256

ChemSpider

5322

BindingDB

50176259

RxNav

10689

ChEBI

75722

ChEMBL

CHEMBL1237044

ZINC

ZINC000000000853

Therapeutic Targets Database

DAP000140

PharmGKB

PA451735

RxList

RxList Drug Page

Drugs.com

Drugs.com Drug Page

Wikipedia

Tramadol

MSDS

Download (74.7 KB)

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
4	Completed	Basic Science	Acute Pain / Osseointegrated Dental Implantation	1
4	Completed	Health Services Research	Ankylosing Spondylitis (AS)	1
4	Completed	Other	Coagulation Disorder / Platelets Dysfunction / Therapeutic Agent Toxicity	1
4	Completed	Other	Healthy Subjects (HS)	1
4	Completed	Other	Nasal Polyps	1

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

Form	Route	Strength
Injection, solution	Parenteral	50 mg/mL
Injection	Intramuscular; Intravenous	50 mg/ml
Tablet, extended release	Oral	300 MG
Tablet, extended release	Oral	400 MG
Tablet, orally disintegrating	Oral	50 mg
Tablet, film coated	Oral
Capsule, coated	Oral	100 mg
Tablet, coated	Oral	150 mg
Tablet	Oral	45.000 mg
Solution	Oral	10.00 mg
Tablet	Oral	325.00 mg
Tablet	Oral	25.000 mg
Injection
Capsule, coated	Oral
Solution	Intramuscular; Intravenous
Solution / drops	Oral	100 MG/ML
Tablet, soluble		50 MG
Tablet, effervescent	Oral
Capsule, extended release	Oral	100 mg/1
Capsule, extended release	Oral	200 mg/1
Capsule, extended release	Oral	300 mg/1
Solution	Oral	100.00 mg
Solution	Parenteral	100.000 mg
Capsule	Oral	50.0 mg
Tablet, orally disintegrating	Oral
Injection, solution	Parenteral	100 mg/2mL
Tablet	Oral	75.000 mg
Tablet, multilayer	Oral
Capsule, extended release	Oral	100 mg
Capsule, extended release	Oral	200 mg
Capsule, extended release	Oral	300 mg
Tablet, extended release	Oral	100.00 mg
Solution	Oral	10.00 g
Granule	Oral
Solution	Intramuscular; Intravenous; Parenteral; Subcutaneous	100 mg
Syrup	Oral
Solution	Oral
Capsule	Oral	50 MG
Injection, solution	Intramuscular; Intravenous	100 mg
Injection, solution	Intramuscular; Intravenous	50 mg
Solution / drops	Oral	10 %
Tablet	Oral	100 MG
Capsule	Oral	50.000 mg
Tablet	Oral	100.000 mg
Tablet, film coated	Oral	100 mg
Tablet, film coated	Oral	150 mg
Tablet, film coated	Oral	200 mg
Granule, for solution	Oral
Solution	Intravenous	100.00 mg
Injection	Intramuscular; Intravenous; Subcutaneous	100 mg/2ml
Tablet, extended release	Oral
Solution	Parenteral	100.00 mg
Solution	Intravenous
Tablet, effervescent	Oral
Capsule	Oral	50.00 mg
Solution	Parenteral
Injection, solution	Intramuscular; Intravenous	50 MG/ML
Capsule	Oral	100.000 mg
Suppository	Rectal	100.00 mg
Solution	Oral	5 mg/1mL
Injection	Intramuscular; Intravenous	100 mg/2ml
Solution	Intramuscular
Tablet, delayed release	Oral	200 mg/1
Solution	Oral	10.000 mg
Tablet	Sublingual
Tablet, film coated	Oral	25 mg
Tablet	Oral
Kit	Oral	5 g/5g
Kit	Oral	5.8 g/5.8g
Capsule, extended release	Oral	150 MG
Solution	Intravenous	50.000 mg
Cream	Topical
Solution	Oral	10 g
Capsule, extended release	Oral
Injection, solution	Intramuscular; Intravenous; Subcutaneous	100 mg
Injection, solution	Parenteral
Capsule	Oral	150 mg
Capsule	Oral	200 mg
