|Systematic (IUPAC) name|
|Trade names||Ryzolt, Tramal, Ultram|
|Licence data||US FDA:|
|Routes||Oral, IV, IM, rectal|
|Bioavailability||70-75% (oral), 77% (rectal), 100% (IM)|
|Metabolism||Liver-mediated demethylation and glucuronidation via CYP2D6 & CYP3A4|
|Half-life||6.3 ± 1.4 hr|
|Mol. mass||263.4 g/mol|
|(what is this?)|
Tramadol (marketed as the hydrochloride salt by Janssen Pharmaceutica as Ultram, and as generics) is used to treat moderate to moderately severe pain. It has two different mechanisms. First, it binds to the μ-opioid receptor. Second, it inhibits the reuptake of serotonin and norepinephrine.
Tramadol is a centrally acting atypical opioid analgesic with additional serotonin-norepinephrine reuptake-inhibiting effects. It is marketed as a racemic mixture of both R- and S-stereoisomers. This is because the two isomers complement each other's analgesic activity. It is often combined with paracetamol as this is known to improve the efficacy of tramadol in relieving pain. Tramadol is an atypical opioid because it is a serotonin-norepinephrine reuptake inhibitor of and, by itself, a fairly weak μ-opioid receptor agonist. Tramadol is metabolised to O-desmethyltramadol, which is a significantly more potent opioid with additional norepinephrine reuptake-inhibiting properties, making it analogous to tapentadol. When taken as an immediate-release oral formulation, the onset of pain relief usually occurs within about an hour.
It was launched and marketed as Tramal by the German pharmaceutical company Grünenthal GmbH in 1977 in West Germany, even though it would take another 20 years for it to be launched in English-speaking countries such as the UK, U.S., and Australia.
- 1 Medical uses
- 2 Adverse effects
- 3 Chemistry
- 4 Mechanism of action
- 5 Pharmacokinetics
- 6 Society and culture
- 7 Veterinary medicine
- 8 Pin cushion tree
- 9 See also
- 10 References
- 11 External links
Tramadol is recommended for the management of pain in fibromyalgia by the European League Against Rheumatism. Its analgesic effects take about one hour to come into effect and 2–4 hours to peak after oral administration with an immediate-release formulation. On a dose-by-dose basis tramadol has about one-tenth the potency of morphine and is approximately equally potent when compared to 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 peak at about 3 hours, post-oral administration and last for approximately 6 hours. These analgesic effects are only partially reversed by naloxone, hence indicating that its opioid action is unlikely the sole contributing factor; tramadol's analgesic effects are also partially reversed by α2 adrenergic receptor antagonists like yohimbine and the 5-HT3 receptor antagonist, ondansetron. Pharmacologically, tramadol is similar to levorphanol and tapentadol in that it not only binds to the mu opioid receptor, 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. Available dosage forms include capsules, tablets, including extended release formulations and injections.
- Diabetic neuropathy 
- postherpetic neuralgia 
- Acute opioid withdrawal management
- Obsessive-compulsive disorder
- Premature ejaculation
- Post-traumatic stress disorder
Use in special populations
Pregnancy and lactation
Its use in pregnancy is generally advised against as it may cause some reversible withdrawal effects in the newborn. Despite this a small prospective study in France found that while there was an increased risk of miscarriages there were no major malformations reported in the newborn. Its use during lactation is also generally advised against but a small trial found that infants breastfed by mothers taking tramadol were exposed to about 2.88% of the dose the mothers were taking and despite this there was no evidence of this dose having a harmful effect on the newborn.
Labour and delivery
Its use as an analgesic during labour is generally advised against due to its long-onset of action (one hour). The ratio of the mean concentration of the drug in the foetus compared to that of the mother when it is given intramuscularly for labour pains has been estimated to be 94.
Its use in children is generally advised against, although it may be done under the supervision of a specialist.
There is an increased risk of opioid-related adverse effects such as respiratory depression, falls, cognitive impairment and sedation.
Liver and kidney failure
It is advised that the drug be used with caution in those with liver or kidney failure, due to the high dependence of the drug on the liver and kidneys for metabolism to O-desmethyltramadol and elimination, respectively.
The most common adverse effects of tramadol include nausea, dizziness, dry mouth, indigestion, abdominal pain, vertigo, vomiting, constipation, drowsiness and headache. Compared to other opioids respiratory depression and constipation is considered less of a problem with tramadol.
