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{{Druginfo
{{Headerpanel|{{DepressantOD|opiates}}}}
|author        = [[User:Km39|Km39]] 16:31, 21 March 2007 (PDT)
{{SummarySheet}}
|certifier      = [[User:Lap22|Lap22]] 09:28, 28 March 2007 (PDT)
{{SubstanceBox/Tramadol}}
|drug name      = Tramadol
|image          = Tramadol
|Review Color  = green
|phonetics      = TRA ma dole
|brand          = Ultram, Ultram ER
|supplied      = Tablets: 50 mg<br>Extended-release tablets: 100 mg, 200 mg, 300 mg
|gen avail      = immediate-release form only
|patent exp    = September 2008 (Ultram ER)
|class          = opioid analgesic
|schedule      = Rx
|preg cat      = C
|breast feed    = Not indicated for mothers who are breast feeding.
|IUPAC name    = rac-(1R,2R)-2-(dimethylaminomethyl)-1-(3-methoxyphenyl)-cyclohexanol
|emp formula    = (C<sub>16</sub>H<sub>25</sub>NO<sub>2</sub>)•HCl
|MW            = 299.8
|genomicsURL    = http://www.pharmgkb.org/do/serve?objId=PA451735&objCls=Drug
}}


== Description ==
'''Tramadol''' (also known as '''Ultram''', '''Ralivia''' or '''Tramal''') is a synthetic [[psychoactive class::opioid]] substance of the [[chemical class::phenylpropylamine]] class that is structurally related to [[codeine]] and [[morphine]]. It acts as a weak [[μ-opioid]] [[receptor]] [[agonist]] and a [[reuptake inhibitor]] of [[norepinephrine]] and [[serotonin]].<ref>{{cite journal | vauthors=((Reimann, W.)), ((Schneider, F.)) | journal=European Journal of Pharmacology | title=Induction of 5-hydroxytryptamine release by tramadol, fenfluramine and reserpine | volume=349 | issue=2 | pages=199–203 | date=22 May 1998 | url=https://www.sciencedirect.com/science/article/pii/S0014299998001952 | issn=0014-2999 | doi=10.1016/S0014-2999(98)00195-2}}</ref><ref name="Gobbi2002">{{cite journal | vauthors=((Gobbi, M.)), ((Moia, M.)), ((Pirona, L.)), ((Ceglia, I.)), ((Reyes-Parada, M.)), ((Scorza, C.)), ((Mennini, T.)) | journal=Journal of Neurochemistry | title=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: Effects of MTA and mCPP in synaptosomes | volume=82 | issue=6 | pages=1435–1443 | date=19 September 2002 | url=http://doi.wiley.com/10.1046/j.1471-4159.2002.01073.x | issn=00223042 | doi=10.1046/j.1471-4159.2002.01073.x}}</ref>
Tramadol is a centrally-acting synthetic opioid analgesic that is not a controlled substance.<ref name=a/> Tramadol is used to treat moderate to moderately severe chronic pain. It can also be used to treat breakthrough pain.<ref name=B/> Tramadol can lower the seizure threshold to a rate of < 1/100,000 (spontaneous seizures), which can be exacerbated by the use of other medications such [[Selective serotonin reuptake inhibitor (SSRI)|SSRIs]], [[Tricyclic antidepressant (TCA)|TCAs]], and opioids. Additionally tramadol and [[sertraline]], when given in the same regimen, were found to cause a mild serotonin syndrome.<ref name=sert/> Tramadol does not cause GI bleeding, hypertension or heart failure.


There is a small chance of tramadol abuse. The rate is 0.75/100,000 patients and of these, 97% of patients who became addicted had a history of drug and alcohol abuse.<ref name=cicerot>Cicero TJ, Adams EH, Geller A, Inciardi JA, Munoz A, Schnoll SH, et al. A postmarketing surveillance program to monitor Ultram (tramadol hydrochloride) abuse in the United States. Drug and alcohol dependence. 1999 Nov 1;57(1):7-22</ref>
Tramadol was developed in 1962 and launched under the name "Tramal" by the German pharmaceutical company Grünenthal GmbH in 1977. In the mid-1990s, it was approved for use in the United Kingdom and the United States.<ref name="Leppert2009">{{cite journal | vauthors=((Leppert, W.)) | journal=Pharmacological Reports | title=Tramadol as an analgesic for mild to moderate cancer pain | volume=61 | issue=6 | pages=978–992 | date= November 2009 | url=https://linkinghub.elsevier.com/retrieve/pii/S1734114009701598 | issn=17341140 | doi=10.1016/S1734-1140(09)70159-8}}</ref> It is commonly prescribed to treat moderate to moderately severe pain.


A number of studies have proven the efficacy of tramadol. It is more effective than placebo for osteoarthritis and comparable in efficacy to [[ibuprofen]] 2400 mg/day.<ref name=B/>  Osteoarthritis is an off-label use. Tramadol was found to be substandard to [[Hydrocodone Bitartrate and Acetaminophen|hydrocodone/acetaminophen]] for patients entering the emergency department with acute musculoskeletal pain.<ref name=hydroc>Turturro MA, Paris PM, Larkin GL. Tramadol versus hydrocodone-acetaminophen in acute musculoskeletal pain: a randomized, double-blind clinical trial. Ann Emerg Med. 1998 Aug;32(2):139-43.]</ref>  Pain relief tyically begins about one hour after administration.<ref name=a/>
[[Subjective effects]] are largely consistent with that of traditional opioids and include [[sedation]], [[pain relief]], [[anxiety suppression]], [[muscle relaxation]], and [[euphoria]]. Tramadol is also known to produce mild to moderate [[entactogenic]] effects like [[increased music appreciation]] and [[empathy, affection, and sociability enhancement]], which is thought to be due to its [[serotonergic]] effects.  


== Mechanism of Action ==
Unlike other [[opioids]], tramadol has been established to lower the seizure threshold in humans<ref>{{cite journal | vauthors=((Talaie, H.)), ((Panahandeh, R.)), ((Fayaznouri, M. R.)), ((Asadi, Z.)), ((Abdollahi, M.)) | journal=Journal of Medical Toxicology | title=Dose-independent occurrence of seizure with tramadol | volume=5 | issue=2 | pages=63–67 | date= June 2009 | url=http://link.springer.com/10.1007/BF03161089 | issn=1556-9039 | doi=10.1007/BF03161089}}</ref> as well as increase the risk of [[serotonin syndrome]]. This makes its effects and interactions relatively unpredictable. As a result, high doses or combinations with other [[psychoactive substances]] are strongly advised against.
Tramadol is a synthetic analgesic which acts centrally through binding to the opioid µ-receptors and via a tricyclic-like mechanism whereby it inhibits neuronal reuptake of serotonin and norepinephrine within the CNS.<ref name=B>Stitik TP, Altschuler E, Foye PM, Stitik TP, Altschuler E, Foye PM. Pharmacotherapy of osteoarthritis. American Journal of Physical Medicine & Rehabilitation. 2006 Nov;85(11 Suppl):S15-28; quiz S9-31.</ref><ref name=C>Ripple MG, Pestaner JP, Levine BS, Smialek JE. Lethal combination of tramadol and multiple drugs affecting serotonin. Am J Forensic Med Pathol. 2000 Dec;21(4):370-4.</ref> The opioid activity of tramadol is due to tramadol binding to the µ-receptors and the M1 metabolite, which is O-demethylated, binding to the opioid µ-receptors. M1 is 6-times more potent than tramadol when compared for their analgesic qualities. M1 binds to the µ-receptors 200-times stronger than does tramadol. Additionally, tramadol inhibits the reuptake of serotonin and norepinephrine which is believed to contribute to its analgesic properties.<ref name=a/>


== Time Required for Therapeutic Response ==
It is highly advised to use [[harm reduction practices]] if using this substance.
* Initial: One hour<ref name=B/>


== Pharmacokinetics ==
==History and culture==
'''Absorption'''<br>
{{historyStub}}
Tramadol is almost completely absorbed. The bioavailability of a 100 mg dose is 75%. The peak plasma concentrations of racemic tramadol occur 2 hours after the dose. The peak plasma concentrations of M1 occur 3 hours after the dose is given. Steady state is realized 2 days after dosing tramadol four times a day. Food does not impact the rate or extent of absorption.<ref name=a>Ortho-McNeil Pharmaceutical INC. Ultram (tramadol hydrochloride tablets) prescribing information. 2004.</ref>


'''Distribution'''<br>
Tramadol was synthesized in 1962 by chemists employed by the German pharmaceutical company Grünenthal.<ref name="Leppert2009" /> However, it was not approved in Germany until 1977, entering the market as Tramal. It became the leading analgesic drug in Germany and during the past 38 years it has been approved in over 100 countries, including the UK, USA, Republic of China and Canada.<ref>{{cite journal | vauthors=((Lassen, D.)), ((Damkier, P.)), ((Brøsen, K.)) | journal=Clinical Pharmacokinetics | title=The Pharmacogenetics of Tramadol | volume=54 | issue=8 | pages=825–836 | date= August 2015 | url=http://link.springer.com/10.1007/s40262-015-0268-0 | issn=0312-5963 | doi=10.1007/s40262-015-0268-0}}</ref>
The volume of distribution was 2.6 L/kg in males and 2.9 L/kg in females. Tramadol binds to proteins about 20%. Saturation of plasma proteins is only of concern if one exceeds the recommended dosage.<ref name=a/>


