Tramadol, sold under the brand name Ultram among others, is an opioidpain medication used to treat moderate to moderately severe pain. When taken by mouth in an immediate-release formulation, the onset of pain relief usually begins within an hour. It is also available by injection. It may be sold in combination with paracetamol (acetaminophen) or as longer-acting formulations.
Tramadol was patented in 1963 and launched under the name "Tramal" in 1977 by the West German pharmaceutical companyGrünenthal GmbH. In the mid-1990s, it was approved in the United Kingdom and the United States. It is available as a generic medication and marketed under many brand names worldwide. In the United States, the wholesale cost is less than US$0.05 per dose as of 2018. In 2016, it was the 39th most prescribed medication in the United States, with more than 19 million prescriptions.
Generic tramadol HCl tablets marketed by Amneal Pharmaceuticals
Tramadol HCl for injection
Tramadol is used primarily to treat mild to severe pain, both acute and chronic.
Its analgesic effects take about one hour to come into effect and 2 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 practically 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 about 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.
As of 2015, tramadol was not approved in the United States for fibromyalgia. Based on three small trials with weak study design, fair evidence was found for tramadol as a second-line treatment.
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, while an increased risk of miscarriages existed, no major malformations were 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. No evidence of this dose having a harmful effect on the newborn was seen.
Labour and delivery
Its use as an analgesic during labour is generally advised against due to its long onset of action (1 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 1:94.
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.
The risk of opioid-related adverse effects such as respiratory depression, falls, cognitive impairment and sedation is increased.
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 desmetramadol) and elimination by the kidneys.
Long-term use of high doses of tramadol causes physical dependence and withdrawal syndrome. These include both symptoms typical of opioid withdrawal and those associated with serotonin–norepinephrine reuptake inhibitor 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 3 or 4 days for other codeine analogues.
A 2014 report by the World Health Organizations Expert Committee on Drug Dependence found:
... 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, and loss of appetite compared with opioids, which could deter recreational use. Compared to hydrocodone, fewer persons choose to use tramadol recreationally.
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.
Deaths with tramadol overdose have been reported and are increasing in frequency in Northern Ireland; the majority of these overdoses involves other drugs including alcohol. There were 254 tramadol-related deaths in England and Wales in 2013, and 379 in Florida in 2011. In 2011, 21,649 emergency room visits in the United States were related to tramadol.
Tramadol induces analgesic effects through a variety of different targets on the noradrenergic system, serotoninergic system and opioid receptors system. 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. Tramadol has also been shown to act as a serotonin releasing agent. Both enantiomers of tramadol are agonists of the mu-opioid receptor and its M1 metabolite, O-demethylate, is also a mu-opoid receptor agonist but is 6 times more potent than tramadol itself. 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. 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.
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. 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). 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). This is close to that of 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). 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.Positron emission tomography imaging studies have reportedly found that tramadol levels are at least four-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, thus bioactive.
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. 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 α2-adrenergic receptor antagonists such as 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-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). 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 are 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.
Tramadol undergoes hepatic metabolism 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.
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.
Tramadol is marketed as a racemic mixture of both R- and S-stereoisomers, because the two isomers complement each other's analgesic activities. 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:
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.
Society and culture
The U.S. Food and Drug Administration (FDA) approved tramadol in March 1995 and an extended-release (ER) formulation in September 2005. ER Tramadol was 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, 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.
Effective August 18, 2014, tramadol has been placed into Schedule IV of the federal Controlled Substances Act in the United States. Before that, some US states had already classified tramadol as a Schedule IV controlled substance under their respective state laws.
The UK classified tramadol as a Class C, Schedule 3 controlled drug on 10 June 2014, but exempted it from the safe custody requirement.
Illicit use of the drug is thought to be a major factor in the success of the Boko Haram terrorist organization. When used at higher doses, the drug "can produce similar effects to heroin." 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.” Tramadol misuse is also found as a coping mechanism in the Gaza Strip.