Common (1–10% frequency) adverse effects include:
- Emotional lability
- Dyspepsia (indigestion)
- Asthenia (weakness)
- Pruritus (itchiness)
- Dry mouth
- Vasodilation (dilation (widening) of blood vessels)
- Coordination disturbance
- Sleep disorder
- Abdominal pain
- Weight loss
- Visual disturbance
- Menopausal symptoms
- Urinary frequency
- Urinary retention (being unable to urinate)
Uncommon (0.1-1% incidence) adverse effects include:
- Cardiovascular regulation anomalies (palpitation, tachycardia, postural hypotension or cardiovascular collapse)
- Gastrointestinal irritation (a feeling of pressure in the stomach, bloating)
- Urticaria (hives)
Rare (0.01–0.1% incidence) adverse effects include:
- Hypertension (high blood pressure)
- Allergic reactions (e.g. dyspnoea (shortness of breath), bronchospasm, wheezing, angioneurotic oedema)
- Changes in appetite
- Paraesthesia (pins and needles)
- Respiratory depression
- Epileptiform convulsions
- Involuntary muscle contractions
- Abnormal coordination
- Syncope (fainting)
- Blurred vision
- Dyspnoea (shortness of breath)
- Tinnitus (ringing in the ears)
- Stevens-Johnson syndrome/Toxic epidermal necrolysis (potentially fatal skin reactions)
- Motorial weakness
- Creatinine increase
- Elevated liver enzymes
- Hepatitis (liver swelling)
- Stomatitis (mouth swelling)
- Liver failure
- Pulmonary oedema (fluid in the lungs)
- Gastrointestinal bleeding
- Pulmonary embolism
- Myocardial ischaemia (lack of blood supply to the heart muscles)
- Speech disorders
- Haemoglobin decrease
- Proteinuria (protein in the urine; usually indicative of kidney damage)
There are suggestions that chronic opioid administration may induce a state of immune tolerance, although tramadol, in contrast to typical opioids may enhance immune function. Some have also stressed the negative effects of opioids on cognitive functioning and personality.
Tramadol interacts, potentially fatally, with such serotonergics, monoamine oxidase inhibitors, tricyclic antidepressants, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, noradrenergic and specific serotonergic antidepressants, serotonin antagonist and reuptake inhibitors, certain analgesics (pethidine (meperidine), tapentadol, oxycodone, dextromethorphan and fentanyl), certain anxiolytics (such as the SSRIs and buspirone), certain antibiotics (namely, linezolid and isoniazid), certain herbs (e.g. St. John's wort, passiflora, etc.), amphetamines/subtituited amphetamines, phenethylamines/substituited phenethylamines, phentermine, lithium, methylene blue as well as numerous other therapeutic agents. As it is a substrate of CYP3A4 and CYP2D6, hence any agents with the ability to inhibit or induce these enzymes will likely interact with tramadol. A pressor response similar to the cheese effect was noted in combinations of amphetamine and tramadol which appears to cause dysfunction of or toxicity to epinephrine/norepinephrine receptors.
Its use is advised against in people deficient in CYP2D6 enzymes (which accounts for about 6-10% of Caucasians and 1-2% of Asians) as they are crucial to the therapeutic effects of tramadol, by means of enabling tramadol's metabolism to O-desmethyltramadol.
Fatalities with tramadol overdose have been reported and are increasing in frequency in Northern Ireland; the majority of these overdoses involve other drugs including alcohol. Recognised risk factors for tramadol overdose include depression, addiction and seizures. Naloxone only partially reverses the toxic effects of tramadol overdose and may increase the risk of seizures.
Physical dependence and withdrawal
Long-term use of high doses of tramadol may be associated with physical dependence and a withdrawal syndrome. These include both withdrawal symptoms typical of opiate withdrawal and those associated with SSRI withdrawal, including 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 lasts longer than that of other opioids; seven days or more of acute withdrawal symptoms can occur as opposed to typically three or four days for other codeine analogues.
Psychological dependence and recreational use
Because of the possibility of convulsions at high doses for some users, recreational use can be very dangerous. Tramadol can cause a higher incidence of nausea, dizziness, loss of appetite compared with opiates, which could deter abuse. Compared to hydrocodone, fewer persons choose to abuse tramadol.