Solution	Parenteral	50.000 mg
Injection, solution	Intramuscular; Intravenous; Subcutaneous	100 mg/2ml
Injection, solution	Intramuscular; Intravenous; Subcutaneous	50 mg/ml
Capsule	Oral	100 mg
Injection	Parenteral	50 MG/ML
Injection, solution	Parenteral	100 MG
Capsule, liquid filled	Oral
Capsule, coated	Oral	5000000 mg
Solution	Intramuscular; Intravenous	50 mg
Injection, solution	Parenteral	50 MG
Solution	Oral	100 MG/ML
Capsule, coated	Oral	50 mg
Solution	Intramuscular; Intravenous; Subcutaneous	100 mg
Solution	Intramuscular	100 mg
Solution	Oral	113.9 mg
Solution	Oral	10000000 mg
Capsule, liquid filled	Oral	50 mg
Solution	Intramuscular; Intravenous	5000000 mg
Solution	Intramuscular; Intravenous; Subcutaneous	50 mg
Solution	Intramuscular; Intravenous	100 mg
Injection	Intramuscular; Intravenous; Subcutaneous	100 mg
Tablet, effervescent	Oral	50 MG
Capsule	Oral
Injection	Parenteral
Tablet	Oral	50 mg/1
Solution	Oral	100 mg
Capsule	Oral	150 mg/1
Capsule, coated, extended release	Oral	150 mg/1
Capsule, extended release	Oral	150 mg/1
Tablet	Oral	50 mg/50mg
Tablet, coated	Oral	100 mg/1
Tablet, coated	Oral	200 mg/1
Tablet, coated	Oral	25 mg/1
Tablet, film coated	Oral	50 mg/1
Tablet, film coated, extended release	Oral	100 mg/1
Tablet, film coated, extended release	Oral	200 mg/1
Tablet, film coated, extended release	Oral	300 mg/1
Tablet, film coated	Oral
Capsule, extended release	Not applicable	100 mg/1
Capsule, extended release	Not applicable	150 mg/1
Capsule, extended release	Not applicable	200 mg/1
Capsule, extended release	Not applicable	300 mg/1
Capsule	Oral	100 mg/1
Capsule	Oral	200 mg/1
Capsule	Oral	300 mg/1
Tablet, extended release	Oral	50 MG
Injection	Parenteral	100 MG
Capsule, extended release	Oral	50 MG
Tablet, effervescent	Oral	100 MG
Solution	Parenteral	50 mg
Injection, solution		100 MG/2ML
Injection, solution		50 MG/ML
Tablet, extended release	Oral	150 MG
Tablet, extended release	Oral	200 MG
Injection, solution		50 MG/1ML
Tablet	Oral	150 mg
Tablet	Oral	200 mg
Tablet, extended release	Oral	100 mg
Tablet, film coated, extended release	Oral	100 mg
Tablet, film coated, extended release	Oral	150 mg
Tablet, film coated, extended release	Oral	200 mg
Kit	Oral
Solution	Intramuscular; Intravenous; Subcutaneous
Capsule, gelatin coated	Oral	50 mg
Injection, solution	Intramuscular; Intravenous; Subcutaneous
Solution / drops	Oral
Tablet	Oral	150.00 mg
Tablet, film coated	Oral	50 MG
Tablet, coated	Oral	100 mg
Tablet, coated	Oral	200 mg
Injection	Parenteral	50 MG
Tablet	Oral	91.67 mg
Capsule	Oral
Solution	Intravenous	100.000 mg
Tablet	Oral
Tablet, coated	Oral
Tablet, film coated	Oral	325 mg
Tablet, coated	Oral	50 mg/201
Tablet, coated	Oral	50 mg/1
Tablet, orally disintegrating	Oral	50 mg/1
Tablet	Oral	100 mg/1
Tablet, extended release	Oral	100 mg/1
Tablet, extended release	Oral	200 mg/1
Tablet, extended release	Oral	300 mg/1
Injection, solution
Suppository	Rectal	100 MG
Solution	Oral	100.000 mg
Solution	Parenteral	100 mg
Tablet, extended release	Oral	75 mg
Syrup		500 mg/5ml
Tablet	Oral	50 mg
Solution		50 mg/1ml

