|Systematic (IUPAC) name|
|Trade names||Ryzolt, Tramal, Ultram|
|Licence data||US FDA:|
|Pregnancy cat.||C (AU) C (US)|
|Legal status||Prescription Only (S4) (AU) ℞-only (CA) POM (UK) ℞-only (US) Schedule IV (In some US states)|
|Routes||Oral, IV, IM, rectal, sublingual, buccal, intranasal|
|Bioavailability||75% (IR), 90% (repeated dosing; IR); 64–68% (SR)|
|Metabolism||Hepatic demethylation and glucuronidation via CYP2D6 & CYP3A4|
|Half-life||6.3 ± 1.4 hr|
|Mol. mass||263.4 g/mol|
|(what is this?)|
Tramadol (marketed as the hydrochloride salt by Janssen Pharmaceutica as Ultram in the United States, Ralivia by Biovail in Canada and many other companies throughout the world) is a centrally acting opioid analgesic used to treat moderate to moderately severe pain. The drug has a wide range of applications, including treatment of rheumatoid arthritis, restless legs syndrome, motor neurone disease and fibromyalgia. It was launched and marketed as Tramal by the German pharmaceutical company Grünenthal GmbH in 1977.
Tramadol is a serotonin releaser, reuptake inhibitor of norepinephrine and a weak μ-opioid receptor agonist. Tramadol is metabolized to O-desmethyltramadol, a significantly more potent μ-opioid agonist. Tramadol and its major metabolite(s) are distinguished from other more potent opioid agonists by relative selectivity for μ-opioid receptors.
- 1 Medical uses
- 2 Adverse effects
- 3 Mechanism of action
- 4 Chemistry
- 5 Metabolism
- 6 Legal status
- 7 Brand names
- 8 Formulations
- 9 Research
- 10 Veterinary medicine
- 11 Pin cushion tree
- 12 See also
- 13 References
- 14 External links
Tramadol is used similarly to codeine, to treat moderate to severe nerve pain. Pharmacologically, tramadol is similar to levorphanol (albeit with much lower μ-agonism), both agents have SNRI activity. Dextropropoxyphene (Darvon) & M1-like molecule tapentadol (Nucynta, a new synthetic atypical opioid made to mimic the agonistic properties of tramadol's metabolite, M1(O-Desmethyltramadol)) also have similar activities. Tramadol is also molecularly similar to venlafaxine (Effexor) and has similar SNRI effects, with antinociceptive effects. It has been suggested that tramadol could be effective for alleviating symptoms of depression, anxiety, and phobias because of its action on the noradrenergic and serotonergic systems, such as its "atypical" opioid activity. However, health professionals have not endorsed its use for these disorders, claiming it may be used as a unique treatment (only when other treatments failed), and must be used under the control of a psychiatrist.
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." The company which produced it, the German pharmaceutical company Grünenthal GmbH, were alleged to be guilty of "minimizing" the habituating nature 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 stronger language regarding the habit-forming 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.
Common (1–10% incidence) adverse effects include:
- Emotional lability
- Dyspepsia (indigestion)
- Asthenia (weakness)
- Pruritus (itchiness)
- Dry mouth
- Vasodilation (dilation (widening) of blood vessels)
- Coordination disturbance
- Sleep disorder
- Abdominal pain
- Anorexia (weight loss)
- Visual disturbance
- Menopausal symptoms
- Urinary frequency
- Urinary retention (being unable to urinate)
Uncommon (0.1-1% incidence) adverse effects include:
- Cardiovascular regulation (palpitation, tachycardia, postural hypotension or cardiovascular collapse)
- Gastrointestinal irritation (a feeling of pressure in the stomach, bloating)
- Urticaria (hives)
Rare (0.01–0.1% incidence) adverse effects include:
- Hypertension (high blood pressure)
- Allergic reactions (e.g. dyspnoea (shortness of breath), bronchospasm, wheezing, angioneurotic oedema)
- Changes in appetite
- Respiratory depression
- Epileptiform convulsions
- Involuntary muscle contractions
- Abnormal coordination
- Syncope (fainting)
- Blurred vision
- Dyspnoea (shortness of breath)
- Tinnitus (ringing in the ears)
- Stevens-Johnson syndrome/Toxic epidermal necrolysis (potentially fatal skin reactions)
- Motorial weakness
- Creatinine increase
- Elevated liver enzymes
- Hepatitis (liver swelling)
- Stomatitis (mouth swelling)
- Liver failure
- Pulmonary oedema (fluid in the lungs)
- Gastrointestinal bleeding
- Pulmonary embolism
- Myocardial ischaemia (lack of blood supply to the heart muscles)
- Speech disorders
- Haemoglobin decrease
- Proteinuria (protein in the urine; usually indicative of kidney damage)
There are suggestions that chronic opioid administration may induce a state of immune tolerance, although tramadol, in contrast to typical opioids may enhance immune function. Some have also stressed the negative effects of opioids on cognitive functioning and personality.
