TRAMADOL

Details

Stereochemistry	RACEMIC
Molecular Formula	C16H25NO2
Molecular Weight	263.3752
Optical Activity	( + / - )
Defined Stereocenters	2 / 2
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

COC1=CC=CC(=C1)[C@@]2(O)CCCC[C@@H]2CN(C)C

InChI

InChIKey=TVYLLZQTGLZFBW-ZBFHGGJFSA-N

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

HIDE SMILES / InChI

Molecular Formula	C16H25NO2
Molecular Weight	263.3752
Charge	0
Count

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	2 / 2
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/020281s036s038lbl.pdf
Curator's Comment: description was created based on several sources, including https://www.drugs.com/tramadol.html | https://www.drugbank.ca/drugs/DB00193 | http://reference.medscape.com/drug/ultram-er-tramadol-343324 |

Tramadol (sold under the brand name Ultram) is a narcotic analgesic proposed for moderate to severe pain. Tramadol and its O-desmethyl metabolite (M1) are selective, weak OP3-receptor agonists. Opiate receptors are coupled with G-protein receptors and function as both positive and negative regulators of synaptic transmission via G-proteins that activate effector proteins. As the effector system is adenylate cyclase and cAMP located at the inner surface of the plasma membrane, opioids decrease intracellular cAMP by inhibiting adenylate cyclase. Subsequently, the release of nociceptive neurotransmitters such as substance P, GABA, dopamine, acetylcholine, and noradrenaline is inhibited. The analgesic properties of Tramadol can be attributed to norepinephrine and serotonin reuptake blockade in the CNS, which inhibits pain transmission in the spinal cord. The (+) enantiomer has the higher affinity for the OP3 receptor and preferentially inhibits serotonin uptake and enhances serotonin release. The (-) enantiomer preferentially inhibits norepinephrine reuptake by stimulating alpha(2)-adrenergic receptors. Tramadol is used primarily to treat mild-severe pain, both acute and chronic. Its analgesic effects take about one hour to come into effect and 2 h to 4 h to peak after oral administration with an immediate-release formulation. On a dose-by-dose basis, tramadol has about one-tenth the potency of morphine and is approximately equally potent when compared to pethidine and codeine. The most common adverse effects of tramadol include nausea, dizziness, dry mouth, indigestion, abdominal pain, vertigo, vomiting, constipation, drowsiness, and headache. Compared to other opioids, respiratory depression and constipation are considered less of a problem with tramadol.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Mu opioid receptor 221 Target ID: CHEMBL233 Sources: https://www.ncbi.nlm.nih.gov/pubmed/24900459	Agonist 2678	1300.0 nM [EC50]
Kappa opioid receptor 108 Target ID: CHEMBL237 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19027293	Agonist 2678	14.0 nM [Ki]
Delta opioid receptor 77 Target ID: CHEMBL236 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19027293	Agonist 2678	9.4 nM [Ki]
Serotonin transporter 178 Target ID: CHEMBL228 Sources: https://www.ncbi.nlm.nih.gov/pubmed/18242987	Inhibitor 8297	1493.0 nM [IC50]
Norepinephrine transporter 191 Target ID: CHEMBL222 Sources: https://www.ncbi.nlm.nih.gov/pubmed/18242987	Inhibitor 8297	3861.0 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Mild-severe pain 3 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/020281s036s038lbl.pdf	Primary	Approved 8429	ULTRAM Approved Use Tramadol hydrochloride extended-release tablets are indicated for the management of moderate to moderately severe chronic pain in adults who require around-the-clock treatment of their pain for an extended period of time. Launch Date 1995
Osteoarthritis 157 Sources: https://clinicaltrials.gov/ct2/show/NCT01063842	Primary	Phase IV 63	ULTRAM Approved Use Tramadol hydrochloride extended-release tablets are indicated for the management of moderate to moderately severe chronic pain in adults who require around-the-clock treatment of their pain for an extended period of time. Launch Date 1995
Low back pain 22 Sources: https://clinicaltrials.gov/ct2/show/NCT01843660	Primary	Phase IV 63	ULTRAM Approved Use Tramadol hydrochloride extended-release tablets are indicated for the management of moderate to moderately severe chronic pain in adults who require around-the-clock treatment of their pain for an extended period of time. Launch Date 1995

C_max

Value	Dose	Co-administered	Analyte	Population
332 ng/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022370s000lbl.pdf	200 mg 1 times / day steady-state, oral dose: 200 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		TRAMADOL plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: FASTED
70 ng/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022370s000lbl.pdf	200 mg 1 times / day steady-state, oral dose: 200 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		O-DESMETHYLTRAMADOL plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: FASTED

