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Tramadol
Identifiers
CAS	27203-92-5
ATC	N02AX02
PubChem	33741
DrugBank	APRD00028
Chemical data
IUPAC name	rac-(1R,2R)-2-(dimethylaminomethyl)-1- (3-methoxyphenyl)-cyclohexanol
Formula	C16H25NO2
Mol. weight	263.4 g/mol
Pharmacokinetic data
Bioavailability	68-72% Increases with repeated dosing.
%Protein Bound	{{{protein_bound}}}
Metabolism	Hepatic demethylated & glucuronidated
Half life	5-7 hours
Excretion	Renal
Therapeutic considerations
Pregnancy	C (USA) C (Australia)
Legal status	Schedule 4 (Australia)
Dependence Liability	{{{dependency_liability}}}
Routes	Oral, IV, IM

Tramadol (INN) (IPA: [ˈtræmədɒl]) is an atypical opioid which is a centrally acting analgesic, used for treating moderate to severe pain. It is a synthetic agent, unrelated to other opioids, and appears to have actions on the GABAergic, noradrenergic and serotonergic systems. Tramadol was developed by the German pharmaceutical company Grünenthal GmbH and marketed under the trade name Tramal. Grünenthal has also cross licensed the drug to many other pharmaceutical companies that market it under various names, some of which are listed below. Tramadol structure. ... CAS registry numbers are unique numerical identifiers for chemical compounds, polymers, biological sequences and alloys. ... The Anatomical Therapeutic Chemical Classification System is used for the classification of drugs. ... A section of the Anatomical Therapeutic Chemical Classification System. ... PubChem is a database of chemical molecules . ... DrugBank is a database available at the University of Alberta that provides information about thousands of products. ... IUPAC nomenclature is a systematic way of naming organic chemical compounds. ... A chemical formula (also called molecular formula) is a concise way of expressing information about the atoms that constitute a particular chemical compound. ... General Name, Symbol, Number carbon, C, 6 Chemical series nonmetals Group, Period, Block 14, 2, p Appearance black (graphite) colorless (diamond) Atomic mass 12. ... General Name, Symbol, Number hydrogen, H, 1 Chemical series nonmetals Group, Period, Block 1, 1, s Appearance colorless Atomic mass 1. ... General Name, Symbol, Number nitrogen, N, 7 Chemical series nonmetals Group, Period, Block 15, 2, p Appearance colorless Atomic mass 14. ... General Name, Symbol, Number oxygen, O, 8 Chemical series Nonmetals, chalcogens Group, Period, Block 16, 2, p Appearance colorless Atomic mass 15. ... The molecular mass of a substance (less accurately called molecular weight and abbreviated as MW) is the mass of one molecule of that substance, relative to the unified atomic mass unit u (equal to 1/12 the mass of one atom of carbon-12). ... The gram or gramme, symbol g, is a unit of mass. ... The mole and its simple conversions into different units of measurements. ... In pharmacology, bioavailability is used to describe the fraction of an administered dose of medication that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. ... You may be looking for albumen, or egg white. ... Santorio Santorio (1561-1636) in his steelyard balance, from Ars de statica medecina, first published 1614 Metabolism (from μεταβολισμος (metabolismos)) is the biochemical modification of chemical compounds in living organisms anggjgjhnd cell (b). ... The liver is the largest internal organ of the human body. ... The elimination half-life of a drug (or any xenobiotic agent) refers to the timecourse necessary for the quantity of the xenobiotic agent in the body (or plasma concentration) to be reduced to half of its original level through various elimination processes. ... The hour (symbol: h) is a unit of time. ... Excretion is the biological process by which an organism chemically separates waste products from its body. ... Human kidneys viewed from behind with spine removed The kidneys are bean-shaped excretory organs in vertebrates. ... The pregnancy category of a pharmaceutical agent is an assessment of the risk of fetal injury due to the pharmaceutical, if it is used as directed by the mother. ... The regulation of therapeutic goods, that is drugs and therapeutic devices, varies by jurisdiction. ... Sagittal section of nose mouth, pharynx, and larynx. ... An intravenous drip in a hospital Intravenous therapy or IV therapy is the administration of liquid substances directly into a vein. ... Intramuscular injection is an injection of a substance directly into a muscle. ... An International Nonproprietary Name (INN) is the official non-proprietary or generic name given to a pharmaceutical substance, as designated by the World Health Organization. ... The International Phonetic Alphabet (IPA) is a system of phonetic notation devised by linguists to accurately and uniquely represent each of the wide variety of sounds (phones or phonemes) used in spoken human language. ... An opioid is any agent that binds to opioid receptors, found principally in the central nervous system and gastrointestinal tract. ... An analgesic (colloquially known as a painkiller) is any member of the diverse group of drugs used to relieve pain and to achieve analgesia. ... Chemical structure of GABA Gamma-aminobutyric acid (GABA) is a neurotransmitter in widely divergent species. ... Norepinephrine, known as noradrenaline outside the USA, is a catecholamine and a phenethylamine with chemical formula C8H11NO3. ... Serotonin (5-hydroxytryptamine, or 5-HT) is a monoamine neurotransmitter synthesised in serotonergic neurons in the central nervous system and enterochromaffin cells in the gastrointestinal tract. ... A pharmaceutical company (or drug company) is a company licensed to discover, develop, market and distribute drugs. ... Grünenthal is a German pharmaceutical company. ...

