Tramadol , sold under the brand name Ultram , among others, are pain medications such as opioids used to treat moderate to moderate pain. When taken in a direct release formulation, the onset of pain usually occurs within an hour. It is often combined with paracetamol (acetaminophen) because it is known to increase the effectiveness of tramadol in relieving pain.
Common side effects include: constipation, itching and nausea. Serious side effects may include seizures, increased risk of serotonin syndrome, decreased alertness, and drug addiction. Dose changes can be recommended to those with kidney or liver problems. It is not recommended for those at risk of suicide. Although not recommended in women who are breastfeeding, those taking a single dose should not stop breastfeeding in general.
It works by binding to -opioid receptors and by acting as a serotonin-norepinephrine reuptake inhibitor (SNRI). Tramadol is in the benzenoid class. In the body is converted into desmetramadol, which is a stronger opioid.
Tramadol was launched and marketed as "Tramal" by German pharmaceutical company GrÃÆ'¼nenthal GmbH in 1977 in West Germany, and 20 years later launched in the UK, US, and Australia. It is marketed under many brand names worldwide.
Video Tramadol
Medical use
Tramadol is used primarily to treat mild-severe pain, both acute and chronic.
Its analgesic effect takes about an hour to take effect and 2 hours to 4 hours to the top after oral administration with an immediate release formulation. At dose-on-dose, tramadol has about one-tenth of the potency of morphine and is practically as potent as pethidine and codeine.
For moderate pain in severity, its effectiveness is equivalent to morphine; for severe pain is less effective than morphine. This painkiller effect lasts about 6 hours.
Available dosage forms include liquids, syrups, drops, herbs, efervescent tablets and powders for mixing with water, capsules, tablets including extended release formulations, suppositories, compound powders, and injections.
Fibromyalgia
By 2015 tramadol is not approved in the United States for fibromyalgia. Based on three small trials with weak study designs, there is fair evidence for tramadol as second-line treatment.
Maps Tramadol
Contraindications
Use of tramadol is not recommended for people lacking the CYP2D6 enzyme. Enzymes are essential for the therapeutic effect of tramadol, by allowing the metabolism of tramadol into desmetramadol.
Pregnancy and lactation
The use of tramadol in pregnancy is generally avoided as it may cause some reversible withdrawal effects in newborns. A small prospective study in France found that, while there was an increased risk of miscarriage, no major malformations were reported in newborns. Its use during breastfeeding is also generally advised to fight, but a small trial found that infants who were breastfed by mothers taking tramadol were exposed to about 2.88% of the dose consumed by the mother. There is no evidence that this dose has a harmful effect on the newborn.
Labor and delivery
Its use as an analgesic during labor is generally recommended because of its long onset (one hour). The ratio of median drug concentrations to fetuses compared to mothers when administered intramuscularly to labor pain is estimated 94.
Children
Its use in children is generally advised against, although it can be done under the supervision of a specialist. On September 21, 2015 the FDA began investigating the safety of tramadol used in people under the age of 17. The investigation is done because some of these people experience slowing or difficulty breathing. The FDA registers under 12 years of age as contraindicated.
Elderly
There is an increased risk of adverse effects associated with opioids such as respiratory depression, fall, cognitive impairment and sedation.
Liver and kidney failure
It is recommended that the drug be used with caution in those with liver or kidney failure, due to metabolism in the liver (for desmetramadol) and elimination through the kidneys.
Side effects
The most common adverse effects of tramadol include nausea, dizziness, dry mouth, indigestion, abdominal pain, vertigo, vomiting, constipation, drowsiness and headaches. Compared with other opioids, respiratory depression and constipation are thought to be less problematic with tramadol.
There are suggestions that chronic opioid administration may lead to a state of immune tolerance, although tramadol, in contrast to typical opioids, may enhance immune function.
Dependence and tethering
Long-term use of high doses of tramadol will lead to physical dependence and withdrawal syndrome. These include both typical symptoms of opioid withdrawal and 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 be set within 12-20 hours after the last dose, but this may vary. Tramadol withdrawal usually lasts longer than other opioids. Seven days or more of acute withdrawal symptoms may occur as opposed to usually three or four days for other analogs of codeine.