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.
^Lee CR, McTavish D, Sorkin EM (1993). "Tramadol. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in acute and chronic pain states". Drugs. 46 (2): 313–40. doi:10.2165/00003495-199346020-00008. PMID7691519.
^Langley PC, Patkar AD, Boswell KA, Benson CJ, Schein JR (2010). "Adverse event profile of tramadol in recent clinical studies of chronic osteoarthritis pain". Current Medical Research and Opinion. 26 (1): 239–51. doi:10.1185/03007990903426787. PMID19929615.
^Bryant et al. 1988 and Rouveix 1992 cited by Collett BJ (July 2001). "Chronic opioid therapy for non-cancer pain". British Journal of Anaesthesia. 87 (1): 133–43. doi:10.1093/bja/87.1.133. PMID11460802.
^Adams EH, Breiner S, Cicero TJ, Geller A, Inciardi JA, Schnoll SH, Senay EC, Woody GE (2006). "A comparison of the abuse liability of tramadol, NSAIDs, and hydrocodone in patients with chronic pain". Journal of Pain and Symptom Management. 31 (5): 465–76. doi:10.1016/j.jpainsymman.2005.10.006. PMID16716877.
^ 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. Retrieved 14 August 2017.
^ abcWentland MP, Lou R, Lu Q, Bu Y, VanAlstine MA, Cohen DJ, Bidlack JM (2009). "Syntheses and opioid receptor binding properties of carboxamido-substituted opioids". Bioorg. Med. Chem. Lett. 19 (1): 203–8. doi:10.1016/j.bmcl.2008.10.134. PMID19027293.
^ abcdeCodd EE, Shank RP, Schupsky JJ, Raffa RB (1995). "Serotonin and norepinephrine uptake inhibiting activity of centrally acting analgesics: structural determinants and role in antinociception". J. Pharmacol. Exp. Ther. 274 (3): 1263–70. PMID7562497.
^ abGillen C, Haurand M, Kobelt DJ, Wnendt S (2000). "Affinity, potency and efficacy of tramadol and its metabolites at the cloned human mu-opioid receptor". Naunyn Schmiedebergs Arch. Pharmacol. 362 (2): 116–21. doi:10.1007/s002100000266. PMID10961373.
^ abcdefghiFrink MC, Hennies HH, Englberger W, Haurand M, Wilffert B (1996). "Influence of tramadol on neurotransmitter systems of the rat brain". Arzneimittelforschung. 46 (11): 1029–36. PMID8955860.
^ abcdBarann M, Urban B, Stamer U, Dorner Z, Bönisch H, Brüss M (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". Eur. J. Pharmacol. 531 (1–3): 54–8. doi:10.1016/j.ejphar.2005.11.054. PMID16427041.
^Raffa RB, Friderichs E, Reimann W, Shank RP, Codd EE, Vaught JL (1992). "Opioid and nonopioid components independently contribute to the mechanism of action of tramadol, an 'atypical' opioid analgesic". J. Pharmacol. Exp. Ther. 260 (1): 275–85. PMID1309873.
^ abOgata J, Minami K, Uezono Y, Okamoto T, Shiraishi M, Shigematsu A, Ueta Y (2004). "The inhibitory effects of tramadol on 5-hydroxytryptamine type 2C receptors expressed in Xenopus oocytes". Anesth. Analg. 98 (5): 1401–6, table of contents. doi:10.1213/01.ANE.0000108963.77623.A4. PMID15105221.
^Horishita T, Minami K, Uezono Y, Shiraishi M, Ogata J, Okamoto T, Shigematsu A (2006). "The tramadol metabolite, O-desmethyl tramadol, inhibits 5-hydroxytryptamine type 2C receptors expressed in Xenopus Oocytes". Pharmacology. 77 (2): 93–9. doi:10.1159/000093179. PMID16679816.
