TRAMADOL HYDROCHLORIDE

Details

Stereochemistry	RACEMIC
Molecular Formula	C16H25NO2.ClH
Molecular Weight	299.836
Optical Activity	( + / - )
Defined Stereocenters	2 / 2
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

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

InChI

InChIKey=PPKXEPBICJTCRU-XMZRARIVSA-N

InChI=1S/C16H25NO2.ClH/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;1H/t14-,16+;/m1./s1

HIDE SMILES / InChI

Molecular Formula	ClH
Molecular Weight	36.461
Charge	0
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

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 2637	1300.0 nM [EC50]
Kappa opioid receptor 108 Target ID: CHEMBL237 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19027293	Agonist 2637	14.0 nM [Ki]
Delta opioid receptor 78 Target ID: CHEMBL236 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19027293	Agonist 2637	9.4 nM [Ki]
Serotonin transporter 172 Target ID: CHEMBL228 Sources: https://www.ncbi.nlm.nih.gov/pubmed/18242987	Inhibitor 8146	1493.0 nM [IC50]
Norepinephrine transporter 183 Target ID: CHEMBL222 Sources: https://www.ncbi.nlm.nih.gov/pubmed/18242987	Inhibitor 8146	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 8307	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 7.9418878E11
Osteoarthritis 155 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 7.9418878E11
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 7.9418878E11

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 1670		substrate 1168	inhibitor 1570

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
	CYP2B6 648 P-gp 1491

Drug as victim

Target	Modality	Activity	Clinical evidence
P-gp 1491	substrate 3264 Sources: https://pubmed.ncbi.nlm.nih.gov/23331900/	unlikely
CYP2B6 648	substrate 3264 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022370s000lbl.pdf#page=9 Page: 9.0	yes
CYP2D6 1168	substrate 3264 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 1670	substrate 3264 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 1603	inhibitor 1584 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
Maintenance of the long-term effectiveness of tramadol in treatment of the pain of diabetic neuropathy.	2000 Mar-Apr	10959067
WHO Expert Committee on Drug Dependence. Thirty-second report.	2001	11851193
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
[Sensory neuropathy in HIV infection: pathogenesis and therapy].	2001 Apr 14	11332255
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
Prevention of chronic pain in whiplash injury.	2001 Feb	11302121
Response variability to analgesics: a role for non-specific activation of endogenous opioids.	2001 Feb 15	11207392
The effects of two single doses of tramadol on sleep: a randomized, cross-over trial in healthy volunteers.	2001 Jan	11270008
[Tramadol and oxazepam. Effect on pulmonry function in elderly patients with chronic obstructive lung disease].	2001 Jan 22	11218788
[Adiuvants in the axillary brachial plexus blockade. Comparison between clonidine, sufentanil and tramadol].	2001 Jan-Feb	11279374
Metabolism of the analgesic drug, tramadol hydrochloride, in rat and dog.	2001 Jul	11531006
Comparison of caudal morphine and tramadol for postoperative pain control in children undergoing inguinal herniorrhaphy.	2001 Jul	11442865
Caudal bupivacaine-tramadol combination for postoperative analgesia in pediatric herniorrhaphy.	2001 Jul	11421842
The analgesic efficacy of tramadol is impaired by concurrent administration of ondansetron.	2001 May	11323369
Effects of tramadol on T lymphocyte proliferation and natural killer cell activity in rats with sciatic constriction injury.	2001 May	11323127
A comparison of tramadol, amitriptyline, and meperidine for postepidural anesthetic shivering in parturients.	2001 Nov	11682416
Distribution of enantiomers of trans-tramadol and trans-O-demethyltramadol in central nervous system of rats.	2001 Oct	11749767
Tramadol/acetaminophen combination tablets and codeine/acetaminophen combination capsules for the management of chronic pain: a comparative trial.	2001 Sep	11589258
Psychosomatic reactions to a stressful environment and an attempt at pharmacological modification.	2001 Sep-Oct	11535941
How to taper tramadol dose.	2002 Feb	11868307
Combination analgesic efficacy: individual patient data meta-analysis of single-dose oral tramadol plus acetaminophen in acute postoperative pain.	2002 Feb	11844632
In vivo microdialysis and conditioned place preference studies in rats are consistent with abuse potential of tramadol.	2002 Feb	11754490
Monocomponent chemoembolization in oral and oropharyngeal cancer using an aqueous crystal suspension of cisplatin.	2002 Jan 21	11870505
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 16 16:27:46 UTC 2022` Edited by `admin` on `Fri Dec 16 16:27:46 UTC 2022`
Record UNII	9N7R477WCK
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

TRAMADOL HYDROCHLORIDE

Official Name

English

ZERTANE

Brand Name

English

TRAMADOL HYDROCHLORIDE [VANDF]

Common Name

English

ULTRAM

Brand Name

English

CG-315

Code

English

TRADONAL

Brand Name

English

TRAMADOL HYDROCHLORIDE [MART.]

Common Name

English

NSC-759105

Code

English

TRAMADOL HYDROCHLORIDE CIV

Common Name

English

TRAMADOL HCL

Common Name

English

CONTRAMAL

Brand Name

English

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

Common Name

English

TRAMADOL HYDROCHLORIDE [USAN]

Common Name

English

TRAMADOL HYDROCHLORIDE CIV [USP-RS]

Common Name

English

TRAMADOL HYDROCHLORIDE [JAN]

Common Name

English

CONZIP

Brand Name

English

TRAMADOL HYDROCHLORIDE [USP MONOGRAPH]

Common Name

English

TRAMADOL HYDROCHLORIDE [EP MONOGRAPH]

Common Name

English

NIH-10969

Code

English

ULTRACET COMPONENT TRAMADOL HYDROCHLORIDE

Common Name

English

TRAMADOL HYDROCHLORIDE [MI]

Common Name

English

ZYDOL

Brand Name

English

AMADOL

Brand Name

English

U-26,225A

Code

English

U-26225A

Code

English

TRAMADOL HYDROCHLORIDE [HSDB]

Common Name

English

ZAMUDOL

Brand Name

English

QDOLO

Brand Name

English

TRAMAL

Brand Name

English

Tramadol hydrochloride [WHO-DD]

Common Name

English

TRAMADOL HYDROCHLORIDE COMPONENT OF ULTRACET

Common Name

English

TRAMADOL HYDROCHLORIDE [ORANGE BOOK]

Common Name

English

CYCLOHEXANOL, 2-((DIMETHYLAMINO)METHYL)-1-(3-METHOXYPHENYL)-, HYDROCHLORIDE, (1R,2R)-REL-

Common Name

English

Classification Tree Code System Code

NCI_THESAURUS

C241