Tramadol, sold under the brand name Ultram among others, is an opioid pain medication used to treat moderate to moderately severe pain. When taken by mouth in an immediate-release formulation, the onset of pain relief usually occurs within an hour. It is often combined with paracetamol (acetaminophen) as this is known to improve the efficacy of tramadol in relieving pain.
Serious side effects may include seizures, increased risk of serotonin syndrome, decreased alertness, and drug addiction, although the risk of serotonin syndrome appears to be low. Common side effects include: constipation, itchiness and nausea, among others. A change in dosage may be recommended in those with kidney or liver problems. It is not recommended in those who are at risk of suicide. While not recommended in women who are breastfeeding, those who take it should not stop breastfeeding.
It has two different mechanisms. First, it works by binding to the ?-opioid receptor. Second, it acts as a serotonin-norepinephrine reuptake inhibitor (SNRI). Tramadol is a synthetic opioid of the benzenoid class. In the body it is metabolized to desmetramadol, also known as O-desmethyltramadol, which is a more potent opioid.
Tramadol was launched and marketed as "Tramal" by the German pharmaceutical company Grünenthal GmbH in 1977 in West Germany, and 20 years later it was launched in countries such as the UK, US, and Australia. It is marketed under many brand names worldwide.
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Medical uses
Tramadol is used primarily to treat mild-severe pain, both acute and chronic.
Its analgesic effects take about one hour to come into effect and 2 h to 4 h 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 with 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 last for approximately 6 h.
Available dosage forms include liquids, syrups, drops, elixirs, effervescent tablets and powders for mixing with water, capsules, tablets including extended release formulations, suppositories, compounding powder, and injections.
Fibromyalgia
As of 2015 tramadol was not approved in the United States for fibromyalgia. Based on three small trials with weak study design, there is fair evidence for tramadol as a second line treatment.
Contraindications
Use of tramadol is not advised for people deficient in CYP2D6 enzymes. The enzymes are crucial to the therapeutic effects of tramadol, by means of enabling tramadol's metabolism to desmetramadol.
Pregnancy and lactation
Tramadol's use in pregnancy is generally avoided as it may cause some reversible withdrawal effects in the newborn. 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. 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 fetus compared to that of the mother when it is given intramuscularly for labour pains has been estimated to be 94.
Children
Its use in children is generally advised against, although it may be done under the supervision of a specialist. On September 21, 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. The FDA lists age under 12 years old as a contraindication.
Elderly
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 desmetramadol and elimination, respectively.
Side effects
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 are considered less of a problem with tramadol.
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.
Dependence and withdrawal
Long-term use of high doses of tramadol will cause physical dependence and withdrawal syndrome. These include both symptoms typical of opioid withdrawal and those associated with SSRI withdrawal; symptoms include numbness, tingling, paresthesia, and tinnitus. Psychiatric symptoms may include hallucinations, paranoia, extreme anxiety, panic attacks, and confusion. In most cases, tramadol withdrawal will set in 12-20 hours after the last dose, but this can vary. Tramadol withdrawal typically 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.
However, according to a 2014 report by the World Health Organizations Expert Committee on Drug Dependence '"....in many cases of tramadol dependence, a history of substance abuse is present....but....the evidence for physical dependence was considered minimal. Consequently, Tramadol is generally considered as a drug with low potential for dependence. In a recent German study (including a literature study, an analysis of two drug safety databases, and questionnaires analyses), the low abuse and low dependence potential of Tramadol were re-confirmed. The German expert group found a low prevalence of abuse or dependence in clinical practice in Germany, and concluded that Tramadol has a low potential for misuse, abuse, and dependence in Germany".
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 opioids, which could deter recreational use. Compared to hydrocodone, fewer persons choose to use tramadol recreationally.
Overdose
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, addiction and seizures. Naloxone only partially reverses the toxic effects of tramadol overdose and may increase the risk of seizures.