'''Metabolism'''<br>
For a period of time it was believed tramadol was not a purely synthetic drug after its apparent discovery in the roots of the pin cushion tree.<ref>{{cite journal | vauthors=((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, J.-L.)), ((Bonaz, B.)), ((De Waard, M.)) | journal=Angewandte Chemie International Edition | title=Occurrence of the Synthetic Analgesic Tramadol in an African Medicinal Plant | volume=52 | issue=45 | pages=11780–11784 | date=4 November 2013 | url=https://onlinelibrary.wiley.com/doi/10.1002/anie.201305697 | issn=14337851 | doi=10.1002/anie.201305697}}</ref> These reports later proved to be erroneous; the tramadol had been excreted by cows treated with the drug, resulting in the tramadol having seeped into the roots through their urine.<ref>{{cite journal | vauthors=((Kusari, S.)), ((Tatsimo, S. J. N.)), ((Zühlke, S.)), ((Talontsi, F. M.)), ((Kouam, S. F.)), ((Spiteller, M.)) | journal=Angewandte Chemie International Edition | title=Tramadol-A True Natural Product? | volume=53 | issue=45 | pages=12073–12076 | date=3 November 2014 | url=https://onlinelibrary.wiley.com/doi/10.1002/anie.201406639 | issn=14337851 | doi=10.1002/anie.201406639}}</ref>
M1 (O-desmethyl-tramadol) is formed by CYP2D6.<ref name= old>Likar R, Wittels M, Molnar M, Kager I, Ziervogel G, Sittl R. Pharmacokinetic and pharmacodynamic properties of tramadol IR and SR in elderly patients: a prospective, age-group-controlled study. Clin Ther. 2006 Dec;28(12):2022-39.</ref> About 7% of the population are considered poor metabolizers of CYP2D6. The concnetrations of tramadol will be about 20% higher in these patients. The M1 concentrations will be about 40% lower when compared to patients who are considered extensive metabolizers of CYP2D6.<ref name=a/> A study looking at poor metabolizers of CYP2D6 versus extensive metabolizers found that for the positive (+) enantiomer, the AUC was 1.98-fold and the negative (-) enantiomer's AUC was 1.74-fold when compared to extensive metabolizers. The oral clearance was examined and was found to be 1.91-fold in poor metabolizers for the (+) enantiomer and 1.71-fold for the negative enantiomer when compared to extensive metabolizers.<ref name=enta>Garcia-Quetglas E, Azanza JR, Sadaba B, Munoz MJ, Gil I, Campanero MA. Pharmacokinetics of tramadol enantiomers and their respective phase I metabolites in relation to CYP2D6 phenotype. Pharmacol Res. 2007 Feb;55(2):122-30.</ref>


'''Excretion'''<br>
==Chemistry==
30% of tramadol will be excreted in the urine unchanged. 60% of the drug will be excreted in the urine as metabolites. The rest is unidentified or is a metabolite which could not be extracted. Tramadol itself is eliminated via the liver. The half-life of tramadol is 6.3 hours and the half-life of M1 is 7.4 hours. After repeated dosing of tramadol, the half-life of tramadol increases to about 7 hours.<ref name=a/>
(+/-)Tramadol, or 2-[(Dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol, is an atypical synthetic opioid. The chemical structure of tramadol consists of two rings that include a [[cyclohexane]] ring bonded to a [[phenyl]] ring at R<sub>1</sub>. This phenyl ring is substituted at R<sub>3</sub> with a methoxy group (CH<sub>3</sub>O-). At the same location (R<sub>1</sub>)  the cyclohexane ring is bonded to the phenyl ring, an additional hydroxy group is found. Tramadol features a second substitution on its cyclohexane ring at R<sub>2</sub>. Here, the ring is bonded to a dimethylamine group connected through a methyl bridge.
<br>
<br>


== Special Population Pharmacokinetics ==
Tramadol is unique as it is found in a racemate (combination) of its stereoisomers. These are two molecules that share the same chemical structure, but are three-dimensional mirror images of each other. Tramadol is produced as a racemate of its two isomers because the combination is proven to be more effective. The picture seen above is the R- enantiomer of tramadol, switching the dashed and solid wedges seen on the molecule skeleton results in the S- enantiomer. It is produced as a hydrochloride salt.<ref>{{cite journal | vauthors=((Dayer, P.)), ((Desmeules, J.)), ((Collart, L.)) | journal=Drugs | title=[Pharmacology of tramadol] | volume=53 Suppl 2 | pages=18–24 | date= 1997 | issn=0012-6667 | doi=10.2165/00003495-199700532-00006}}</ref>
* '''Renal insufficiency:''' Renal insufficiency decreases the rate and extent of elimination of both tramadol and its metabolites. When a patient's creatinine clearance is less than 30 mL/min, a decreased dose of tramadol is recommended, and extended-release tramadol is not recommended.<ref name=a/> 
* '''Hepatic insufficiency:''' The metabolism of tramadol is lowered in patients with hepatic insufficiency. This causes a larger area-under the concentration-time curve for tramadol. Tramadol and M1 will have longer elimination half-lives which have been reported to extend to 13 hours for tramadol and 19 hours for M1. Extended-release tramadol is not recommended in this patient population.<ref name=a/>
* '''Hemodialysis:''' After a 4 hour hemodialysis session, less than 7% of the dose of tramadol is cleared from the blood. Extended-release tramadol is not recommended in this patient population.<ref name=a/>
* '''Geriatric:''' In patients over the age of 75, the peak serum concentrations increase from 162 to 208 ng/mL. Additionally, the elimination half-life of tramadol is increased by an hour, from 6 to 7 hours. Based on this pharmacokinetic data, the dosage of tramadol should be adjusted in patients over the age of 75. No PK differences were noted in the population from 65-75 years of age.<ref name=a/> A randomized controlled trial measured serum concentrations of M1 and tramadol in 100 patients. The 100 patients were split up into three groups, greater than or equal to 75 years, 65 to less than 75, and less than 65 years. There were no PK differences between the groups. The group greater than or equal to 75 years used 20% less tramadol than did the group which was less than 65 years of age.<ref name=old/>
* '''Pediatric:''' No data.
* '''Gender:''' The bioavailability was slightly different between males (73%) and females (79%). The plasma clearance was slightly greater in males at 6.4 mL/min/kg vs. 5.7 mL/min/kg in females. Females had a 12% higher peak tramadol concentration than males. Females also had a 35% greater area under the concentration-time curve than did males. Currently, the clinical significance is not known.<ref name=a/>


== Indications and Dosages ==
Tramadol is a 4-phenylpiperidine analog of [[codeine]]. Notably, it is not a morphinan opiate.


=== FDA Approved Indications ===
==Pharmacology==
The R- and S- enantiomers of tramadol act on different receptors in a complimentary manner. The R- enantiomer is a selective agonist of the mu receptors and inhibits serotonin reuptake while the S- enantiomer inhibits noradrenaline reuptake. Tramadol acts as an [[opioid|opioid]] [[receptor|receptor]] [[agonist|agonist]],<ref>{{cite journal | vauthors=((Hennies, H. H.)), ((Friderichs, E.)), ((Schneider, J.)) | journal=Arzneimittel-Forschung | title=Receptor binding, analgesic and antitussive potency of tramadol and other selected opioids | volume=38 | issue=7 | pages=877–880 | date= July 1988 | issn=0004-4172}}</ref><ref name="Frink1996">{{cite journal | vauthors=((Frink, M. C.)), ((Hennies, H. H.)), ((Englberger, W.)), ((Haurand, M.)), ((Wilffert, B.)) | journal=Arzneimittel-Forschung | title=Influence of tramadol on neurotransmitter systems of the rat brain | volume=46 | issue=11 | pages=1029–1036 | date= November 1996 | issn=0004-4172}}</ref> [[serotonin]] [[releasing agent]],<ref name="Frink1996" /><ref name="Gobbi2002" /><ref>{{cite journal | vauthors=((Driessen, B.)), ((Reimann, W.)) | journal=British Journal of Pharmacology | title=Interaction of the central analgesic, tramadol, with the uptake and release of 5-hydroxytryptamine in the rat brain in vitro. | volume=105 | issue=1 | pages=147–151 | date= January 1992 | url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1908625/ | issn=0007-1188}}</ref><ref>{{cite journal | vauthors=((Bamigbade, T. A.)), ((Davidson, C.)), ((Langford, R. M.)), ((Stamford, J. A.)) | journal=British Journal of Anaesthesia | title=Actions of tramadol, its enantiomers and principal metabolite, O-desmethyltramadol, on serotonin (5-HT) efflux and uptake in the rat dorsal raphe nucleus | volume=79 | issue=3 | pages=352–356 | date= September 1997 | url=https://linkinghub.elsevier.com/retrieve/pii/S0007091217398598 | issn=00070912 | doi=10.1093/bja/79.3.352}}</ref> [[norepinephrine]] [[reuptake inhibitor]],<ref name="Frink1996" /> [[NMDA receptor antagonist]],<ref>{{cite journal | vauthors=((Hara, K.)), ((Minami, K.)), ((Sata, T.)) | journal=Anesthesia & Analgesia | title=The Effects of Tramadol and Its Metabolite on Glycine, γ-Aminobutyric Acid<sub>A</sub>, and N-Methyl-d-Aspartate Receptors Expressed in Xenopus Oocytes: | volume=100 | issue=5 | pages=1400–1405 | date= May 2005 | url=http://journals.lww.com/00000539-200505000-00037 | issn=0003-2999 | doi=10.1213/01.ANE.0000150961.24747.98}}</ref> 5-HT2C receptor antagonist,<ref name="Ogata2004">{{cite journal | vauthors=((Ogata, J.)), ((Minami, K.)), ((Uezono, Y.)), ((Okamoto, T.)), ((Shiraishi, M.)), ((Shigematsu, A.)), ((Ueta, Y.)) | journal=Anesthesia & Analgesia | title=The Inhibitory Effects of Tramadol on 5-Hydroxytryptamine Type 2C Receptors Expressed in Xenopus Oocytes: | pages=1401–1406 | date= May 2004 | url=http://journals.lww.com/00000539-200405000-00038 | issn=0003-2999 | doi=10.1213/01.ANE.0000108963.77623.A4}}</ref> (α7)5 nicotinic acetylcholine receptor antagonist,<ref name="Ogata2004" /> and M1 and M3 muscarinic [[acetylcholine]] [[receptor]] [[antagonist]].<ref>{{cite journal | vauthors=((Shiraishi, M.)), ((Minami, K.)), ((Uezono, Y.)), ((Yanagihara, N.)), ((Shigematsu, A.)) | journal=The Journal of Pharmacology and Experimental Therapeutics | title=Inhibition by tramadol of muscarinic receptor-induced responses in cultured adrenal medullary cells and in Xenopus laevis oocytes expressing cloned M1 receptors | volume=299 | issue=1 | pages=255–260 | date= October 2001 | issn=0022-3565}}</ref><ref>{{cite journal | vauthors=((Shiga, Y.)), ((Minami, K.)), ((Shiraishi, M.)), ((Uezono, Y.)), ((Murasaki, O.)), ((Kaibara, M.)), ((Shigematsu, A.)) | journal=Anesthesia & Analgesia | title=The Inhibitory Effects of Tramadol on Muscarinic Receptor-Induced Responses in Xenopus Oocytes Expressing Cloned M3 Receptors | volume=95 | issue=5 | pages=1269–1273 | date= November 2002 | url=https://journals.lww.com/00000539-200211000-00031 | issn=0003-2999 | doi=10.1097/00000539-200211000-00031}}</ref>


