Tramadol
tramadol
Generic Name: tramadol
Brand Name: Ultram
Drug Class And Mechanism: Tramadol is an effective pain reliever (analgesic). Its mode of action resembles that of narcotics, but it has significantly less potential for abuse and addiction than the narcotics. Tramadol is as effective as narcotics in relieving pain but does not depress respiration, a side effect of most narcotics. Tramadol is not a nonsteroidal antiinflammatory drug (NSAID), and does not have the increased risk of stomach ulceration and internal bleeding that can occur with the use of NSAIDs.
Prescription: Yes
Generic Available: Yes
Preparations: Tablet: 50mg.
Storage: Store at room temperature, sealed container.
Prescribed For: Tramadol is used in the management of moderate to moderately severe pain.
Dosing: May be taken with or without food.
Drug Interactions: Tramadol can impair thinking and the physical abilities required for driving or operating machinery. Tramadol should be avoided in patients intoxicated with alcohol, hypnotics, and narcotics. Large doses of tramadol administered with alcohol or anesthetic agents can impair breathing. Tramadol can increase the risk of seizure in epileptic patients, especially with simultaneous use of tricyclic antidepressants, such as Elavil. No dosage adjustment or reduction is necessary in healthy elderly patients 65-75 years of age. Patients over the age of 75 years, and those with liver and kidney dysfunction may need lower dosages. The safety of tramadol in children has not been established. Tramadol may rarely be habit forming. Tramadol should be avoided in patients with a history of opiate addiction or hypersensitivity to opiate medications.
Pregnancy: The safety of tramadol during pregnancy has not been established.
Nursing Mothers: The safety of tramadol in nursing mothers has not been established.
Side Effects: Tramadol is generally well tolerated and side effects are usually transient. Commonly reported side effects include nausea, constipation, dizziness, headache, drowsiness, and vomiting. Less commonly reported side effects include itching, sweating, dry mouth, diarrhea, rash, visual disturbances, and vertigo.
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| rac-(1R,2R)-2-(dimethylaminomethyl)-1- (3-methoxyphenyl)-cyclohexanol IUPAC name |
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| CAS number 27203-92-5 |
ATC code N02AX02 |
| PubChem 33741 |
DrugBank APRD00028 |
| Chemical formula | C16H25NO2 |
| Molecular weight | 263.4 g/mol |
| Bioavailability | 68-72% Increases with repeated dosing. |
| Metabolism | Hepatic demethylated & glucuronidated |
| Elimination half-life | 5-7 hours |
| Excretion | Renal |
| Pregnancy category | C (USA) C (Australia) |
| Legal status | Schedule 4 (Australia) |
| Routes of administration | Oral, IV, IM |
Tramadol (INN) (IPA: ['træm?d?l]) 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).
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.
Tramadol has a limited popularity as a recreational drug, and is referred to as "Tram-Tram" amongst users.
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.
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 psychic 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, 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.
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
Picture of Tramadol