Interactions
Tramadol may interact with serotonergics, monoamine oxidase inhibitors, tricyclic antidepressants, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, noradrenergic and specific serotonergic antidepressants, serotonin antagonists and reuptake inhibitors, other opioid analgesics (pethidine (meperidine), tapentadol, oxycodone, and fentanyl), dextromethorphan, certain migraine medications (triptans, ergots), certain anxiolytics (such as the SSRIs and buspirone), certain antibiotics (namely, linezolid and isoniazid), certain herbs (e.g. St. John's wort, passiflora, etc.), amphetamines, substituted amphetamines, phenethylamine and substituted phenethylamines, phentermine, lithium, methylene blue as well as numerous other therapeutic agents. As it is a substrate of CYP3A4 and CYP2D6, any agents with the ability to inhibit or induce these enzymes will likely interact with tramadol. A pressor response similar to the so-called "cheese effect" was noted in combinations of amphetamine and tramadol, which appears to cause dysfunction of or toxicity to epinephrine/norepinephrine receptors. Cyclobenzaprine, a commonly-used muscle relaxant, atypical analgesic adjunct, as well as a potentiator often used with analgesics like codeine, dihydrocodeine, hydrocodone and the like, is structurally related to the tricyclic antidepressants and therefore should not be used with tramadol; this is also the case for trazodone
Pharmacology
Mechanism of action
Tramadol has been found to possess the following actions:
- Agonist of the ?-opioid receptor (MOR) and to a far lesser extent of the ?-opioid receptor (DOR) and ?-opioid receptor (KOR)
- Serotonin reuptake inhibitor (SRI) and norepinephrine reuptake inhibitor (NRI); hence, an SNRI
- Serotonin 5-HT2C receptor antagonist
- M1 and M3 muscarinic acetylcholine receptor antagonist
- ?7 nicotinic acetylcholine receptor antagonist
- NMDA receptor antagonist (very weak)
- TRPA1 inhibitor
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. 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). As such, desmetramadol is exclusively responsible for the opioid effects of tramadol. Both tramadol and desmetramadol have pronounced selectivity for the MOR over the DOR and KOR in terms of binding affinity.
Tramadol is well-established as a serotonin reuptake inhibitor. In addition, a few studies have found that it also acts as a serotonin releasing agent (1-10 ?M), similar in effect to fenfluramine. The serotonin releasing effects of tramadol could be blocked by sufficiently high concentrations of the serotonin reuptake inhibitor 6-nitroquipazine, which is in accordance with other serotonin releasing agents like fenfluramine and MDMA. However, two more recent studies failed to find a releasing effect of tramadol at respective concentrations up to 10 and 30 ?M. In addition to serotonergic activity, tramadol is also a norepinephrine reuptake inhibitor. It is not a norepinephrine releasing agent. Tramadol does not inhibit the reuptake or induce the release of dopamine.
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. 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). It was also estimated that the 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). This is close to that of selective serotonin reuptake inhibitors (SSRIs), which occupy the SERT by 80% or more.
Peak plasma concentrations during treatment with clinical dosages of tramadol have generally been found to be in the range of 70 to 592 ng/mL (266-2,250 nM) for tramadol and 55 to 143 ng/mL (221-573 nM) for desmetramadol. The highest levels of tramadol were observed with the maximum oral daily dosage of 400 mg per day divided into one 100 mg dose every 6 hours (i.e., four 100 mg doses evenly spaced out per day). There is some accumulation of tramadol with chronic administration; peak plasma levels of tramadol with the maximum oral daily dosage (100 mg q.i.d.) are about 16% higher and the area-under-the-curve levels 36% higher than following a single oral 100 mg dose. Positron emission tomography imaging studies have reportedly found that tramadol levels are at least 4-fold higher in the brain than in plasma. Conversely, brain levels of desmetramadol "only slowly approach those in plasma". The plasma protein binding of tramadol is only 4 to 20%; hence, almost all tramadol in circulation is free and thus bioactive.