It may also have a large effect on sleeping patterns and high doses may cause insomnia. (Especially for those on methadone, both for maintenance and recreation. Though there is no scientific proof tramadol lessens effects of opiates or is a mixed agonist-antagonist, some people get the impression it is, while someone else might benefit being prescribed both for pain and breakthrough pain.)
Detection in biological fluids
Tramadol and O-desmethyltramadol 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 traffic or other criminal violation or 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 concentrations of O-desmethyltramadol in the blood or plasma of a person who has taken tramadol are generally 10–20% those of the parent drug.
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.
Mechanism of action
Tramadol acts as a μ-opioid receptor agonist, serotonin releasing agent, norepinephrine reuptake inhibitor, NMDA receptor antagonist (IC50=16.5 μM), 5-HT2C receptor antagonist (EC50=26 nM), (α7)5 nicotinic acetylcholine receptor antagonist, TRPV1 receptor agonist, and M1 and M3 muscarinic acetylcholine receptor antagonist.
Tramadol has inhibitory actions on the 5-HT2C receptor. Antagonism of 5-HT2C could be partially responsible for tramadol's reducing effect on depressive and obsessive-compulsive symptoms in patients with pain and co-morbid neurological illnesses. 5-HT2C blockade may also account for its lowering of the seizure threshold, as 5-HT2C knockout mice display significantly increased vulnerability to epileptic seizures, sometimes resulting in spontaneous death. However, the reduction of seizure threshold could be attributed to tramadol's putative inhibition of GABAA receptors at high doses. In addition, tramadol's major active metabolite, O-desmethyltramadol, is a high-affinity ligand of the δ- and κ-opioid receptors, and activity at the former receptor could be involved in tramadol's ability to provoke seizures in some individuals, as δ-opioid receptor agonists are well known to induce seizures.
Tramadol undergoes hepatic metabolism via the cytochrome P450 isozyme CYP2B6, CYP2D6 and CYP3A4, being O- and N-demethylated to five different metabolites. Of these, O-desmethyltramadol is the most significant since it has 200 times the μ-affinity of (+)-tramadol, and furthermore has an elimination half-life of nine hours, compared with six hours for tramadol itself. As with codeine, in the 6% of the population that have reduced CYP2D6 activity (hence reducing metabolism), there is therefore a reduced analgesic effect. Those with decreased CYP2D6 activity require a dose increase of 30% in order to achieve the same degree of pain relief than those with a normal level of CYP2D6 activity.
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. It is covered by U.S. patents nos. 6,254,887 and 7,074,430. The FDA lists the patents as scheduled for expiration on 10 May 2014. However, in August 2009, U.S. District Court for the District of Delaware ruled the patents invalid, which, if it survives appeal, would permit manufacture and distribution of generic equivalents of Ultram ER in the United States.
Effective August 18, 2014, Tramadol has been placed into Schedule IV of the federal Controlled Substances Act. In addition, several states, including Arkansas, Georgia, Kentucky, Illinois, Mississippi, New York, North Dakota, Ohio, Oklahoma, Tennessee, West Virginia, Wyoming and the U.S. military have already classified Tramadol as a schedule IV controlled substance under state law.
Sweden, as of May 2008, has chosen to classify tramadol as a controlled substance in the same way as codeine and dextropropoxyphene. This means that the substance is a scheduled drug. But unlike codeine and dextropropoxyphene, a normal prescription can be used at this time.
The UK government has decided that tramadol will become a Schedule 3 controlled drug (CD) on 10 June 2014, but will have exemption from the safe custody requirement.
Grünenthal GmbH, which still owns the patent on tramadol, has cross-licensed the drug to pharmaceutical companies internationally. Thus, tramadol is marketed under many trade names around the world, including:
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.
