WARNINGDANGER OF DEATH
High doses alone or ordinary doses in combination with other depressants can fatally stop breathing.
Tramadol
Tramadol is a synthetic opioid analgesic of the phenylpropylamine class, structurally related to codeine and morphine. Developed in 1962 by German pharmaceutical company Grünenthal GmbH and launched commercially in 1977,1 it is widely prescribed for moderate to moderately severe pain.1 Tramadol is distinguished by its atypical dual mechanism, acting as both a weak μ-opioid receptor agonist and a serotonin-norepinephrine reuptake inhibitor (SNRI), with roughly one-tenth the potency of morphine.1 It is listed among the WHO's Essential Medicines.
Dosage & Duration
Dosage
Doses are population estimates that vary widely between individuals.
Taking more than 300 mg increases the likelihood of harmful physical effects, especially for those without opioid tolerance or with lower body weight. Beyond standard opioid-related risks, tramadol poses additional dangers at elevated doses, including seizures and serotonin syndrome.
Duration
Subjective Effects
Effects vary widely by individual, dose, and context.
Physical
The cognitive effects of tramadol can be broken down into several components which progressively intensify proportional to dosage. The general head space of codeine is described by many as one of intense euphoria, relaxation, anxiety suppression and pain relief.
Cognitive
The physical effects of tramadol can be broken down into three components which progressively intensify proportional to dosage.
Reagent Testing
Expected colorimetric results for common reagent tests. Colors show reaction change over 1–2 minutes.
Pharmacology
Pharmacodynamics
Tramadol is a centrally acting analgesic with a dual mechanism involving monoamine reuptake inhibition and μ-opioid receptor activation.2 As a racemic mixture, the (+)-enantiomer primarily inhibits serotonin reuptake while the (-)-enantiomer primarily inhibits norepinephrine reuptake.3 The μ-opioid component is predominantly mediated by the active metabolite O-desmethyltramadol, which displays approximately 700-fold higher affinity for the μ-opioid receptor than the parent compound4 and activates it with intrinsic activity comparable to morphine,5 while tramadol itself does not appear to possess functional efficacy at this receptor. Tramadol has additionally been shown to act as a serotonin releasing agent at micromolar concentrations.6 Secondary targets include antagonism of NMDA, 5-HT2C, α7 nicotinic acetylcholine, and M1/M3 muscarinic acetylcholine receptors, as well as agonism at adenosine A1 receptors.
Pharmacokinetics
Tramadol is rapidly and nearly completely absorbed after oral administration, with a bioavailability of approximately 75% due to 20-30% first-pass metabolism in the liver.7 It undergoes extensive hepatic metabolism through O-demethylation (catalyzed primarily by CYP2D6) to produce the active metabolite O-desmethyltramadol and through N-demethylation (catalyzed by CYP3A4 and CYP2B6) to produce N-desmethyltramadol, with at least 23 metabolites identified overall.4 The parent compound has an elimination half-life of approximately 5-6 hours, while O-desmethyltramadol has a longer half-life of 8-9 hours.3 Individuals with reduced CYP2D6 activity (approximately 6% of the population) produce less O-desmethyltramadol, which can result in diminished analgesic effect since this metabolite is the primary mediator of opioid activity.3
Dangerous
Highest riskThese combinations are considered extremely harmful and should always be avoided. Reactions to these drugs taken in combination are highly unpredictable and have a potential to cause death.
Unsafe
AvoidThere is considerable risk of physical harm when taking these combinations, they should be avoided where possible.
Caution
Use cautionThese combinations are not usually physically harmful, but may produce undesirable effects, such as physical discomfort or overstimulation. Extreme use may cause physical health issues. Synergistic effects may be unpredictable. Care should be taken when choosing to use this combination.
Tolerance
Tolerance timelines are rules of thumb, not exact schedules, and vary widely between individuals and use patterns.
Opioids
Harm Potential
Addiction & Dependence
Psychological
ModerateTramadol is described as moderately addictive, with high abuse potential and the ability to cause psychological dependence.87 Compulsive redosing is reported, and its capacity to relieve stress and improve mood without significant impairment contributes to its abuse potential.
Physical
ModeratePhysical dependence develops with chronic use. Withdrawal symptoms include both opioid-typical effects (body aches, diarrhea, nausea, tremors, sweating, tachycardia) and SNRI-related symptoms (numbness, tingling, paresthesia, tinnitus).9 Withdrawal typically lasts longer than other opioids, with acute symptoms persisting seven days or more compared to three to four days for similar compounds.
Toxicity
Tramadol produces respiratory depression by direct action on brainstem respiratory centres; this effect is dose-dependent and becomes clinically significant at high doses or in combination with other depressants.10 Long-term use may be associated with diminished libido, apathy, and memory loss.
Acute cardiovascular effects include hypotension in susceptible individuals and mild QTc prolongation at higher doses; serious cardiac events are rare at typical doses.10
Chronic opioid use may influence the hypothalamic-pituitary-adrenal and gonadal axes, with potential increases in serum prolactin and decreases in cortisol and testosterone.