A 2014 report by the World Health Organization Expert Committee for Drug Addiction found:
... in many cases of tramadol dependence, history of substance abuse is present.... but.... evidence for physical dependence is considered minimal. As a result, Tramadol is generally regarded as a drug with a low potential for dependence. In recent German studies (including literature studies, analysis of two drug safety databases, and analytical questionnaires), low abuses and low dependency potential of Tramadol were reconfirmed. The German group of experts found a low prevalence of abuse or dependence in clinical practice in Germany, and concluded that Tramadol has low potential for misuse, abuse and dependence in Germany.
Because of the possibility of seizures at high doses for some users, recreational use can be very dangerous. Tramadol can cause the incidence of nausea, dizziness, loss of appetite higher than opioids, which may hinder the use of recreation. Compared to hydrocodone, fewer people choose to use recreational tramadol.
Overdose
The recognized 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.
Deaths with tramadol overdose have been reported and increased in frequency in Northern Ireland; The majority of these overdoses involve other drugs including alcohol. There are 254 tramadol-related deaths in England and Wales in 2013, and 379 in Florida in 2011. In 2011 there were 21,649 emergency room visits in the United States linked to tramadol.
Interactions
Tramadol may interact with serotonergic, 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 drugs (triptans, ergots), certain anxiolytics (such as SSRIs and buspirones), certain antibiotics (ie, linezolid and isoniazid), certain herbs (eg St. John's wort, passiflora, etc.), amphetamines, substituted amphetamines, phenethylamine and substituted phenethylamine, phentermine, lithium, methylene blue as well as many other therapeutic agents. Because it is a CYP3A4 and CYP2D6 substrate, any agent with the ability to inhibit or induce this enzyme is likely to interact with tramadol. A pressure response similar to the so-called "cheese effect" is noted in the combination of amphetamine and tramadol, which appears to cause dysfunction or toxicity in epinephrine/norepinephrine receptors. Cyclobenzaprine, commonly used muscle relaxants, additional atypical analgesics, as well as potentiators often used with analgesics such as codeine, dihydrocodine, hydrocodone and the like, are structurally associated with tricyclic antidepressants and therefore should not be used with tramadol; this also applies to trazodone.
Pharmacology
Action mechanism
Tramadol has been found to have the following actions:
- Agonis of? -opioid receptor (MOR) and at a much lower rate than the -opioid receptor (DOR) and? -opioid receptor (KOR)
- Serotonin reuptake inhibitor (SRI) and norepinephrine reuptake inhibitor (NRI); hence, a SNRI
- Serotonin 5-HT receptor antagonist 2C
- M 1 and M 3 muscarinic acetylcholine receptor antagonist
- ? 7 nicotinic acetylcholine receptor antagonists
- NMDA receptor antagonist (very weak)
- TRPA1 inhibitor
Tramadol acts on the opioid receptor via the main active metabolite of desmetramadol, which has a high affinity up to 700 fold for MOR relative to tramadol. In addition, tramadol itself has been found to have no efficacy in activating MOR in functional activity tests, whereas desmetramadol activates receptors with high intrinsic activity (E max equals morphine). Thus, desmetramadol is exclusively responsible for the opioid effects of tramadol. Both tramadol and desmetramadol have expressed selectivity for MOR over DOR and KOR in terms of binding affinities.
Tramadol is well established as a serotonin reuptake inhibitor. In addition, several studies have found that it also acts as a serotonin release agent (1-10Ã,? M), similarly applicable to fenfluramine. The effects of serotonin release from tramadol may be blocked by a high enough serotonin reuptake inhibitor 6-nitroquipazine, which corresponds to other serotonin-releasing agents such as fenfluramine and MDMA. However, two recent studies failed to find tramadol release effects at their respective concentrations of up to 10 and 30Ã, Â ° M. In addition to serotonergic activity, tramadol is also a norepinephrine reuptake inhibitor. This is not an agent releasing norepinephrine. Tramadol does not inhibit reuptake or induce dopamine release.
A positron emission tomography imaging study found that a single tramadol 50 mg and 100 mg single dose for human volunteers yielded 34.7% and 50.2% respectively meaning serotonin transporter (SERT) work on the thalamus. The effective median dose estimate (ED 50 ) for SERT occupancy was 98.1 mg, which was associated with a plasma tramadol level of about 330 ng/mL (1,300 m). It is estimated that the maximum daily dose of tramadol 400 mg (100 mg qid ) will produce as much as 78.7% occupancy of the SERT (corresponding to plasma concentrations of 1.220 ng/mL or 4.632 mM ). This is close to selective serotonin reuptake inhibitors (SSRIs), which occupy SERT up to 80% or more.