|Species||Half-life (h) for parent drug||Half-life (h) for O-desmethyltramadol||Maximum plasma concentration (ng/mL) for parent drug||Maximum plasma concentration (ng/mL) for O-desmethyltramadol|
|Camel||3.2 (IM), 1.3 (IV)||-||0.44 (IV)||-|
|Cat||3.40 (oral), 2.23 (IV)||4.82 (oral), 4.35 (IV)||914 (oral), 1323 (IV)||655 (oral), 366 (IV)|
|Dog||1.71 (oral), 1.80 (IV), 2.24 (rectal)||2.18 (oral), 90-5000 (IV)||1402.75 (oral),||449.13 (oral), 90-350 (IV)|
|Donkey||4.2 (oral), 1.5 (IV)||-||2817 (oral)||-|
|Goat||2.67 (oral), 0.94 (IV)||-||542.9 (oral)||-|
|Horses||1.29-1.53 (IV), 10.1 (oral)||4 (oral)||637 (IV), 256 (oral)||47 (oral)|
|Llama||2.54 (IM), 2.12 (IV)||7.73 (IM), 10.4 (IV)||4036 (IV), 1360 (IM)||158 (IV), 158 (IM)|
Pin cushion tree
In 2013, researchers reported that tramadol was found in relatively high concentrations (1%+) in the roots of the African pin cushion tree (Nauclea latifolia). It has more recently been reported that the tramadol was present in the tree roots due to the synthetic drug being administered to cattle by farmers in the region. Tramadol and its metabolites were excreted by these animals and 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.
- Brayfield, A, ed. (13 December 2013). "Tramadol Hydrochloride". Martindale: The Complete Drug Reference. Pharmaceutical Press. Retrieved 5 April 2014.
- "Ultram, Ultram ER (tramadol) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 28 November 2013.
- "PRODUCT INFORMATION Tramadol SANDOZ 50 mg capsules" (PDF). TGA eBusiness Services. Sandoz Pty Ltd. 4 November 2011. Retrieved 6 April 2014.
- Now What? DEA Tosses Tramadol in Schedule IV, By Nadia Awad, MedPage Today, Jul 10, 2014
- Leppert, W (November–December 2009). "Tramadol as an analgesic for mild to moderate cancer pain." (PDF). Pharmacological reports 61 (6): 978–92. doi:10.1016/s1734-1140(09)70159-8. PMID 20081232.
- Reimann W, Schneider F (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. PMID 9671098.
- Gobbi 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. PMID 12354291.
- Raffa RB, Buschmann H, Christoph T, Eichenbaum G, Englberger W, Flores CM, Hertrampf T, Kögel B, Schiene K, Straßburger W, Terlinden R, Tzschentke TM (2012). "Mechanistic and functional differentiation of tapentadol and tramadol". Expert Opinion on Pharmacotherapy 13 (10): 1437–49. doi:10.1517/14656566.2012.696097. PMID 22698264.
- Katz WA (1996). "Pharmacology and clinical experience with tramadol in osteoarthritis". Drugs. 52 Suppl 3: 39–47. doi:10.2165/00003495-199600523-00007. PMID 8911798.
- Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3.
- Grond S, Sablotzki A (2004). "Clinical pharmacology of tramadol". Clinical Pharmacokinetics 43 (13): 879–923. doi:10.2165/00003088-200443130-00004. PMID 15509185.
- Carville SF, Arendt-Nielsen S, Bliddal H, Blotman F, Branco JC, Buskila D, Da Silva JA, Danneskiold-Samsøe B, Dincer F, Henriksson C, Henriksson KG, Kosek E, Longley K, McCarthy GM, Perrot S, Puszczewicz M, Sarzi-Puttini P, Silman A, Späth M, Choy EH (2008). "EULAR evidence-based recommendations for the management of fibromyalgia syndrome". Annals of the Rheumatic Diseases 67 (4): 536–41. doi:10.1136/ard.2007.071522. PMID 17644548.
- 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. PMID 7691519.
- Micó JA, Ardid D, Berrocoso E, Eschalier A (2006). "Antidepressants and pain". Trends in Pharmacological Sciences 27 (7): 348–54. doi:10.1016/j.tips.2006.05.004. PMID 16762426.
- 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): 1842–6. doi:10.1212/WNL.50.6.1842. PMID 9633738.
- 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. PMID 10959067.
- Barber J (2011). "Examining the use of tramadol hydrochloride as an antidepressant". Experimental and Clinical Psychopharmacology 19 (2): 123–30. doi:10.1037/a0022721. PMID 21463069.
- 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: 34–9. doi:10.2165/00003495-199700532-00008. PMID 9190323.
- 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): 323–31. doi:10.1016/S0304-3959(03)00020-4. PMID 12855342.
- Sobey PW, Parran TV, Grey SF, Adelman CL, Yu J (2003). "The use of tramadol for acute heroin withdrawal: a comparison to clonidine". Journal of Addictive Diseases 22 (4): 13–25. doi:10.1300/J069v22n04_03. PMID 14723475.
