Tramadol, sold under the brand name Ultram among others,[1] is an opioidpain medication and a serotonin–norepinephrine reuptake inhibitor (SNRI) used to treat moderately severe pain.[3][14] When taken by mouth in an immediate-release formulation, the onset of pain relief usually begins within an hour.[3] It is also available by injection.[15] It is available in combination with paracetamol (acetaminophen).
Tramadol was patented in 1972 and launched under the name "Tramal" in 1977 by the West German pharmaceutical companyGrünenthal GmbH.[14][18] In the mid-1990s, it was approved in the United Kingdom and the United States.[14] It is available as a generic medication and marketed under many brand names worldwide.[1][3] In 2021, it was the 41st most commonly prescribed medication in the United States, with more than 15million prescriptions.[19][20]
Medical uses
Generic tramadol HCl tablets marketed by Amneal PharmaceuticalsTramadol HCl for injection
Tramadol is used primarily to treat mild to severe pain, both acute and chronic.[21][22] There is moderate evidence for use as a second-line treatment for fibromyalgia but it is not FDA approved for this use.[23] Its use is approved for treatment of fibromyalgia as a secondary painkiller by the NHS.[24]
Its analgesic effects take approximately an hour to be realized, and it takes from two to four hours to reach peak effect after oral administration with an immediate-release formulation.[21][22] 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.[25] For moderate pain, 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.[21]
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.[13][21]
Sleep medicine physicians sometimes prescribe tramadol (or other opiate medications) for refractoryrestless legs syndrome (RLS);[26][27] 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.[28]
Contraindications
Individuals with certain genetic variations of CYP2D6 enzymes, which convert tramadol into an inactive molecule, may not experience enough pain relief from tramadol.[13][21] These genetic polymorphisms are not currently routinely tested for in clinical practice.[29]
Pregnancy and lactation
Use of Tramadol during pregnancy is generally avoided, as it may cause some reversible withdrawal effects in the newborn.[30] A small prospective study in France found, while an increased risk of miscarriages existed, no major malformations were reported in the newborn.[30] 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.[30]
Labor and delivery
Its use as an analgesic during labor is not advised due to its long onset of action (1 hour).[30] The ratio of the mean concentration of the drug in the fetus compared to that of the mother when it is given intramuscularly for labor pains has been estimated to be 1:94.[30]
Children
Its use in children is generally advised against, although it may be done under the supervision of a specialist.[21] 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.[31] The FDA lists age under 12 years old as a contraindication.[32][33]
Elderly
The risk of opioid-related adverse effects such as respiratory depression, falls, cognitive impairment and sedation is increased.[21] Tramadol may interact with other medications and increase the risk for adverse events.[29]
Liver and kidney failure
The drug should be used with caution in those with liver or kidney failure, due to metabolism in the liver (to the active molecule desmetramadol) and elimination by the kidneys.[21]
Main side effects of tramadol: Red color denotes more serious effects, requiring immediate contact with health provider.[4]
Dependence and withdrawal
Long-term use of high doses of tramadol causes physical dependence and withdrawal syndrome.[37] These include both symptoms typical of opioid withdrawal and those associated with serotonin–norepinephrine reuptake inhibitor (SNRI) withdrawal; symptoms include numbness, tingling, paresthesia, and tinnitus.[38] Psychiatric symptoms may include hallucinations, paranoia, extreme anxiety, panic attacks, and confusion.[39] In most cases, tramadol withdrawal will set in 12–20 hours after the last dose, but this can vary.[38] Tramadol withdrawal typically lasts longer than that of other opioids. Seven days or more of acute withdrawal symptoms can occur as opposed to typically 3 or 4 days for other codeine analogs.[38]
Overdose
The clinical presentation in overdose cases can vary but typically includes neurological, cardiovascular, and gastrointestinal manifestations.[40] The predominant neurological symptoms are seizures and altered levels of consciousness, ranging from somnolence to coma. Seizures are particularly notable due to tramadol's lowering of the seizure threshold, occurring in approximately half of acute poisoning cases.[41] Patients often exhibit tachycardia and mild hypertension. Gastrointestinal disturbances such as nausea and vomiting are common, and agitation, anxiety, and cold and clammy skin may also be present.[42]
While less common, severe complications like respiratory depression and serotonin syndrome can occur, particularly in polydrug overdoses involving other CNS depressants (such as benzodiazepines, opioids, and alcohol) and agents with serotonergic activity.[43][44] Additionally, Individuals with genetic variations leading to CYP2D6 enzyme duplication (rapid metabolizers) may have an increased risk of adverse effects, due to faster conversion of tramadol to its active metabolite.[45]
Acute tramadol overdose is generally not life-threatening, with most fatalities resulting from polysubstance overdose.[46] Management includes cardiovascular monitoring, activated charcoal administration, hydration, and treatment of seizures.[47]Naloxone, an opioid antagonist, can partially reverse some effects of tramadol overdose, particularly respiratory depression. However, its use may increase the risk of seizures due to unopposed alpha-adrenergic stimulation.[21] For suspected serotonin syndrome, cyproheptadine, a serotonin antagonist, is considered an effective antidote.[43]