Peak plasma concentrations during treatment with clinical doses 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 m) for desmetramadol.. The highest level of tramadol observed with a daily maximum dose of 400 mg per day divided into one 100 mg dose every 6 hours (ie, four doses of 100 mg evenly daily). There are several accumulations of tramadol with chronic administration; peak plasma levels of tramadol with a maximum daily dose of oral (100 mg qid ) is about 16% higher and the area under the 36% level curve is higher than following a single 100mg oral dose. Positron emission tomographic imaging studies have reportedly found that tramadol levels are at least 4 times higher in the brain than in plasma. In contrast, the level of brain desmetramadol "only slowly approaches them in the plasma". The binding of tramadol plasma proteins is only 4 to 20%; therefore, almost all tramadol are free-circulating and thus bioactive.
Correspondence to clinical effects
Giving alongside quinidine, a potent CYP2D6 inhibitor, with tramadol, a combination that results in decreased desmetramadol levels, was found to not 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 metabolism. The analgesic effect of tramadol is only partially reversed by naloxone in human volunteers, which indicates that opioid action may not be a single factor; The analgesic effects of tramadol are also partially reversed by a -adrenergic receptor antagonist such as yohimbine such as yohimbine, 5-HT receptor antagonist 3 ondansetron, and 5-HT 7 SB-269970 and SB receptor antagonists -258719. Pharmacologically, tramadol is similar to tapentadol and methadone because it not only binds MOR, but also inhibits reuptake of serotonin and norepinephrine because of its action on the noradrenergic and serotonergic systems, such as "atypical" opioid activity.
Tramadol has an inhibitory action on the 5-HT receptor 2C . The 5-HT 2C antagonism can be partially responsible for reducing the effects of tramadol on depressive and obsessive-compulsive symptoms in patients with neurologic pain and co-morbid disease. 5-HT 2C blockade can also cause a decrease in seizure threshold, since 5-HT knockouts 2C significantly increase susceptibility to epileptic seizures, sometimes resulting in spontaneous death.. However, a reduction in the seizure threshold can be attributed to tramadol-putting inhibition of GABA receptors A at high doses (significant inhibition of 100 °, M). In addition, desmetramadol is a high affinity ligand of DOR, and activation of these receptors may be involved in the ability of tramadol to provoke seizures in some individuals, as DOR agonists are notorious for inducing seizures.
The nausea and vomiting caused by tramadol is thought to be due to the activation of 5-HT receptors 3 through elevated serotonin levels. Accordingly, 5-HT 3 metoclopramide receptor antagonists may be used to treat tramadol associated with nausea and vomiting. Tramadol and desmetramadol alone do not bind to 5-HT receptors 3 .
Pharmacokinetics
Tramadol undergoes liver metabolism through the CYP2B6, CYP2D6 and CYP3A4 cytochrome P450, being O - and N -immitted to five different metabolites. From this, desmetramadol ( O -desmethyltramadol) is the most significant because it has 200 times? -afinity of () - tramadol, and subsequently has a nine-hour half-life elimination, compared to six hours for tramadol itself. Like codeine, in 6% of the population that has reduced CYP2D6 activity (therefore reduces metabolism), there is less analgesic effect. Those with reduced activity of CYP2D6 require a 30% dose increase to achieve the same pain relief rate as normal CYP2D6 activity levels.
Phase II liver metabolism makes water-soluble metabolites, which are excreted by the kidneys. Thus, a reduced dose can be used for kidney and liver disorders.
Distribution volume is about 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 two isomers complement each other's analgesic activity. Isomers () - dominant isomers active as opiates with higher affinity for μ-opio receptors (affinity 20 times higher than isomers (-) -).