AUC

Value	Dose	Co-administered	Analyte	Population
5678 ng × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022370s000lbl.pdf	200 mg 1 times / day steady-state, oral dose: 200 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		TRAMADOL plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: FASTED
1319 ng × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022370s000lbl.pdf	200 mg 1 times / day steady-state, oral dose: 200 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		O-DESMETHYLTRAMADOL plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: FASTED

F_unbound

Value	Dose	Co-administered	Analyte	Population
80% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022370s000lbl.pdf	200 mg 1 times / day steady-state, oral dose: 200 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		TRAMADOL plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: FASTED

Doses

Dose	Population	Adverse events
600 mg 1 times / day multiple, oral Dose: 600 mg, 1 times / day Route: oral Route: multiple Dose: 600 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/28881493/	healthy, 28 n = 8 Health Status: healthy Age Group: 28 Sex: M+F Population Size: 8 Sources: https://pubmed.ncbi.nlm.nih.gov/28881493/	Other AEs: Nausea, Vomiting... Other AEs: Nausea (75%) Vomiting (50%) Headache (25%) Dizziness postural (25%) Vertigo (25%) Dizziness (12.5%) Pruritus (37.5%) Decreased appetite (25%) Hot flush (12.5%) Sources: https://pubmed.ncbi.nlm.nih.gov/28881493/
1500 mg single, oral (median) Dose: 1500 mg Route: oral Route: single Dose: 1500 mg Sources: https://pubmed.ncbi.nlm.nih.gov/31208192/	unknown, 41 n = 359 Health Status: unknown Age Group: 41 Sex: M+F Population Size: 359 Sources: https://pubmed.ncbi.nlm.nih.gov/31208192/	Other AEs: Seizure, Nausea and vomiting... Other AEs: Seizure (14.5%) Nausea and vomiting (53.5%) Tachycardia (4.8%) Hypertension (mild, 38.4%) Arrhythmia (5.3%) Sources: https://pubmed.ncbi.nlm.nih.gov/31208192/
300 mg 1 times / day multiple, oral Recommended Dose: 300 mg, 1 times / day Route: oral Route: multiple Dose: 300 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022370s000lbl.pdf	unhealthy, adult n = 1054 Health Status: unhealthy Condition: osteoarthritis Age Group: adult Population Size: 1054 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022370s000lbl.pdf	Other AEs: Dry mouth, Sweating... Other AEs: Dry mouth (13.1%) Sweating (6.7%) Asthenia (8.6%) Pruritus (7.3%) Arthralgia (5%) Headache (19%) Nausea (25.1%) Somnolence (16.1%) Dizziness (13.6%) Constipation (21.3%) Vomiting (9.3%) Anorexia (5.7%) Insomnia (5%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022370s000lbl.pdf

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1737		substrate 1217	inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
	CYP2B6 664 P-gp 1537

Drug as victim

Target	Modality	Activity	Clinical evidence
P-gp 1537	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/23331900/	unlikely
CYP2B6 664	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022370s000lbl.pdf#page=9 Page: 9.0	yes
CYP2D6 1217	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022370s000lbl.pdf#page=5 Page: 5.0	yes	likely (co-administration study) Comment: Coadministration of quinidine, a selective inhibitor of CYP2D6, with tramadol ER resulted in a 50 60% increase in tramadol exposure; pharmacogenomic studies were also conducted: rapid conversion to active metabolite results in higher than expected serum M1 levels. Individuals who are ultra-rapid metabolizers should not use drug. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022370s000lbl.pdf#page=5 Page: 5.0
CYP3A4 1737	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022370s000lbl.pdf#page=5 Page: 5.0	yes	likely (co-administration study) Comment: The concomitant use of ULTRAM with cytochrome P450 3A4 inhibitors, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir) or discontinuation of a cytochrome P450 3A4 inducer such as rifampin, carbamazepine, and phenytoin, may result in an increase in tramadol plasma concentrations; Concomitant administration of tramadol immediate-release tablets with cimetidine, a weak CPY3A4 inhibitor, does not result in clinically significant changes in tramadol pharmacokinetics; Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022370s000lbl.pdf#page=5 Page: 5.0

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1647	inhibitor 1626 Sources: https://accp1.onlinelibrary.wiley.com/doi/pdf/10.1002/cpdd.473#page=9 Page: 9.0