The incidence of tramadol-related overdose deaths has been on the rise in certain regions. For instance, Northern Ireland has reported an increased frequency of such cases.[48] In 2013, England and Wales recorded 254 tramadol-related deaths, while Florida reported 379 cases in 2011.[49][50] In 2011, 21,649 emergency room visits in the United States were related to tramadol.[51] The likely explanation for these observations is due to increase in frequency of prescriptions and use due to easier access due to lighter regulatory scheduling by authorities[52] but this is starting to change. In 2021, Health Canada announced tramadol would be added to Schedule I of the Controlled Drugs and Substances Act and to the Narcotic Control Regulations due to tramadol being suspected of having contributed to 18 reported deaths in Canada between 2006 and 2017.[53]
Interactions
Tramadol Hydrochloride (50mg) capsules made by Bristol Laboratories and provided by a pharmacy in England
Tramadol is metabolized by CYP2D6 enzymes which contribute to the metabolism of approximately 25% of all medications.[54] Any medications with the ability to inhibit or induce these enzymes may interact with tramadol. These include common antiarrhythmics, antiemetics, antidepressants (sertraline, paroxetine, and fluoxetine in particular),[55] antipsychotics, analgesics, and tamoxifen.[56]
Due to tramadol's serotonergic effects, tramadol has the potential to contribute to the development of an acute or chronic hyper-serotonin state called serotonin syndrome when used concurrently with other pro-serotonergic medications such as antidepressants (SSRIs, SNRIs, tricyclics, MAOIs), antipsychotics, triptans, cold medications containing dextromethorphan, and some herbal products such as St. John's wort.[56][57]
Tramadol increases the risk for seizures by lowering the seizure threshold. Using other medications that lower seizure threshold - such as antipsychotic medications, bupropion (an anti-depressant and smoking cessation drug), and amphetamines - can further increases this risk.[60]
Pharmacology
Mechanism of action
Tramadol induces analgesic effects through a variety of different targets on the noradrenergic system, serotoninergic system, and opioid receptors system.[61] 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.[62][12] 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.[63] All these effects work synergistically to induce analgesia.
Tramadol acts on the opioid receptors through its major active metabolitedesmetramadol, which has as much as 700-fold higher affinity for the MOR relative to tramadol.[17] 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).[72][17][89] As such, desmetramadol is exclusively responsible for the opioid effects of tramadol.[90] Both tramadol and desmetramadol have pronounced selectivity for the MOR over the DOR and KOR in terms of binding affinity.[73][68][70]
Tramadol is well-established as an SRI.[65][66] In addition, a few studies have found that it also acts as a serotonin releasing agent (1–10 μM), similar in effect to fenfluramine.[91][92][93][94] 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 such as fenfluramine and MDMA.[91][93][94] However, two more recent studies failed to find a releasing effect of tramadol at respective concentrations up to 10 and 30 μM.[95][94][88] In addition to serotonergic activity, tramadol is also a norepinephrine reuptake inhibitor.[65][66] It is not a norepinephrine releasing agent.[96][97][98][88] Tramadol does not inhibit the reuptake or induce the release of dopamine.[96][88]
A positron emission tomographyimaging 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.[99] 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).[99] 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).[99] This is close to that of SSRIs, which occupy the SERT by 80% or more.[99]
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.[22] 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).[22][100] Some accumulation of tramadol occurs with chronic administration; peak plasma levels 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.[22]Positron emission tomography imaging studies have reportedly found that tramadol levels are at least four-fold higher in the brain than in plasma.[96][101] Conversely, brain levels of desmetramadol "only slowly approach those in plasma".[96] The plasma protein binding of tramadol is only 4–20%; hence, almost all tramadol in circulation is free, thus bioactive.[102][103][104]
Correspondence to effects
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.[17][103] However, other studies have found that the analgesic effects of tramadol are significantly decreased or even absent in CYP2D6 poor metabolizers.[17][90] The analgesic effects of tramadol are only partially reversed by naloxone in human volunteers,[17] 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.[22][105] 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[10] due to its action on the noradrenergic and serotonergic systems, such as its "atypical" opioid activity.[106]
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.[76] 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 GABAA receptors at high doses (significant inhibition at 100 μM).[85][62] 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.[70]
Nausea and vomiting caused by tramadol are thought to be due to activation of the 5-HT3 receptor via increased serotonin levels.[74] In accordance, the 5-HT3 receptor antagonist ondansetron can be used to treat tramadol-associated nausea and vomiting.[74] Tramadol and desmetramadol themselves do not bind to the 5-HT3 receptor.[74][66]