Prices

Unit description	Cost	Unit
Tramadol hcl powder	29.08USD	g
Ultram ER 300 mg 24 Hour tablet	10.66USD	tablet
Ultram er 300 mg tablet	10.25USD	tablet
Ultram ER 200 mg 24 Hour tablet	7.64USD	tablet
Ultram er 200 mg tablet	7.35USD	tablet
TraMADol HCl 200 mg 24 Hour tablet	6.25USD	tablet
Ultram ER 100 mg 24 Hour tablet	4.62USD	tablet
Ultram er 100 mg tablet	4.44USD	tablet
TraMADol HCl 100 mg 24 Hour tablet	3.78USD	tablet
Ultram 50 mg tablet	1.99USD	tablet
Tramadol-Acetaminophen 37.5-325 mg tablet	1.07USD	tablet
Tramadol hcl 50 mg tablet	0.7USD	tablet

DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
US5464632	No	1995-11-07	2013-03-22
CA2476201	No	2009-09-01	2023-02-21
CA2123160	No	2003-04-29	2014-05-09
US6339105	Yes	2002-01-15	2020-04-12
US6106861	No	2000-08-22	2017-12-05
US6607748	No	2003-08-19	2020-06-29
US7988998	No	2011-08-02	2023-10-27
US7858118	No	2010-12-28	2022-04-11
US11103452	No	2021-08-31	2040-09-01
US10238668	No	2019-03-26	2030-04-19
US10548909	No	2020-02-04	2030-04-19
US9012440	No	2015-04-21	2030-04-19
US8846744	No	2014-09-30	2031-06-03
US8598152	No	2013-12-03	2030-04-19
US10245276	No	2019-04-02	2030-04-19
US11478488	No	2010-04-19	2030-04-19
US11752103	No	2020-09-01	2040-09-01

Properties

State

Solid

Experimental Properties

Property	Value	Source
melting point (°C)	178-181 °C	'MSDS'
boiling point (°C)	406.6 ºC	Chemical Book
water solubility	Soluble	'MSDS'
logP	1.34	'MSDS'
pKa	9.41	'FDA label'

Predicted Properties

Property	Value	Source
Water Solubility	0.75 mg/mL	ALOGPS
logP	2.71	ALOGPS
logP	2.45	Chemaxon
logS	-2.6	ALOGPS
pKa (Strongest Acidic)	13.8	Chemaxon
pKa (Strongest Basic)	9.23	Chemaxon
Physiological Charge	1	Chemaxon
Hydrogen Acceptor Count	3	Chemaxon
Hydrogen Donor Count	1	Chemaxon
Polar Surface Area	32.7 Å2	Chemaxon
Rotatable Bond Count	4	Chemaxon
Refractivity	78.27 m3·mol-1	Chemaxon
Polarizability	30.51 Å3	Chemaxon
Number of Rings	2	Chemaxon
Bioavailability	1	Chemaxon
Rule of Five	Yes	Chemaxon
Ghose Filter	Yes	Chemaxon
Veber's Rule	Yes	Chemaxon
MDDR-like Rule	No	Chemaxon

Predicted ADMET Features

Property	Value	Probability
Human Intestinal Absorption	+	0.9924
Blood Brain Barrier	+	0.9382
Caco-2 permeable	+	0.8866
P-glycoprotein substrate	Substrate	0.6283
P-glycoprotein inhibitor I	Inhibitor	0.7807
P-glycoprotein inhibitor II	Inhibitor	0.9589
Renal organic cation transporter	Non-inhibitor	0.6398
CYP450 2C9 substrate	Non-substrate	0.7678
CYP450 2D6 substrate	Substrate	0.8919
CYP450 3A4 substrate	Substrate	0.7726
CYP450 1A2 substrate	Non-inhibitor	0.7136
CYP450 2C9 inhibitor	Non-inhibitor	0.704
CYP450 2D6 inhibitor	Inhibitor	0.6566
CYP450 2C19 inhibitor	Non-inhibitor	0.6841
CYP450 3A4 inhibitor	Non-inhibitor	0.6256
CYP450 inhibitory promiscuity	Low CYP Inhibitory Promiscuity	0.7832
Ames test	Non AMES toxic	0.7899
Carcinogenicity	Non-carcinogens	0.6663
Biodegradation	Not ready biodegradable	0.9975
Rat acute toxicity	3.0316 LD50, mol/kg	Not applicable
hERG inhibition (predictor I)	Weak inhibitor	0.6136
hERG inhibition (predictor II)	Inhibitor	0.7098

ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	splash10-0a4i-9240000000-d88e376d4789078f0d94
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	splash10-03di-0090000000-2f2e32268017807fcb78
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	splash10-0a4i-9100000000-fcd77413a4e34063bf40
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	splash10-03di-0290000000-2888090bf6ec29ea87c1
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	splash10-0a4i-9110000000-f52d3d2fc9af6f072faf
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	splash10-000j-4910000000-adf9783c96d34d4ac409
Predicted 1H NMR Spectrum	1D NMR	Not Applicable
Predicted 13C NMR Spectrum	1D NMR	Not Applicable

Chromatographic Properties

Collision Cross Sections (CCS)

Not Available

Targets

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Binding Properties

×

Property	Measurement	pH	Temperature (°C)	References
IC 50 (nM)	>10000	N/A	N/A	A27389
IC 50 (nM)	5300	N/A	N/A	A27389
IC 50 (nM)	7600	N/A	N/A	A27389 / A27390
Ki (nM)	2000	N/A	N/A	A27391
Ki (nM)	1600	N/A	N/A	A15383