^Okamoto T, Minami K, Uezono Y, Ogata J, Shiraishi M, Shigematsu A, Ueta Y (2003). "The inhibitory effects of ketamine and pentobarbital on substance p receptors expressed in Xenopus oocytes". Anesth. Analg. 97 (1): 104–10, table of contents. doi:10.1213/01.ANE.0000066260.99680.11. PMID12818951.
^Minami K, Yokoyama T, Ogata J, Uezono Y (2011). "The tramadol metabolite O-desmethyl tramadol inhibits substance P-receptor functions expressed in Xenopus oocytes". J. Pharmacol. Sci. 115 (3): 421–4. doi:10.1254/jphs.10313sc. PMID21372504.
^Shiraishi M, Minami K, Uezono Y, Yanagihara N, Shigematsu A (2001). "Inhibition by tramadol of muscarinic receptor-induced responses in cultured adrenal medullary cells and in Xenopus laevis oocytes expressing cloned M1 receptors". J. Pharmacol. Exp. Ther. 299 (1): 255–60. PMID11561087.
^ abNakamura M, Minami K, Uezono Y, Horishita T, Ogata J, Shiraishi M, Okamoto T, Terada T, Sata T (2005). "The effects of the tramadol metabolite O-desmethyl tramadol on muscarinic receptor-induced responses in Xenopus oocytes expressing cloned M1 or M3 receptors". Anesth. Analg. 101 (1): 180–6, table of contents. doi:10.1213/01.ANE.0000154303.93909.A3. PMID15976229.
^Shiga Y, Minami K, Shiraishi M, Uezono Y, Murasaki O, Kaibara M, Shigematsu A (2002). "The inhibitory effects of tramadol on muscarinic receptor-induced responses in Xenopus oocytes expressing cloned M(3) receptors". Anesth. Analg. 95 (5): 1269–73, table of contents. doi:10.1097/00000539-200211000-00031. PMID12401609.
^Sánchez-Fernández C, Montilla-García Á, González-Cano R, Nieto FR, Romero L, Artacho-Cordón A, Montes R, Fernández-Pastor B, Merlos M, Baeyens JM, Entrena JM, Cobos EJ (2014). "Modulation of peripheral μ-opioid analgesia by σ1 receptors". J. Pharmacol. Exp. Ther. 348 (1): 32–45. doi:10.1124/jpet.113.208272. PMID24155346.
^ abcdHara K, Minami K, Sata T (2005). "The effects of tramadol and its metabolite on glycine, gamma-aminobutyric acidA, and N-methyl-D-aspartate receptors expressed in Xenopus oocytes". Anesth. Analg. 100 (5): 1400–5, table of contents. doi:10.1213/01.ANE.0000150961.24747.98. PMID15845694.
^ abMiyano K, Minami K, Yokoyama T, Ohbuchi K, Yamaguchi T, Murakami S, Shiraishi S, Yamamoto M, Matoba M, Uezono Y (2015). "Tramadol and its metabolite m1 selectively suppress transient receptor potential ankyrin 1 activity, but not transient receptor potential vanilloid 1 activity". Anesth. Analg. 120 (4): 790–8. doi:10.1213/ANE.0000000000000625. PMID25642661.
^Bamigbade TA, Davidson C, Langford RM, Stamford JA (September 1997). "Actions of tramadol, its enantiomers and principal metabolite, O-desmethyltramadol, on serotonin (5-HT) efflux and uptake in the rat dorsal raphe nucleus". British Journal of Anaesthesia. 79 (3): 352–56. doi:10.1093/bja/79.3.352. PMID9389855.
^ abcGobbi M, Moia M, Pirona L, Ceglia I, Reyes-Parada M, Scorza C, Mennini T (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): 1435–43. doi:10.1046/j.1471-4159.2002.01073.x. PMID12354291.