Physical dependence and withdrawal
Long-term use of high doses of tramadol may be associated with physical dependence and a withdrawal syndrome. Tramadol causes typical opiate-like withdrawal symptoms as well as atypical withdrawal symptoms including seizures. The atypical withdrawal symptoms are probably related to tramadol's effect on serotonin and norepinephrine re-uptake. Symptoms may include those of SSRI discontinuation syndrome, such as anxiety, depression, anguish, severe mood swings, aggressiveness, brain "zaps", electric-shock-like sensations throughout the body, paresthesias, sweating, palpitations, restless legs syndrome, sneezing, insomnia, vivid dreams or nightmares, micropsia and/or macropsia, tremors, and headache among others. In most cases, tramadol withdrawal will set in 12–20 hours after the last dose, but this can vary. Tramadol withdrawal lasts longer than that of other opioids; seven days or more of acute withdrawal symptoms can occur as opposed to typically three or four days for other codeine analogues. It is recommended that patients physically dependent on pain killers take their medication regularly to prevent onset of withdrawal symptoms and this is particularly relevant to tramadol because of its SSRI and SNRI properties, and, when the time comes to discontinue their tramadol, to do so gradually over a period of time that will vary according to the individual patient and dose and length of time on the drug.
Psychological dependence and recreational use
Some controversy regarding the abuse potential of tramadol exists. Grünenthal has promoted it as having a lower risk of opioid dependence than traditional opioids, claiming little evidence of such dependence in clinical trials (which is true; Grünenthal never claimed it to be non-addictive). They offer the theory that, since the M1 metabolite is the principal agonist at μ-opioid receptors, the delayed agonist activity reduces abuse liability. The norepinephrine reuptake inhibitor effects may also play a role in reducing dependence.
Rarely, dependence may occur after as little as three months of use at the maximum dose—generally depicted at 400 mg per day. However, both physicians and health authorities generally consider dependence liability relatively low. Thus, tramadol is classified as a Schedule 4 in the US, Schedule 4 in Australia and been rescheduled in Sweden rather than as a Schedule 8 Controlled Drug like opioids. Similarly, unlike opioid analgesics, tramadol is not currently scheduled as a controlled substance by the U.S. Drug Enforcement Administration. However, it is controlled in certain states. Nevertheless, the prescribing information for Ultram warns that tramadol "may induce psychological and physical dependence of the morphine-type".
Because of the possibility of convulsions at high doses for some users, recreational use can be very dangerous. Tramadol can cause a higher incidence of nausea, dizziness, loss of appetite compared with opiates, which could deter abuse. Compared to hydrocodone, fewer patients choose to abuse tramadol. It may also have a 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 of opiates or is a mixed agonist-antagonist, some people get the impression it is, while someone else might benefit being prescribed both for pain and breakthrough pain.)