Synthesis and stereoisomerism
Chemical synthesis of tramadol is described in the literature. Tramadol <2> (2-dimethylaminomethyl) -1- (3-methoxyphenyl) cyclohexanol] has two stereogenic centers on cyclohexane rings. Thus, 2- (dimethylaminomethyl) -1- (3-methoxyphenyl) cyclohexanol may exist in four different configurations:
- (1 R , 2 R ) - isomer
- (1 S , 2 S ) - isomer
- (1 R , 2 S ) - isomer
- (1 S , 2 R ) - isomer
The synthetic path leads to racemate (1: 1 mixture) of (1 R , 2 R ) - isomers and (1 S > S ) - isomer as the main product. The small number of raceme mixtures from (1 R , 2 S ) - isomers and (1 S , 2 R ) - isomers are formed too. Isolation of (1 R , 2 R ) - isomers and (1 S , 2 S 2) i isomer and (1 S , 2 R ) - isomer] is realized by recrystallization of hydrochloride. Tramadol drugs are rascano hydrochloride (1 R , 2 R ) - () - and (1 S , 2 S ) - (-) - enansiomer. 2 S , 2 R ) - () - isomer/(1 S ) - (-) - isomer] described using ( R ) - (-) - or ( S ) - () - mandelic acid. This process does not find industrial applications, because tramadol is used as a rasm, although it is known that different physiological effects of (1 R , 2 R ) - and (1 > S , 2 S ) - isomers, because racism shows higher analgesic activity than enansiomers in animals and in humans.
Detection in biological fluid
Tramadol and desmetramadol can be quantified in blood, plasma or serum to monitor abuse, confirm the diagnosis of poisoning or assist in a sudden forensic death investigation. Most commercial opiate immunoassay screening tests do not cross-react significantly with tramadol or its major metabolites, so chromatographic techniques should be used to detect and quantify these substances. The concentration of desmetramadol in the blood or plasma of people who have taken tramadol is generally 10-20% of the parent drug.
History
The US Food and Drug Administration (FDA) approved tramadol in March 1995 and the extended-release (ER) formulation in September 2005. Tramadol is protected by US patent no. 6,254,887 and 7,074,430. The FDA notes the expiration date of the patent as of May 10, 2014. However, in August 2009, the US District Court for the Delaware District ruled that the patent is invalid, which, if retained, would allow generating and generating the generic equivalent of Ultram ER in the United States.
Abuse
Tramadol is used in Nigeria both by Boko Haram and the vigilant groups that fight against Boko Haram. Fighters are given to make them feel strong and courageous. There are also a large number of youth who are addicted to tramadol in the area. It costs about five US cents for 200 mg pills. It is common to take twice the maximum daily dose of 400 mg. Users get angry and irritable when using it, but experience headaches, stomach aches, and depression if they do not get the dose. Tramadol is imported legally from India, as there are no international regulations for tramadol trading.
Society and culture
Legal status
Effective August 18, 2014, tramadol has been incorporated into Schedule IV of the federal Controlled Substances Act in the United States. Prior to that, several US states have classified tramadol as a substance set forth in Schedule IV under the laws of each state.
Tramadol is classified in Schedule 4 (recipe only) in Australia, not as Schedule 8 Controlled Drug (Possession without illegal authority) like most other opioids.
Effective May 2008, Sweden classified tramadol as a controlled substance in the same category as codeine and dextropropoxyphene, but allows normal prescriptions to be used today.
The UK classifies tramadol as Class C, a drug controlled Schedule 3 on June 10, 2014, but exempts it from safe storage requirements.
Research
Investigation using
- diabetic neuropathy
- Antidepressants
- 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 African pin cushion tree roots ( Nauclea latifolia ). In 2014, however, it was reported that the presence of tramadol at the root of the tree is the result of tramadol that has been given to cattle by farmers in the region: tramadol and its metabolites present in animal feces, which contaminate the surrounding soil. trees. Therefore, tramadol and mammalian metabolites are found in tree roots at the northern end of Cameroon, but not in the south where it is not given to farm animals.
A 2014 editorial at the online Times Lab contradicts the idea that tramadol in tree roots is the result of anthropogenic contamination, stating that samples were taken from trees grown in national parks, where cattle were forbidden; it also cites researcher Michel de Waard, who states that "thousands and tramadol of livestock treated around a tree and urinating there" will be required to produce the concentrations found.
By 2015, radiocarbon analysis confirms that the tramadol found in the roots of N.latifolia can not be derived from plants and comes from synthetics.
Veterinary
Tramadol can be used to treat post-operative, related, and chronic injuries (eg, cancer related) pain in dogs and cats as well as rabbits, coatis, many small mammals including mice and flying squirrels, guinea pigs, weasels and raccoons.
See also
- List of antidepressants studied
- List of sexually explored sexual dysfunction drugs
References
External links
- Medline Plus - Patient Information Medline Plus (Service from U.S. National Medical Library)
- US. National Medical Library: Drug Information Portal - Tramadol
Source of the article : Wikipedia
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