What Is Tramadol
Its analgesic effects take approximately an hour to be realized two to four hours to reach peak effect after oral administration with an immediate-release formulation.[20][21] On a dose-by-dose basis, tramadol has about one-tenth the potency of morphine (thus 100 mg is commensurate with 10 mg morphine but may vary) and is practically equally potent when compared with pethidine and codeine.[24] For pain moderate in severity, its effectiveness is roughly equivalent to that of codeine in low doses and hydrocodone at very high doses. For severe pain it is less effective than morphine.[20]
what is tramadol
Pain reducing effects last approximately six hours. The potency of analgesia varies considerably as it depends on an individual's genetics. People with specific variants of CYP2D6 enzymes may not produce adequate amounts of the active metabolite (desmetramadol) for effective pain control.[11][20]
Sleep medicine physicians sometimes prescribe tramadol (or other opiate medications) for refractory restless legs syndrome (RLS);[25][26] that is, RLS that does not respond adequately to treatment with first-line medications such as dopamine agonists (like pramipexole) or alpha-2-delta (α2δ) ligands (gabapentinoids), often due to augmentation.[27]
Individuals with certain genetic variations of CYP2D6 enzymes, which convert tramadol into an inactive molecule, may not experience enough pain relief from tramadol.[11][20] These genetic polymorphisms are not currently routinely tested for in clinical practice.[28]
Tramadol's use in pregnancy is generally avoided, as it may cause some reversible withdrawal effects in the newborn.[29] A small prospective study in France found, while an increased risk of miscarriages existed, no major malformations were reported in the newborn.[29] 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. No evidence of this dose harming the newborn was seen.[29]
Its use in children is generally advised against, although it may be done under the supervision of a specialist.[20] On 21 September 2015, the FDA started investigating the safety of tramadol in use in persons under the age of 17. The investigation was initiated because some of these people have experienced slowed or difficult breathing.[30] The FDA lists age under 12 years old as a contraindication.[31][32]
The most common adverse effects of tramadol include nausea, dizziness, dry mouth, indigestion, abdominal pain, vertigo, vomiting, constipation, drowsiness, and headache.[33][34] Other side effects may result from interactions with other medications. Tramadol has the same dose-dependent adverse effects as morphine including respiratory depression.[35]
Recognised risk factors for tramadol overdose include respiratory depression, addiction, and seizures.[39] Naloxone only partially reverses the toxic effects of tramadol overdose and may increase the risk of seizures.[20]
Deaths with tramadol overdose have been reported and are increasing in frequency in Northern Ireland; the majority of these overdoses involve other drugs including alcohol.[39] There were 254 tramadol-related deaths in England and Wales in 2013, and 379 in Florida in 2011.[40][41] In 2011, 21,649 emergency room visits in the United States were related to tramadol.[42]
Tramadol is metabolized by CYP2D6 enzymes which contribute to the metabolism of approximately 25% of all medications. Any medications with the ability to inhibit or induce these enzymes may interact with tramadol.[43]
Tramadol induces analgesic effects through a variety of different targets on the noradrenergic system, serotoninergic system and opioid receptors system.[45] Tramadol exists as a racemic mixture, the positive enantiomer inhibits serotonin reuptake while the negative enantiomer inhibits noradrenaline re-uptake, by binding to and blocking the transporters.[46][10] Tramadol has also been shown to act as a serotonin releasing agent. Both enantiomers of tramadol are agonists of the μ-opioid receptor and its M1 metabolite, O-desmetramadol, is also a μ-opioid receptor agonist but is 6 times more potent than tramadol itself.[47] All these effects work synergistically to induce analgesia.