'''Moderate to moderately-severe pain in patients 17 years of age and older'''<ref name=a/><ref name=chr>Schnitzer TJ, Gray WL, Paster RZ, Kamin M. Efficacy of tramadol in treatment of chronic low back pain. The Journal of rheumatology. 2000 Mar;27(3):772-8.</ref><ref name=com>Moore RA, McQuay HJ. Single-patient data meta-analysis of 3453 postoperative patients: oral tramadol versus placebo, codeine and combination analgesics. Pain. 1997 Feb;69(3):287-94.</ref>
Tramadol is metabolised to [[O-Desmethyltramadol]] ('''O-DSMT'''), a significantly more potent opioid.
* Starting dose for chronic pain:
** 25 mg daily in the morning
* Starting dose for acute pain:
** 50 to 100 mg daily every 4 to 6 hours as needed for pain
* Maintenance dose:
** 200 mg daily
** After the titration period is over, additional doses may be given as needed for pain every 4-6 hours.
** The maximum daily dose is 400 mg (300 mg for ages 75 and up).
* Titration schedule: titrate in 25 mg increments as separate doses every three days until 25 mg by mouth four times a day is reached. Then the total daily dosage of tramadol may be increased by 50mg every three days to 50 mg by mouth four times a day. Adverse effects will be more likely if tramadol is not titrated.


=== Non-FDA Approved Indications ===
The euphoric effects of tramadol stem from the way in which opioids bind to and activate the [[Opioid#Receptor_types|μ-opioid]] [[receptor]]. This occurs because opioids structurally mimic endogenous endorphins which are naturally found within the body and also work upon the μ-opioid receptor set. The way in which opioids structurally mimic these natural endorphins results in their [[physical euphoria|euphoria]], [[pain relief]] and [[anxiolytic]] effects. This is because endorphins are responsible for reducing pain, causing sleepiness, and feelings of pleasure. They can be released in response to pain, strenuous exercise, orgasm, or general excitement.
* arthralgia<ref name=arth>Akinci SB, Saricaoglu F, Atay OA, Doral MN, Kanbak M. Analgesic effect of intra-articular tramadol compared with morphine after arthroscopic knee surgery. Arthroscopy. 2005 Sep;21(9):1060-5.</ref>
* bone pain<ref name=ext>Cander B, Girisgin S, Koylu R, Gul M, Kocak S. The effectiveness of analgesics in traumatic injuries of the extremities. Advances in therapy. 2005 Sep-Oct;22(5):462-6.</ref><ref name=spine>Sekar C, Rajasekaran S, Kannan R, Reddy S, Shetty TA, Pithwa YK. Preemptive analgesia for postoperative pain relief in lumbosacral spine surgeries: a randomized controlled trial. Spine J. 2004 May-Jun;4(3):261-4.</ref>
* dental pain<ref name=tooth>Moore PA. Pain management in dental practice: tramadol vs. codeine combinations. Journal of the American Dental Association (1939). 1999 Jul;130(7):1075-9.</ref>
* headache<ref name=headache>Silberstein SD, Freitag FG, Rozen TD, Kudrow DB, Hewitt DJ, Jordan DM, et al. Tramadol/acetaminophen for the treatment of acute migraine pain: findings of a randomized, placebo-controlled trial. Headache. 2005 Nov-Dec;45(10):1317-27.</ref>
* fibromyalgia<ref name=fib>Bennett RM, Kamin M, Karim R, Rosenthal N. Tramadol and acetaminophen combination tablets in the treatment of fibromyalgia pain: a double-blind, randomized, placebo-controlled study. The American journal of medicine. 2003 May;114(7):537-45.</ref>
* neuropathic pain<ref name=neuro>Chong MS, Hester J. Diabetic painful neuropathy : current and future treatment options. Drugs. 2007;67(4):569-85.</ref>
* osteoarthritis<ref name=B/><ref name=OA>Cepeda MS, Camargo F, Zea C, Valencia L. Tramadol for osteoarthritis: a systematic review and metaanalysis. The Journal of rheumatology. 2007 Mar;34(3):543-55.</ref>
* postoperative shivering<ref name=shi>le Roux PJ, Coetzee JF. Tramadol today. Current opinion in anaesthesiology. 2000 Aug;13(4):457-61.</ref>
* premature ejaculation<ref name=premature>Salem EA, Wilson SK, Bissada NK, Delk JR, Hellstrom WJ, Cleves MA. Tramadol HCL has Promise in On-Demand Use to Treat Premature Ejaculation. J Sex Med. 2007 Mar 14.</ref>
* restless legs syndrome <ref name=leg>Vetrugno R, La Morgia C, D'Angelo R, Loi D, Provini F, Plazzi G, et al. Augmentation of restless legs syndrome with long-term tramadol treatment. Mov Disord. 2007 Feb;22(3):424-7.</ref>


=== Dosage Adjustment === <!--IF NO DOSAGE ADJUSTMENT NEEDED, ERASE THE LINE. KEEP THE BREAKS (<br>) BETWEEN LINES FOR STYLING PURPOSES-->
==Subjective effects==
'''Renal insufficiency:''' For patients with a CrCl <30 mL/min, the dosage interval should be extended to 12 hours. The maximum daily dose should be lowered to 200 mg/day.<ref name=a/><br>
{{Preamble/SubjectiveEffects}}
'''Hepatic insufficiency:''' The recommended dose is 50 mg every 12 hours for patients with hepatic cirrhosis. It is not recommended that patients with hepatic impairment receive extended-release tramadol.<ref name=a/><br>
'''Hemodialysis:''' Patients can receive their regular dose on dialysis days. Only 7% of the dose is removed by a four-hour hemodialysis session. No studies have been completed with hemodialysis patients taking extended-release tramadol, therefore it is not recommended it is given to this patient population.<br>
'''Geriatric:''' In patients over the age of 65, dosage should initially be lower than an adult patient. It is be titrated based on tolerability, not to exceed the rate of titration recommended for adult patients. Patients over the age of 75 years, should not exceed 300 mg of tramadol per day.<ref name=a/><br>
'''Pediatric:''' Not indicated.


=== Dosage Limits ===
{{effects/base
* '''Ages 17 to 75:''' 400 mg/day
* '''Elderly over age 75:''' 300 mg/day
* '''Adolescents under age 17 and children:''' Not indicated


|{{effects/physical|
*'''[[Effect::Sedation]]''' & '''[[Effect::Stimulation]]''' - At lower to common doses, tramadol is considerably more, and highly stimulating than traditional opiates like [[codeine]] and [[heroin]] due to its action as a [[norepinephrine]] [[reuptake inhibitor]]. Higher doses are marked by sedation and lethargy characteristic of traditional opiates.
*'''[[Effect::Pain relief]]'''{{citation needed}}
*'''[[Effect::Physical euphoria]]''' - Tramadol is considered as less intense in its physical euphoria when compared with that of [[morphine]] or [[heroin]].  The sensation itself can be described as extreme feelings of intense physical comfort, warmth, love and bliss.
*'''[[Effect::Itchiness]]''' - Itchiness is comparably greater than other opioids due to higher amounts of histamine release.
*'''[[Effect::Constipation]]'''{{citation needed}}
*'''[[Effect::Cough suppression]]'''{{citation needed}}
*'''[[Effect::Dehydration]]'''{{citation needed}} - Tramadol can produce significant dehydration, particularly with higher doses. Users are advised to drink water throughout the experience to help mitigate the comedown and side effects like headaches.
*'''[[Effect::Difficulty urinating]]'''
*'''[[Effect::Nausea]]'''{{citation needed}}
*'''[[Effect::Pupil constriction]]'''{{citation needed}}
*'''[[Effect::Decreased libido]]'''{{citation needed}}
*'''[[Effect::Appetite suppression]]'''
*'''[[Effect::Orgasm suppression]]'''{{citation needed}}
*'''[[Effect::Seizure]]'''{{citation needed}}
*'''[[Effect::Teeth grinding]]''' - This effect typically occurs only at lower dosages where the stimulation is more pronounced, this is likely due to its action as a serotonin [[reuptake inhibitor]].
*'''[[Effect::Headaches]]''' - Headaches seem to occur more frequently on tramadol than other [[opiates]], although they don't occur for everyone. The underlying cause is unclear, although it may be related to its [[SNRI]] properties.
*'''[[Effect::Restless legs]]'''<ref>{{cite journal | vauthors=((Hoque, R.)), ((Chesson, A. L.)) | journal=Journal of clinical sleep medicine: JCSM: official publication of the American Academy of Sleep Medicine | title=Pharmacologically induced/exacerbated restless legs syndrome, periodic limb movements of sleep, and REM behavior disorder/REM sleep without atonia: literature review, qualitative scoring, and comparative analysis | volume=6 | issue=1 | pages=79–83 | date=15 February 2010 | issn=1550-9389}}</ref>


== Administration ==
}}
* '''Route:''' Oral
|{{effects/cognitive|
* '''Method:'''
** May be taken with or without food. Take with a drink of water or other beverage.
** Extended-release tablets should be swallowed whole and not crushed or chewed.


