General
Preferred name
TRAMADOL
Synonyms
TRAMADOL HYDROCHLORIDE ()
Rel-Tramadol ()
(R,R)-TRAMADOL ()
cis-Tramadol-d6 (hydrochloride) ()
cis-Tramadol (hydrochloride ()
cis-Tramadol-13C-d3 (hydrochloride) (CRM) ()
P&D ID
PD010176
CAS
148229-78-1
194602-08-9
53611-16-8
27203-92-5
103-90-2
36282-47-0
123154-38-1
Tags
natural product
drug
available
Approved by
PMDA
FDA
First approval
1995
Drug indication
Pain
Drug Status
approved
Structure
Probe scores
P&D probe-likeness score
[[ v.score ]]%
Structure formats
[[ format ]]
[[ compound[format === 'MOL' ? 'molblock' : format.toLowerCase()] ]]
Description
(extracted from source data)
MOA Tramadol has a dual action of pain relief by acting as both a central opiate agonist and a central nervous system reuptake inhibitor of norepinephrine and serotonin. (+)-Tramadol and its O-desmethyl metabolite (M1) are selective and weak mu receptor agonist which in order, alter the release of nociceptive neurotransmitters. From these two molecules, the metabolite M1 metabolite has 300 times more affinity for this receptor while (+)-tramadol also inhibits serotonin reuptake. On the other hand, (-)-tramadol inhibits norepinephrine reuptake.[A173980] Other than this major mechanism of action, tramadol is known and fully studied due to its inhibitory activity against alpha2-adrenoreceptors, neurokinin 1 receptors, and muscarinic receptors as well as the inhibition of ion channels via nicotinic acetylcholine receptor and N-methyl-D-aspartate receptor.[A173989]
INDICATION Tramadol is approved for the management of moderate to severe pain in adults.[FDA label] As an off-label indication, tramadol has been investigated to be used for the treatment of premature ejaculation.[A173986]
ROE 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.[A173980] Approximately 30% of the dose is excreted in the urine as unchanged drug, whereas 60% of the dose is excreted as metabolites.[A174010]
HALF-LIFE Tramadol reported a half-life of 5-6 hours while the M1 metabolite presents a half-life of 8 hours.[A173980]
TOXICITY The reported LD50 for tramadol, when administered orally in mice, is 350 mg/kg.[A174010] Overdose can be observed as a coma or stupor driven from somnolence, constricted pupils, seizures, respiratory depression, bradycardia, hypotension, cardiac arrest, and death. In case of overdose, re-establish patient airway and institute assisted or controlled ventilation. In presence of cardiac arrest or arrhythmias, it might be needed the use of cardiac massage or defibrillation.[FDA label] 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.[FDA label]
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. The main metabolic pathways are marked by two pathways; the first one, marked by the generation of O-desmethyl-tramadol (M1), which is pharmacologically active, is catalyzed by CYP2D6 while CYP3A4 and while the second pathway, performed by CYP2B6 facilitates the biotransformation of tramadol to N-desmethyl-tramadol.[A173980] After the initial metabolic passage of O-demethylation, there have been identified the metabolites M2 and M5 as main metabolites of this initial route.[A173980]
ABSORPTION Oral administration of a dose of 100 mg of racemic tramadol has been shown to present a very rapid absorption and distribution. The reported peak concentration of 0.31 mg/L is reached after only 2 hours of the administration.[A173980] The bioavailability of tramadol has ranged from 75 to 90% depending on the tested individual and this bioavailability does not change according to any diet.[A173989]
PHARMACODYNAMICS Tramadol inhibits the descending pain pathways at the spinal level.[A173983] There are reports supporting the fact that tramadol activity goes beyond the inhibition of opioid receptors. In this reports the administration of [naloxone] only reduced the activity of tramadol by 30%. Those reports also indicate that the inhibition of metabolic enzymes, used for the generation of M1 which has a very high affinity for opioids, does not affect tramadol-induced analgesia.[A174007]; ; The inhibition of neurotransmitters by both tramadol enantiomers has been shown to enhance the inhibitory descending pathways associated with pain transmission in the CNS.[A173980] At the same time, it presents local anesthetic properties by blocking potassium channels[A173983] and its secondary mechanisms of action are thought to increase the activity of endogenous inhibitory control and decrease pain transmission which would explain the central analgesic effects of tramadol.[A173989]; ; From the racemic form, the (+)-tramadol seems to be more effective but less tolerated if administered alone. This indicates the importance of having the racemic mix in order to have the most optimal results. The effect of this racemic mix is compared to be of about 20% of the effect of morphine.[L5128]