Tramadol is metabolised in the liver via the cytochrome P450isozymeCYP2B6, 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.[107][108]
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.[22]
Its volume of distribution is around 306 L after oral administration and 203 L after parenteral administration.[22]
Chemistry
Tramadol is marketed as a racemic mixture of both R- and S-stereoisomers,[10] because the two isomers complement each other's analgesic activities.[10] The (+)-isomer is predominantly active as an opiate with a higher affinity for the μ-opiate receptor (20 times higher affinity than the (-)-isomer).[109]
Synthesis and stereoisomerism
(1R,2R)-tramadol
(1S,2S)-tramadol
(1R,2S)-tramadol
(1S,2R)-tramadol
The chemical synthesis of tramadol is described in the literature.[110] 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[111] 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[112] of the (1R,2R)- and (1S,2S)-isomers, because the racemate showed higher analgesic activity than either enantiomer in animals[113] and in humans.[114]
Detection in biological fluids
Tramadol and desmetramadol may be quantified in blood, plasma, serum, or saliva 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.[115][116][117]
In 2014, Michael Spiteller (Technische Universität Dortmund) and collaborators reported results, also in Angewandte Chemie, that supported the conclusion that the presence of tramadol in those tree roots was the result of tramadol having been ingested by humans and having been administered to cattle (by farmers in the region); Spiteller et al. presented data that tramadol and its metabolites were present in animal excreta, which they then argue contaminated soil around the trees.[118] They further observed that tramadol and its mammalian metabolites were found in tree roots in the far north of Cameroon where the commercial drug was in use, but not in the south where it was not being administered.[118]
A news report appearing in Lab Times at the time of the latter, 2014 paper, and reporting on its contents, also reported that Michel de Waard (communicating author of the original paper) continued to contest the notion that tramadol in tree roots was the result of anthropogenic contamination.[120] The point was made that samples were taken from trees that grew in national parks, where livestock were forbidden, and it quoted de Waard extensively, who stated that "thousands and thousands of tramadol-treated cattle sitting around a single tree and urinating" would be required to produce the concentrations discovered.[120][better source needed]
In 2016, Spiteller and colleagues followed up their preceding work with a radiocarbon analysis that supported their contention that the tramadol found in N. latifolia roots was of human synthetic origin rather being plant-derived.[121]
Society and culture
Formulations
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.[21]
Patent history
The U.S. Food and Drug Administration (FDA) approved tramadol in March 1995, and an extended-release (ER) formulation in September 2005.[122] ER Tramadol was protected by US patents nos. 6,254,887[123] and 7,074,430.[124][125] The FDA listed the patents' expiration as 10 May 2014.[124] 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.[126]
Legal status
Effective 18 August 2014, tramadol has been placed into Schedule IV of the federal Controlled Substances Act in the United States.[127][128] Before that, some US states had already classified tramadol as a Schedule IV controlled substance under their respective state laws.[129][130][131]
Tramadol is classified in Schedule 4 (prescription only) in Australia, rather than as a Schedule 8 Controlled Drug (Possession without authority illegal) like most other opioids.[21]
On 10 June 2014, the United Kingdom's Home Office classified tramadol as a Class C, Schedule 3 controlled drug, but exempted it from the safe custody requirement.[133]
On 1 October 2023, New Zealand's Medsafe reclassified tramadol as a Class C2 Controlled Drug (in addition to its existing status as a prescription only medication).[134]
Misuse
Illicit use of the drug is thought to be a major factor in the success of the Boko Haram terrorist organization.[135][136][137] When used at higher doses, the drug "can produce similar effects to heroin."[135] One former member said, "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."[135] Tramadol is also used as a coping mechanism in the Gaza Strip.[138] It is also abused in the United Kingdom, inspiring the title of the TV show Frankie Boyle's Tramadol Nights (2010).[139][140]
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.[151]
Pharmacokinetics of tramadol across the species[151]
Species
Half-life (h) for parent drug
Half-life (h) for desmetramadol
Maximum plasma concentration (ng/mL) for parent drug
Maximum plasma concentration (ng/mL) for desmetramadol
^Polsten GR, Wallace MS (21 June 2016). "Analgesic Agents in Rheumatic Disease". In Firestein GS, Budd R, Gabriel SE, McInnes IB, O'Dell JR (eds.). Kelley and Firestein's Textbook of Rheumatology. Elsevier Health Sciences. pp. 1081–. ISBN978-0-323-41494-4.
^ abcdeBrayfield, A, ed. (13 December 2013). "Tramadol Hydrochloride". Martindale: The Complete Drug Reference. Pharmaceutical Press. Archived from the original on 29 August 2021. Retrieved 5 April 2014.
^ abcdefghijRaffa RB, Buschmann H, Christoph T, Eichenbaum G, Englberger W, Flores CM, et al. (July 2012). "Mechanistic and functional differentiation of tapentadol and tramadol". Expert Opinion on Pharmacotherapy. 13 (10): 1437–1449. doi:10.1517/14656566.2012.696097. PMID22698264. S2CID24226747.
^ abcdefghijkRossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN978-0-9805790-9-3.