== Monitoring Parameters ==
The general head space of tramadol is described by many as one of stimulation, euphoria, relaxation, anxiety suppression and pain relief.
* Not needed


== Contraindications/Precautions  ==
*'''[[Effect::Disinhibition]]'''
=== Contraindications ===
*'''[[Effect::Cognitive euphoria]]''' - This particular substance can be considered as less intense in its cognitive euphoria when compared with that of [[morphine]] or [[diacetylmorphine]] (heroin). The sensation itself can be described as powerful and overwhelming feeling of emotional bliss, contentment, and happiness.
* '''Hypersensitivity to tramadol or any of its components'''
*'''[[Effect::Empathy, affection and sociability enhancement]]'''
* '''Hypersensitivity to opioids'''
*'''[[Effect::Anxiety suppression]]'''
* '''Patients acutely intoxicated with alcohol, hypnotics, narcotics, centrally acting analgesics, opioids or psychotropic drugs'''
*'''[[Effect::Anxiety]]''' - While tramadol has a greater tendency to suppress anxiety, it can also potentially cause it under certain conditions. This effect can possibly be attributed to the noradrenergic properties of this substance.
 
*'''[[Effect::Irritability]]''' - While opioids are well known for their ability to improve mood, they can also have the paradoxical effect of increasing the user's sensitivity to irritable stimuli. This can manifest as aloofness and sudden outbursts of anger and aggression (colloquially known as "opiate rage"). It appears to occur more frequently during the comedown of the experience and/or with heavy use. Tramadol's noradrenergic properties may also have a part in this effect.
=== Precautions ===
*'''[[Effect::Thought acceleration]]'''
* Acute abdominal conditions
*'''[[Effect::Compulsive redosing]]'''
* Renal impairment (caution with immediate-release, extended-release not recommended in severe renal impairment)
*'''[[Effect::Motivation enhancement]]'''
* Hepatic impairment (caution with immediate-release, extended-release not recommended)
*'''[[Effect::Dream potentiation]]'''
* Respiratory depression
*'''[[Effect::Increased music appreciation]]''' Music may sound more immersive when under the influence of tramadol.
* Patients receiving anesthetic medications
*'''[[Effect::Wakefulness]]'''
* Patients who consume alcohol
}}
* Patients with epilepsy, a history of seizures, head trauma, metabolic disorder, alcohol withdrawal, drug withdrawal, or CNS infections: seizures may occur with tramadol, even within typical dosage limits. Tramadol can lower the seizure threshold to a rate of < 1/100,000 (spontaneous seizures).<ref name=d>Mason BJ, Blackburn KH. Possible serotonin syndrome associated with tramadol and sertraline coadministration. The Annals of pharmacotherapy. 1997 Feb;31(2):175-7.</ref> Risk of seizures increases when the following drugs are used concomitantly: [[Selective serotonin reuptake inhibitor (SSRI)|selective serotonin reuptake inhibitors (SSRIs)]], [[Tricyclic antidepressant (TCA)|tricyclic antidepressants (TCAs)]], tricyclic compounds ([[cyclobenzaprine]], [[promethazine]]), opioids, [[Monoamine oxidase inhibitor (MAOI)|monoamine oxidase inhibitors (MAOIs)]], neuroleptics, alcohol,<ref name=f>Jovanovic-Cupic V, Martinovic Z, Nesic N. Seizures associated with intoxication and abuse of tramadol. Clinical toxicology (Philadelphia, Pa. 2006;44(2):143-6.</ref> [[naloxone]] (given for overdose of tramadol), or any other drug which may lower the seizure threshold.
}}
* Increased intracranial pressure
* Abrupt discontinuation: withdrawal may occur if tramadol is stopped without downward titration. Symptoms of withdrawal include anxiety, sweating, insomnia, pain, nausea, tremors, diarrhea, piloerection and hallucinations.
 
=== Pregnancy indications ===
'''Category C'''
Tramadol has been shown to be embryotoxic and fetotoxic in mice, rats and rabbits. Tramadol has not been shown to be teratogenic in mice, rats and rabbits.
 
=== Breast-feeding indications ===
Tramadol is not indicated for breastfeeding mothers. The excretion into breast milk is 0.1% of the maternal dose.<ref name=a/>
 
 
== [[Tramadol drug interactions | Drug-Drug, -Food, -Herb Interactions]] ==
Click the link above to go to the drug interactions page.
 
== Adverse Reactions/Side Effects ==
 
In a clinical trial of 550 patients with moderate pain (375 patients 65 years or older), the rates of side effects were comparable to acetaminophen with codeine, but the rate of withdrawal for side effects was greater in patients treated with tramadol.<ref name=a/> The most frequent adverse effects include constipation (38%), nausea (34%), dizziness (31%), headache (26%), somnolence (23%) and vomiting (13%).<ref name=B/>
<!--
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{| style="width:100%" border="1" align="center"
|+ '''Tramadol Adverse Reactions Chart'''
|- style="background:#EFEFFF" align="center"
| '''Incidence''' || '''Body System''' || '''Adverse Reactions'''
|- style="background:#FFFFCC" align="center"
| '''>10%''' || All || style="padding-left:0.5em" align="left"| Dizziness (26-33%), nausea (24-40%), constipation (24-46%), headache (18-32%), somnolence (16-25%), vomiting (9-25%), dyspepsia (5-13%), pruritis (8-11%), diarrhea (5-10%), CNS stimulation (7-14%), asthenia (6-12%), sweating (6-12%)
|- style="background:#FFFEDD" align="center"
| rowspan="7" | '''1-10%'''|| CNS || style="padding-left:0.5em" align="left"| Sleep changes (1-5%), anxiety, confusion, coordination disturbances, euphoria, nervousness
|- style="background:#FFFEDD" align="center"
| Cardiovascular || style="padding-left:0.5em" align="left"| Vasodilation (1-5%)
|- style="background:#FFFEDD" align="center"
| Dermatologic || style="padding-left:0.5em" align="left"| Rash (1-5%)
|- style="background:#FFFEDD" align="center"
| GI || style="padding-left:0.5em" align="left"| Dry mouth (5-10%), abdominal pain (1-5%), anorexia (1-5%), flatulence (1-5%)
|- style="background:#FFFEDD" align="center"
| Genitourinary || style="padding-left:0.5em" align="left"| Menopausal symptoms (1-5%), urinary frequency or retention (1-5%)
|- style="background:#FFFEDD" align="center"
| Neuromuscular/skeletal || style="padding-left:0.5em" align="left"| Hypertonia (1-5%)
|- style="background:#FFFEDD" align="center"
| Miscellaneous || style="padding-left:0.5em" align="left"| Malaise (1-5%)
|- style="background:#FEFEEF" align="center"
| '''<1%''' || All || style="padding-left:0.5em" align="left"| Accidental injury, allergic reaction, anaphylaxis, death, suicide, weight loss, serotonin syndrome, orthostatic hypotension, tachycardia, Stevens-Johnson syndrome, tremor, gait changes, amnesia, dysuria, dysgeusia, menstrual disorder, hallucinations, paresthesias
|}
 
== Overdosage Measures ==
Symptoms of overdosage include respiratory depression, lethargy, coma, seizure, or cardiac arrest.<ref name=a/>
<br>
'''Treatment:'''
* Use general supportive measuresand maintain ventilation.
* Naloxone reverses some, but not all symptoms and can increase the risk for seizure.
* Convulsions can be suppressed with barbiturates or benzodiazepines.
 
== Product Information and Distribution ==
 
 
{| style="width:100%;" border="1" align="center"
|+ '''Note: appearance only available for brand-name product'''
|- style="background:#EFEFFF" align="center"
| '''Dose/form''' || '''Drug color(s)'''|| '''Drug shape''' || '''Markings or odor/flavor'''
|- style="background:#FEFEEF" align="center"
| style="background:#EFEFFF" | '''50 mg tablet''' || white || oblong || ULTRAM/06 59
|- style="background:#FEFEEF" align="center"
| style="background:#EFEFFF" | '''100 mg extended-release tablet''' || white || round || '100' over 'ER'
|- style="background:#FEFEEF" align="center"
| style="background:#EFEFFF" | '''200 mg extended-release tablet''' || white || round || '200' over 'ER'
|- style="background:#FEFEEF" align="center"
| style="background:#EFEFFF" | '''300 mg extended-release tablet''' || white || round || '300' over 'ER'
|}


* '''Inactive ingredients for tablets:''' corn starch, hypromellose, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium glycolate, titanium dioxide, wax
<br />
* '''Inactive ingredients for extended-release tablets:''' colloidal silicon dioxide, dibutyl sebacate, ethylcellulose, polyvinyl alcohol, polyvinyl pyrrolidone, sodium stearyl fumarate
===Experience reports===
Anecdotal reports which describe the effects of this compound within our [[experience index]] include:
{{#ask: [[Category:Tramadol]][[Category:Experience]]|format=ul|Columns=1}}
Additional experience reports can be found here:


== Patient Information ==
*[https://www.erowid.org/experiences/subs/exp_Pharms_Tramadol.shtml Erowid Experience Vaults: Tramadol]
* May be taken with or without food.
* May cause dizziness or drowsiness. Use caution when driving or operating heavy machinery.
* DO NOT take with alcohol.
* Extended-release tablets should be swallowed whole and not be crushed or chewed.
* Use caution when taking tranquilizers, hypnotics, or other opiate containing analgesics
* Contact your doctor if you are planning on becoming pregnant or think that you are pregnant
* Do not take more often than directed, this may cause respiratory depression, seizures and death
* Contact a health-care professional right away if: you are having difficulty breathing, have had a seizure, develop a rash, experience a change in vision, hallucinate, or have a fast heart beat.
* Other side-effects that you may notice include constipation or diarrhea, dry mouth, and headache.


