Desmetramadol (), also known as ''O''-desmethyltramadol (''O''-DSMT), is an

opioid Opioids are substances that act on opioid receptors to produce morphine-like effects. Medically they are primarily used for pain relief, including anesthesia. Other medical uses include suppression of diarrhea, replacement therapy for opioid us ...

analgesic An analgesic drug, also called simply an analgesic (American English), analgaesic (British English), pain reliever, or painkiller, is any member of the group of drugs used to achieve relief from pain (that is, analgesia or pain management). It ...

and the main

active metabolite An active metabolite is an active form of a drug after it has been processed by the body. Metabolites of drugs An active metabolite results when a drug is metabolized by the body into a modified form which continues to produce effects in the body ...

tramadol Tramadol, sold under the brand name Ultram among others, is an opioid pain medication used to treat moderate to moderately severe pain. When taken by mouth in an immediate-release formulation, the onset of pain relief usually begins within an ...

. Tramadol is demethylated by the

liver The liver is a major Organ (anatomy), organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of proteins and biochemicals necessary for ...

enzyme

CYP2D6 Cytochrome P450 2D6 (CYP2D6) is an enzyme that in humans is encoded by the ''CYP2D6'' gene. ''CYP2D6'' is primarily expressed in the liver. It is also highly expressed in areas of the central nervous system, including the substantia nigra. CYP2D ...

in the same way as

codeine Codeine is an opiate and prodrug of morphine mainly used to treat pain, coughing, and diarrhea. It is also commonly used as a recreational drug. It is found naturally in the sap of the opium poppy, ''Papaver somniferum''. It is typically use ...

, and so similarly to the variation in effects seen with codeine, individuals who have a less active form of CYP2D6 ("poor metabolizers") will tend to get reduced analgesic effects from tramadol. This also results in a ceiling effect (dependent on CYP2D6 availability) which limits tramadol's range of therapeutic benefits to the treatment of moderate pain.

Pharmacology

Pharmacodynamics

(+)-Desmetramadol is a G-protein biased

μ-opioid receptor The μ-opioid receptors (MOR) are a class of opioid receptors with a high affinity for enkephalins and beta-endorphin, but a low affinity for dynorphins. They are also referred to as μ(''mu'')-opioid peptide (MOP) receptors. The prototypical � ...

full

agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...

. It shows comparatively far lower affinity for the δ- and

κ-opioid receptor The κ-opioid receptor or kappa opioid receptor, abbreviated KOR or KOP, is a G protein-coupled receptor that in humans is encoded by the ''OPRK1'' gene. The KOR is coupled to the G protein Gi/G0 and is one of four related receptors that bind op ...

s. The two enantiomers of desmetramadol show quite distinct pharmacological profiles; both (+) and (−)-desmetramadol are inactive as

serotonin reuptake inhibitor A serotonin reuptake inhibitor (SRI) is a type of drug which acts as a reuptake inhibitor of the neurotransmitter serotonin (5-hydroxytryptamine, or 5-HT) by blocking the action of the serotonin transporter (SERT). This in turn leads to increase ...

s, but (−)-desmetramadol retains activity as a

norepinephrine reuptake inhibitor A norepinephrine reuptake inhibitor (NRI, NERI) or noradrenaline reuptake inhibitor or adrenergic reuptake inhibitor (ARI), is a type of drug that acts as a reuptake inhibitor for the neurotransmitters norepinephrine (noradrenaline) and epineph ...

, and so the mix of both the parent compound and metabolites contributes significantly to the complex pharmacological profile of tramadol. While the multiple receptor targets can be beneficial in the treatment of pain (especially complex pain syndromes such as neuropathic pain), it increases the potential for drug interactions compared to other opioids, and may also contribute to

side effect In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...

s. Desmetramadol is also an

antagonist An antagonist is a character in a story who is presented as the chief foe of the protagonist. Etymology The English word antagonist comes from the Greek ἀνταγωνιστής – ''antagonistēs'', "opponent, competitor, villain, enemy, riv ...

of the

serotonin Serotonin () or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Its biological function is complex and multifaceted, modulating mood, cognition, reward, learning, memory, and numerous physiological processes such as vomiting and vas ...

5-HT_2C receptor, at pharmacologically relevant concentrations, via competitive inhibition. This suggests that the apparent anti-depressant properties of tramadol may be at least partially mediated by desmetramadol, thus prolonging the duration of therapeutic benefit. Inhibition of the 5-HT_2C receptor is a suggested factor in the mechanism of anti-depressant effects of agomelatine and

maprotiline Maprotiline, sold under the brand name Ludiomil among others, is a tetracyclic antidepressant (TeCA) that is used in the treatment of depression. It may alternatively be classified as a tricyclic antidepressant (TCA), specifically a secondary am ...