Detection in biological fluids
Tramadol and O-desmethyltramadol may be quantified in blood, plasma or serum to monitor for abuse, confirm a diagnosis of poisoning or assist in the forensic investigation of a traffic or other criminal violation or a sudden death. Most commercial opiate immunoassay screening tests do not cross-react significantly with tramadol or its major metabolites, so chromatographic techniques must be used to detect and quantitate these substances. The concentrations of O-desmethyltramadol in the blood or plasma of a person who has taken tramadol are generally 10–20% those of the parent drug.
Mechanism of action
Tramadol acts as a μ-opioid receptor agonist, serotonin releasing agent, norepinephrine reuptake inhibitor, NMDA receptor antagonist (IC50=16.5 μM), 5-HT2C receptor antagonist (EC50=26 nM), (α7)5 nicotinic acetylcholine receptor antagonist, TRPV1 receptor agonist, and M1 and M3 muscarinic acetylcholine receptor antagonist.
The analgesic action of tramadol is not fully understood, but it is believed to work through modulation of serotonin and norepinephrine in addition to its relatively weak μ-opioid receptor agonism. The contribution of non-opioid activity is demonstrated by the fact that the analgesic effect of tramadol is not fully antagonised by the μ-opioid receptor antagonist naloxone.
Tramadol is marketed as a racemic mixture of the (1R,2R)- and (1S,2S)-enantiomers with a weak affinity for the μ-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 μ-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 it 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. 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 obsessive-compulsive symptoms in patients with pain and co-morbid neurological illnesses. 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.
The overall analgesic profile of tramadol supports use in the treatment of intermediate pain, especially chronic pain. 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 misuse relatively low amongst intermediate strength analgesics.
Tramadol's primary active metabolite, O-desmethyltramadol, is a considerably more potent μ-opioid receptor agonist than tramadol itself. Thus, tramadol is in part 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.
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 (which one? needs citation) and mechanism to the stronger opioid, phenol agonist analogs. For codeine, this is morphine, and for tramadol, it is the O-desmethyltramadol.
When administered through IV, patients notice very little clinical difference in subjective potency compared to morphine.
Structurally, tapentadol is the closest chemical relative of tramadol in clinical use. Tapentadol is also an opioid, but unlike both tramadol and venlafaxine, tapentadol represents only one stereoisomer and is the weaker of the two, in terms of opioid effect. Both tramadol and venlafaxine are racemic mixtures. Structurally, tapentadol also differs from tramadol in being a phenol, and not an ether. Also, both tramadol and venlafaxine incorporate a cyclohexyl moiety, attached directly to the aromatic, while tapentadol lacks this feature.
Synthesis and stereoisomerism
The chemical synthesis of tramadol is described in the literature. Tramadol [2-(dimethylaminomethyl)-1-(3-methoxyphenyl)cyclohexanol] has two stereogenic centers at the cyclohexane ring. Thus, 2-(dimethylaminomethyl)-1-(3-methoxyphenyl)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 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 of the (1R,2R)- and (1S,2S)-isomers, because the racemate showed higher analgesic activity than either enantiomer in animals and in humans.
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 μ-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 an increased analgesic effect. Those with decreased CYP2D6 activity will experience less analgesia. 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.
O-Desmethyltramadol, as well as tramadol's inactive metabolite, N-desmethyltramadol, both metabolize into the pharmacologically active N,O-didesmethyltramadol via CYP2D6.
Tramadol (as the racemic, cis-hydrochloride salt), is available as a generic in the U.S. from any number of different manufacturers, including Amneal, Caraco, Mylan, Cor Pharma, Mallinckrodt, Pur-Pak, APO, Teva, and many more. Typically, the generic tablets are sold in 50 mg tablets. Brand name formulations include Ultram ER, and the original Ultram from Ortho-McNeil, (cross-licensed from Grünenthal GmbH) which is now produced by Janssen.
The extended-release formulation of tramadol—which, among other factors, was intended to be more abuse-deterrent than the instant release—allegedly possesses more abuse liability than the instant release formulation. The U.S. Food and Drug Administration (FDA) approved tramadol in March 1995 and an extended-release (ER) formulation in September 2005. It is covered by U.S. patents nos. 6,254,887 and 7,074,430. The FDA lists the patents as scheduled for expiration on 10 May 2014. However, in August 2009, U.S. District Court for the District of Delaware ruled the patents invalid, which, if it survives appeal, would permit manufacture and distribution of generic equivalents of Ultram ER in the United States.