Tramadol acts on the opioid receptors through its major active metabolite desmetramadol, which has as much as 700-fold higher affinity for the MOR relative to tramadol.[14] Moreover, tramadol itself has been found to possess no efficacy in activating the MOR in functional activity assays, whereas desmetramadol activates the receptor with high intrinsic activity (Emax equal to that of morphine).[56][14][73] As such, desmetramadol is exclusively responsible for the opioid effects of tramadol.[74] Both tramadol and desmetramadol have pronounced selectivity for the MOR over the DOR and KOR in terms of binding affinity.[57][52][54]
A positron emission tomography imaging study found that single oral 50-mg and 100-mg doses of tramadol to human volunteers resulted in 34.7% and 50.2% respective mean occupation of the serotonin transporter (SERT) in the thalamus.[83] The estimated median effective dose (ED50) for SERT occupancy hence was 98.1 mg, which was associated with a plasma tramadol level of about 330 ng/ml (1,300 nM).[83] The estimated maximum daily dosage of tramadol of 400 mg (100 mg q.i.d.) would result in as much as 78.7% occupancy of the SERT (in association with a plasma concentration of 1,220 ng/ml or 4,632 nM).[83] This is close to that of SSRIs, which occupy the SERT by 80% or more.[83]
Co-administration of quinidine, a potent CYP2D6 enzyme inhibitor, with tramadol, a combination which results in markedly reduced levels of desmetramadol, was found not to significantly affect the analgesic effects of tramadol in human volunteers.[14][87] However, other studies have found that the analgesic effects of tramadol are significantly decreased or even absent in CYP2D6 poor metabolizers.[14][74] The analgesic effects of tramadol are only partially reversed by naloxone in human volunteers,[14] hence indicating that its opioid action is unlikely the sole factor; tramadol's analgesic effects are also partially reversed by α2-adrenergic receptor antagonists such as yohimbine, the 5-HT3 receptor antagonist ondansetron, and the 5-HT7 receptor antagonists SB-269970 and SB-258719.[21][89] Pharmacologically, tramadol is similar to tapentadol and methadone in that it not only binds to the MOR, but also inhibits the reuptake of serotonin and norepinephrine[8] due to its action on the noradrenergic and serotonergic systems, such as its "atypical" opioid activity.[90]
Nausea and vomiting caused by tramadol are thought to be due to activation of the 5-HT3 receptor via increased serotonin levels.[58] In accordance, the 5-HT3 receptor antagonist ondansetron can be used to treat tramadol-associated nausea and vomiting.[58] Tramadol and desmetramadol themselves do not bind to the 5-HT3 receptor.[58][50]
Tramadol undergoes hepatic metabolism via the cytochrome P450 isozyme CYP2B6, CYP2D6, and CYP3A4, being O- and N-demethylated to five different metabolites. Of these, desmetramadol (O-desmethyltramadol) 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 with 6 hours for tramadol itself. As with codeine, in the 6% of the population who have reduced CYP2D6 activity (hence reducing metabolism), a reduced analgesic effect is seen. Those with decreased CYP2D6 activity require a dose increase of 30% to achieve the same degree of pain relief as those with a normal level of CYP2D6 activity.[91][92]
The chemical synthesis of tramadol is described in the literature.[94] 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 U.S. Food and Drug Administration (FDA) approved tramadol in March 1995, and an extended-release (ER) formulation in September 2005.[102] ER Tramadol was protected by US patents nos. 6,254,887[103] and 7,074,430.[104][105] The FDA listed the patents' expiration as 10 May 2014.[104] However, in August 2009, US District Court for the District of Delaware ruled the patents invalid, a decision upheld the following year by the Court of Appeals for the Federal Circuit. Manufacture and distribution of generic equivalents of Ultram ER in the United States was therefore permitted prior to the expiration of the patents.[106]
Effective 18 August 2014, tramadol has been placed into Schedule IV of the federal Controlled Substances Act in the United States.[107][108] Before that, some US states had already classified tramadol as a Schedule IV controlled substance under their respective state laws.[109][110][111]
Illicit use of the drug is thought to be a major factor in the success of the Boko Haram terrorist organization.[114][115][116] When used at higher doses, the drug "can produce similar effects to heroin."[114] Said one former member, "whenever we took tramadol, nothing mattered to us anymore except what we were sent to do because it made us very high and very bold, it was impossible to go on a mission without taking it."[114] Tramadol is also used as a coping mechanism in the Gaza Strip.[117] It is also abused in the United Kingdom, inspiring the title of the TV show Frankie Boyle's Tramadol Nights (2010).[118][119]
In 2013, researchers reported that tramadol was found in relatively high concentrations (1%+) in the roots of the African pin cushion tree (Nauclea latifolia).[130] In 2014, however, it was reported that the presence of tramadol in the tree roots was the result of tramadol having been administered to cattle by farmers in the region:[131] tramadol and its metabolites were present in the animals' excreta, which contaminated the soil around the trees. Therefore, tramadol and its mammalian metabolites were found in tree roots in the far north of Cameroon, but not in the south where it is not administered to farm animals.[131] 041b061a72