MOA Tramadol has a dual action of pain relief by acting as both a central opiate agonist and a central nervous system reuptake inhibitor of norepinephrine and serotonin. (+)-Tramadol and its O-desmethyl metabolite (M1) are selective and weak mu receptor agonist which in order, alter the release of nociceptive neurotransmitters. From these two molecules, the metabolite M1 metabolite has 300 times more affinity for this receptor while (+)-tramadol also inhibits serotonin reuptake. On the other hand, (-)-tramadol inhibits norepinephrine reuptake.[A173980] ; ; Other than this major mechanism of action, tramadol is known and fully studied due to its inhibitory activity against alpha2-adrenoreceptors, neurokinin 1 receptors, and muscarinic receptors as well as the inhibition of ion channels via nicotinic acetylcholine receptor and N-methyl-D-aspartate receptor.[A173989]
INDICATION Tramadol is approved for the management of moderate to severe pain in adults.[FDA label]; ; As an off-label indication, tramadol has been investigated to be used for the treatment of premature ejaculation.[A173986]
TOXICITY The reported LD50 for tramadol, when administered orally in mice, is 350 mg/kg.[A174010] Overdose can be observed as a coma or stupor driven from somnolence, constricted pupils, seizures, respiratory depression, bradycardia, hypotension, cardiac arrest, and death. In case of overdose, re-establish patient airway and institute assisted or controlled ventilation. In presence of cardiac arrest or arrhythmias, it might be needed the use of cardiac massage or defibrillation.[FDA label]; ; 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.[FDA label]
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. The main metabolic pathways are marked by two pathways; the first one, marked by the generation of O-desmethyl-tramadol (M1), which is pharmacologically active, is catalyzed by CYP2D6 while CYP3A4 and while the second pathway, performed by CYP2B6 facilitates the biotransformation of tramadol to N-desmethyl-tramadol.[A173980] ; ; After the initial metabolic passage of O-demethylation, there have been identified the metabolites M2 and M5 as main metabolites of this initial route.[A173980]
PHARMACODYNAMICS Tramadol inhibits the descending pain pathways at the spinal level.[A173983] There are reports supporting the fact that tramadol activity goes beyond the inhibition of opioid receptors. In this reports the administration of [naloxone] only reduced the activity of tramadol by 30%. Those reports also indicate that the inhibition of metabolic enzymes, used for the generation of M1 which has a very high affinity for opioids, does not affect tramadol-induced analgesia.[A174007] The inhibition of neurotransmitters by both tramadol enantiomers has been shown to enhance the inhibitory descending pathways associated with pain transmission in the CNS.[A173980] At the same time, it presents local anesthetic properties by blocking potassium channels[A173983] and its secondary mechanisms of action are thought to increase the activity of endogenous inhibitory control and decrease pain transmission which would explain the central analgesic effects of tramadol.[A173989] From the racemic form, the (+)-tramadol seems to be more effective but less tolerated if administered alone. This indicates the importance of having the racemic mix in order to have the most optimal results. The effect of this racemic mix is compared to be of about 20% of the effect of morphine.[L5128]
Compound Sets
11
Cayman Chemical Bioactives
9001917
15919
23748
DrugCentral
2711
DrugCentral Approved Drugs
2711
DrugMAP
DMRQD04
DrugMAP Approved Drugs
DMRQD04
NCATS Inxight Approved Drugs
39J1LGJ30J
NIH Clinical Collections (NCC)
Novartis Chemogenetic Library (NIBR MoA Box)
NPC Screening Collection
Prestwick Chemical Library
ReFrame library
External IDs
55
Properties
(calculated by RDKit )
Molecular Weight
263.19
Hydrogen Bond Acceptors
3
Hydrogen Bond Donors
1
Rotatable Bonds
4
Ring Count
2
Aromatic Ring Count
1
cLogP
2.63
TPSA
32.7
Fraction CSP3
0.62
Chiral centers
2.0
Largest ring
6.0
QED
0.91
Structural alerts
0
No structural alerts detected
Related compounds
Custom attributes
(extracted from source data)
Member status
virtual
MOA
5-HT Reuptake Inhibitors
mu-Opioid Agonists
Norepinephrine Reuptake Inhibitors
Therapeutic Class
Analgesics
Source data