In November 2013, the United States Drug Enforcement Administration initiated classification of Tramadol as a schedule IV controlled substance, pending a review process.  Several states, including Arkansas, Kentucky, Illinois, Mississippi, New York, North Dakota, Oklahoma, Tennessee, West Virginia, Wyoming and the U.S. military have classified Tramadol as a schedule IV controlled substance under state law. Other states have legislation pending concerning scheduling tramadol.
Sweden, as of May 2008, has chosen to classify tramadol as a controlled substance in the same way as codeine and dextropropoxyphene. This means that the substance is a scheduled drug. But unlike codeine and dextropropoxyphene, a normal prescription can be used at this time. In Mexico, combined with paracetamol and sold under the brand name Tramacet, it is widely available without a prescription, but this is currently under re-evaluation. In most Asian countries such as the Philippines, it is sold as a capsule under the brand name Tramal, where it is mostly used to treat labor pains.
Grünenthal GmbH, which still owns the patent on tramadol, has cross-licensed the drug to pharmaceutical companies internationally. Thus, tramadol is marketed under many trade names around the world, including:
Tramadol is classified as a central nervous system drug usually marketed as the hydrochloride salt (tramadol hydrochloride); the tartrate is seen on rare occasions, and rarely (in the US at least) tramadol is available for both injection (intravenous and/or intramuscular) and oral administration. The most well known dosing unit is the 50 mg generic tablet made by several manufacturers. It is also commonly available in conjunction with APAP (paracetamol, acetaminophen) as Ultracet or Tramacet, in the form of a smaller dose of 37.5 mg tramadol and 325 mg of APAP.
Tramadol comes in many forms, including:
- 50 mg immediate-release tablets.
- 50 mg orally disintegrating tablets.
- 100 mg, 200 mg, and 300 mg extended-release tablets.
- 100 mg, 150 mg, 200 mg, and 300 mg extended-release capsules.
- 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 is regularly 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. This different flavouring is considered to be a standard. 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).
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 
- postherpetic neuralgia 
- acute opioid withdrawal management
- obsessive-compulsive disorder 
- premature ejaculation
Tramadol may be used to treat post-operative, injury-related, and chronic (e.g., cancer-related) pain in dogs and cats as well as rabbits, coatis, many small mammals including rats and flying squirrels, guinea pigs, ferrets, and raccoons.
Tramadol comes in ampules in addition to the tablets, capsules, powder for reconstitution, and oral syrups and liquids; the fact that its characteristic taste is distasteful to dogs, but can be masked in food, makes for a means of administration.
No data that would lead to a definitive determination of the efficacy and safety of tramadol in reptiles or amphibians are available, and, following the pattern of all other drugs, it appears that tramadol can be used to relieve pain in marsupials, such as North American opossums, short-tailed opossums, sugar gliders, wallabies, and kangaroos among others.
Tramadol for animals is one of the most reliable and useful active principles available to veterinarians for treating animals in pain. It has a dual mode of action: weak mu agonism and mono-amine reuptake inhibition, which produces mild anti-anxiety results. This is an advantage because the use of some non-steroidal anti-inflammatory substances in these animals may be dangerous.
When animals are administered tramadol, adverse reactions can occur. The most common are constipation, upset stomach, decreased heart rate. In case of overdose, mental alteration, pinpoint pupils and seizures may appear. In such cases, veterinarians should evaluate the correct treatment for these events. Some contraindications have been noted in treated animals taking certain other drugs.
Tramadol should not be co-administered with selegiline or any other psychoactive class of medication such as selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, or monoamine oxidase inhibitors.
In animals, tramadol is removed from the body via liver and kidney excretion. Animals suffering from diseases in these systems should be monitored by a veterinarian, as it may be necessary to adjust the dose.
Pin cushion tree
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