^Gobbi M, Mennini T (1999). "Release studies with rat brain cortical synaptosomes indicate that tramadol is a 5-hydroxytryptamine uptake blocker and not a 5-hydroxytryptamine releaser". Eur. J. Pharmacol. 370 (1): 23–6. doi:10.1016/s0014-2999(99)00123-5. PMID10323276.
^Halfpenny DM, Callado LF, Hopwood SE, Bamigbade TA, Langford RM, Stamford JA (1999). "Effects of tramadol stereoisomers on norepinephrine efflux and uptake in the rat locus coeruleus measured by real time voltammetry". Br J Anaesth. 83 (6): 909–15. doi:10.1093/bja/83.6.909. PMID10700792.
^ abcdOgawa K, Tateno A, Arakawa R, Sakayori T, Ikeda Y, Suzuki H, Okubo Y (2014). "Occupancy of serotonin transporter by tramadol: a positron emission tomography study with [11C]DASB". Int. J. Neuropsychopharmacol. 17 (6): 845–50. doi:10.1017/S1461145713001764. PMID24423243.
^Nobilis M, Kopecký J, Kvetina J, Chládek J, Svoboda Z, Vorísek V, Perlík F, Pour M, Kunes J (March 2002). "High-performance liquid chromatographic determination of tramadol and its O-desmethylated metabolite in blood plasma. Application to a bioequivalence study in humans". J Chromatogr A. 949 (1–2): 11–22. doi:10.1016/S0021-9673(01)01567-9. PMID11999728.
^Pharmaceutical Substances, Axel Kleemann, Jürgen Engel, Bernd Kutscher and Dieter Reichert, 4. ed. (2000) 2 volumes, Thieme-Verlag Stuttgart (Germany), p. 2085 bis 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, Jacoby HI, Selve N (1993). "Complementary and synergistic antinociceptive interaction between the enantiomers of tramadol". J. Pharmacol. Exp. Ther. 267 (1): 331–40. PMID8229760.
^Grond S, Meuser T, Zech D, Hennig U, Lehmann KA (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): 313–20. doi:10.1016/0304-3959(94)00274-I. PMID8657431.
^Karhu D, El-Jammal A, Dupain T, Gaulin D, Bouchard S (2007). "Pharmacokinetics and dose proportionality of three Tramadol Contramid OAD tablet strengths". Biopharmaceutics & Drug Disposition. 28 (6): 323–30. doi:10.1002/bdd.561. PMID17575561.
^Harati Y, Gooch C, Swenson M, Edelman S, Greene D, Raskin P, Donofrio P, Cornblath D, Sachdeo R, Siu CO, Kamin M (1998). "Double-blind randomized trial of tramadol for the treatment of the pain of diabetic neuropathy". Neurology. 50 (6): 1842–46. doi:10.1212/WNL.50.6.1842. PMID9633738.
^Harati Y, Gooch C, Swenson M, Edelman SV, Greene D, Raskin P, Donofrio P, Cornblath D, Olson WH, Kamin M (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.
^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.
^Wu T, Yue X, Duan X, Luo D, Cheng Y, Tian Y, Wang K (2012). "Efficacy and safety of tramadol for premature ejaculation: a systematic review and meta-analysis". Urology. 80 (3): 618–24. doi:10.1016/j.urology.2012.05.035. PMID22840860.
^Ryan, T (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.
^Boumendjel A, Sotoing Taïwe G, Ngo Bum E, Chabrol T, Beney C, Sinniger V, Haudecoeur R, Marcourt L, Challal S, Ferreira Queiroz E, Souard F, Le Borgne M, Lomberget T, Depaulis A, Lavaud C, Robins R, Wolfender JL, Bonaz B, De Waard M (November 2013). "Occurrence of the Synthetic Analgesic Tramadol in an African Medicinal Plant". Angewandte Chemie International Edition. 52 (45): 11780–84. doi:10.1002/anie.201305697. PMID24014188.