Tramadol is marketed as a racemic mixture of both R and S stereoisomers. This is because the two isomers complement each other's analgesic activity. It is often combined with paracetamol as this is known to improve the efficacy of tramadol in relieving pain. Tramadol is an atypical opioid because it is a serotonin-norepinephrine reuptake inhibitor of and, by itself, a fairly weak μ-opioid receptoragonist. Tramadol is metabolised to O-desmethyltramadol, which is a significantly more potent opioid with additional norepinephrine reuptake-inhibiting properties, making it analogous to tapentadol. When taken as an immediate-release oral formulation, the onset of pain relief usually occurs within about an hour.
Despite the original belief that tramadol was a purely synthetic opioid it has been found in a South African tree.
Generic tramadol HCl tablets marketed by Amneal Pharmaceuticals.
Tramadol HCl for injection
Tramadol is used primarily to treat moderate-severe pain, both acute and chronic.
Tramadol is recommended for the management of pain in fibromyalgia by the European League Against Rheumatism. Its analgesic effects take about one hour to come into effect and 2–4 hours to peak after oral administration with an immediate-release formulation. On a dose-by-dose basis tramadol has about one-tenth the potency of morphine and is approximately equally potent when compared to pethidine and codeine.
For pain moderate in severity its effectiveness is equivalent to that of morphine; for severe pain it is less effective than morphine. These painkilling effects peak at about 3 hours, post-oral administration and last for approximately 6 hours. These analgesic effects are only partially reversed by naloxone, hence indicating that its opioid action is unlikely the sole contributing factor; tramadol's analgesic effects are also partially reversed by α2 adrenergic receptor antagonists like yohimbine and the 5-HT3 receptor antagonist, ondansetron. Pharmacologically, tramadol is similar to levorphanol and tapentadol in that it not only binds to the mu opioid receptor, but also inhibits the reuptake of serotonin and norepinephrine due to its action on the noradrenergic and serotonergic systems, such as its "atypical" opioid activity. Available dosage forms include capsules, tablets, including extended release formulations and injections.
Its use in pregnancy is generally advised against as it may cause some reversible withdrawal effects in the newborn. Despite this a small prospective study in France found that while there was an increased risk of miscarriages there were no major malformations reported in the newborn. Its use during lactation is also generally advised against but a small trial found that infants breastfed by mothers taking tramadol were exposed to about 2.88% of the dose the mothers were taking and despite this there was no evidence of this dose having a harmful effect on the newborn.
Labour and delivery
Its use as an analgesic during labour is generally advised against due to its long-onset of action (one hour). The ratio of the mean concentration of the drug in the foetus compared to that of the mother when it is given intramuscularly for labour pains has been estimated to be 94.
Its use in children is generally advised against, although it may be done under the supervision of a specialist.
There is an increased risk of opioid-related adverse effects such as respiratory depression, falls, cognitive impairment and sedation.
Liver and kidney failure
It is advised that the drug be used with caution in those with liver or kidney failure, due to the high dependence of the drug on the liver and kidneys for metabolism to O-desmethyltramadol and elimination, respectively.
Main side effects of tramadol. Red color denotes more serious effects, requiring immediate contact with health provider.
The most common adverse effects of tramadol include nausea, dizziness, dry mouth, indigestion, abdominal pain, vertigo, vomiting, constipation, drowsiness and headache. Compared to other opioids respiratory depression and constipation is considered less of a problem with tramadol.
The most common side effects in order of decreasing incidence are: Note: Serious adverse effects are in bold. Very common (>10% frequency) adverse effects include:
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.
Its use is advised against in people lacking any CYP2D6 enzymes (which accounts for about 6-10% of Caucasians and 1-2% of Asians) as they are crucial to the therapeutic effects of tramadol, by means of enabling tramadol's metabolism to O-desmethyltramadol.
Fatalities with tramadol overdose have been reported and are increasing in frequency in Northern Ireland; the majority of these overdoses involve other drugs including alcohol. Recognised risk factors for tramadol overdose include depression, male gender, addiction and seizures.Naloxone only partially reverses the toxic effects of tramadol overdose and may increase the risk of seizures.
Physical dependence and withdrawal
Long-term use of high doses of tramadol may be associated with physical dependence and a withdrawal syndrome. The atypical withdrawal symptoms are probably related to tramadol's effect on serotonin and norepinephrine reuptake. 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 those 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 SNRI properties and, when the time comes to discontinue their tramadol, they do so gradually over a period of time that will vary according to the individual, dose and length of time on the drug.
Psychological dependence and recreational use
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 persons 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.
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 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-HT2Cknockout 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.
Tramadol undergoes hepatic metabolism via the cytochrome P450isozymeCYP2B6, 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 reduced CYP2D6 activity (hence reducing metabolism), there is therefore a reduced analgesic effect. Those with decreased CYP2D6 activity require a dose increase of 30% in order to achieve the same degree of pain relief than those with a normal level of CYP2D6 activity.
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.
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.
The DEA announced that, effective August 18, 2014, Tramadol will be placed into Schedule 4 of the federal Controlled Substances Act. In addition, several states, including Arkansas, Georgia, Kentucky, Illinois, Mississippi, New York, North Dakota, Oklahoma, Tennessee, West Virginia, Wyoming and the U.S. military have already classified Tramadol as a schedule IV controlled substance under state law.
The UK government has decided that tramadol will become a Schedule 3 controlled drug (CD) on 10 June 2014, but will have exemption from the safe custody requirement.
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:
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