Desmetramadol

Summary

Desmetramadol, also known by its International Nonproprietary Name (INN) as O-desmethyltramadol (O-DSMT), is an opioid analgesic and serves as the primary active metabolite of tramadol. Tramadol undergoes demethylation via the liver enzyme CYP2D6, leading to the formation of desmetramadol, a process akin to the way codeine is metabolized. Consequently, just as variations in the effects of codeine are observed, individuals with a less active form of CYP2D6 are likely to experience diminished analgesic effects from tramadol. However, desmetramadol, in contrast, does not require further metabolism to elicit its analgesic properties, making it a suitable option for individuals with low CYP2D6 activity, unlike tramadol.

Identifiers

IUPAC name
CAS Number	80456-81-1
PubChem CID	130829
ChemSpider	115703
UNII	2WA8F50C3F
ChEMBL	ChEMBL1400
CompTox Dashboard (EPA)	DTXSID40894102
Chemical and physical data
Formula	C15H23NO2
Molar mass	249.354 g·mol−1

Pharmacology

Pharmacodynamics:

1. (+)-Desmetramadol serves as a G-protein biased μ-opioid receptor full agonist. It exhibits notably lower affinity for the δ- and κ-opioid receptors.
2. The two enantiomers of desmetramadol present distinct pharmacological profiles; both (+) and (−)-desmetramadol lack serotonin reuptake inhibitory activity,[7] but (−)-desmetramadol retains norepinephrine reuptake inhibitory properties. Consequently, the combined presence of the parent compound and metabolites contributes significantly to tramadol’s complex pharmacological profile. While this multifaceted action on various receptor targets can be advantageous for pain treatment, it raises the potential for drug interactions when compared to other opioids and may contribute to side effects.
3. Desmetramadol also functions as an antagonist of the serotonin 5-HT2C receptor at pharmacologically relevant concentrations through competitive inhibition. This suggests that the apparent antidepressant effects of tramadol may, in part, be mediated by desmetramadol, prolonging the duration of therapeutic benefits.
4. Inhibition of the 5-HT2C receptor is thought to play a role in the mechanism of action of antidepressants such as agomelatine and maprotiline. The selectivity and favourable side effect profile of desmetramadol, as compared to its prodrug tramadol, make it a more suitable clinical option, although large-scale controlled trials with patients are yet to be conducted.
5. Upon receptor inhibition, downstream signalling triggers the release of dopamine and norepinephrine. The 5-HT2C receptor is believed to significantly regulate mood, anxiety, feeding, and reproductive behaviour. 5-HT2C receptors modulate dopamine release in various brain regions, including the striatum, prefrontal cortex, nucleus accumbens, hippocampus, hypothalamus, and amygdala, among others.
6. Research suggests that individuals who have died by suicide may exhibit an abnormally high number of 5-HT2C receptors in the prefrontal cortex. There is mixed evidence regarding the efficacy of agomelatine, a 5-HT2C antagonist, as an antidepressant. Antagonism of 5-HT2C receptors by agomelatine results in increased dopamine and norepinephrine activity in the frontal cortex.

Pharmacokinetics:

Desmetramadol is metabolized in the liver into the active metabolite N, O-didesmethyltramadol via CYP3A4 and CYP2B6. The inactive tramadol metabolite N-desmethyltramadol is metabolized into the active metabolite N, O-didesmethyltramadol by CYP2D6.

History

The history of desmetramadol is intrinsically linked to its discovery and development within the pharmaceutical industry. This journey commences with its synthesis in the research laboratories of Grünenthal GmbH, a prominent German pharmaceutical establishment, during the late 1970s.

This innovative synthesis marked the inception of desmetramadol as a pharmacological entity. While tramadol, its precursor, was introduced to the global pharmaceutical market in the early 1980s under various brand names and gained recognition as a pain-relieving medication noted for its dual-action properties, desmetramadol emerged as a significant metabolite resulting from tramadol’s metabolism.

