Article: Tramadol

Tramadol
Systematic (IUPAC) name
rac-(1R,2R)-2-(dimethylaminomethyl)-1- (3-methoxyphenyl)-cyclohexanol
Identifiers
CAS number	27203-92-5
ATC code	N02AX02
PubChem	33741
DrugBank	APRD00028
Chemical data
Formula	C16H25NO2
Mol. weight	263.4 g/mol
Pharmacokinetic data
Bioavailability	68-72% Increases with repeated dosing.
Metabolism	Hepatic demethylated & glucuronidated
Half life	5-7 hours
Excretion	Renal
Therapeutic considerations
Pregnancy cat.	C(AU) C(US)
Legal status	S4(AU) POM(UK)
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 is available in both injectable (intravenous and/or intramuscular) and oral preparations. It is usually marketed as the hydrochloride salt (tramadol hydrochloride), which is associated with the brand name Ultram in the United States. It is also available in conjunction with acetaminophen as Ultracet.

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.

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).

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.

It is suggested that tramadol could be effective for alleviating symptoms of depression and anxiety because of it's action on GABAergic, noradrenergic and serotonergic systems. However, use of the drug for treatment of such disorders by a health professional is unlikely.

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.

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.

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 psychological and physical dependence of the morphine-type."

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, Lumidol, Nobligan, Siverol, Tiparol, Toplagic, Tradol, Tradolan, Tralgit, Tramacet, Tramacip, Tramadin, Tramal, Tramahexal, Tramazac, Tramedo, Ultracet, Ultram, Zamadol and Zydol.

Trivia

• Rapper Russell Jones (a.k.a. Ol' Dirty Bastard) died from a combination of cocaine and a Tramadol overdose on November 13, 2004.