^Lee CR, McTavish D, Sorkin EM (August 1993). "Tramadol. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in acute and chronic pain states". Drugs. 46 (2): 313–340. doi:10.2165/00003495-199346020-00008. PMID7691519. S2CID218465760.
^Silber MH, Becker PM, Buchfuhrer MJ, Earley CJ, Ondo WG, Walters AS, et al. (January 2018). "The Appropriate Use of Opioids in the Treatment of Refractory Restless Legs Syndrome". Mayo Clinic Proceedings. 93 (1): 59–67. doi:10.1016/j.mayocp.2017.11.007. PMID29304922. In summary, a number of opioid medications in low dose appear effective in refractory RLS. The risks of opioid use are relatively low, taking into account the much lower doses used for RLS compared with those in patients with pain syndromes. As long as reasonable precautions are taken, the risk-benefit ratio is acceptable and opioids should not be unreasonably withheld from such patients.
^Lipford MC, Silber MH (December 2012). "Long-term use of pramipexole in the management of restless legs syndrome". Sleep Medicine. 13 (10): 1280–1285. doi:10.1016/j.sleep.2012.08.004. PMID23036265. For the purposes of this study, augmentation was defined as earlier onset, increased severity, [increased] duration, or new anatomic distribution of RLS symptoms during treatment.
^ abcdeBloor M, Paech MJ, Kaye R (April 2012). "Tramadol in pregnancy and lactation". International Journal of Obstetric Anesthesia. 21 (2): 163–167. doi:10.1016/j.ijoa.2011.10.008. PMID22317891.
^Langley PC, Patkar AD, Boswell KA, Benson CJ, Schein JR (January 2010). "Adverse event profile of tramadol in recent clinical studies of chronic osteoarthritis pain". Current Medical Research and Opinion. 26 (1): 239–251. doi:10.1185/03007990903426787. PMID19929615. S2CID20703694.
^""Weak" opioid analgesics. Codeine, dihydrocodeine and tramadol: no less risky than morphine". Prescrire International. 25 (168): 45–50. February 2016. PMID27042732.
^"Withdrawal syndrome and dependence: tramadol too". Prescrire International. 12 (65): 99–100. June 2003. PMID12825576.
^Senay EC, Adams EH, Geller A, Inciardi JA, Muñoz A, Schnoll SH, et al. (April 2003). "Physical dependence on Ultram (tramadol hydrochloride): both opioid-like and atypical withdrawal symptoms occur". Drug and Alcohol Dependence. 69 (3): 233–241. CiteSeerX10.1.1.524.5426. doi:10.1016/S0376-8716(02)00321-6. PMID12633909.
^Marquardt KA, Alsop JA, Albertson TE (June 2005). "Tramadol exposures reported to statewide poison control system". The Annals of Pharmacotherapy. 39 (6): 1039–1044. doi:10.1345/aph.1e577. PMID15870139. S2CID20959808.
^Jovanović-Cupić V, Martinović Z, Nesić N (1 August 2012). "Seizures associated with intoxication and abuse of tramadol". Clinical Toxicology. 44 (2): 143–146. doi:10.1080/1556365050014418. PMID16615669. S2CID25269342.
^Randall C, Crane J (March 2014). "Tramadol deaths in Northern Ireland: a review of cases from 1996 to 2012". Journal of Forensic and Legal Medicine. 23: 32–36. doi:10.1016/j.jflm.2014.01.006. PMID24661703.
^Kostev K, Von Vultée C, Usinger DM, Reese JP (January 2018). "Tramadol prescription patterns in patients followed by general practitioners and orthopedists in Germany in the year 2015". Postgraduate Medicine. 130 (1): 37–41. doi:10.1080/00325481.2018.1407205. PMID29157058. S2CID32933111.
^Bernard S, Neville KA, Nguyen AT, Flockhart DA (February 2006). "Interethnic differences in genetic polymorphisms of CYP2D6 in the U.S. population: clinical implications". The Oncologist. 11 (2): 126–135. doi:10.1634/theoncologist.11-2-126. PMID16476833.
^ abMiotto K, Cho AK, Khalil MA, Blanco K, Sasaki JD, Rawson R (January 2017). "Trends in Tramadol: Pharmacology, Metabolism, and Misuse". Anesthesia and Analgesia. 124 (1): 44–51. doi:10.1213/ANE.0000000000001683. PMID27861439. S2CID24224625.
^Nelson EM, Philbrick AM (December 2012). "Avoiding serotonin syndrome: the nature of the interaction between tramadol and selective serotonin reuptake inhibitors". The Annals of Pharmacotherapy. 46 (12): 1712–1716. doi:10.1345/aph.1q748. PMID23212934. S2CID23707808.
^Stevens AJ, Woodman RJ, Owen H (February 2015). "The effect of ondansetron on the efficacy of postoperative tramadol: a systematic review and meta-analysis of a drug interaction". Anaesthesia. 70 (2): 209–218. doi:10.1111/anae.12948. PMID25490944. S2CID38180309.