== References ==
==Toxicity and harm potential==
<references/>
{{toxicity}}
Tramadol has a [[Toxicity::low toxicity]] relative to dose. As with all opioids, long-term effects can vary but can include diminished libido, apathy and memory loss. It is also [[Toxicity::potentially [[respiratory depression|lethal]] when mixed with [[depressants]] like [[alcohol]] or [[benzodiazepines]]]] and generally has a wider range of substances which it is [[Tramadol#Dangerous interactions|dangerous to combine with]] in comparison to other opioids. It should not be taken during [[Benzodiazepine#Discontinuation|benzodiazepine withdrawals]] as this can potentially cause [[seizure]]s.


== PUBMED References ==
It is strongly recommended that one use [[responsible drug use|harm reduction practices]] when using this drug.
=== Efficacy Trial Articles ===
# [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=10743823&query_hl=19&itool=pubmed_docsum Schnitzer TJ, Gray WL, Paster RZ, Kamin M. Efficacy of tramadol in treatment of chronic low back pain. The Journal of rheumatology. 2000 Mar;27(3):772-8.]
# [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=11029125&query_hl=17&itool=pubmed_docsum Pendeville PE, Von Montigny S, Dort JP, Veyckemans F. Double-blind randomized study of tramadol vs. paracetamol in analgesia after day-case tonsillectomy in children. European journal of anaesthesiology. 2000 Sep;17(9):576-82.]
# [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=9676769&query_hl=17&itool=pubmed_DocSum Roth SH. Efficacy and safety of tramadol HCl in breakthrough musculoskeletal pain attributed to osteoarthritis. The Journal of rheumatology. 1998 Jul;25(7):1358-63.]


===Dependence and abuse potential===
As with other [[opioids]], the chronic use of tramadol can be considered [[Addiction potential::moderately addictive with a high potential for abuse]] and is capable of causing psychological dependence among certain users. When addiction has developed, cravings and [[Opioids#Discontinuation|withdrawal symptoms]] may occur if a person suddenly stops their usage.


=== Therapeutic Class Comparison Articles ===
Tolerance to many of the effects of tramadol [[Time to full tolerance::develops with prolonged and repeated use]]. The rate at which this occurs develops at different rates for different effects, with tolerance to the constipation-inducing effects developing particularly slowly for instance. This results in users having to administer increasingly large doses to achieve the same effects. After that, it takes about [[Time to half tolerance::3 - 7 days]] for the tolerance to be reduced to half and [[Time to zero tolerance::1 - 2 weeks]] to be back at baseline (in the absence of further consumption). Tramadol presents cross-tolerance with [[Cross-tolerance::all other [[opioids]]]], meaning that after the consumption of tramadol all [[opioid]]s will have a reduced effect.
# [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=9085303&query_hl=19&itool=pubmed_DocSum Moore RA, McQuay HJ. Single-patient data meta-analysis of 3453 postoperative patients: oral tramadol versus placebo, codeine and combination analgesics. Pain. 1997 Feb;69(3):287-94.]
# [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16731323&query_hl=17&itool=pubmed_DocSum Ng KF, Yuen TS, Ng VM. A comparison of postoperative cognitive function and pain relief with fentanyl or tramadol patient-controlled analgesia. Journal of clinical anesthesia. 2006 May;18(3):205-10.]
# [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16476920&query_hl=17&itool=pubmed_DocSum Ekman EF, Ruoff G, Kuehl K, Ralph L, Hormbrey P, Fiechtner J, et al. The COX-2 specific inhibitor Valdecoxib versus tramadol in acute ankle sprain: a multicenter randomized, controlled trial. The American journal of sports medicine. 2006 Jun;34(6):945-55.]
# [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=9701294&query_hl=17&itool=pubmed_DocSum Turturro MA, Paris PM, Larkin GL. Tramadol versus hydrocodone-acetaminophen in acute musculoskeletal pain: a randomized, double-blind clinical trial. Ann Emerg Med. 1998 Aug;32(2):139-43.]


=== Pharmacokinetics Articles ===
===Dangerous interactions===
# [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17296459&query_hl=1&itool=pubmed_docsumhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17296459&query_hl=1&itool=pubmed_docsum Likar R, Wittels M, Molnar M, Kager I, Ziervogel G, Sittl R. Pharmacokinetic and pharmacodynamic properties of tramadol IR and SR in elderly patients: a prospective, age-group-controlled study. Clin Ther. 2006 Dec;28(12):2022-39.]
{{DangerousInteractions/Intro}}
# [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17288681&query_hl=1&itool=pubmed_docsum Murthy BP, Skee DM, Danyluk AP, Brett V, Vorsanger GJ, Moskovitz BL. Pharmacokinetic model and simulations of dose conversion from immediate- to extended-release tramadol. Current medical research and opinion. 2007 Feb;23(2):275-84.]
{{DangerousInteractions/PhenylpropylamineOpioids}}
# [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17175164&query_hl=1&itool=pubmed_DocSum Garcia-Quetglas E, Azanza JR, Sadaba B, Munoz MJ, Gil I, Campanero MA. Pharmacokinetics of tramadol enantiomers and their respective phase I metabolites in relation to CYP2D6 phenotype. Pharmacol Res. 2007 Feb;55(2):122-30.]
# [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16951997&query_hl=17&itool=pubmed_docsum Garrido MJ, Habre W, Rombout F, Troconiz IF. Population pharmacokinetic/pharmacodynamic modelling of the analgesic effects of tramadol in pediatrics. Pharmaceutical research. 2006 Sep;23(9):2014-23.]
 


=== Drug Interaction Articles ===
===[[Serotonin syndrome]] risk===
# [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16051647&query_hl=31&itool=pubmed_docsum Gillman PK. Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity. British journal of anaesthesia. 2005 Oct;95(4):434-41.]
Combinations with the following substances can lead to dangerously high [[serotonin]] levels. Serotonin syndrome requires immediate medical attention and can be fatal if left untreated.
# [http://ajp.psychiatryonline.org/cgi/content/full/161/6/1129 Mahlberg R, Kunz D, Sasse J, Kirchheiner J. Serotonin syndrome with tramadol and citalopram. The American journal of psychiatry. 2004 Jun;161(6):1129.]
# [http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1297365&blobtype=pdf Kesavan S, Sobala GM. Serotonin syndrome with fluoxetine plus tramadol. Journal of the Royal Society of Medicine. 1999 Sep;92(9):474-5.]
# [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17064212&query_hl=2&itool=pubmed_docsum Dumo PA, Kielbasa LA. Successful anticoagulation and continuation of tramadol therapy in the setting of a tramadol-warfarin interaction. Pharmacotherapy. 2006 Nov;26(11):1654-7.]
# [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=9692666&query_hl=2&itool=pubmed_docsum Sabbe JR, Sims PJ, Sims MH. Tramadol-warfarin interaction. Pharmacotherapy. 1998 Jul-Aug;18(4):871-3.]


==Proprietary preparations==
*'''[[DangerousInteraction::MAOIs|MAOIs]]''' such as '''[[syrian rue]]''', '''[[banisteriopsis caapi]]''', '''phenelzine''', '''selegiline''', and '''moclobemide'''<ref>{{cite journal | vauthors=((Gillman, P. K.)) | journal=British Journal of Anaesthesia | title=Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity | volume=95 | issue=4 | pages=434–441 | date= October 2005 | url=https://linkinghub.elsevier.com/retrieve/pii/S0007091217349565 | issn=00070912 | doi=10.1093/bja/aei210}}</ref>
Grünenthal, which still owns the patent to tramadol, has cross-licensed the agent to pharmaceutical companies internationally. Thus, tramadol is marketed under many trade names around the world, including:
*'''[[Serotonin releasers]]''' such as '''[[DangerousInteraction::MDMA]]''', '''[[4-FA]]''', '''[[methamphetamine]]''', '''[[methylone]]''' and '''[[DangerousInteraction::aMT]]'''
*'''[[UnsafeInteraction::2C-T-x|2C-T-x]]'''
*'''[[DangerousInteraction::DXM|DXM]]'''