Tramadol is available in both injectable (intravenous and/or intramuscular) and oral preparations. It is usually marketed as the hydrochloride salt (tramadol hydrochloride). Injection has multiple meanings: In mathematics, the term injection refers to an injective function. ... An intravenous drip in a hospital Intravenous therapy or IV therapy is the administration of liquid substances directly into a vein. ... Intramuscular injection is an injection of a substance directly into a muscle. ...

Dosages vary depending on the degree of pain experienced by the patient. Tramadol is approximately 10% as potent as morphine, when given by the IV/IM route. Oral doses range from 50–400 mg daily, with up to 600 mg daily when given IV/IM.

Mechanism of action

The mechanism of action of tramadol has yet to be fully elucidated, but it is believed to work through modulation of the GABAergic, noradrenergic and serotonergic systems. The contribution of non-opioid activity is demonstrated by the analgesic effects of tramadol not being fully antagonised by the μ-opioid receptor antagonist naloxone. Naloxone is a drug used to counter the effects of opioid overdose, for example heroin and morphine overdose. ...

Tramadol is marketed as a racemic mixture with a weak affinity for the μ-opioid receptor (approximately 1/6000th that of morphine). The (+)-enantiomer is approximately four times more potent than the (-)-enantiomer in terms of μ-opioid receptor affinity and 5-HT reuptake, whereas the (-)-enantiomer is responsible for noradrenaline reuptake effects (Shipton, 2000). These actions appear to produce a synergistic analgesic effect, with (+)-tramadol exhibiting 10-fold higher analgesic activity than (-)-tramadol (Goeringer et al., 1997). In chemistry, a racemate is a mixture of equal amounts of left- and right-handed stereoisomers of a chiral molecule. ... Morphine (INN), the principal active agent in opium, is a powerful opioid analgesic drug. ... In chemistry, two stereoisomers are said to be enantiomers if they are mirror images of each other. ... Serotonin (5_hydroxytryptamine, or 5_HT) is a monoamine neurotransmitter synthesised in serotonergic neurons in the central nervous system and enterochromaffin cells in the gastrointestinal tract. ...

The serotonergic modulating properties of tramadol mean that it has the potential to interact with other serotonergic agents. There is an increased risk of serotonin syndrome when tramadol is taken in combination with serotonin reuptake inhibitors (e.g. SSRIs), since these agents not only potentiate the effect of 5-HT but also inhibit tramadol's metabolism. Serotonin syndrome (or hyperserotonemia) is a hyperserotonergic state, that is an excess of 5-HT (serotonin) in the central nervous system. ... Selective serotonin reuptake inhibitors (SSRIs) are a class of antidepressants for treating depression, anxiety disorders and some personality disorders. ...

