Tramadol

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Death may result 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
Tramadol
Tramadol (Racemate).svg
Chemical Nomenclature
Common names Tramadol, Tramal, Tadol, Tramacur, Tramundin
Substitutive name Tramadol
Systematic name 2-[(Dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol
Class Membership
Psychoactive class Opioid
Chemical class Cyclohexanol
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.



Oral
Dosage
Bioavailability 70 - 90%[2]
Threshold 25 mg
Light 50 - 100 mg
Common 100 - 250 mg
Strong 250 - 300 mg
Heavy 300 mg +
Duration
Total 6 - 10 hours
Onset 15 - 60 minutes
Peak 2 - 6 hours
Offset 2 - 4 hours









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
Amphetamines
MAOIs
Nitrous
PCP
ArrayC-T-x
MAOIs
MDMA
aMT
DXM
Alcohol
Benzodiazepines
Cocaine
GHB/GBL
Ketamine
MXE
Tramadol


Tramadol (also known as Ultram, Ralivia or Tramal) is a synthetic opioid substance of the cyclohexanol 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

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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.[7] 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.[8]

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.[9] 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.[10]

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.[11]

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,[12][13] serotonin releasing agent,[14][15][16][17] norepinephrine reuptake inhibitor,[18] NMDA receptor antagonist,[19] 5-HT2C receptor antagonist,[20] (α7)5 nicotinic acetylcholine receptor antagonist,[21] TRPV1 receptor agonist,[22] and M1 and M3 muscarinic acetylcholine receptor antagonist.[23][24]

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

The effects listed below are based on the subjective effect index, which is based on anecdotal reports and the personal experiences of PsychonautWiki contributors. As a result, they should be treated with a healthy amount of skepticism. It is worth noting that these effects will rarely (if ever) occur all at once but heavier doses will increase the chances of inducing a full range of effects. Likewise, adverse effects become much more likely on higher doses and may include serious injury or death.

Physical effects
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Cognitive effects
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Experience reports

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

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This toxicity and harm potential section is a stub.

As such, it may contain incomplete or even dangerously wrong information. You can help by expanding or correcting it.
We also recommend that you conduct independent research and use harm reduction practices when 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 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.

Dangerous interactions

Although many psychoactive substances are reasonably safe to use on their own, they can quickly become dangerous or even life-threatening when taken with other substances. The following lists some known dangerous combinations, but cannot be guaranteed to include all of them. Independent research should always be conducted to ensure that a combination of two or more substances is safe to consume. Some interactions listed have been sourced from TripSit.

  • 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
  • Amphetamines - Stimulants increase respiration rate which allows for a higher dose of opiates than would otherwise be used. If the stimulant wears off first then the opiate may overcome the user and cause respiratory arrest.
  • 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.
  • Cocaine - Stimulants increase respiration rate which allows for a higher dose of opiates than would otherwise be used. If the stimulant wears off first then the opiate may overcome the patient and cause respiratory arrest.
  • DXM - CNS depression, difficult breathing, heart issues, hepatoxic, just very unsafe combination all around. Additionally if one takes DXM, their tolerance of opiates goes down slightly, thus causing additional synergistic effects.
  • 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
  • Ketamine - Both substances bring a risk of vomiting and unconsciousness. If the user falls unconscious while under the influence there is a severe risk of vomit aspiration if they are not placed in the recovery position.
  • MAOIs - Coadministration of monoamine oxidase inhibitors (MAOIs) with certain opioids has been associated with rare reports of severe and fatal 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.
  • MXE - This combination can potentiate the effects of the opioid
  • 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 likely.
  • PCP - PCP can reduce opioid tolerance, increasing the risk of overdose.
  • Tramadol - Concomitant use of tramadol increases the seizure risk in patients taking other opioids. These agents are often individually epileptogenic and may have additive effects on seizure threshold during coadministration. Central nervous system- and/or respiratory-depressant effects may be additively or synergistically present

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]
  • Germany: Tramadol is a prescription medicine, according to Anlage 1 AMVV.[27]
  • 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.[28]
  • United Kingdom: On June 10th, 2014, tramadol was made a Class C drug under the Misuse of Drugs Act.[29]
  • United States: Tramadol is a Schedule IV controlled substance in the United States.[30]