Details

Binding Properties1. 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. [Article]
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. [Article]
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. [Article]
4. Grond S, Sablotzki A: Clinical pharmacology of tramadol. Clin Pharmacokinet. 2004;43(13):879-923. [Article]
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. [Article]
6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
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. [Article]
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. [Article]
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. [Article]

Binding Properties

×

Property	Measurement	pH	Temperature (°C)	References
IC 50 (nM)	790	N/A	N/A	A27389
IC 50 (nM)	3600	N/A	N/A	A27389
IC 50 (nM)	2000	N/A	N/A	A27389
IC 50 (nM)	3200	N/A	N/A	A27389
IC 50 (nM)	3861	N/A	N/A	A27390

Details

Binding Properties2. Sodium-dependent noradrenaline transporter

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. [Article]
2. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
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. [Article]
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. [Article]
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. [Article]

Binding Properties

×

Property	Measurement	pH	Temperature (°C)	References
IC 50 (nM)	4300	N/A	N/A	A27389
IC 50 (nM)	1900	N/A	N/A	A27389
IC 50 (nM)	3100	N/A	N/A	A27389
IC 50 (nM)	1100	N/A	N/A	A27389
IC 50 (nM)	1493	N/A	N/A	A27390

Details

Binding Properties3. Sodium-dependent serotonin transporter

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. [Article]
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. [Article]
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. [Article]
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. [Article]

Details4. Sodium channel protein type 2 subunit alpha

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. [Article]
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. [Article]

Details5. NMDA receptor (Protein Group)

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:

Name	UniProt ID
Glutamate receptor ionotropic, NMDA 1	Q05586
Glutamate receptor ionotropic, NMDA 2A	Q12879
Glutamate receptor ionotropic, NMDA 2B	Q13224
Glutamate receptor ionotropic, NMDA 2C	Q14957
Glutamate receptor ionotropic, NMDA 2D	O15399
Glutamate receptor ionotropic, NMDA 3A	Q8TCU5
Glutamate receptor ionotropic, NMDA 3B	O60391

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. [Article]
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. [Article]

Details6. Adenosine receptor A1

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Agonist

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. [Article]
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. [Article]
3. Abdalla HB, Napimoga MH, de Macedo Maganin AG, Lopes AH, Cunha TM, Gill HS, Clemente-Napimoga JT: The role of adenosine A1 receptor in the peripheral tramadol's effect in the temporomandibular joint of rats. Int Immunopharmacol. 2021 Aug;97:107680. doi: 10.1016/j.intimp.2021.107680. Epub 2021 Apr 28. [Article]

Details7. Alpha-2 adrenergic receptors (Protein Group)

Kind

Protein group

Organism

Humans

Pharmacological action

Yes

Actions

Inducer

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:

Name	UniProt ID
Alpha-2A adrenergic receptor	P08913
Alpha-2B adrenergic receptor	P18089
Alpha-2C adrenergic receptor	P18825

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. [Article]
2. Abdalla HB, Napimoga MH, de Macedo Maganin AG, Lopes AH, Cunha TM, Gill HS, Clemente-Napimoga JT: The role of adenosine A1 receptor in the peripheral tramadol's effect in the temporomandibular joint of rats. Int Immunopharmacol. 2021 Aug;97:107680. doi: 10.1016/j.intimp.2021.107680. Epub 2021 Apr 28. [Article]

Details8. 5-hydroxytryptamine receptor 2C

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. [Article]
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. [Article]

Binding Properties

×

Property	Measurement	pH	Temperature (°C)	References
Ki (nM)	14	N/A	N/A	A15383

Details

Binding Properties9. Kappa-type opioid receptor

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. [Article]
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. [Article]

Details10. Delta-type opioid receptor

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. [Article]
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. [Article]

Details11. Neuronal acetylcholine receptor subunit alpha-7

Kind

Protein

Organism

Humans

Pharmacological action

Unknown

Actions

Antagonist

General Function

Toxic substance binding

Specific Function

After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane. The cha...

Gene Name

CHRNA7

Uniprot ID

P36544

Uniprot Name

Neuronal acetylcholine receptor subunit alpha-7

Molecular Weight

56448.925 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. [Article]
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. [Article]

Details12. Muscarinic acetylcholine receptor M3

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. [Article]
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. [Article]
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. [Article]

Details13. Muscarinic acetylcholine receptor M1

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. [Article]
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. [Article]

Details14. Neurokinin 1 receptor

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. [Article]

Details15. Transient receptor potential cation channel subfamily V member 1

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. [Article]
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. [Article]

×

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Drug created at June 13, 2005 13:24 / Updated at February 13, 2024 02:57