Metabolism

Tramadol undergoes hepatic metabolism via the cytochrome P450 isozyme CYP2D6, being O- and N-demethylated to 5 different metabolites. Of these, M1 is the most significant since it has 200 times the μ-affinity of (+)-tramadol, and furthermore has an elimination half-life of 9 hours compared to 6 hours for tramadol itself. In the 6% of the population who have slow CYP2D6 activity, there is therefore a slightly reduced analgesic effect. Phase II hepatic metabolism renders the metabolites water-soluble and they are renally excreted. Thus reduced doses may be used in renal and hepatic impairment. Cytochrome P450 Oxidase (CYP2E1) Cytochrome P450 oxidase (commonly abbreviated CYP) is a generic term for a large number of related, but distinct, oxidative enzymes (EC 1. ... Cytochrome P450 2D6 (abbreviated CYP2D6, EC 1. ...

Adverse effects

The most commonly reported adverse drug reactions are nausea, vomiting and sweating. Drowsiness is reported, although it is less of an issue compared to other opioids. Respiratory depression, a common side effect of most opioids, is not clinically significant in normal doses. By itself, it does not increase the seizure threshold, though it may do if used in combination with SSRIs, tricyclic antidepressants, or in patients with epilepsy. An adverse drug reaction (abbreviated ADR) is a term to describe the unwanted, negative consequences sometimes associated with the use of medications. ...

Dependence

Some controversy exists regarding the dependence liability of tramadol. Grünenthal has promoted it as an opioid with a low risk of dependence compared to traditional opioids, claiming little evidence of such dependence in clinical trials. They offer the theory that since the M1 metabolite is the principal agonist at μ-opioid receptors, the delayed agonist activity reduces dependence liability. The noradrenaline reuptake effects may also play a role in reducing dependence.

Despite these claims it is apparent, in community practice, that dependence to this agent does occur. This would be expected since analgesic and dependence effects mediated by the same μ-opioid receptor. However, this dependence liability is considered relatively low by health authorities, such that tramadol is classified as a Schedule 4 Prescription Only Medicine in Australia, rather than as a Schedule 8 Controlled Drug like other opioids (Rossi, 2004). Similarly, tramadol is not currently scheduled by the U.S. DEA, unlike other opioid analgesics. Nevertheless, the Prescribing Information for Ultram warns that tramadol "may induce psychic and physical dependence of the morphine-type." Since 1973, the DEA has enforced the drug laws in the United States. ...

Proprietary preparations

Grünenthal, which still owns the patent to tramadol, has cross-licensed the agent to various pharmaceutical companies internationally. Thus tramadol is marketed under many trade names including: Adolonta, Contramal, Crispin, Nobligan, Siverol, Tiparol, Toplagic, Tradol, Tradolan, Tralgit, Tramacet, Tramadin, Tramal, Tramahexal, Tramazac, Ultracet, Ultram, Zamadol and Zydol.

Abuse

Late reports of abuse have been encountered in the United Kingdom through stolen prescriptions. The drug has been discovered to be sold for around £4-5.00 a gram. It is either snorted, injected or taken oraly per two 50mg capsules, also poured into 1g capsules and taken as a "shot". Usually followed by an increased dose due to metabolic variation. Yes.

References

• Goeringer KE, Logan BK, Christian GD. Identification of tramadol and its metabolites in blood from drug-related deaths and drug-impaired drivers. J Anal Toxicol 1997;21(7):529-37. PMID 9399121
• Rossi S, editor. Australian Medicines Handbook 2004 (AMH). Adelaide: Australian Medicines Handbook; 2004. ISBN 0-9578521-4-2.
• Shipton EA. Tramadol – present and future. Anaesth Intensive Care 2000;28(4):363-74. PMID 10969362
• Ultram – U.S. Prescribing Information
• McDiarmid T. What is the addiction risk associated with tramadol? Jour Fam Prac. January 2005 Vol. 54, No. 1