Correspondence to clinical effects
Co-administration of quinidine, a potent CYP2D6 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. However, other studies have found that the analgesic effects of tramadol are significantly decreased or even absent in CYP2D6 poor metabolizers. The analgesic effects of tramadol are only partially reversed by naloxone in human volunteers, hence indicating that its opioid action is unlikely the sole factor; tramadol's analgesic effects are also partially reversed by ?2-adrenergic receptor antagonists like yohimbine, the 5-HT3 receptor antagonist ondansetron, and the 5-HT7 receptor antagonists SB-269970 and SB-258719. 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 due to its action on the noradrenergic and serotonergic systems, such as its "atypical" opioid activity.
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 GABAA receptors at high doses (significant inhibition at 100 ?M). In addition, desmetramadol is a high-affinity ligand of the DOR, and activation of this receptor could be involved in tramadol's ability to provoke seizures in some individuals, as DOR agonists are well-known for inducing seizures.
Nausea and vomiting caused by tramadol is thought to be due to activation of the 5-HT3 receptor via increased serotonin levels. In accordance, the 5-HT3 receptor antagonist metoclopramide can be used to treat tramadol-associated nausea and vomiting. Tramadol and desmetramadol themselves do not bind to the 5-HT3 receptor.
Pharmacokinetics
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 ?-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 as 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.
Its volume of distribution is approximately 306 L after oral administration and 203 L after parenteral administration.
Chemistry
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. The (+)-isomer is predominantly active as an opiate with a higher affinity for the µ-opiate receptor (20 times higher affinity than the (-)-isomer).
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:
- (1R,2R)-isomer
- (1S,2S)-isomer
- (1R,2S)-isomer
- (1S,2R)-isomer
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.
Detection in biological fluids
Tramadol and desmetramadol 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 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 concentration of desmetramadol in the blood or plasma of a person who has taken tramadol is generally 10-20% those of the parent drug.
History
The U.S. Food and Drug Administration (FDA) approved tramadol in March 1995 and an extended-release (ER) formulation in September 2005. Tramadol is protected by US patents nos. 6,254,887 and 7,074,430. The FDA listed the patents' expiration as 10 May 2014. However, in August 2009, US 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.
Society and culture
Legal status
Effective August 18, 2014, tramadol has been placed into Schedule IV of the federal Controlled Substances Act. In addition, many states, including Arkansas, Georgia, Kentucky, Illinois, Mississippi, New York, North Dakota, Ohio, Oklahoma, South Carolina, Tennessee, West Virginia, Wyoming and the U.S. military have already classified tramadol as a Schedule IV controlled substance under state law.
Tramadol is classified in Schedule 4, in Australia, rather than as a Schedule 8 Controlled Drug like most other opioids.
Effective May 2008, Sweden classified tramadol as a controlled substance in the same category as codeine and dextropropoxyphene, but allows a normal prescription be used currently.
The UK classified tramadol as a Schedule 3 controlled drug (CD) on 10 June 2014, but exempted it from the safe custody requirement.
Research
Investigational uses
- Diabetic neuropathy
- Antidepressant
- Postherpetic neuralgia
- Premature ejaculation
- Obsessive-compulsive disorder
False findings about sources in nature
In 2013, researchers reported that tramadol was found in relatively high concentrations (1%+) in the roots of the African pin cushion tree (Nauclea latifolia). 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: 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.
A 2014 editorial in Lab Times online contested the notion that tramadol in tree roots was the result of anthropogenic contamination, stating that samples were taken from trees which grew in national parks, where livestock were forbidden; it also quoted researcher Michel de Waard, who stated that "thousands and thousands of tramadol-treated cattle sitting around a single tree and urinating there" would be required to produce the concentrations discovered.
In 2015, radiocarbon analysis confirmed that the Tramadol found in N.latifolia roots could not be plant-derived and was of synthetic origin.
Veterinary medicine
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.
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