- Threlkeld M, Parran TV, Adelman CA, Grey SF, Yu J (2006). "Tramadol versus buprenorphine for the management of acute heroin withdrawal: a retrospective matched cohort controlled study". The American Journal on Addictions 15 (2): 186–91. doi:10.1080/10550490500528712. PMID 16595358.
- Goldsmith TB, Shapira NA, Keck PE (1999). "Rapid remission of OCD with tramadol hydrochloride". American Journal of Psychiatry 156 (4): 660–1. PMID 10200754.
- 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. PMID 22840860.
- Wong BL, Malde S (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. PMID 23102445.
- "Tramadol Extended-Release (ER) for Posttraumatic Stress Disorder (PTSD)". 23 January 2012. Retrieved 23 January 2012.
- Bloor M, Paech MJ, Kaye R (2012). "Tramadol in pregnancy and lactation". International Journal of Obstetric Anesthesia 21 (2): 163–7. doi:10.1016/j.ijoa.2011.10.008. PMID 22317891.
- "Tramadol". MedlinePlus. American Society of Health-System Pharmacists. 1 September 2008. Retrieved 29 September 2009.
- 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. PMID 19929615.
- Keating GM (2006). "Tramadol sustained-release capsules". Drugs 66 (2): 223–30. doi:10.2165/00003495-200666020-00006. PMID 16451094.
- "Tramadol Hydrochloride 50mg Capsules – Summary of Product Characteristics (SPC)". electronic Medicines Compendium. Actavis UK Ltd. 12 June 2013. Retrieved 28 November 2013.
- "Tilodol SR 100 mg Prolonged-Release Tablets – Summary of Product Characteristics (SPC)". electronic Medicines Compendium. Sandoz Limited. 6 March 2013. Retrieved 28 November 2013.
- "PRODUCT INFORMATION TRAMADOL SANDOZ® SR 100MG, 150MG and 200MG SUSTAINED RELEASE TABLETS" (PDF). TGA eBusiness Services. Sandoz Pty Ltd. 21 November 2013. Retrieved 28 November 2013.
- "ULTRAM (TRAMADOL HYDROCHLORIDE) TABLET, COATED [LAKE ERIE MEDICAL DBA QUALITY CARE PRODUCTS LLC]". DailyMed. LAKE ERIE MEDICAL DBA QUALITY CARE PRODUCTS LLC. November 2012. Retrieved 28 November 2013.
- "ULTRAM ER (TRAMADOL HYDROCHLORIDE) TABLET, EXTENDED RELEASE [REBEL DISTRIBUTORS CORP]". DailyMed. Rebel Distributors Corp. December 2010. Retrieved 28 November 2013.
- 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. PMID 11460802.
- Sacerdote P, Bianchi M, Gaspani L, Manfredi B, Maucione A, Terno G, Ammatuna M, Panerai AE (2000). "The effects of tramadol and morphine on immune responses and pain after surgery in cancer patients". Anesthesia & Analgesia 90 (6): 1411–4. doi:10.1097/00000539-200006000-00028. PMID 10825330.
- Liu Z, Gao F, Tian Y (2006). "Effects of morphine, fentanyl and tramadol on human immune response". J. Huazhong Univ. Sci. Technol. Med. Sci. 26 (4): 478–81. doi:10.1007/s11596-006-0427-5. PMID 17120754.
- Sacerdote P, Bianchi M, Manfredi B, Panerai AE (1997). "Effects of tramadol on immune responses and nociceptive thresholds in mice". Pain 72 (3): 325–30. doi:10.1016/S0304-3959(97)00055-9. PMID 9313273.
- Maruta 1978 and McNairy et al. 1984 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. PMID 11460802.
- Randall C, Crane J (2014). "Tramadol deaths in Northern Ireland: a review of cases from 1996 to 2012". Journal of Forensic and Legal Medicine 23: 32–6. doi:10.1016/j.jflm.2014.01.006. PMID 24661703.
- "Withdrawal syndrome and dependence: tramadol too". Prescrire Int 12 (65): 99–100. 2003. PMID 12825576.
- Barsotti CE, Mycyk MB, Reyes J (2003). "Withdrawal syndrome from tramadol hydrochloride". The American Journal of Emergency Medicine 21 (1): 87–8. doi:10.1053/ajem.2003.50039. PMID 12563592.
