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Tramadol
Clinical data Pregnancy cat. C(AU) C(US) Legal status Prescription Only (S4) (AU) POM (UK) only (US)
Prescription only
Routes
Bioavailability 6872%(Increases with repeat dosing.) Protein binding 20% Metabolism Hepatic demethylation and glucuronidation
Half-life Excretion
CAS number ATC code PubChem DrugBank ChemSpider UNII KEGG ChEMBL
27203-92-5 N02AX02 CID 33741 APRD00028 31105 39J1LGJ30J D08623 CHEMBL1237044 Chemical data
InChI[show]
(what is this?) [2]
Tramadol hydrochloride (Ultram, Tramal) is a centrally acting opioid analgesic, used in treating moderate to severe pain. The drug has a wide range of applications, including treatment for restless leg syndrome and fibromyalgia. It was developed by the pharmaceutical company Grnenthal GmbH in the late 1970s.[1][2] Tramadol possesses weak agonist actions at the -opioid receptor, releases serotonin, and inhibits the reuptake of norepinephrine.[3][4]
Tramadol is a synthetic analog of the phenanthrene alkaloid codeine and, as such, is an opioid and also a prodrug (codeine is metabolized to morphine, tramadol is converted to O-desmethyltramadol). Opioids are chemical compounds which act upon one or more of the human opiate receptors. The euphoria and respiratory depression are mainly caused by the 1 and 2 receptors; the addictive nature of the drug is due to these effects as well as its serotonergic/noradrenergic effects. The opioid agonistic effect of tramadol and its major metabolite(s) are almost exclusively mediated by the substance's action at the -opioid receptor. This characteristic distinguishes tramadol from many other substances (including morphine) of the opioid drug class, which generally do not possess tramadol's degree of subtype selectivity.
Contents
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1 Medical uses o 1.1 Availability and usage o 1.2 Investigational uses o 1.3 Pregnancy and breastfeeding 2 Adverse effects o 2.1 Physical dependence and withdrawal o 2.2 Psychological dependence and recreational use o 2.3 Detection in biological fluids 3 Mechanism of action 4 Chemistry o 4.1 Characteristics o 4.2 Comparison with related substances o 4.3 Synthesis and stereoisomerism 5 Metabolism 6 Legal status 7 Proprietary preparations 8 Veterinary medicine 9 Notes 10 External links
[8][9]
claiming it may be used as a unique treatment (only when other treatments failed), and must be used under the control of a psychiatrist.[10][11] In May 2009, the United States Food and Drug Administration issued a Warning Letter to Johnson & Johnson, alleging that a promotional website commissioned by the manufacturer had "overstated the efficacy" of the drug, and "minimized the serious risks".[12] The company which produced it, the German pharmaceutical company Grnenthal GmbH, were the ones alleged to be guilty of "minimizing" the addictive nature and proposed efficacy of the drug, although it showed little abuse liability in preliminary tests. The 2010 Physicians Desk Reference contains several warnings from the manufacturer, which were not present in prior years. The warnings include more compelling language regarding the addictive potential of tramadol, the possibility of difficulty breathing while on the medication, a new list of more serious side effects, and a notice that tramadol is not to be used in place of opiate medications for addicts. Tramadol is also not to be used in efforts to wean addict patients from opiate drugs, nor to be used to manage long-term opiate addiction.
capsules (regular and extended release) tablets (regular, extended release, chewable, low-residue and/or uncoated tablets that can be taken by the sublingual and buccal routes) suppositories effervescent tablets and powders ampules of sterile solution for SC, IM, and IV injection preservative-free solutions for injection by the various spinal routes (epidural, intrathecal, caudal, and others) powders for compounding liquids both with and without alcohol for oral and sub-lingual administration, available in regular phials and bottles, dropper bottles, bottles with a pump similar to those used with liquid soap and phials with droppers built into the cap tablets and capsules containing (acetaminophen/APAP), aspirin and other agents.
