Fatal overdose may occur when opiates are combined with other depressants such as benzodiazepines, barbiturates, gabapentinoids, thienodiazepines, alcohol or other GABAergic substances.
It is strongly discouraged to combine these substances, particularly in common to heavy doses.
|Summary sheet: Tramadol|
|Common names||Tramadol, Tramal, Tadol, Tramacur, Tramundin|
|Routes of Administration|
Tramadol (also known as Ultram, Ralivia or Tramal) is a synthetic opioid substance of the 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.
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. 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 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
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. 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.
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. 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.
(+/-)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.
Tramadol is a 4-phenylpiperidine analog of codeine. Notably, it is not a morphinan opiate.
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, serotonin releasing agent, norepinephrine reuptake inhibitor, NMDA receptor antagonist, 5-HT2C receptor antagonist, (α7)5 nicotinic acetylcholine receptor antagonist, and M1 and M3 muscarinic acetylcholine receptor antagonist.
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.
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 ☠.
- Sedation & Stimulation - At lower to common doses, tramadol is considerably more 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.
- Pain relief
- 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.
- Constipation
- Cough suppression
- Dehydration - 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.
- Difficulty urinating
- Nausea
- Pupil constriction
- Decreased libido
- Appetite suppression
- Orgasm suppression
- Seizure
- 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.
- Restless legs
The general head space of tramadol is described by many as one of stimulation, euphoria, relaxation, anxiety suppression and pain relief.
- 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.
- Empathy, affection and sociability enhancement
- Anxiety suppression
- 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.
- Thought acceleration
- Compulsive redosing
- Motivation enhancement
- Dream potentiation
- Increased music appreciation
Anecdotal reports which describe the effects of this compound within our experience index include:
Additional experience reports can be found here:
Toxicity and harm potential
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.
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 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 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 all other opioids, meaning that after the consumption of tramadol all opioids will have a reduced effect.
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. 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. 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.
- MAOIs such as syrian rue, banisteriopsis caapi, phenelzine, selegiline, and moclobemide
- Serotonin releasers such as MDMA, 4-FA, methamphetamine, methylone and aMT
- 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).
- Malaysia: Tramadol is not listed as a First Schedule drug in the Dangerous Drugs Act 1952 of Malaysia.
- Germany: Tramadol is a prescription medicine, according to Anlage 1 AMVV.
- 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.
- Switzerland: Tramadol is listed as a "Abgabekategorie A" pharmaceutical, which requires a prescription.
- Turkey: Tramadol is a 'green prescription' only substance and illegal when sold or possessed without a prescription.
- United Kingdom: On June 10th, 2014, tramadol was made a Class C drug under the Misuse of Drugs Act.
- United States: Tramadol is a Schedule IV controlled substance in the United States.
- ↑ Risks of Combining Depressants - TripSit
- ↑ 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.
- ↑ 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.
- ↑ 4.0 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.
- ↑ 5.0 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 12.0 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 16.0 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.
- ↑ 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.
- ↑ 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.
- ↑ 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. ISSN 1550-9389.
- ↑ 20.0 20.1 
- ↑ 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.
- ↑ First Schedule Drugs Dangerous Drugs Act 1952 and Regulations
- ↑ AMVV - Verordnung über die Verschreibungspflicht von Arzneimitteln
- ↑ http://www.lakemedelsverket.se/Alla-nyheter/NYHETER-2008/Substansen-tramadol-nu-narkotikaklassad-pa-samma-satt-som-kodein-och-dextropropoxifen/
- ↑ 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
- ↑ The Misuse of Drugs and Misuse of Drugs (Safe Custody) (Amendment) (England, Wales and Scotland) Regulations 2014
- ↑ DEA Controlled Drugs | https://www.deadiversion.usdoj.gov/schedules/orangebook/e_cs_sched.pdf