* '''Acugesic''' (in [[Malaysia]] and [[Singapore]])
==Legal status==
* '''Algifeno''' (in [[Bolivia]])
* '''Adolan'''
* '''Adolonta''' (in [[Spain]])
* '''Anadol''' (in [[Portugal]])
* '''Boldol''' (in [[Bosnia and Herzegovina]])
* '''Calmador''' (in [[Argentina]])
* '''Campex''' (in [[Pakistan]])
* '''Contramal''' (in [[India]] and [[Italy]])
* '''Crispin'''
* '''Dolcet''' (in the [[Philippines]])
* '''Dolol''' (in [[Denmark]])
* '''Dolzam''' (in [[Belgium]])
* '''Dromadol''' (in [[UK]])
* '''Exopen''' (in [[South Korea]])
* '''Ixprim''' (in [[France]])
* '''Lumidol''' (in [[Croatia]])
* '''Mandolgin''' (in [[Denmark]])
* '''Mandolgine'''
* '''Mosepan'''
* '''Nobligan'''
* '''Osteodol''' (Fem India)
* '''Poltram'''
* '''Ralivia''' (In [[Canada]])
* '''Sintradon'''
* '''Siverol''' (in the [[Philippines]])
* '''Tamool'''
* '''Tandol''' (in [[South Korea]])
* '''Tedool'''
* '''Tiparol'''
* '''Toplagic'''
* '''Tradol'''
* '''Tradolan'''
* '''Tradonal''' (in the [[Philippines]])
* '''Tralgit'''
* '''Tralodie''' (in [[Italy]])
* '''Tramacet''' (combined with [[paracetamol]])
* '''Tramacip'''
* '''Tramadex''' (in [[Israel]])
* '''Tramadin'''
* '''Tramadol'''
* '''Tramadolor'''
* '''Tramahexal'''
* '''Tramajack'''
* '''Tramake Insts''' (in [[United Kingdom]])
* '''Trama-Klosidol'''
* '''Tramal''' (in the [[Netherlands]], [[Finland]], [[Slovenia]], [[Chile]], [[Romania]], [[Australia]], [[New Zealand]] and [[Switzerland]])
* '''Tramalgic''' (in [[Hungary]])
* '''Tramal Gotas''' (in [[Ecuador]])
* '''Tramauydin'''
* '''Tramazac''' (in India)
* '''Tramedo'''
* '''Tramoda''' (in [[Thailand]])
* '''Tramundal''' (various Austrian solid and liquid forms manufacturd by Mundipharma Ges. m.b.H, in Vienna and available elsewhere in Central Europe as well)
* '''Tridol''' (in [[South Korea]])
* '''Tridural''' (in [[Canada]])
* '''Trodon''' (in [[Serbia]])
* '''Ultracet''' (combined with [[paracetamol]])
* '''Ultradol'''
* '''Ultram''' and '''Ultram ER''' (in the [[US]])
* '''Ultramed''' (combined with [[paracetamol]]) in [[India]]
* '''Veldrol''' (in [[Mexico]])
* '''Zafin''' (combined with [[paracetamol]], in [[Chile]])
* '''Zaldiar''' (combined with [[paracetamol]], in [[Spain]], [[Poland]], [[Russia]], [[Chile]])
* '''Zaledor''' (combined with [[paracetamol]], in [[Chile]])
* '''Zamadol''' (in UK)
* '''Zamudol'''
* '''Zodol''' (in [[Ecuador]])
* '''Zydol''' (in the [[UK]] and [[Australia]])
* '''Zytram'''
* '''Zytrim''' (in [[Spain]])


=== Adverse Effects Articles ===
*'''Austria:''' Tramadol is legal for medical use under the AMG (Arzneimittelgesetz Österreich) and illegal when sold or possessed without a prescription under the SMG (Suchtmittelgesetz Österreich).{{citation needed}}
*'''Malaysia:''' Tramadol is not listed as a First Schedule drug in the Dangerous Drugs Act 1952 of Malaysia.<ref>[https://www.pharmacy.gov.my/v2/sites/default/files/document-upload/first-schedule-05.07.2021_0.pdf ''First Schedule Drugs'']


[https://www.pharmacy.gov.my/v2/en/documents/dangerous-drugs-act-1952-and-regulations.html ''Dangerous Drugs Act 1952 and Regulations''] </ref>
*'''Germany:''' Tramadol is a prescription medicine, according to Anlage 1 AMVV.<ref>{{Citation | title=AMVV - Verordnung über die Verschreibungspflicht von Arzneimitteln | url=https://www.gesetze-im-internet.de/amvv/BJNR363210005.html}}</ref>
*'''South Africa:''' Tramadol is legal for prescribed medical use only and is considered a Schedule 5 controlled substance. Sale and possession is decriminalized and considered misdemeanor.<ref>https://strathprints.strath.ac.uk/71305/1/Fynn_etal_HP_2020_Drug_utilization_review_of_tramadol_hydrochloride_in_a_regional_hospital.pdf</ref>
*'''Sweden:''' As of May 2008, Sweden 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.<ref>http://www.lakemedelsverket.se/Alla-nyheter/NYHETER-2008/Substansen-tramadol-nu-narkotikaklassad-pa-samma-satt-som-kodein-och-dextropropoxifen/</ref>
*'''Switzerland:''' Tramadol is listed as a "Abgabekategorie A" pharmaceutical, which requires a prescription.{{citation needed}}
*'''Turkey''': Tramadol is a 'green prescription' only substance<ref>YEŞİL REÇETEYE TABİ İLAÇLAR | https://www.titck.gov.tr/storage/Archive/2019/contentFile/01.04.2019%20SKRS%20Ye%C5%9Fil%20Re%C3%A7eteli%20%C4%B0la%C3%A7lar%20Aktif%20SON%20-%20G%C3%9CNCEL_58b1ff4a-2e1c-4867-bad7-eec855d6162a.pdf</ref> and illegal when sold or possessed without a prescription.{{citation needed}}
*'''United Kingdom:''' On June 10th, 2014, tramadol was made a Class C drug under the Misuse of Drugs Act.<ref>{{Citation | title=The Misuse of Drugs and Misuse of Drugs (Safe Custody) (Amendment) (England, Wales and Scotland) Regulations 2014 | url=https://www.legislation.gov.uk/uksi/2014/1275/regulation/5/made}}</ref>
*'''United States:''' Tramadol is a Schedule IV controlled substance in the United States.<ref>DEA Controlled Drugs | https://www.deadiversion.usdoj.gov/schedules/orangebook/e_cs_sched.pdf</ref>


=== Compliance Articles ===
==See also==


=== Pharmacoeconomic Articles ===
*[[Responsible use]]
*[[Depressants]]
*[[Opioids]]
*[[Serotonin]]
*[[Norepinephrine]]
*[[O-Desmethyltramadol]] (O-DSMT)


== External Links ==
==External links==
'''Clinical treatment guidelines'''
* [http://www.aapa.org/clinissues/pain/guidelines.html Pain Management Resource Center]


'''Patient information pages'''
*[http://en.wikipedia.org/wiki/Tramadol Tramadol (Wikipedia)]
* [http://www.nlm.nih.gov/medlineplus/pain.html Pain (Medline Plus)]
*[https://www.erowid.org/pharms/tramadol/ Tramadol (Erowid Vault)]
* [http://www.mayoclinic.com/health/pain/PN00017 How you feel pain? (Mayo Clinic)]
*[https://isomerdesign.com/PiHKAL/explore.php?id=10528 Tramadol (Isomer Design)]
*[https://go.drugbank.com/drugs/DB00193 Tramadol (DrugBank)]
*[https://www.drugs.com/tramadol.html Tramadol (Drugs.com)]


'''Other resources'''
==References==
* [http://www.vachronicpain.org/pages/pain_resources.htm VA pain resources]
{{reflist|2}}
* [http://www.arthritis.org/ Arthritis Foundation]
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[[Category:Drugs]]
[[Category:Psychoactive substance]]
[[Category:Medicines]]
[[Category:Cycloalkylamine]]
[[sv:Läkemedel]]
[[Category:Phenylpropylamine]]
[[es:Farmacos]]
[[Category:Opioid]]

Revision as of 19:17, 31 January 2025

File:Skull and crossbones darktextred2.png

Fatal overdose may occur when opiates are combined with other depressants such as benzodiazepines, barbiturates, gabapentinoids, thienodiazepines, alcohol or other GABAergic substances.[1]

It is strongly discouraged to combine these substances, particularly in common to heavy doses.

Summary sheet: Tramadol
{{#arraydefine: InhaledDosage | Threshold;, Light;, Common;, Strong;, Heavy; }} {{#arraydefine: InhaledDuration | Total;, Onset;, Come up;, Peak;, Offset;, After effects; }} {{#arraydefine: SmokedDosage | Threshold;, Light;, Common;, Strong;, Heavy; }} {{#arraydefine: SmokedDuration | Total;, Onset;, Come up;, Peak;, Offset;, After effects; }} {{#arraydefine: OralDosage | Threshold;Oral threshold dose::25Oral dose units::mg, Light;Oral min light dose::25 - Oral max light dose::100 mg, Common;Oral min common dose::100 - Oral max common dose::250 mg, Strong;Oral min strong dose::250 - Oral max strong dose::300 mg, Heavy;Oral heavy dose::300 mg + }} {{#arraydefine: OralDuration | Total;Oral min total time::6 - Oral max total time::10Oral total time units::hours, Onset;Oral min onset time::15 - Oral max onset time::60Oral onset time units::minutes, Come up;Oral min comeup time::30 - Oral max comeup time::60Oral comeup time units::minutes, Peak;Oral min peak time::2 - Oral max peak time::6Oral peak time units::hours, Offset;Oral min offset time::2 - Oral max offset time::4Oral offset time units::hours, After effects; }} {{#arraydefine: SublingualDosage | Threshold;, Light;, Common;, Strong;, Heavy; }} {{#arraydefine: SublingualDuration | Total;, Onset;, Come up;, Peak;, Offset;, After effects; }} {{#arraydefine: BuccalDosage | Threshold;, Light;, Common;, Strong;, Heavy; }} {{#arraydefine: BuccalDuration | Total;, Onset;, Come up;, Peak;, Offset;, After effects; }} {{#arraydefine: InsufflatedDosage | Threshold;, Light;, Common;, Strong;, Heavy; }} {{#arraydefine: InsufflatedDuration | Total;, Onset;, Come up;, Peak;, Offset;, After effects; }} {{#arraydefine: RectalDosage | Threshold;, Light;, Common;, Strong;, Heavy; }} {{#arraydefine: RectalDuration | Total;, Onset;, Come up;, Peak;, Offset;, After effects; }} {{#arraydefine: TransdermalDosage | Threshold;, Light;, Common;, Strong;, Heavy; }} {{#arraydefine: TransdermalDuration | Total;, Onset;, Come up;, Peak;, Offset;, After effects; }} {{#arraydefine: SubcutaneousDosage | Threshold;, Light;, Common;, Strong;, Heavy; }} {{#arraydefine: SubcutaneousDuration | Total;, Onset;, Come up;, Peak;, Offset;, After effects; }} {{#arraydefine: IntramuscularDosage | Threshold;, Light;, Common;, Strong;, Heavy; }} {{#arraydefine: IntramuscularDuration | Total;, Onset;, Come up;, Peak;, Offset;, After effects; }} {{#arraydefine: IntravenousDosage | Threshold;, Light;, Common;, Strong;, Heavy; }} {{#arraydefine: IntravenousDuration | Total;, Onset;, Come up;, Peak;, Offset;, After effects; }} {{#arraydefine: uncertaininteractions | {{#ask:Tramadol |?UncertainInteraction |headers=hide |format=list |mainlabel=- |link=none }} }} {{#arraydefine: unsafeinteractions | {{#ask:Tramadol |?UnsafeInteraction |headers=hide |format=list |mainlabel=- |link=none }} }} {{#arraydefine: dangerousinteractions | {{#ask:Tramadol |?DangerousInteraction |headers=hide |format=list |mainlabel=- |link=none }} }} {{#arrayprint:uncertaininteractions||@@@@| }} {{#arrayprint:unsafeinteractions||@@@@| }} {{#arrayprint:dangerousinteractions||@@@@| }}
Tramadol
File:Tramadol (Racemate).svg
Chemical Nomenclature
Common names common name::Tramadol, common name::Tramal, common name::Tadol, common name::Tramacur, common name::Tramundin
Substitutive name Tramadol
Systematic name 2-[(Dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol
Class Membership
Psychoactive class psychoactive class::Opioid
Chemical class chemical class::Phenylpropylamine
Routes of Administration

WARNING: Always start with lower doses due to differences between individual body weight, tolerance, metabolism, and personal sensitivity. See responsible use section.