^Hitchings A, Lonsdale D, Burrage D, Baker E (2015). Top 100 drugs : clinical pharmacology and practical prescribing. Churchill Livingstone Elsevier. pp. 168–169. ISBN978-0-7020-5516-4.
^"Tramadol". drugbank.ca. Archived from the original on 28 May 2019. Retrieved 21 January 2019.
^ abcRoth BL, Driscol J. "PDSP Ki Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Archived from the original on 29 August 2021. Retrieved 14 August 2017.
^ abcdeCodd EE, Shank RP, Schupsky JJ, Raffa RB (September 1995). "Serotonin and norepinephrine uptake inhibiting activity of centrally acting analgesics: structural determinants and role in antinociception". The Journal of Pharmacology and Experimental Therapeutics. 274 (3): 1263–1270. PMID7562497.
^ abGillen C, Haurand M, Kobelt DJ, Wnendt S (August 2000). "Affinity, potency and efficacy of tramadol and its metabolites at the cloned human mu-opioid receptor". Naunyn-Schmiedeberg's Archives of Pharmacology. 362 (2): 116–121. doi:10.1007/s002100000266. PMID10961373. S2CID10459734.
^ abcdefghiFrink MC, Hennies HH, Englberger W, Haurand M, Wilffert B (November 1996). "Influence of tramadol on neurotransmitter systems of the rat brain". Arzneimittel-Forschung. 46 (11): 1029–1036. PMID8955860.
^ abcdBarann M, Urban B, Stamer U, Dorner Z, Bönisch H, Brüss M (February 2006). "Effects of tramadol and O-demethyl-tramadol on human 5-HT reuptake carriers and human 5-HT3A receptors: a possible mechanism for tramadol-induced early emesis". European Journal of Pharmacology. 531 (1–3): 54–58. doi:10.1016/j.ejphar.2005.11.054. PMID16427041.
^Raffa RB, Friderichs E, Reimann W, Shank RP, Codd EE, Vaught JL (January 1992). "Opioid and nonopioid components independently contribute to the mechanism of action of tramadol, an 'atypical' opioid analgesic". The Journal of Pharmacology and Experimental Therapeutics. 260 (1): 275–285. PMID1309873.
^Shiraishi M, Minami K, Uezono Y, Yanagihara N, Shigematsu A (October 2001). "Inhibition by tramadol of muscarinic receptor-induced responses in cultured adrenal medullary cells and in Xenopus laevis oocytes expressing cloned M1 receptors". The Journal of Pharmacology and Experimental Therapeutics. 299 (1): 255–260. PMID11561087.
^Minami K, Sudo Y, Miyano K, Murphy RS, Uezono Y (June 2015). "μ-Opioid receptor activation by tramadol and O-desmethyltramadol (M1)". Journal of Anesthesia. 29 (3): 475–479. doi:10.1007/s00540-014-1946-z. PMID25394761. S2CID7091648.
^ abColler JK, Christrup LL, Somogyi AA (February 2009). "Role of active metabolites in the use of opioids". European Journal of Clinical Pharmacology. 65 (2): 121–139. doi:10.1007/s00228-008-0570-y. PMID18958460. S2CID9977741.
^ abReimann W, Schneider F (May 1998). "Induction of 5-hydroxytryptamine release by tramadol, fenfluramine and reserpine". European Journal of Pharmacology. 349 (2–3): 199–203. doi:10.1016/S0014-2999(98)00195-2. PMID9671098.
^ abcGobbi M, Moia M, Pirona L, Ceglia I, Reyes-Parada M, Scorza C, et al. (September 2002). "p-Methylthioamphetamine and 1-(m-chlorophenyl)piperazine, two non-neurotoxic 5-HT releasers in vivo, differ from neurotoxic amphetamine derivatives in their mode of action at 5-HT nerve endings in vitro". Journal of Neurochemistry. 82 (6): 1435–1443. doi:10.1046/j.1471-4159.2002.01073.x. hdl:10533/173421. PMID12354291. S2CID13397864.
^Gobbi M, Mennini T (April 1999). "Release studies with rat brain cortical synaptosomes indicate that tramadol is a 5-hydroxytryptamine uptake blocker and not a 5-hydroxytryptamine releaser". European Journal of Pharmacology. 370 (1): 23–26. doi:10.1016/s0014-2999(99)00123-5. PMID10323276.
^Gibson TP (July 1996). "Pharmacokinetics, efficacy, and safety of analgesia with a focus on tramadol HCl". The American Journal of Medicine. 101 (1A): 47S–53S. doi:10.1016/s0002-9343(96)00138-6. PMID8764760.
^Nobilis M, Kopecký J, Kvetina J, Chládek J, Svoboda Z, Vorísek V, et al. (March 2002). "High-performance liquid chromatographic determination of tramadol and its O-desmethylated metabolite in blood plasma. Application to a bioequivalence study in humans". Journal of Chromatography A. 949 (1–2): 11–22. doi:10.1016/S0021-9673(01)01567-9. PMID11999728.