Tramadol has been experimentally used in the form of an ingredient in multi-agent topical gels, creams, and solutions for nerve pain, rectal foam, concentrated retention
enema, and a skin plaster (transdermal patch) quite similar to those used with lidocaine. Tramadol has a characteristic and unpleasant taste which is mildly bitter but much less so than morphine and codeine. Oral and sublingual drops and liquid preparations come with and without added flavoring. Its relative effectiveness via transmucosal routes (i.e. sublingual, buccal, rectal) is similar to that of codeine, and, like codeine, it is also metabolized in the liver to stronger metabolites (see below). The maximum dosage per day is 400 mg for oral use and 600 mg for parenteral use. Certain manufacturers or formulations have lower maximum doses. For example, Ultracet (37.5 mg/325 mg tramadol/APAP tablets) is capped at 8 tablets per day (300 mg/day) due to its acetaminophen content. Ultram ER is available in 100, 200, and 300 mg/day doses and is explicitly capped at 300 mg/day as well. Patients taking SSRIs (Prozac, Zoloft, etc.), SNRIs (Effexor, etc.), TCAs, MAOIs, or other strong opioids (oxycodone, methadone, fentanyl, morphine), as well as the elderly (> 75 years old), pediatric (< 18 years old), and those with severely reduced renal (kidney) or hepatic (liver) function should consult their doctor regarding adjusted dosing or whether to use Tramadol at all.
diabetic neuropathy [13][14] postherpetic neuralgia [15][16] opiate withdrawal management[17][18] / antidepressant withdrawal aid (proven to be effective, especially with withdrawal from its distant relative venlafaxine (Effexor))[citation needed]. obsessive-compulsive disorder [19] premature ejaculation [20]
(%) Any adverse effect Drowsiness Nausea Dizziness Constipation Headache Vomiting Diarrhea Dry Mouth Fatigue Indigestion Seizure[25] 71 17 17 15 11 11 7 6 5 5 5 <1
Main side effects of tramadol. Red color denotes more serious effects, requiring immediate contact with health provider.[26] The most commonly reported adverse drug reactions are nausea, vomiting, sweating, itching and constipation. Drowsiness is reported, although it is less of an issue than for non-synthetic opioids. Patients prescribed tramadol for general pain relief with or without other agents have reported withdrawal symptoms including uncontrollable nervous tremors, muscle contracture, and 'thrashing' in bed (similar to restless leg syndrome) if weaning off the medication happens too quickly. Anxiety, 'buzzing', 'electrical shock' and other sensations may also be present, similar to those noted in Effexor withdrawal. 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). However, there have been several rare cases of people having grand-mal seizures at doses as low as 100400 mg orally.[27][28][29] An Australian study found that of 97 confirmed new-onset seizures, eight were associated with tramadol, and that in the authors' First Seizure Clinic, "tramadol is the most frequently suspected cause of provoked seizures".[30] There appears to be growing evidence that Tramadol use may
have serious risks in some individuals and it is contra-indicated in patients with uncontrolled epilepsy (BNF 59). Seizures caused by tramadol are most often tonicclonic seizures, more commonly known in the past as grand mal seizures. Also when taken with SSRIs, there is an increased risk of serotonin toxicity, which can be fatal. Fewer than 1% of users have a presumed incident seizure claim after their first tramadol prescription. Risk of seizure claim increases two- to six-fold among users adjusted for selected comorbidities and concomitant drugs. Risk of seizure is highest among those aged 2554 years, those with more than four tramadol prescriptions, and those with a history of alcohol abuse, stroke, or head injury.[25] Dosages of warfarin may need to be reduced for anticoagulated patients to avoid bleeding complications. Constipation can be severe especially in the elderly requiring manual evacuation of the bowel.[citation needed] Furthermore, there are suggestions that chronic opioid administration may induce a state of immune tolerance,[31] although tramadol, in contrast to typical opioids may enhance immune function.[32][33][34] Some have also stressed the negative effects of opioids on cognitive functioning and personality.[35]
Medicine in Australia, and been rescheduled in Sweden rather than as a Schedule 8 Controlled Drug like opioids.[41] Similarly, tramadol is not currently scheduled by the U.S. DEA, unlike opioid analgesics. It is, however, scheduled in certain states.[42] Nevertheless, the prescribing information for Ultram warns that tramadol "may induce psychological and physical dependence of the morphine-type". Dependence on Tramadol has been reported to be a major social problem in the Gaza Strip. The Hamas government has attempted to cut off supplies of the drug, and in April 2010 burnt 2 million tablets which had been intercepted while being smuggled into the territory.[43] Due to the possibility of convulsions at high doses for some users, recreational use can be very dangerous.[44] Tramadol can, however, via agonism of opioid receptors, produce effects similar to those of other opioids (Codeine and other weak opioids), although not nearly as intense due to tramadol's much lower affinity for this receptor. Tramadol can cause a higher incidence of nausea, dizziness, loss of appetite compared with opiates which could deter abuse to some extent.[45] Tramadol can help alleviate withdrawal symptoms from opiates, and it is much easier to lower the quantity of its usage, compared with opioids such as hydrocodone and oxycodone.[46] It may also have large effect on sleeping patterns and high doses may cause insomnia.