Sourcing

Vendor/Aggregator	ID	URL
3B Scientific (Wuhan) Corp	3B3-032272	http://www.3bsc.com/index/pro_info.php?id=53536
AHH Chemical co.,ltd	MT-22547	http://www.ahhchemical.com/product/MT-22547.html
Achemo Scientific Limited	AC-14871	http://www.achemo.com/product_view.asp?ID=4761
Acorn PharmaTech	ACN-038323	http://www.acornpharmatech.com/
Aurora Fine Chemicals LLC	A17.944.638	http://online.aurorafinechemicals.com/info?ID=A17.944.638
Avantor Inc	100568-126	https://us.vwr.com/store/catalog/product.jsp?catalog_number=100568-126
Capot Chemical	20420	http://www.capotchem.com/en/20420.htm
Capot Chemical	PubChem20420	http://www.capotchem.com/en/20420.htm
ChemMol	99056526	http://www.chemmol.com/chemmol/99056526.html
Chiralblock Biosciences	CB10321	http://www.chiralblock.com/products/27203-92-5.html
Finetech	FT-0675346	http://www.finetechnology-ind.com/product/All%20product%20List/123154-38-1.html
Finetech	FT-0604438	http://www.finetechnology-ind.com/product/All%20product%20List/181289-58-7.html
MuseChem	R001869	https://www.musechem.com/product/R001869.html
OChem	30414	http://www.ocheminc.com/index.php?act=psearch&pid=914T774
Sigma-Aldrich	PH003072_ALDRICH	https://www.sigmaaldrich.com/catalog/product/aldrich/ph003072
Smolecule	S589647	https://www.smolecule.com/products/s589647
Yuhao Chemical	RT7364	http://www.chemyuhao.com/123154-38-1.html
mcule	MCULE-8198453745	https://mcule.com/MCULE-8198453745/

PubMed

Title	Date	PubMed
WHO Expert Committee on Drug Dependence. Thirty-second report.	2001	11851193
Interactions between systemic analgesics.	2001	11799572
Control of non-malignant chronic pain conditions in Japan and the possible future role of tramadol.	2001	11798225
Postanaesthetic shivering: epidemiology, pathophysiology, and approaches to prevention and management.	2001	11772130
Transition between anesthesia and post-operative analgesia: relevance of intra-operative administration of analgesics.	2001	11732383
Single-dose dipyrone for acute postoperative pain.	2001	11687057
Use of remifentanil in combination with desflurane or propofol for ambulatory oral surgery.	2001	11534310
Nalbuphine by PCA-pump for analgesia following hysterectomy: bolus application versus continuous infusion with bolus application.	2001	11465987
Analgesic efficacy of tramadol 2 mg kg(-1) for paediatric day-case adenoidectomy.	2001 Apr	11573636
[Clinical remission of an HLA B27-positive sacroiliitis on vegan diet].	2001 Aug	11574747
Efficacy and safety of patient-controlled opioid analgesia for acute postoperative pain. A quantitative systematic review.	2001 Aug	11472277
Identification of cytochrome P-450 isoforms responsible for cis-tramadol metabolism in human liver microsomes.	2001 Aug	11454734
Nefopam reduces thermal hypersensitivity in acute and postoperative pain models in the rat.	2001 Dec	11735363
Analgesic efficacy of tramadol if coadministered with ondansetron.	2001 Dec	11726465
Plasma glucose-lowering effect of tramadol in streptozotocin-induced diabetic rats.	2001 Dec	11723065
Direct chiral assay of tramadol and detection of the phase II metabolite O-demethyl tramadol glucuronide in human urine using capillary electrophoresis with laser-induced native fluorescence detection.	2001 Dec 5	11817307
Pharmacokinetics of enantiomers of trans-tramadol and its active metabolite, trans-O-demethyltramadol, in human subjects.	2001 Jan	11730570
Association of Dental Anaesthetists. Summer Scientific Meeting Stirling, Scotland 8-9 June, 2001. ADA meeting report.	2001 Jul	11862652
[Analysis of prehospital analgesia administered to victims with traumatic injuries].	2001 Jul-Aug	11586642
A comparison of tramadol, amitriptyline, and meperidine for postepidural anesthetic shivering in parturients.	2001 Nov	11682416
Gas chromatographic method using nitrogen-phosphorus detection for the measurement of tramadol and its O-desmethyl metabolite in plasma and brain tissue of mice and rats.	2001 Nov 5	11710575
Acetaminophen, aspirin, or Ibuprofen in combination analgesic products.	2001 Nov-Dec	11704782
Urinary disorders on tramadol.	2001 Oct	11824434
Distribution of enantiomers of trans-tramadol and trans-O-demethyltramadol in central nervous system of rats.	2001 Oct	11749767
Ketorolac vs tramadol in the treatment of postoperative pain during maxillofacial surgery.	2001 Sep	11731754
Multidimensional on-line solid-phase extraction (SPE) using restricted access materials (RAM) in combination with molecular imprinted polymers (MIP).	2001 Sep	11605750
Intravenous regional anaesthesia using lignocaine and tramadol.	2001 Sep	11603137
Tramadol/acetaminophen combination tablets and codeine/acetaminophen combination capsules for the management of chronic pain: a comparative trial.	2001 Sep	11589258
Managing postoperative pain.	2001 Sep	11584617
Effects of chronic tramadol on pre- and post-synaptic measures of monoamine function.	2001 Sep	11565620
Tramadol and acetaminophen tablets for dental pain.	2001 Summer	11724223
How to taper tramadol dose.	2002 Feb	11868307
New, non-NSAID alternative.	2002 Feb	11858591
Randomized clinical trial of Ligasure versus open haemorrhoidectomy.	2002 Feb	11856126
Combination analgesic efficacy: individual patient data meta-analysis of single-dose oral tramadol plus acetaminophen in acute postoperative pain.	2002 Feb	11844632
[Recovery of lung function after laparoscopic cholecystectomy: the role of postoperative pain].	2002 Feb	11844438
The addition of tramadol to lidocaine does not reduce tourniquet and postoperative pain during iv regional anesthesia.	2002 Feb	11823394
Pharmacological treatment of postoperative shivering: a quantitative systematic review of randomized controlled trials.	2002 Feb	11812718
The role of tricyclic antidepressants and tramadol in palliative care.	2002 Feb	11807215
In vivo microdialysis and conditioned place preference studies in rats are consistent with abuse potential of tramadol.	2002 Feb	11754490
Stereoselectivity in renal clearance of trans-tramadol and its active metabolite, trans-O-demethyltramadol.	2002 Jan	11860743
Concordance between tramadol and dextromethorphan parent/metabolite ratios: the influence of CYP2D6 and non-CYP2D6 pathways on biotransformation.	2002 Jan	11808821
Use of nonopioid analgesics and adjunctive agents in the management of pain in rheumatic diseases.	2002 Jan	11790999
A systematic review of adjuncts for intravenous regional anesthesia for surgical procedures.	2002 Jan	11782326
Physical compatibility and in vivo evaluation of drug mixtures for subcutaneous infusion to cancer patients in palliative care.	2002 Jan	11777190
Monocomponent chemoembolization in oral and oropharyngeal cancer using an aqueous crystal suspension of cisplatin.	2002 Jan 21	11870505
Meeting the therapeutic challenge of the patient with osteoarthritis.	2002 Jan-Feb	11833521
Patient reporting of potential adverse drug reactions: a methodological study.	2002 Mar	11874396
Tramadol has no effect on cortical renal blood flow--despite increased serum catecholamine levels--in anesthetized rats: implications for analgesia in renal insufficiency.	2002 Mar	11867386
Tramadol infusion for postthoracotomy pain relief: a placebo-controlled comparison with epidural morphine.	2002 Mar	11867369