. The potential selectivity and favorable side effect profile of desmetramadol compared to its prodrug, tramadol, makes it more suitable for clinical use, although no such large scale controlled trials have been conducted with patients. Upon inhibition of the receptor, downstream signaling causes dopamine and norepinephrine release, and the receptor is thought to significantly regulate mood, anxiety, feeding, and reproductive behavior. 5-HT_2C receptors regulate dopamine release in the striatum, prefrontal cortex, nucleus accumbens, hippocampus, hypothalamus, and amygdala, among others. Research indicates that some suicide victims have an abnormally high number of 5-HT_2C receptors in the prefrontal cortex. There is some mixed evidence that agomelatine, a 5-HT_2C

, is an effective

antidepressant Antidepressants are a class of medication used to treat major depressive disorder, anxiety disorders, chronic pain conditions, and to help manage addictions. Common side-effects of antidepressants include dry mouth, weight gain, dizziness, hea ...

. Antagonism of 5-HT_2C receptors by agomelatine results in an increase of dopamine and norepinephrine activity in the frontal cortex.

Pharmacokinetics

Metabolites

Desmetramadol is metabolized in the liver into the active metabolite ''N'',''O''-didesmethyltramadol via

CYP3A4 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine. It oxidizes small foreign organic molecules (xenobiotics), such as toxins or drugs, so that they can be removed from t ...

and

CYP2B6 Cytochrome P450 2B6 is an enzyme that in humans is encoded by the ''CYP2B6'' gene. CYP2B6 is a member of the cytochrome P450 group of enzymes. Along with CYP2A6, it is involved with metabolizing nicotine, along with many other substances. Funct ...

. The inactive tramadol metabolite ''N''-desmethyltramadol is metabolized into the active metabolite ''N'',''O''-didesmethyltramadol by

History

Society and culture

Recreational use

Desmetramadol has been sold in a blend called ''Krypton'' and marketed as powdered

kratom ''Mitragyna speciosa'' (commonly known as kratom, an herbal leaf from a tree of the Rubiaceae family, ) is a tropical evergreen tree in the coffee family native to Southeast Asia. It is indigenous to Thailand, Indonesia, Malaysia, Myanmar, and ...

leaf (''Mitragyna speciosa''). ''Krypton'' was reportedly linked to at least 9 accidental deaths from

overdose A drug overdose (overdose or OD) is the ingestion or application of a drug or other substance in quantities much greater than are recommended.

Sweden Sweden, formally the Kingdom of Sweden,The United Nations Group of Experts on Geographical Names states that the country's formal name is the Kingdom of SwedenUNGEGN World Geographical Names, Sweden./ref> is a Nordic country located on ...

during 2010–2011.

Medicinal use

Unusually for a compound that first came to prominence as a recreational

designer drug A designer drug is a structural or functional analog of a controlled substance that has been designed to mimic the pharmacological effects of the original drug, while avoiding classification as illegal and/or detection in standard drug tests. Des ...

, desmetramadol has recently been reevaluated as a potential novel

drug for use in medicine, with its well studied pharmacology and toxicology as an active metabolite of the widely used analgesic drug tramadol offering advantages over more structurally novel alternatives. Human

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, dietar ...

s have shown it to offer similar analgesic benefits to drugs such as

oxycodone Oxycodone, sold under various brand names such as Roxicodone and OxyContin (which is the extended release form), is a strong, semi-synthetic opioid used medically for treatment of moderate to severe pain. It is highly addictive and a commonly ...

and

fentanyl Fentanyl, also spelled fentanil, is a very potent synthetic opioid used as a pain medication. Together with other drugs, fentanyl is used for anesthesia. It is also used illicitly as a recreational drug, sometimes mixed with heroin, cocaine ...

but with reduced respiratory depression and a comparatively favorable safety profile.

Legality

United Kingdom

Desmetramadol was made a Class A drug in the United Kingdom on 26 Feb 2013. Controlled substance in NY.

References

{{DEFAULTSORT:Desmethyltramadol, O- 5-HT2C antagonists Dimethylamino compounds Analgesics Cyclohexanols Designer drugs Mu-opioid receptor agonists Norepinephrine reuptake inhibitors Opioid metabolites Phenols Synthetic opioids Human drug metabolites