^Kleemann A, Engel J, Kutscher B, Reichert D, eds. (2000). Pharmaceutical Substances (4th ed.). Stuttgart (Germany): Thieme-Verlag. pp. 2085–2086. ISBN978-1-58890-031-9.; since 2003 online with biannual actualizations.
^Zynovy Z, Meckler H (2000). "A Practical Procedure for the Resolution of (+)- and (−)-Tramadol". Organic Process Research & Development. 4 (4): 291–294. doi:10.1021/op000281v.
^Raffa RB, Friderichs E, Reimann W, Shank RP, Codd EE, Vaught JL, et al. (October 1993). "Complementary and synergistic antinociceptive interaction between the enantiomers of tramadol". The Journal of Pharmacology and Experimental Therapeutics. 267 (1): 331–340. PMID8229760.
^Grond S, Meuser T, Zech D, Hennig U, Lehmann KA (September 1995). "Analgesic efficacy and safety of tramadol enantiomers in comparison with the racemate: a randomised, double-blind study with gynaecological patients using intravenous patient-controlled analgesia". Pain. 62 (3): 313–320. doi:10.1016/0304-3959(94)00274-I. PMID8657431. S2CID34150137.
^Karhu D, El-Jammal A, Dupain T, Gaulin D, Bouchard S (September 2007). "Pharmacokinetics and dose proportionality of three Tramadol Contramid OAD tablet strengths". Biopharmaceutics & Drug Disposition. 28 (6): 323–330. doi:10.1002/bdd.561. PMID17575561. S2CID22720069.
^Tjäderborn M, Jönsson AK, Hägg S, Ahlner J (December 2007). "Fatal unintentional intoxications with tramadol during 1995-2005". Forensic Science International. 173 (2–3): 107–111. doi:10.1016/j.forsciint.2007.02.007. PMID17350197.
^Baselt R (2017). Disposition of Toxic Drugs and Chemicals in Man (11th ed.). Biomedical Publications, Seal Beach, CA. pp. 2185–2188. ISBN978-0-692-77499-1.
^Harati Y, Gooch C, Swenson M, Edelman S, Greene D, Raskin P, et al. (June 1998). "Double-blind randomized trial of tramadol for the treatment of the pain of diabetic neuropathy". Neurology. 50 (6): 1842–1846. doi:10.1212/WNL.50.6.1842. PMID9633738. S2CID45709223.
^Harati Y, Gooch C, Swenson M, Edelman SV, Greene D, Raskin P, et al. (2000). "Maintenance of the long-term effectiveness of tramadol in treatment of the pain of diabetic neuropathy". Journal of Diabetes and Its Complications. 14 (2): 65–70. doi:10.1016/S1056-8727(00)00060-X. PMID10959067.
^Barber J (April 2011). "Examining the use of tramadol hydrochloride as an antidepressant". Experimental and Clinical Psychopharmacology. 19 (2): 123–130. doi:10.1037/a0022721. PMID21463069.
^Göbel H, Stadler T (1997). "[Treatment of post-herpes zoster pain with tramadol. Results of an open pilot study versus clomipramine with or without levomepromazine]". Drugs (in French). 53 (Suppl 2): 34–39. doi:10.2165/00003495-199700532-00008. PMID9190323. S2CID46986791.
^Boureau F, Legallicier P, Kabir-Ahmadi M (July 2003). "Tramadol in post-herpetic neuralgia: a randomized, double-blind, placebo-controlled trial". Pain. 104 (1–2): 323–331. doi:10.1016/S0304-3959(03)00020-4. PMID12855342. S2CID42979548.
^Wu T, Yue X, Duan X, Luo D, Cheng Y, Tian Y, et al. (September 2012). "Efficacy and safety of tramadol for premature ejaculation: a systematic review and meta-analysis". Urology. 80 (3): 618–624. doi:10.1016/j.urology.2012.05.035. PMID22840860.
^Wong BL, Malde S (January 2013). "The use of tramadol "on-demand" for premature ejaculation: a systematic review". Urology. 81 (1): 98–103. doi:10.1016/j.urology.2012.08.037. PMID23102445.
^Ryan T, Hodge A, Holyoak R, Vlok R, Melhuish T, Binks M, et al. (July 2019). "Tramadol as an adjunct to intra-articular local anaesthetic infiltration in knee arthroscopy: a systematic review and meta-analysis". ANZ Journal of Surgery. 89 (7–8): 827–832. doi:10.1111/ans.14920. PMID30684306. S2CID59275648.
^ abSouza MJ, Cox SK (January 2011). "Tramadol use in zoologic medicine". The Veterinary Clinics of North America. Exotic Animal Practice. 14 (1): 117–130. doi:10.1016/j.cvex.2010.09.005. PMID21074707.