{{#arrayunique: OralDosage}} {{#loop: i | 0 | {{#arraysize: OralDosage}} | {{#arraydefine: val | {{#arrayindex: OralDosage | {{#var: i}} }} | ; }} }} {{#arrayunique: OralDuration}} {{#loop: i | 0 | {{#arraysize: OralDuration}} | {{#arraydefine: val | {{#arrayindex: OralDuration | {{#var: i}} }} | ; }} }}
⇣ Oral
Dosage
Bioavailability Oral min bioavailability::70 - Oral max bioavailability::90%[2]
[[Dosage_classification#{{#arrayindex: val | 0 }}|{{#arrayindex: val | 0 }}]] {{#arrayindex: val | 1 }}
Duration
[[Duration#{{#arrayindex: val | 0 }}|{{#arrayindex: val | 0 }}]] {{#arrayindex: val | 1 }}









DISCLAIMER: PW's dosage information is gathered from users and resources for educational purposes only. It is not a recommendation and should be verified with other sources for accuracy.

Interactions
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Tramadol (also known as Ultram, Ralivia or Tramal) is a synthetic psychoactive class::opioid substance of the chemical class::phenylpropylamine class that is structurally related to codeine and morphine. It acts as a weak μ-opioid receptor agonist and a reuptake inhibitor of norepinephrine and serotonin.[3][4]

Tramadol was developed in 1962 and launched under the name "Tramal" by the German pharmaceutical company Grünenthal GmbH in 1977. In the mid-1990s, it was approved for use in the United Kingdom and the United States.[5] It is commonly prescribed to treat moderate to moderately severe pain.

Subjective effects are largely consistent with that of traditional opioids and include sedation, pain relief, anxiety suppression, muscle relaxation, and euphoria. Tramadol is also known to produce mild to moderate entactogenic effects like increased music appreciation and empathy, affection, and sociability enhancement, which is thought to be due to its serotonergic effects.

Unlike other opioids, tramadol has been established to lower the seizure threshold in humans[6] as well as increase the risk of serotonin syndrome. This makes its effects and interactions relatively unpredictable. As a result, high doses or combinations with other psychoactive substances are strongly advised against.

It is highly advised to use harm reduction practices if using this substance.

History and culture

File:History icon.svg

This History and culture section is a stub.

As a result, it may contain incomplete or wrong information. You can help by expanding it.

Tramadol was synthesized in 1962 by chemists employed by the German pharmaceutical company Grünenthal.[5] However, it was not approved in Germany until 1977, entering the market as Tramal. It became the leading analgesic drug in Germany and during the past 38 years it has been approved in over 100 countries, including the UK, USA, Republic of China and Canada.[7]

For a period of time it was believed tramadol was not a purely synthetic drug after its apparent discovery in the roots of the pin cushion tree.[8] These reports later proved to be erroneous; the tramadol had been excreted by cows treated with the drug, resulting in the tramadol having seeped into the roots through their urine.[9]

Chemistry

(+/-)Tramadol, or 2-[(Dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol, is an atypical synthetic opioid. The chemical structure of tramadol consists of two rings that include a cyclohexane ring bonded to a phenyl ring at R1. This phenyl ring is substituted at R3 with a methoxy group (CH3O-). At the same location (R1) the cyclohexane ring is bonded to the phenyl ring, an additional hydroxy group is found. Tramadol features a second substitution on its cyclohexane ring at R2. Here, the ring is bonded to a dimethylamine group connected through a methyl bridge.

Tramadol is unique as it is found in a racemate (combination) of its stereoisomers. These are two molecules that share the same chemical structure, but are three-dimensional mirror images of each other. Tramadol is produced as a racemate of its two isomers because the combination is proven to be more effective. The picture seen above is the R- enantiomer of tramadol, switching the dashed and solid wedges seen on the molecule skeleton results in the S- enantiomer. It is produced as a hydrochloride salt.[10]

Tramadol is a 4-phenylpiperidine analog of codeine. Notably, it is not a morphinan opiate.

Pharmacology

The R- and S- enantiomers of tramadol act on different receptors in a complimentary manner. The R- enantiomer is a selective agonist of the mu receptors and inhibits serotonin reuptake while the S- enantiomer inhibits noradrenaline reuptake. Tramadol acts as an opioid receptor agonist,[11][12] serotonin releasing agent,[12][4][13][14] norepinephrine reuptake inhibitor,[12] NMDA receptor antagonist,[15] 5-HT2C receptor antagonist,[16] (α7)5 nicotinic acetylcholine receptor antagonist,[16] and M1 and M3 muscarinic acetylcholine receptor antagonist.[17][18]

Tramadol is metabolised to O-Desmethyltramadol (O-DSMT), a significantly more potent opioid.

The euphoric effects of tramadol stem from the way in which opioids bind to and activate the μ-opioid receptor. This occurs because opioids structurally mimic endogenous endorphins which are naturally found within the body and also work upon the μ-opioid receptor set. The way in which opioids structurally mimic these natural endorphins results in their euphoria, pain relief and anxiolytic effects. This is because endorphins are responsible for reducing pain, causing sleepiness, and feelings of pleasure. They can be released in response to pain, strenuous exercise, orgasm, or general excitement.

Subjective effects

Disclaimer: The effects listed below cite the Subjective Effect Index (SEI), an open research literature based on anecdotal user reports and the personal analyses of PsychonautWiki contributors. As a result, they should be viewed with a healthy degree of skepticism.

It is also worth noting that these effects will not necessarily occur in a predictable or reliable manner, although higher doses are more liable to induce the full spectrum of effects. Likewise, adverse effects become increasingly likely with higher doses and may include addiction, severe injury, or death ☠.


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Experience reports

Anecdotal reports which describe the effects of this compound within our experience index include: {{#ask: |format=ul|Columns=1}} Additional experience reports can be found here:

Toxicity and harm potential

File:Ambulance2.png

This toxicity and harm potential section is a stub.

As a result, it may contain incomplete or even dangerously wrong information! You can help by expanding upon or correcting it.
Note: Always conduct independent research and use harm reduction practices if using this substance.

Tramadol has a Toxicity::low toxicity relative to dose. As with all opioids, long-term effects can vary but can include diminished libido, apathy and memory loss. It is also [[Toxicity::potentially lethal when mixed with depressants like alcohol or benzodiazepines]] and generally has a wider range of substances which it is dangerous to combine with in comparison to other opioids. It should not be taken during benzodiazepine withdrawals as this can potentially cause seizures.

It is strongly recommended that one use harm reduction practices when using this drug.

Dependence and abuse potential

As with other opioids, the chronic use of tramadol can be considered Addiction potential::moderately addictive with a high potential for abuse and is capable of causing psychological dependence among certain users. When addiction has developed, cravings and withdrawal symptoms may occur if a person suddenly stops their usage.

Tolerance to many of the effects of tramadol Time to full tolerance::develops with prolonged and repeated use. The rate at which this occurs develops at different rates for different effects, with tolerance to the constipation-inducing effects developing particularly slowly for instance. This results in users having to administer increasingly large doses to achieve the same effects. After that, it takes about Time to half tolerance::3 - 7 days for the tolerance to be reduced to half and Time to zero tolerance::1 - 2 weeks to be back at baseline (in the absence of further consumption). Tramadol presents cross-tolerance with [[Cross-tolerance::all other opioids]], meaning that after the consumption of tramadol all opioids will have a reduced effect.

Dangerous interactions

Warning: Many psychoactive substances that are reasonably safe to use on their own can suddenly become dangerous and even life-threatening when combined with certain other substances. The following list provides some known dangerous interactions (although it is not guaranteed to include all of them).

Always conduct independent research (e.g. Google, DuckDuckGo, PubMed) to ensure that a combination of two or more substances is safe to consume. Some of the listed interactions have been sourced from TripSit.