- Epstein DH, Preston KL, Jasinski DR (2006). "Abuse liability, behavioral pharmacology, and physical-dependence potential of opioids in humans and laboratory animals: lessons from tramadol". Biological Psychology 73 (1): 90–9. doi:10.1016/j.biopsycho.2006.01.010. PMC 2943845. PMID 16497429.
- Senay EC, Adams EH, Geller A, Inciardi JA, Muñoz A, Schnoll SH, Woody GE, Cicero TJ (April 2003). "Physical dependence on Ultram (tramadol hydrochloride): both opioid-like and atypical withdrawal symptoms occur". Drug Alcohol Depend 69 (3): 233–41. doi:10.1016/S0376-8716(02)00321-6. PMID 12633909.
- Jovanović-Cupić V, Martinović Z, Nesić N (2006). "Seizures associated with intoxication and abuse of tramadol". Clinical Toxicology (Philadelphia) 44 (2): 143–6. doi:10.1080/1556365050014418. PMID 16615669.
- Rodriguez RF, Bravo LE, Castro F, Montoya O, Castillo JM, Castillo MP, Daza P, Restrepo JM, Rodriguez MF (2007). "Incidence of weak opioids adverse events in the management of cancer pain: a double-blind comparative trial". Journal of Palliative Medicine 10 (1): 56–60. doi:10.1089/jpm.2006.0117. PMID 17298254.
- 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. PMID 16716877.
- Vorsanger GJ, Xiang J, Gana TJ, Pascual ML, Fleming RR (2008). "Extended-release tramadol (tramadol ER) in the treatment of chronic low back pain". Journal of Opioid Management 4 (2): 87–97. PMID 18557165.
- 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. PMID 17575561.
- Tjäderborn M, Jönsson AK, Hägg S, Ahlner J (2007). "Fatal unintentional intoxications with tramadol during 1995-2005". Forensic Sci. Int. 173 (2-3): 107–11. doi:10.1016/j.forsciint.2007.02.007. PMID 17350197.
- Baselt, R. (2011) Disposition of Toxic Drugs and Chemicals in Man, 9th edition, Biomedical Publications, Seal Beach, CA, pp. 1712–1715, ISBN 978-0-9626523-8-7.
- Pharmaceutical Substances, Axel Kleemann, Jürgen Engel, Bernd Kutscher and Dieter Reichert, 4. ed. (2000) 2 volumes, Thieme-Verlag Stuttgart (Germany), p. 2085 bis 2086, ISBN 978-1-58890-031-9; 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.
- Burke D, Henderson DJ (2002). "Chirality: a blueprint for the future". British Journal of Anaesthesia 88 (4): 563–76. doi:10.1093/bja/88.4.563. PMID 12066734.
- 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. PMID 8229760.
- 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. PMID 8657431.
- Hennies HH, Friderichs E, Schneider J (July 1988). "Receptor binding, analgesic and antitussive potency of tramadol and other selected opioids". Arzneimittel-Forschung 38 (7): 877–80. PMID 2849950.
- Frink 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): 1029–36. PMID 8955860.
- Driessen B, Reimann W (January 1992). "Interaction of the central analgesic, tramadol, with the uptake and release of 5-hydroxytryptamine in the rat brain in vitro". British Journal of Pharmacology 105 (1): 147–51. doi:10.1111/j.1476-5381.1992.tb14226.x. PMC 1908625. PMID 1596676.
- 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): 352–6. doi:10.1093/bja/79.3.352. PMID 9389855.
- Hara K, Minami K, Sata T (May 2005). "The effects of tramadol and its metabolite on glycine, gamma-aminobutyric acidA, and N-methyl-D-aspartate receptors expressed in Xenopus oocytes". Anesthesia and Analgesia 100 (5): 1400–5, table of contents. doi:10.1213/01.ANE.0000150961.24747.98. PMID 15845694.
- Ogata 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". Anesthesia and Analgesia 98 (5): 1401–6, table of contents. doi:10.1213/01.ANE.0000108963.77623.A4. PMID 15105221.