In the field of pharmacology, desmetramadol garnered attention for its unique pharmacological profile. Researchers and healthcare professionals acknowledged its distinct attributes and utility. This recognition proved especially critical in cases where tramadol’s effectiveness was affected by individual variations in CYP2D6 enzyme activity. Today, desmetramadol stands as a noteworthy component of the pharmaceutical landscape, offering valuable insights into pain management and pharmacogenetics.

Society and Culture

1. Recreational Use:
2. Desmetramadol has been distributed as part of a blend called Krypton and marketed as powdered kratom leaf (Mitragyna speciosa). Krypton was reportedly associated with at least 9 accidental overdose deaths in Sweden during 2010–2011.
3. Medicinal Use:
4. Unusually for a compound that initially gained prominence as a recreational designer drug, desmetramadol has recently been reevaluated as a potential novel analgesic for medical use. Its well-studied pharmacology and toxicology, as an active metabolite of the widely employed analgesic tramadol, offer advantages over more structurally novel alternatives. Human clinical trials have shown that it provides similar analgesic benefits to drugs like oxycodone and fentanyl but with reduced respiratory depression and a comparatively favourable safety profile.

Legality

• In the United Kingdom, desmetramadol was classified as a Class A drug on February 26, 2013.

FAQ

• What is Desmetramadol?
• Desmetramadol, also known as (+)-Desmetramadol, is an opioid analgesic and the primary active metabolite of tramadol. It plays a crucial role in pain management and offers a pharmacological profile distinct from its precursor, tramadol.
• How does Desmetramadol work?
• Desmetramadol acts as a G-protein biased μ-opioid receptor full agonist, which means it binds to and activates specific receptors in the brain and spinal cord to relieve pain. It has a lower affinity for δ- and κ-opioid receptors. Additionally, it has other properties, such as inhibiting the serotonin 5-HT2C receptor and retaining norepinephrine reuptake inhibitory activity.
• What are the effects of Desmetramadol?
• Desmetramadol primarily provides pain relief, making it a valuable component in pain management. It may also have potential antidepressant effects due to its action on the 5-HT2C receptor. Desmetramadol’s products can be both beneficial for pain treatment and raise the potential for drug interactions and side effects.
• What is the significance of Desmetramadol in medicine?
• Desmetramadol has been reevaluated for use in medicine as a potential novel analgesic. Clinical trials have indicated that it offers similar pain relief to drugs like oxycodone and fentanyl but with a reduced risk of respiratory depression and a more favourable safety profile.
• How is Desmetramadol metabolized in the body?
• Desmetramadol is metabolized in the liver into its active form, N, O-didesmethyltramadol, through the actions of specific cytochrome P450 enzymes, mainly CYP3A4, CYP2B6, and CYP2D6. The inactive tramadol metabolite N-desmethyltramadol can be further metabolized into the active metabolite N, O-didesmethyltramadol by CYP2D6.
• What is the legal status of Desmetramadol?
• In the United Kingdom, Desmetramadol was classified as a Class A drug on February 26, 2013, indicating strict legal control over its possession, use, and distribution.
• Is Desmetramadol associated with any recreational use or health risks?
• Desmetramadol has been marketed as part of a blend called Krypton and sold as powdered kratom leaf. However, it has been linked to accidental overdose deaths, emphasizing the importance of responsible use and controlled access to this substance.
• Is Desmetramadol used in clinical practice?
• While Desmetramadol is still being studied for potential medical applications, it has shown promise as a novel analgesic with fewer side effects than some alternative pain relief medications. Further research may lead to its clinical use in pain management.
• What distinguishes Desmetramadol from other opioids?
• Desmetramadol’s unique pharmacological profile, especially its activity at the 5-HT2C receptor, sets it apart from other opioids and contributes to its potential in pain management and mental health treatment.
• Are there ongoing studies or developments related to Desmetramadol?
• Ongoing research aims to understand further Desmetramadol’s full potential, including its applications in clinical medicine and its role in pain management, and to assess its safety and efficacy.

