Tramadol

Tramadol

Clinical data
Pregnancy category	AU: C
Routes of administration	oral, IV, IM
ATC code	N02AX02 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) UK: POM (Prescription only)
Pharmacokinetic data
Bioavailability	68–72% Increases with repeated dosing.
Protein binding	20%
Metabolism	Hepatic demethylation and glucuronidation
Elimination half-life	5–7 hours
Excretion	Renal
Identifiers
IUPAC name rac-(1R,2R)-2-(dimethylaminomethyl)-1- (3-methoxyphenyl)-cyclohexanol
CAS Number	27203-92-5
PubChem CID	33741
DrugBank	APRD00028
CompTox Dashboard (EPA)	DTXSID401167150 DTXSID90858931, DTXSID401167150
ECHA InfoCard	100.043.912
Chemical and physical data
Formula	C16H25NO2
Molar mass	263.4 g/mol g·mol−1

Tramadol (INN) (IPA: [ˈtræməˌdɒl]) is an atypical opioid which is a centrally acting analgesic, used for treating moderate to severe pain. It is a synthetic agent, as a 4-phenyl-piperidine analogue of codeine, 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 usually marketed as the hydrochloride salt (tramadol hydrochloride) and is available in both injectable (intravenous and/or intramuscular) and oral preparations (e.g. Zydol in UK, Ultram in U.S., Zytrim in Spain and Canada, and Calmador in Argentina). It is also available in conjunction with paracetamol (acetaminophen) as Ultracet or Tramacet.

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. The 'combination' pills each contain 37.5 mg of tramadol and 325 mg of paracetamol, with the recommended dose being one or two pills every four to six hours.

Unlike most other opioids/opiates, Tramadol is not considered a controlled substance in many countries (U.S. and Canada, among others), and is available with a normal prescription. Tramadol is available over-the-counter without prescription in a few countries.

Mechanism of action

The mode of action of tramadol has yet to be fully understood, 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 1/6th 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 metabolism.

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 excreted by the kidneys. 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 can decrease the seizure threshold. When combined with SSRIs, tricyclic antidepressants, or in patients with epilepsy, the seizure threshold is further decreased. Seizures have been reported in humans receiving excessive single oral doses (700 mg) or large intravenous doses (300 mg). Dosages of coumadin/warfarin may need to be reduced for anticoagulated patients to avoid bleeding complications.

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 are 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." In addition, there are widespread reports by consumers of extremely difficult withdrawal experiences.

Recreational use

As a narcotic analgesic, tramadol can be abused. Its low agonism of the μ opiate receptor produces effects similar to other narcotics (i.e. morphine, hydrocodone), albeit not nearly as intense. In addition to acting as an opiate, tramadol is also a rapidly-acting SSRI. At higher-than-therapeutic doses, tramadol can cause seizures (typically grand mal) and severe nausea, which could deter abuse to some extent. Tramadol has been known to produce severe withdrawal symptoms with abrupt cessation of prolonged use.

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: Adolan, Adolonta, Anadol, Calmador, Contramal, Crispin, Lumidol, Mandolgine, Mosepan, Nobligan, Poltram, Siverol, Tiparol, Toplagic, Tradol, Tradolan, Tralgit, Tramacet, Tramacip, Tramadin, Tramal, Tramahexal, Tramazac, Trama-Klosidol, Tramedo, Ultracet, Ultram, Zamadol, Zydol and Zytram.

Uses

Tramadol is often used to treat moderate and severe pain and most types of neuralgia, including trigeminal neuralgia.

It is suggested that tramadol could be effective for alleviating symptoms of depression and anxiety because of its action on GABAergic, noradrenergic and serotonergic systems. However, health professionals generally do not suggest use of the drug for treatment of such disorders.

Veterinary

Tramadol is used to treat post-operative pain in dogs.

Trivia

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

References

• Goeringer K, Logan B, Christian G. "Identification of tramadol and its metabolites in blood from drug-related deaths and drug-impaired drivers". J Anal Toxicol. 21 (7): 529–37. PMID 9399121.{{cite journal}}: CS1 maint: multiple names: authors list (link)
• Ed. Rossi S, ed. (2004). Australian Medicines Handbook. Adelaide: Australian Medicines Handbook. ISBN 0-9578521-4-2.
• Shipton E (2000). "Tramadol--present and future". Anaesth Intensive Care. 28 (4): 363–74. PMID 10969362.
• "Ultram" (PDF). Ortho-McNeil. – U.S. Prescribing Information
• McDiarmid T, Mackler L, Schneider D (2005). "Clinical inquiries. What is the addiction risk associated with tramadol?". J Fam Pract. 54 (1): 72–3. PMID 15623411. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)

External links

• Press release from Johnson & Johnson regarding tramadol/acetaminophen combination pill now available in Canada

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