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{{Tramadol}}
{{Headerpanel|{{DepressantOD|opiates}}}}
'''Tramadol''' (marketed as the hydrochloride salt by Janssen Pharmaceutica as Ultram in the United States, Ralivia by Biovail in Canada and many other companies throughout the world) is a centrally acting [[opioid]] analgesic used to treat moderate to moderately severe pain. 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, US and Australia.<ref>Tramadol as an analgesic for mild to moderate cancer pain | http://www.if-pan.krakow.pl/pjp/pdf/2009/6_978.pdf</ref>
{{SummarySheet}}
{{SubstanceBox/Tramadol}}
Tramadol is marketed as a racemic mixture of both R and S stereoisomers. This is because the two isomers compliment 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 a [[reuptake inhibitor]] of [[norepinephrine]] and [[serotonin]] and a weak μ-opioid receptor agonist.<ref>Induction of 5-hydroxytryptamine release by tramadol, fenfluramine and reserpine | http://www.sciencedirect.com/science/article/pii/S0014299998001952</ref><ref>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 | http://onlinelibrary.wiley.com/doi/10.1046/j.1471-4159.2002.01073.x/abstract</ref> Tramadol is metabolised to [[O-desmethyltramadol]], a significantly more potent opioid.
'''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>
Despite the original belief that tramadol was a purely synthetic opioid it has been recently found in a South African tree.<ref>Occurrence of the Synthetic Analgesic Tramadol in an African Medicinal Plant | http://onlinelibrary.wiley.com/doi/10.1002/anie.201305697/abstract</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.
=Chemistry=
[[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.
=Pharmacology=
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 acts as a [[μ-opioid receptor]] [[agonist]],<ref>Receptor binding, analgesic and antitussive potency of tramadol and other selected opioids | http://www.ncbi.nlm.nih.gov/pubmed/2849950</ref><ref>Influence of tramadol on neurotransmitter systems of the rat brain | http://www.ncbi.nlm.nih.gov/pubmed/8955860</ref> [[serotonin]] releasing agent,<ref>Induction of 5-hydroxytryptamine release by tramadol, fenfluramine and reserpine | http://www.ncbi.nlm.nih.gov/pubmed/8955860</ref><ref>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 | http://onlinelibrary.wiley.com/doi/10.1046/j.1471-4159.2002.01073.x/abstract</ref><ref>Interaction of the central analgesic, tramadol, with the uptake and release of 5-hydroxytryptamine in the rat brain in vitro | http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1908625/</ref><ref>Actions of tramadol, its enantiomers and principal metabolite, O-desmethyltramadol, on serotonin (5-HT) efflux and uptake in the rat dorsal raphe nucleus | http://bja.oxfordjournals.org/content/79/3/352</ref> [[norepinephrine]] [[reuptake inhibitor]],<ref>Influence of tramadol on neurotransmitter systems of the rat brain | http://www.ncbi.nlm.nih.gov/pubmed/8955860</ref> [[NMDA receptor]] [[antagonist]],<ref>The Effects of Tramadol and Its Metabolite on Glycine, γ-Aminobutyric AcidA, and N-Methyl-d-Aspartate Receptors Expressed in Xenopus Oocytes | http://journals.lww.com/anesthesia-analgesia/pages/articleviewer.aspx?year=2005&issue=05000&article=00037&type=abstract</ref> 5-HT2C receptor antagonist,<ref>The Inhibitory Effects of Tramadol on 5-Hydroxytryptamine Type 2C Receptors Expressed in Xenopus Oocytes | http://journals.lww.com/anesthesia-analgesia/pages/articleviewer.aspx?year=2004&issue=05000&article=00038&type=abstract</ref> (α7)5 nicotinic acetylcholine receptor antagonist,<ref>The Inhibitory Effects of Tramadol on 5-Hydroxytryptamine Type 2C Receptors Expressed in Xenopus Oocytes | http://journals.lww.com/anesthesia-analgesia/pages/articleviewer.aspx?year=2004&issue=05000&article=00038&type=abstract</ref> TRPV1 receptor agonist,<ref>The analgesic drug, tramadol, acts as an agonist of the transient receptor potential vanilloid-1 | http://www.ncbi.nlm.nih.gov/pubmed/18499628</ref> and M1 and M3 muscarinic acetylcholine receptor antagonist.<ref>Inhibition by tramadol of muscarinic receptor-induced responses in cultured adrenal medullary cells and in Xenopus laevis oocytes expressing cloned M1 receptors | http://www.ncbi.nlm.nih.gov/pubmed/11561087</ref><ref>The Inhibitory Effects of Tramadol on Muscarinic Receptor-Induced Responses in Xenopus Oocytes Expressing Cloned M3 Receptors | http://journals.lww.com/anesthesia-analgesia/pages/articleviewer.aspx?year=2002&issue=11000&article=00031&type=abstract</ref>
=Subjective effects=
It is highly advised to use [[harm reduction practices]] if using this substance.
The [[Opioids#Subjective effects|subjective effects of opioids]] are extremely similar across individual substances with very little variation. These usually only differ in terms of their potency, intensity and duration. In comparison to other opioids, this particular substance can be considered as less intense in its [[Physical effects: Euphoria|physical]] and [[Cognitive effects: Euphoria|cognitive]] euhoria when compared with that of [[morphine]] or [[diacetylmorphine]] (heroin). It also presents greater amounts of [[Physical effects: Itchiness|itchiness]] due to higher amounts of histamine release and is considerably more stimulating than that of [[Codiene]] and [[Diacetylmorphine]] due to its effects as a [[serotonin]] [[reuptake inhibitor]].