(Especially for those on methadone, both for maintenance and recreation. Though there is no scientific proof tramadol lessens effects or is a mixed agonist-antagonist, some people get the impression it is, while someone else might benefit being prescribed both for pain and B/T pain)[47]
Tramadol is marketed as a racemic mixture of the (1R,2R)- and (1S,2S)-enantiomers with a weak affinity for the -opioid receptor (approximately 1/6000th that of morphine; Gutstein & Akil, 2006). The (1R,2R)-(+)-enantiomer is approximately four times more potent than the (1S,2S)-()-enantiomer in terms of -opioid receptor affinity and 5-HT reuptake, whereas the (1S,2S)-()-enantiomer is responsible for noradrenaline reuptake effects (Shipton, 2000). These actions appear to produce a synergistic analgesic effect, with (1R,2R)-(+)-tramadol exhibiting 10-fold higher analgesic activity than (1S,2S)-()-tramadol (Goeringer et al., 1997). The serotonergic-modulating properties of tramadol give tramadol the potential to interact with other serotonergic agents. There is an increased risk of serotonin toxicity 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.[citation needed] Tramadol is also thought to have some NMDA antagonistic effects, which has given it a potential application in neuropathic pain states. Tramadol has inhibitory actions on the 5-HT2C receptor. Antagonism of 5-HT2C could be partially responsible for tramadol's reducing effect on depressive and obsessivecompulsive symptoms in patients with pain and co-morbid neurological illnesses.[61] 5-HT2C blockade may also account for its lowering of the seizure threshold, as 5-HT2C knockout mice display significantly increased vulnerability to epileptic seizures, sometimes resulting in spontaneous death. However, the reduction of seizure threshold could be attributed to tramadol's putative inhibition of GABA-A receptors at high doses.[55] The overall analgesic profile of tramadol supports intermediate pain, especially chronic states. It is slightly less effective for acute pain than hydrocodone, but more effective than codeine. It has a dosage ceiling similar to codeine, a risk of seizures when overdosed, and a relatively long half-life making its potential for abuse relatively low amongst intermediate strength analgesics. Tramadol's primary active metabolite, O-desmethyltramadol, is a considerably more potent -opioid receptor agonist than tramadol itself, and is so much more so that tramadol can partially be thought of as a prodrug to O-desmethyltramadol. Similarly to tramadol, O-desmethyltramadol has also been shown to be a norepinephrine reuptake inhibitor, 5-HT2C receptor antagonist, and M1 and M3 muscarinic acetylcholine receptor antagonist.[citation needed]
[edit] Chemistry
[edit] Characteristics
Structurally, tramadol closely resembles a stripped down version of codeine. Both codeine and tramadol share the 3-methyl ether group, and both compounds are metabolized along the same hepatic pathway and mechanism to the stronger opioid, phenol agonist analogs. For codeine, this is morphine, and for tramadol, it is the Odesmethyltramadol.
(1R,2R)-Tramadol
(1S,2S)-Tramadol
(1R,2S)-Tramadol
(1S,2R)-Tramadol
The chemical synthesis of tramadol is described in the literature.[62] Tramadol [2(dimethylaminomethyl)-1-(3-methoxyphenyl)cyclohexanol] has two stereogenic centers at the cyclohexane ring. Thus, 2-(dimethylaminomethyl)-1-(3methoxyphenyl)cyclohexanol may exist in four different configurational forms:
The synthetic pathway leads to the racemate (1:1 mixture) of (1R,2R)-isomer and the (1S,2S)-isomer as the main products. Minor amounts of the racemic mixture of the (1R,2S)-isomer and the (1S,2R)-isomer are formed as well. The isolation of the (1R,2R)-isomer and the (1S,2S)-isomer from the diastereomeric minor racemate [(1R,2S)-isomer and (1S,2R)-isomer] is realized by the recrystallization of the hydrochlorides. The drug tramadol is a racemate of the hydrochlorides of the (1R,2R)(+)- and the (1S,2S)-()-enantiomers. The resolution of the racemate [(1R,2R)-(+)-