See also

External links

References

  1. Risks of Combining Depressants (Tripsit) | https://tripsit.me/combining-depressants/
  2. Klotz, U. (2003). Tramadol—the impact of its pharmacokinetic and pharmacodynamic properties on the clinical management of pain. Arzneimittelforschung, 53(10), 681-687. https://doi.org/10.1055/s-0031-1299812
  3. Induction of 5-hydroxytryptamine release by tramadol, fenfluramine and reserpine (ScienceDirect) | http://www.sciencedirect.com/science/article/pii/S0014299998001952
  4. 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
  5. Tramadol as an analgesic for mild to moderate cancer pain | http://www.if-pan.krakow.pl/pjp/pdf/2009/6_978.pdf
  6. Talaie, H., Panahandeh, R., Fayaznouri, M. R., Asadi, Z., & Abdollahi, M. (2009). Dose-independent occurrence of seizure with tramadol. Journal of medical toxicology, 5(2), 63-67. https://doi.org/10.1007/BF03161089
  7. Tramadol as an analgesic for mild to moderate cancer pain | http://www.if-pan.krakow.pl/pjp/pdf/2009/6_978.pdf
  8. Lassen, D., Damkier, P., & Brøsen, K. (2015). The pharmacogenetics of tramadol. Clinical pharmacokinetics, 54(8), 825-836. https://doi.org/10.1007/s40262-015-0268-0
  9. Occurrence of the Synthetic Analgesic Tramadol in an African Medicinal Plant | http://onlinelibrary.wiley.com/doi/10.1002/anie.201305697/abstract
  10. Kusari, S., Tatsimo, S. J. N., Zühlke, S., Talontsi, F. M., Kouam, S. F., Spiteller, M. "Tramadol- A True Natural Product?". Angewandte Chemie International Edition. http://dx.doi.org/10.1002%2Fanie.201406639
  11. 1: Dayer P, Desmeules J, Collart L. [Pharmacology of tramadol]. Drugs. 1997;53 Suppl 2:18-24. Review. French. PubMed PMID: 9190321.
  12. Receptor binding, analgesic and antitussive potency of tramadol and other selected opioids (PubMed.gov / NCBI) | http://www.ncbi.nlm.nih.gov/pubmed/2849950
  13. Influence of tramadol on neurotransmitter systems of the rat brain (PubMed.gov / NCBI) | http://www.ncbi.nlm.nih.gov/pubmed/8955860
  14. Induction of 5-hydroxytryptamine release by tramadol, fenfluramine and reserpine (PubMed.gov / NCBI) | http://www.ncbi.nlm.nih.gov/pubmed/8955860
  15. 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
  16. Interaction of the central analgesic, tramadol, with the uptake and release of 5-hydroxytryptamine in the rat brain in vitro (PubMed.gov / NCBI) | http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1908625/
  17. 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
  18. Influence of tramadol on neurotransmitter systems of the rat brain (PubMed.gov / NCBI) | http://www.ncbi.nlm.nih.gov/pubmed/8955860
  19. 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
  20. 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
  21. 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
  22. The analgesic drug, tramadol, acts as an agonist of the transient receptor potential vanilloid-1 (PubMed.gov / NCBI) | http://www.ncbi.nlm.nih.gov/pubmed/18499628
  23. Inhibition by tramadol of muscarinic receptor-induced responses in cultured adrenal medullary cells and in Xenopus laevis oocytes expressing cloned M1 receptors (PubMed.gov / NCBI) | http://www.ncbi.nlm.nih.gov/pubmed/11561087
  24. 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
  25. 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. (PubMed.gov / NCBI) | https://www.ncbi.nlm.nih.gov/pubmed/20191944
  26. Gillman, P. K. (2005). Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity. British Journal of Anaesthesia, 95(4), 434-441. https://doi.org/10.1093/bja/aei210
  27. https://www.gesetze-im-internet.de/amvv/BJNR363210005.html
  28. http://www.lakemedelsverket.se/Alla-nyheter/NYHETER-2008/Substansen-tramadol-nu-narkotikaklassad-pa-samma-satt-som-kodein-och-dextropropoxifen/
  29. http://www.legislation.gov.uk/uksi/2014/1275/regulation/5/made
  30. DEA Controlled Drugs | https://www.deadiversion.usdoj.gov/schedules/orangebook/e_cs_sched.pdf