=Toxicity and harm potential=
==History and culture==
Tramadol has not been shown to be toxic and is physically benign at reasonable dosages. As with all opiates, longer-term effects can vary but can include diminished libido, apathy and memory loss.
{{historyStub}}
==Tolerance and addiction potential==
Tolerance to many of the effects of tramdol develops with prolonged use, including therapeutic effects. 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.
As with other opiate-based pain killers, chronic use of tramadol can be considered as highly addictive and is capable of causing both physical and psychological dependence. When physical dependence has developed, [[Opioids#Discontinuation|withdrawal symptoms]] may occur if a person suddenly stops their usage.
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>
==Interactions==
Its serotonergic effects enable it to interact, potentially fatally, with other serotonergics such as antidepressants (such as monoamine oxidase inhibitors, tricyclic antidepressants, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, noradrenergic and specific serotonergic antidepressants, serotonin antagonist and reuptake inhibitors, etc.), certain analgesics (such as 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, syrian rue, passiflora, etc.), certain recreational drugs (e.g. MDMA), phentermine, lithium, methylene blue and numerous other therapeutic agents.<ref>https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-03844-3</ref><ref>Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3</ref> 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.<ref>Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3</ref><ref>Tramadol sustained release capsules | http://link.springer.com/article/10.2165%2F00003495-200666020-00006</ref>
=Legal issues=
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>
*'''USA:''' In November 2013, the United States Drug Enforcement Administration initiated classification of Tramadol as a schedule IV controlled substance, pending a review process. Several states, including Arkansas, Kentucky, Illinois, Mississippi, New York, North Dakota, Oklahoma, Tennessee, West Virginia, Wyoming and the U.S. military have classified Tramadol as a schedule IV controlled substance under state law.<ref>http://www.nabp.net/news/tennessee-news-tramadol-and-carisoprodol-now-classified-schedule-iv</ref>
*'''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.<ref>http://www.lakemedelsverket.se/Alla-nyheter/NYHETER-2008/Substansen-tramadol-nu-narkotikaklassad-pa-samma-satt-som-kodein-och-dextropropoxifen/</ref>
=See also=
==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 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.
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>
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|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>
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 [[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.
==Subjective effects==
{{Preamble/SubjectiveEffects}}
{{effects/base
|{{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::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::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>
}}
|{{effects/cognitive|
The general head space of tramadol is described by many as one of stimulation, euphoria, relaxation, anxiety suppression and pain relief.
*'''[[Effect::Disinhibition]]'''
*'''[[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.
*'''[[Effect::Empathy, affection and sociability enhancement]]'''
*'''[[Effect::Anxiety suppression]]'''
*'''[[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.
*'''[[Effect::Thought acceleration]]'''
*'''[[Effect::Compulsive redosing]]'''
*'''[[Effect::Motivation enhancement]]'''
*'''[[Effect::Dream potentiation]]'''
*'''[[Effect::Increased music appreciation]]''' Music may sound more immersive when under the influence of tramadol.
*'''[[Effect::Wakefulness]]'''
}}
}}
<br />
===Experience reports===
Anecdotal reports which describe the effects of this compound within our [[experience index]] include:
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.
It is strongly recommended that one use [[responsible drug 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 [[Opioids#Discontinuation|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 [[opioid]]s will have a reduced effect.
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.
*'''[[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>
*'''[[Serotonin releasers]]''' such as '''[[DangerousInteraction::MDMA]]''', '''[[4-FA]]''', '''[[methamphetamine]]''', '''[[methylone]]''' and '''[[DangerousInteraction::aMT]]'''
*'''[[UnsafeInteraction::2C-T-x|2C-T-x]]'''
*'''[[DangerousInteraction::DXM|DXM]]'''
==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.<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>
WARNING: Always start with lower doses due to differences between individual body weight, tolerance, metabolism, and personal sensitivity. See responsible use section.
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.
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.
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.
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.
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-opioidreceptor. 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 PsychonautWikicontributors. 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 ☠.
Physical effects
Sedation & 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 norepinephrinereuptake inhibitor. Higher doses are marked by sedation and lethargy characteristic of traditional opiates.
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.
Itchiness - Itchiness is comparably greater than other opioids due to higher amounts of histamine release.
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.
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.
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.
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.
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.
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.
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 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.
As with other opioids, the chronic use of tramadol can be considered 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 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 3 - 7 days for the tolerance to be reduced to half and 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.
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.
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.
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.
GHB/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
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.
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.
MXE - MXE can potentiate the effects of opioids but also increases the risk of respiratory depression and organ toxicity.
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
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.
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[20]. 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[20]. 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.
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.
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.[22]
Germany: Tramadol is a prescription medicine, according to Anlage 1 AMVV.[23]
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.[24]
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.[25]
Switzerland: Tramadol is listed as a "Abgabekategorie A" pharmaceutical, which requires a prescription.[citation needed]
Turkey: Tramadol is a 'green prescription' only substance[26] 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.[27]
United States: Tramadol is a Schedule IV controlled substance in the United States.[28]
↑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. ISSN1433-7851.
↑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. ISSN0004-4172.
↑ 12.012.112.2Frink, 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. ISSN0004-4172.
↑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. ISSN0022-3565.
↑Hoque, R., Chesson, A. L. (15 February 2010). "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". Journal of clinical sleep medicine: JCSM: official publication of the American Academy of Sleep Medicine. 6 (1): 79–83. ISSN1550-9389.
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