Tramadol causes reduced gut motility and increased smooth muscle tone, resulting in constipation; this effect develops more slowly to tolerance than other opioid effects.
Caution is advised in patients with liver impairment due to hepatic metabolism of tramadol to its active metabolite.
Caution is advised in patients with kidney failure due to renal elimination of tramadol and its metabolites.
Psychosis Risk
Hallucinations, confusion, delirium, and paranoia can occur at high doses or during overdose.9 Psychiatric symptoms including hallucinations, extreme anxiety, and panic attacks may also emerge during withdrawal.9 These effects are not typical at common doses.
Seizure Risk
Tramadol is established to lower the seizure threshold in humans, distinguishing it from other opioids.11 Seizures have been reported within the recommended dosage range, with risk increasing at doses above 300mg.10 Seizures occur in approximately half of acute poisoning cases.12 Risk is further elevated in patients with epilepsy, history of seizures, or concurrent use of other medications that lower seizure threshold.11 Grand mal seizures have been reported at doses as low as 100-400mg orally in rare cases.
History & Culture
Tramadol was developed in 1962 by researchers at Grünenthal, a German pharmaceutical company.1 Despite its early synthesis, the compound did not receive regulatory approval in Germany until 1977, when it entered the market under the trade name…
Legality
International
1961 Single Convention: not internationally scheduled.
1971 Convention on Psychotropic Substances: not internationally scheduled.
1988 Convention: not listed as a controlled precursor.
By Country
References
Source Pages
Citations
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- Robert B Raffa, Helmut Buschmann, Thomas Christoph, Gary Eichenbaum, Werner Englberger, Christopher M Flores, Torsten Hertrampf, Babette Kögel, Klaus Schiene, Wolfgang Straßburger, Rolf Terlinden, & Thomas M Tzschentke. (July 2012). Mechanistic and functional differentiation of tapentadol and tramadol. Expert Opinion on Pharmacotherapy, 13(10), 1437–1449. https://doi.org/10.1517/14656566.2012.6960971
- Pierre Dayer, Jules Desmeules, & Laurence Collart. (1997). [Pharmacology of tramadol]. Drugs, 53(Suppl 2), 18–24. https://doi.org/10.2165/00003495-199700532-0000612345
- Jeong HC, Bae SH, Bae JW, Lee S, Kim A, Jang Y, & Shin KH. (2019). Evaluation of the Effect of CYP2D6 Genotypes on Tramadol and O-Desmethyltramadol Pharmacokinetic Profiles in a Korean Population Using Physiologically-Based Pharmacokinetic Modeling. Pharmaceutics, 11(11), 618. https://doi.org/10.3390/pharmaceutics1111061812
- Zebala JA, Schuler AD, Kahn SJ, & Maeda DY. (2020). Desmetramadol Is Identified as a G-Protein Biased µ Opioid Receptor Agonist. Frontiers in Pharmacology, 10, 1680. https://doi.org/10.3389/fphar.2019.016801
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- Karen Miotto, Arthur K. Cho, Mohamed A. Khalil, Kirsten Blanco, Jun D. Sasaki, & Richard Rawson. (January 2017). Trends in Tramadol: Pharmacology, Metabolism, and Misuse. Anesthesia and Analgesia, 124(1), 44–51. https://doi.org/10.1213/ane.00000000000016831
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- EDE Issue of Permit to Import Medicines for Personal Use. ede.gov.ae (n.d.). https://www.ede.gov.ae/en/w/issue-of-permit-to-import-medicines-for-personal-use1
- Drugs and controlled medicines | Official Platform of the UAE Government. u.ae (n.d.). https://u.ae/information-and-services/health-and-fitness/drugs-and-controlled-medicines1
- The Misuse of Drugs and Misuse of Drugs (Safe Custody) (Amendment) (England, Wales and Scotland) Regulations 2014. (2014). https://www.legislation.gov.uk/uksi/2014/1275/regulation/5/made1
- Misuse of Drugs Act 1971 and Misuse of Drugs Regulations 2001. legislation.gov.uk (n.d.). https://www.legislation.gov.uk/uksi/2014/1106/pdfs/uksi_20141106_en.pdf1
- Misuse of Drugs Act 1971 and Misuse of Drugs Regulations 2001. legislation.gov.uk (n.d.). https://www.legislation.gov.uk/uksi/2014/1275/pdfs/uksi_20141275_en.pdf1
- The Misuse of Drugs Act 1971 (Ketamine etc.) (Amendment) Order 2014. legislation.gov.uk (10 June 2014). https://www.legislation.gov.uk/uksi/2014/1106/made1
- Federal Registrar. gpo.gov (n.d.). https://www.govinfo.gov/content/pkg/FR-2014-07-02/pdf/2014-15548.pdf12
- 21 CFR 1308.14. ecfr.gov (n.d.). https://www.ecfr.gov/current/title-21/chapter-II/part-1308/section-1308.141
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