- Shiraishi M, Minami K, Uezono Y, Yanagihara N, Shigematsu A, Shibuya I (May 2002). "Inhibitory effects of tramadol on nicotinic acetylcholine receptors in adrenal chromaffin cells and in Xenopus oocytes expressing alpha 7 receptors". British Journal of Pharmacology 136 (2): 207–16. doi:10.1038/sj.bjp.0704703. PMC 1573343. PMID 12010769.
- Marincsák R, Tóth BI, Czifra G, Szabó T, Kovács L, Bíró T (June 2008). "The analgesic drug, tramadol, acts as an agonist of the transient receptor potential vanilloid-1". Anesth Analg. 106 (6): 1890–6. doi:10.1213/ane.0b013e318172fefc. PMID 18499628.
- 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". The Journal of Pharmacology and Experimental Therapeutics 299 (1): 255–60. PMID 11561087.
- 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". Anesthesia and Analgesia 95 (5): 1269–73, table of contents. doi:10.1097/00000539-200211000-00031. PMID 12401609.
- Potschka H, Friderichs E, Löscher W (September 2000). "Anticonvulsant and proconvulsant effects of tramadol, its enantiomers and its M1 metabolite in the rat kindling model of epilepsy". Br. J. Pharmacol. 131 (2): 203–12. doi:10.1038/sj.bjp.0703562. PMC 1572317. PMID 10991912.
- Leppert W (2011). "CYP2D6 in the metabolism of opioids for mild to moderate pain". Pharmacology 87 (5-6): 274–85. doi:10.1159/000326085. PMID 21494059.
- Samer CF, Lorenzini KI, Rollason V, Daali Y, Desmeules JA (2013). "Applications of CYP450 testing in the clinical setting". Molecular Diagnosis & Therapy 17 (3): 165–84. doi:10.1007/s40291-013-0028-5. PMC 3663206. PMID 23588782.
- McCarberg B (2007). "Tramadol extended-release in the management of chronic pain". Therapeutics and clinical risk management 3 (3): 401–10. PMC 2386353. PMID 18488071.
- US patent 6254887, Miller RB, Leslie ST, Malkowska ST, Smith KJ, Wimmer S, Winkler H, Hahn U, Prater DA, "Controlled Release Tramadol", issued 3 July 2001
- FDA AccessData entry for Tramadol Hydrochloride. Retrieved 17 August 2009.
- US patent 7074430, Miller RB, Malkowska ST, Wimmer S, Hahn U, Leslie ST, Smith KJ, Winkler H, Prater DA, "Controlled Release Tramadol Tramadol Formulation", issued 11 July 2006
- "Par Pharmaceutical Wins on Invalidity in Ultram(R) ER Litigation" (Press release). Par Pharmaceutical. 17 August 2009.
- "FDA Law Blog: http://www.fdalawblog.net/fda_law_blog_hyman_phelps/2014/07/dea-controls-tramadol-as-a-schedule-iv-controlled-substance-effective-august-18-2014.html". 7/2/14. Check date values in:
- "Federal Registrar".
- TRAMADOL (Trade Names: Ultram®, Ultracet®). Drug Enforcement Administration (February 2011)
- Tennessee News: Tramadol and Carisoprodol Now Classified Schedule IV – News – National Association of Boards of Pharmacy® (NABP®). Nabp.net (8 June 2011). Retrieved on 2012-12-26.
- "Substansen tramadol nu narkotikaklassad på samma sätt som kodein och dextropropoxifen – Läkemedelsverket". Lakemedelsverket.se. 14 May 2008. Retrieved 18 April 2010.
- "Tramadol to become a Controlled Drug in the UK". vetdispense.co.uk. 2 June 2014. Retrieved 3 June 2014.
- Souza MJ, Cox SK (2011). "Tramadol use in zoologic medicine". Vet Clin North Am Exot Anim Pract 14 (1): 117–30. doi:10.1016/j.cvex.2010.09.005. PMID 21074707.
- 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): 11780–11784. doi:10.1002/anie.201305697.
- Kusari, S., Tatsimo, S. J. N., Zühlke, S., Talontsi, F. M., Kouam, S. F., Spiteller, M. "Tramadol- A True Natural Product?". Angewandte Chemie International Edition. doi:10.1002/anie.201406639.
- Medline Plus – Patient Information Medline Plus (A Service of the U.S. National Library of Medicine)
- U.S. National Library of Medicine: Drug Information Portal – Tramadol
- Tramadol in the treatment of RSD (RSD = Reflex Sympathetic Dystrophy)