References

1. What is the significance of Desmetramadol in the study by Sevcik et al. (1993)?The study by Sevcik and colleagues in 1993 investigated the effects of tramadol, a central analgesic, and its primary metabolite, O-desmethyltramadol, on rat locus coeruleus neurones. This research aimed to better understand how tramadol and its metabolite influence neural activity in the rat brain.
2. How is CYP2D6 genotyping relevant to the study by Borlak et al. (2003)?In Borlak et al.’s study from 2003, they developed a quick and straightforward genotyping assay for the cytochrome P450 enzyme CYP2D6. This assay was used as a case study with the analgesic tramadol, highlighting the importance of CYP2D6 genotype in the metabolism of tramadol and its clinical effects.
3. What role does Desmetramadol play as a G-protein biased μ-opioid receptor agonist, as described by Zebala et al. (2019)?Zebala and colleagues’ research in 2019 identifies Desmetramadol as a G-protein biased μ-opioid receptor agonist, indicating that it activates specific receptors in a unique way. This discovery holds significance in understanding the drug’s pharmacological properties and potential clinical use.
4. How does Desmetramadol relate to epilepsy, as explored in the study by Potschka et al. (2000)?The 2000 study by Potschka and team investigated the anticonvulsant and proconvulsant effects of tramadol, its enantiomers, and its M1 metabolite in a rat kindling model of epilepsy. Understanding the effects of Desmetramadol on epilepsy is essential for both its therapeutic applications and potential risks.
5. What is the relevance of the study by Garrido et al. (2000) concerning interactions between opioid agonists and monoamine reuptake inhibitors?In the 2000 study by Garrido and colleagues, they modeled the interaction between an opioid agonist, (+)-O-desmethyltramadol, and a monoamine reuptake inhibitor, (-)-O-desmethyltramadol, in rats. This research sheds light on the combined effects of these substances, which can be vital for optimizing pain management strategies.
6. How does Desmetramadol influence serotonin efflux and uptake, as explored by Bamigbade et al. (1997)?Bamigbade et al.’s study in 1997 investigated the actions of tramadol, its enantiomers, and principal metabolite, O-desmethyltramadol, on serotonin (5-HT) efflux and uptake in the rat dorsal raphe nucleus. Understanding how Desmetramadol affects serotonin is relevant for its potential role in mood regulation.
7. What role does Desmetramadol play in the regulation of noradrenaline and dopamine, as described by Driessen et al. (1993)?The 1993 study by Driessen and colleagues focused on the effects of tramadol on the uptake and release of noradrenaline and dopamine in vitro. Desmetramadol’s influence on these neurotransmitters is important for understanding its pharmacological actions and potential side effects.
8. How does Desmetramadol affect the serotonin 5-HT2C receptor, as indicated in the study by Horishita et al. (2006)?Horishita et al.’s research in 2006 suggests that the tramadol metabolite, O-desmethyltramadol, inhibits 5-HT2C receptors. This has implications for its potential antidepressant effects and mood regulation, which are of clinical interest.
9. What are the implications of serotonin 5-HT(2C) receptors in the study by Heisler et al. (2007)?The 2007 study by Heisler and his team highlights the regulatory role of serotonin 5-HT(2C) receptors in anxiety-like behavior. This information is essential for understanding the broader effects of Desmetramadol on mood, anxiety, and related behaviors.
10. Why is RNA editing of the serotonin 5-HT2C receptor relevant to the study by Niswender et al. (2001)?In Niswender et al.’s study from 2001, they explored RNA editing of the human serotonin 5-HT2C receptor and its potential implications for serotonergic pharmacotherapy. This research contributes to our understanding of how Desmetramadol may affect serotonin receptors and influence its clinical applications.