Західна область Western Region — Область — Вид Західна область Координати: 00°39′ пд. ш. 030°41′ сх. д. / 0.650° пд. ш. 30.683° сх. д. / -0.650; 30.683 Країна Уганда Площа - Повна 55 276 км² Населення (2011) - Усього 8 229 800 - Гус…
Queen's Theatre in 1880–1885 The Queen's Theatre was a playhouse in Melbourne, the capital of Victoria, Australia. Situated on Queen Street, it was Melbourne's first purpose-built venue for staging plays, musicals and opera. History Originally named the Queen's Theatre Royal, it was located on the north-east corner of Queen and Little Lonsdale streets[1] or the south-west corner of Queen and Little Bourke streets. It was built for councillor, later mayor John Smith, licensee of the Ade…
2012 American filmWonder Women! The Untold Story of American SuperheroinesDirected byKristy Guevara-FlanaganProduced byKelcey EdwardsCinematographyGabriel MillerMusic byJimmy LavalleDistributed byPhase 4 FilmsRelease date March 10, 2012 (2012-03-10) Running time79 minutesCountryUnited StatesLanguageEnglish Wonder Women! The Untold Story of American Superheroines is a 2012 documentary film exploring the concept of heroic women from the birth of the superhero in the 1940s to the TV …
Menara Gediminas' Menara Gediminas' (bahasa Lituania: Gedimino pilies bokštas) adalah bagian yang tersisa dari Kastil Atas di Vilnius, Lituania. Benteng kayu pertama dibangun oleh Gediminas, Adipati Agung Lituania. Kastil bata pertama selesai tahun 1409 oleh Adipati Agung Vytautas. Menara tiga lantai ini dibangun kembali pada tahun 1933 oleh arsitek Polandia Jan Borowski. Beberapa sisa-sisa kastil tua telah dipulihkan, dipandu oleh penelitian arkeologi. Dimungkinkan untuk naik ke puncak buk…
Gunung ArfakGunung Arfak terlihat dari telaga dekat Bandar Udara RendaniTitik tertinggiKetinggian2.955 m (9.695 ft)Puncak2.775 m (9.104 ft)Masuk dalam daftarUltraRibuGeografiGunung ArfakSemenanjung Doberai, Papua Barat, IndonesiaPegununganPegunungan ArfakPendakianRute termudahHiking Gunung Arfak adalah titik tertinggi di provinsi Papua Barat. Gunung ini terletak di timur laut Semenanjung Doberai dan merupakan puncak tertinggi dari Pegunungan Arfak. Kota Manokwari dapat terlih…
Biografi ini tidak memiliki sumber tepercaya sehingga isinya tidak dapat dipastikan. Bantu memperbaiki artikel ini dengan menambahkan sumber tepercaya. Materi kontroversial atau trivial yang sumbernya tidak memadai atau tidak bisa dipercaya harus segera dihapus.Cari sumber: Pramesywara Adisendjaya – berita · surat kabar · buku · cendekiawan · JSTOR (Pelajari cara dan kapan saatnya untuk menghapus pesan templat ini) Pramesywara AdisendjayaLahirPramesywara …
老婆這週要出牆이번 주 아내가 바람을 핍니다别名這週妻子要出牆/我配不上她[1]原作《老婆這週要出牆(日语:今週、妻が浮気します)》吉田智子(日语:吉田智子 (脚本家))作品编剧李楠圭、李藝琳导演金鉐潤主演李善均、宋智孝、金希沅、芮智媛、李相燁、權寶雅制作国家/地区 韩国语言韓語集数12每集长度約60分鐘制作制作公司Drama House播出信息 首播频道J…
Professional Canadian football running back (born 1991) Charlie PowerNo. 46 Calgary StampedersPower before a Stampeders game in 2019.Born: (1991-06-01) June 1, 1991 (age 32).Chamblee, Georgia, U.S.Career informationStatusActiveCFL statusNationalPosition(s)RB/FBHeight6 ft 3 in (191 cm)Weight239 lb (108 kg)CollegeSaskatchewanHigh schoolHoly Trinity AcademyCFL Draft2013 / Round: 4 / Pick: 28Drafted byCalgary StampedersCareer …
أدوات ويب جوجلالشعارمعلومات عامةنوع أدوات الويدجت إطار عمل الأجاكس نظام التشغيل لينكس النموذج المصدري حقوق التأليف والنشر محفوظة المطورون جوجل موقع الويب gwtproject.org[1] (الإنجليزية) معلومات تقنيةلغة البرمجة جافاجافا سكريبت الإصدار الأول 16 مايو 2006 [2] الإصدار الأخير 2.10.…
Uang kertas 5 pound Australia (£5) adalah nilai uang kertas yang pertama kali dikeluarkan di Australia pada tahun 1913 sampai desimalisasi di mata uang Australia untuk penggantinya oleh uang kertas 10 dolar Australia pada tahun 1966. Uang kertas ini menampilkan gambar di mantel lengan dan Hawkesbury River. Pranala luar (Inggris) Museum of Australian Currency Notes Diarsipkan 2011-03-12 di Wayback Machine. (Inggris) Australian stamp Diarsipkan 2007-12-22 di Wayback Machine. lbsMata uang Australi…