Patents

Sample Use Guides

In Vivo Use Guide

Chronic: 25 mg PO every morning initially; increased by 25-50 mg/day every 3 days up to 50-100 mg PO q4-6hr PRN; not to exceed 400 mg/day Acute: 50-100 mg PO q4-6hr PRN; not to exceed 400 mg/day

Route of Administration: Oral

In Vitro Use Guide

A malignancy of A549 and PC-9 cells was detected after treatment of 2 μM tramadol for different time (0, 7, 14, or 28 d). The effect of tramadol on the invasion of A549 and PC-9 cells was performed using transwell chambers (6.5 mm diameter and 8 μm pore size; Millipore, Billerica, MA, USA). After treated with 2 μM tramadol for various time, cells were plated onto the Matrigel-coated upper part of the transwell chamber, fetal bovine serum (FBS) medium (20%) was added to the lower wells as a chemoattractant. 48 hours later, non-invading cells were removed, the invaded cells were fixed with 4% paraformaldehyde for 30 min and stained with 1% crystal violet for 30 min. The number of stained cells on the undersurface of the polycarbonate membranes was then counted visually in five random image fields at 200 × magnifications using a microscope (Olympus, Lake Success, NY, USA).

Substance Class	Chemical Created by `admin` on `Fri Dec 15 15:42:56 GMT 2023` Edited by `admin` on `Fri Dec 15 15:42:56 GMT 2023`
Record UNII	39J1LGJ30J
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

TRAMADOL

Official Name

English

E-265

Code

English

ETS6103

Code

English

(±)-TRAMADOL

Common Name

English

(±)-CIS-2-((DIMETHYLAMINO)METHYL)-1-(M-METHOXYPHENYL)CYCLOHEXANOL

Common Name

English

TRAMADOL [MI]

Common Name

English

CG-315E

Code

English

AMANDA

Brand Name

English

Tramadol [WHO-DD]

Common Name

English

E265

Code

English

ETS-6103

Code

English

U-26255A

Code

English

TRAMADOL [JAN]

Common Name

English

tramadol [INN]

Common Name

English

TRAMADOL [VANDF]

Common Name

English

Classification Tree Code System Code

WHO-VATC

QN02AX02