isomer / (1S,2S)-()-isomer] was described[63] employing (R)-()- or (S)-(+)-mandelic acid. This process does not find industrial application, since tramadol is used as a racemate, despite known different physiological effects [64] of the (1R,2R)- and (1S,2S)-isomers, because the racemate showed higher analgesic activity than either enantiomer in animals[65] and in humans.[66]
[edit] Metabolism
Tramadol undergoes hepatic metabolism via the cytochrome P450 isozyme CYP2B6, CYP2D6 and CYP3A4, being O- and N-demethylated to five different metabolites. Of these, O-desmethyltramadol is the most significant since it has 200 times the affinity of (+)-tramadol, and furthermore has an elimination half-life of nine hours, compared with six hours for tramadol itself. As with codeine, in the 6% of the population that have increased CYP2D6 activity (increased metabolism), there is therefore a reduced analgesic effect. Phase II hepatic metabolism renders the metabolites water-soluble, which are excreted by the kidneys. Thus, reduced doses may be used in renal and hepatic impairment.[67]
Acugesic (Malaysia, Singapore) Adolonta (Spain) Algifeno (Bolivia) Algesia (Philippines) Anadol (Bangladesh, Thailand) Boldol (Bosnia, Herzegovina) Calmador (Argentina) Campex (Pakistan) Contramal (Belgium, France, India, Italy, Turkey, Sudan) Crispin Dolcet (combined with paracetamol) (Philippines) Dolol (Denmark) Dolzam (Belgium, Luxembourg) Dromadol (United Kingdom) Exopen (South Korea) Ixprim (France, Ireland) Lumidol (Bosnia, Herzegowina, Croatia) Mabron (Bahrain, Bangladesh, Bulgaria, Czech Republic, Estonia, Iraq, Jordan, Latvia, Lithuania, Malaysia, Oman, Romania, Singapore, Slovakia, Sri
Nobligan (Argentina, Denmark, Iceland, Mexico, Norway, Portugal, Sweden) Osteodol (India) Oxxalgan PR (Greece) Palitex (India) Poltram (Poland) Pyredol (combined with paracetamol ) (Vietnam, Bolivia) Ralivia (Canada) Ryzolt (United States) Sinergix (combined with ketorolac) (Mexico) Sintradon (Serbia) Siverol (Philippines ) Tandol (South Korea) Tiparol (Sweden) Tonoflex (Pakistan) Topalgic (France) Tradol (Bangladesh , Ireland,
Tramadol (Australia, Belgium, Chile, Estonia, France, Netherlands, Romania, New Zealand, Norway, Spain, United States) Tramadol Stada (Sweden) Tramadolor (Austria, Estonia, Germany, Hungary, Latvia, Lithuania, Luxembourg , Romania) Tramagit (Romania) Tramahexal (Australia) Tramake (United Kingdom) TramaKlosidol (Argentina) Tramal (Pakistan, Netherlands, Finland, Croatia, Morocco, Slovenia, Poland, Brazil, Chile, Romania, Australia, New Zealand,
Ultracet (combined with paracetamol) Ultradol Ultram and Ultram ER (United States) Ultramed (combined with paracetamol) (India) Veldrol (Mexico) VAMADOL PLUS (India) Volcidol (Thailand) Zafin (combined with paracetamol) (Chile) Zaldiar (combined with paracetamol) (Belgium, Chile, Croatia, the Czech Republic, Mexico, Poland, Portugal, Slovenia, Spain, Russia) Zaledor (combined with paracetamol) (Chile) Zamadol (United Kingdom) Zamudol
Lanka, Sudan, Yemen) Mandolgin (Denmark) Mandolgine Mosepan Matrix (combined with paracetamol) (Honduras, Guatemala)
Mexico, Singapore, Venezuela) Tradolan (Austria, Denmark, Finland, Iceland, Romania, Sweden) Tradolgesic (Thailand) Tradonal (Belgium, Indonesia, Italy, Luxembour g, Netherlands , Philippines, Spain, Switzerland ) Tralgit (Czech Republic, Georgia, Romania, Slovakia) Tralodie (Italy) Tramacet (combined with paracetamol ) (Canada, Mexico, Costa Rica, South Africa) Tramacip (India) Tramadex (Israel) Tramadin (Finland) Tramadol HEXAL (Denmark,
Germany, Switzerland, Lebanon, Israel, Philippines, Egypt) Tramalgic (Hungary) Tramal Gotas (Ecuador) Tramazac (India, Myanmar, Sri Lanka) Tramed Tramedo (Australia) Tramoda (Thailand) Traml (Iceland) Tramundal (Austria) Tridol (South Korea) Tridural (Canada) Trodon (Serbia)
(France) Zodol (Chile, Ecuador, Peru) Zydol (United Kingdom, Ireland, Australia) Zytram (Canada, Iceland, New Zealand, Spain) Zytrim (Spain)