DNA mitokondria manusia. Mikroskopi Elektron menunjukkan DNA mitokondria dalam foci diskrit. Bar: 200 nm. (A) Bagian sitoplasma setelah diberi label immunogold dengan anti-DNA; partikel emas menandai mtDNA ditemukan dekan membran mitokondria. (B) Seluruh pandangan mount sitoplasma setelah ekstraksi dengan CSK buffer dan diberi label immunogold dengan anti-DNA; mtDNA (ditandai dengan partikel emas) bertahan terhadap ekstraksi. Dari Iborra et al., 2004.[1] DNA mitokondria (Mitochondrial DN…
Cet article est une ébauche concernant le droit et les États-Unis. Vous pouvez partager vos connaissances en l’améliorant (comment ?) selon les recommandations des projets correspondants. Cour d'appel des États-Unis pour le septième circuitCadreType Cour d'appel fédérale des États-UnisPays États-Unismodifier - modifier le code - modifier Wikidata La cour d’appel des États-Unis pour le septième circuit (United States Court of Appeals for the Seventh Circuit), sise à Chi…
2016 single by Louisa JohnsonSo GoodSingle by Louisa JohnsonReleased28 October 2016 (2016-10-28)GenrePopLength3:10LabelSycoSongwriter(s)Steve MacChelcee GrimesEd DrewettProducer(s)Steve MacLouisa Johnson singles chronology Tears (2016) So Good (2016) Best Behaviour (2017) So Good is a song recorded by English singer Louisa Johnson. It was released on 28 October 2016, through Syco.[1] It was written and produced by Steve Mac with additional writing from Chelcee Grimes and E…
Convention center in the southwest section of downtown Los Angeles Los Angeles Convention CenterLos Angeles Convention Center Annex, South Hall entrance at Pico and FigueroaCoordinates34°02′23″N 118°16′13″W / 34.039737°N 118.270293°W / 34.039737; -118.270293OperatorAnschutz Entertainment Group ASM GlobalBuilt1971Expanded1981, 1993, 1997Theatre seating15,000 (West Hall)[1]22,870 (South Hall)[2]Enclosed space • Total space720,000…
Artikel utama: Pemilihan umum Presiden Indonesia 2019 Pemilihan umum Presiden Indonesia di Kepulauan Bangka Belitung 20192014202417 April 2019 (2019-04-17)Jajak pendapat Terdaftar913.934[1]Kandidat Calon Joko Widodo Prabowo Subianto Partai PDI-P Gerindra Aliansi Koalisi Indonesia Kerja[2] Koalisi Indonesia Adil Makmur[2] Pendamping Ma'ruf Amin Sandiaga Uno Suara popular 495.335 288.045 Persentase 63.23% 36.77% Presiden petahanaJoko Widodo PDIP Presid…
For the Robert Silverberg novel, see Robert Silverberg. Recalled to Life First edition (Collins Crime Club)AuthorReginald HillCountryUnited KingdomLanguageEnglishSeriesDalziel and Pascoe series, #13GenreDetective fictionPublished1992 HarperCollinsMedia typePrint (Hardback)ISBN978-0007313136Preceded byOne Small Step Followed byPictures of Perfection Recalled to Life is a 1992 crime novel by Reginald Hill, and part of the Dalziel and Pascoe series, set in Yorkshire. The n…
Fortress in Ganja, AzerbaijanGanja FortressAzerbaijani: Gəncə qalasıThe preserved part of the fortress, built in the XVI century in New GanjaGeneral informationTypeFortressArchitectural styleArchitectural school of ArranAddressGala StreetTown or city GanjaCountry AzerbaijanCoordinates40°40′36.178″N 46°21′18.745″E / 40.67671611°N 46.35520694°E / 40.67671611; 46.35520694Completed3 September 1588ClientMurad IIIFarhad PashaTechnical detailsMaterialBrick Ganja F…
Footballer (born 1986) Adrian Mariappa Mariappa playing for Watford in 2017Personal informationFull name Adrian Joseph Mariappa[1]Date of birth (1986-10-03) 3 October 1986 (age 37)[2]Place of birth Harrow, London, EnglandHeight 6 ft 0 in (1.83 m)[3][4]Position(s) DefenderTeam informationCurrent team Salford CityNumber 5Youth career0000–2005 WatfordSenior career*Years Team Apps (Gls)2005–2012 Watford 216 (4)2012–2013 Reading 29 (1)2013–2…
هذه المقالة بحاجة لصندوق معلومات. فضلًا ساعد في تحسين هذه المقالة بإضافة صندوق معلومات مخصص إليها. لنزاع الاستقلال في أمريكا الإسبانية، طالع حروب استقلال أمريكا الإسبانية. الدول في أمريكا الشمالية والجنوبية حسب تاريخ الاستقلال حروب استقلال أمريكا اللاتينية هي عدة ث…