  • UncertainInteraction::Amphetamines - Stimulants facilitate the activity of the monoamine neurotransmitters, i.e., dopamine, norepinephrine and serotonin, in the central (CNS) and peripheral nervous systems. Because Tramadol has SNRI activity and it also has slight serotonin releasing properties, mixing these two drugs may cause serotonin syndrome.
  • DangerousInteraction::Cocaine - Stimulants facilitate the activity of the monoamine neurotransmitters, i.e., dopamine, norepinephrine and serotonin, in the central (CNS) and peripheral nervous systems. Because Tramadol has SNRI activity and it also has slight serotonin releasing properties, mixing these two drugs may cause serotonin syndrome.
  • DangerousInteraction::DXM - Dextromethorphan has SRI properties. Because Tramadol has SNRI activity and it also has slight serotonin releasing properties, combining these two drugs will cause serotonin syndrome.
  • DangerousInteraction::GHB/DangerousInteraction::GBL - The two substances potentiate each other strongly and unpredictably, very rapidly leading to unconsciousness. While unconscious, vomit aspiration is a risk if not placed in the recovery position
  • DangerousInteraction::MAOIs - Coadministration of monoamine oxidase inhibitors (MAOIs) with certain opioids has been associated with rare reports of severe adverse reactions. There appear to be two types of interaction, an excitatory and a depressive one. Symptoms of the excitatory reaction may include agitation, headache, diaphoresis, hyperpyrexia, flushing, shivering, myoclonus, rigidity, tremor, diarrhea, hypertension, tachycardia, seizures, and coma. Death has occurred in some cases.
  • UncertainInteraction::Benzodiazepines - Central nervous system and/or respiratory-depressant effects may be additively or synergistically present. The two substances potentiate each other strongly and unpredictably, very rapidly leading to unconsciousness. While unconscious, vomit aspiration is a risk if not placed in the recovery position blackouts/memory loss likely.
  • UncertainInteraction::MXE - MXE can potentiate the effects of opioids but also increases the risk of respiratory depression and organ toxicity.
  • UncertainInteraction::Alcohol - Both substances potentiate the ataxia and sedation caused by the other and can lead to unexpected loss of consciousness at high doses. Place affected patients in the recovery position to prevent vomit aspiration from excess. Memory blackouts are likely
  • UncertainInteraction::Nitrous - Both substances potentiate the ataxia and sedation caused by the other and can lead to unexpected loss of consciousness at high doses. While unconscious, vomit aspiration is a risk if not placed in the recovery position. Memory blackouts are common.
  • DangerousInteraction::Grapefruit - While grapefruit is not psychoactive, it may affect the metabolism of certain opioids. Tramadol, oxycodone, and fentanyl are all primarily metabolized by the enzyme CYP3A4, which is potently inhibited by grapefruit juice[19]. This may cause the drug to take longer to clear from the body. it may increase toxicity with repeated doses. Methadone may also be affected[19]. Codeine and hydrocodone are metabolized by CYP2D6. People who are on medicines that inhibit CYP2D6, or that lack the enzyme due to a genetic mutation will not respond to codeine as it can not be metabolized into its active product: morphine.

Serotonin syndrome risk

Combinations with the following substances can lead to dangerously high serotonin levels. Serotonin syndrome requires immediate medical attention and can be fatal if left untreated.

Legal status

  • Austria: Tramadol is legal for medical use under the AMG (Arzneimittelgesetz Österreich) and illegal when sold or possessed without a prescription under the SMG (Suchtmittelgesetz Österreich).[citation needed]
  • Malaysia: Tramadol is not listed as a First Schedule drug in the Dangerous Drugs Act 1952 of Malaysia.[21]
  • Germany: Tramadol is a prescription medicine, according to Anlage 1 AMVV.[22]
  • South Africa: Tramadol is legal for prescribed medical use only and is considered a Schedule 5 controlled substance. Sale and possession is decriminalized and considered misdemeanor.[23]
  • Sweden: As of May 2008, Sweden 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.[24]
  • Switzerland: Tramadol is listed as a "Abgabekategorie A" pharmaceutical, which requires a prescription.[citation needed]
  • Turkey: Tramadol is a 'green prescription' only substance[25] and illegal when sold or possessed without a prescription.[citation needed]
  • United Kingdom: On June 10th, 2014, tramadol was made a Class C drug under the Misuse of Drugs Act.[26]
  • United States: Tramadol is a Schedule IV controlled substance in the United States.[27]

See also

External links

References

  1. ↑ Risks of Combining Depressants - TripSit 
  2. ↑ Klotz, U. (25 December 2011). "Tramadol — the Impact of its Pharmacokinetic and Pharmacodynamic Properties on the Clinical Management of Pain". Arzneimittelforschung. 53 (10): 681–687. doi:10.1055/s-0031-1299812. ISSN 0004-4172. 
  3. ↑ Reimann, W., Schneider, F. (22 May 1998). "Induction of 5-hydroxytryptamine release by tramadol, fenfluramine and reserpine". European Journal of Pharmacology. 349 (2): 199–203. doi:10.1016/S0014-2999(98)00195-2. ISSN 0014-2999. 
  4. ↑ 4.0 4.1 Gobbi, M., Moia, M., Pirona, L., Ceglia, I., Reyes-Parada, M., Scorza, C., Mennini, T. (19 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: Effects of MTA and mCPP in synaptosomes". Journal of Neurochemistry. 82 (6): 1435–1443. doi:10.1046/j.1471-4159.2002.01073.x. ISSN 0022-3042. 
  5. ↑ 5.0 5.1 Leppert, W. (November 2009). "Tramadol as an analgesic for mild to moderate cancer pain". Pharmacological Reports. 61 (6): 978–992. doi:10.1016/S1734-1140(09)70159-8. ISSN 1734-1140. 
  6. ↑ Talaie, H., Panahandeh, R., Fayaznouri, M. R., Asadi, Z., Abdollahi, M. (June 2009). "Dose-independent occurrence of seizure with tramadol". Journal of Medical Toxicology. 5 (2): 63–67. doi:10.1007/BF03161089. ISSN 1556-9039. 
  7. ↑ Lassen, D., Damkier, P., Brøsen, K. (August 2015). "The Pharmacogenetics of Tramadol". Clinical Pharmacokinetics. 54 (8): 825–836. doi:10.1007/s40262-015-0268-0. ISSN 0312-5963. 
  8. ↑ 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, J.-L., Bonaz, B., De Waard, M. (4 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. ISSN 1433-7851. 
  9. ↑ Kusari, S., Tatsimo, S. J. N., Zühlke, S., Talontsi, F. M., Kouam, S. F., Spiteller, M. (3 November 2014). "Tramadol-A True Natural Product?". Angewandte Chemie International Edition. 53 (45): 12073–12076. doi:10.1002/anie.201406639. ISSN 1433-7851. 
  10. ↑ Dayer, P., Desmeules, J., Collart, L. (1997). "[Pharmacology of tramadol]". Drugs. 53 Suppl 2: 18–24. doi:10.2165/00003495-199700532-00006. ISSN 0012-6667. 
  11. ↑ Hennies, H. H., Friderichs, E., Schneider, J. (July 1988). "Receptor binding, analgesic and antitussive potency of tramadol and other selected opioids". Arzneimittel-Forschung. 38 (7): 877–880. ISSN 0004-4172. 
  12. ↑ 12.0 12.1 12.2 Frink, M. C., Hennies, H. H., Englberger, W., Haurand, M., Wilffert, B. (November 1996). "Influence of tramadol on neurotransmitter systems of the rat brain". Arzneimittel-Forschung. 46 (11): 1029–1036. ISSN 0004-4172. 
  13. ↑ 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): 147–151. ISSN 0007-1188. 
  14. ↑ Bamigbade, T. A., Davidson, C., Langford, R. M., Stamford, J. A. (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): 352–356. doi:10.1093/bja/79.3.352. ISSN 0007-0912. 
  15. ↑ Hara, K., Minami, K., Sata, T. (May 2005). "The Effects of Tramadol and Its Metabolite on Glycine, γ-Aminobutyric AcidA, and N-Methyl-d-Aspartate Receptors Expressed in Xenopus Oocytes:". Anesthesia & Analgesia. 100 (5): 1400–1405. doi:10.1213/01.ANE.0000150961.24747.98. ISSN 0003-2999. 
  16. ↑ 16.0 16.1 Ogata, J., Minami, K., Uezono, Y., Okamoto, T., Shiraishi, M., Shigematsu, A., Ueta, Y. (May 2004). "The Inhibitory Effects of Tramadol on 5-Hydroxytryptamine Type 2C Receptors Expressed in Xenopus Oocytes:". Anesthesia & Analgesia: 1401–1406. doi:10.1213/01.ANE.0000108963.77623.A4. ISSN 0003-2999. 
  17. ↑ 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. ISSN 0022-3565. 
  18. ↑ Shiga, Y., Minami, K., Shiraishi, M., Uezono, Y., Murasaki, O., Kaibara, M., Shigematsu, A. (November 2002). "The Inhibitory Effects of Tramadol on Muscarinic Receptor-Induced Responses in Xenopus Oocytes Expressing Cloned M3 Receptors". Anesthesia & Analgesia. 95 (5): 1269–1273. doi:10.1097/00000539-200211000-00031. ISSN 0003-2999. 
  19. ↑ 19.0 19.1 [1]
  20. ↑ Gillman, P. K. (October 2005). "Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity". British Journal of Anaesthesia. 95 (4): 434–441. doi:10.1093/bja/aei210. ISSN 0007-0912. 
  21. ↑ First Schedule Drugs Dangerous Drugs Act 1952 and Regulations
  22. ↑ AMVV - Verordnung über die Verschreibungspflicht von Arzneimitteln 
  23. ↑ https://strathprints.strath.ac.uk/71305/1/Fynn_etal_HP_2020_Drug_utilization_review_of_tramadol_hydrochloride_in_a_regional_hospital.pdf
  24. ↑ http://www.lakemedelsverket.se/Alla-nyheter/NYHETER-2008/Substansen-tramadol-nu-narkotikaklassad-pa-samma-satt-som-kodein-och-dextropropoxifen/
  25. ↑ YEŞİL REÇETEYE TABİ İLAÇLAR | https://www.titck.gov.tr/storage/Archive/2019/contentFile/01.04.2019%20SKRS%20Ye%C5%9Fil%20Re%C3%A7eteli%20%C4%B0la%C3%A7lar%20Aktif%20SON%20-%20G%C3%9CNCEL_58b1ff4a-2e1c-4867-bad7-eec855d6162a.pdf
  26. ↑ The Misuse of Drugs and Misuse of Drugs (Safe Custody) (Amendment) (England, Wales and Scotland) Regulations 2014 
  27. ↑ DEA Controlled Drugs | https://www.deadiversion.usdoj.gov/schedules/orangebook/e_cs_sched.pdf

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