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Pharmacology of Opioids
Published in Pamela E. Macintyre, Stephan A. Schug, Acute Pain Management, 2021
Pamela E. Macintyre, Stephan A. Schug
As noted earlier, the main active metabolite of tramadol is O-desmethyltramadol (M1), which is excreted by the kidney. M1 is a more potent μ-receptor agonist than tramadol itself, thereby contributing to its analgesic efficacy. The formation of M1 depends on the enzyme CYP2D6, therefore, in poor metabolizers the analgesic effect of tramadol may be reduced. Conversely, in ultrarapid metabolizers, opioid-related effects will be increased (Owusu Obeng et al, 2017), including the risk of OIVI, especially in patients with renal impairment (Faria et al, 2018). It is possible that the risk of serotonin syndrome is increased in patients who are poor metabolizers as serotonin reuptake inhibition may be promoted (Faria et al, 2018).
Fentanyl and Related Opioids
Published in Ornella Corazza, Andres Roman-Urrestarazu, Handbook of Novel Psychoactive Substances, 2018
Esther Papaseit, Magí Farré, Clara Pérez-Mañá, Adriana Farré, Francina Fonseca, Marta Torrens
In the United States, the latest official numbers for the opioid epidemic reported 42,249 opioid overdose deaths (prescription and illicit) in 2016, five times higher than in 1999 (Centers for Disease Control and Prevention, 2017). From 281 unintentional overdose fatalities in 24 Ohio counties between January and February 2017, 90% tested positive for fentanyl, 48% for acrylfentanyl, 31% for furafentanyl, 8% for carfentanil, 6% for heroin, and 23% for pharmaceutical opioids (Daniulaityte et al., 2017). From 2013, the rise in synthetic opioid overdoses has been largely due to NPF. Opioid overdose deaths were quadrupled (n = 8,050 in 1999, n = 33,091) in 2015 and doubled in 2016 (n > 60,000 overdoses) and in the last year, driven by a five-fold increase in overdose deaths involving synthetic opioids (O’Donnell, Halpin, Mattson, Goldberger, & Gladden, 2017). In a recent study that examined the presence of fentanyl analogues in forensic cases from January to June 2015, these analogues were implicated in 17% of fentanyl-related deaths (Peterson et al., 2016). In an online survey performed in 619 NPSs users, 3.3% (n = 1551) were opioids. Among these, the most common were kratom (56.6%), AH-7921 (9.4%), and 0-desmethyltramadol (5.7%) (Soussan & Kjellgren, 2016).
Substrates of Human CYP2D6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
In addition, bufuralol, a β-adrenoceptor blocker, has been extensively used as a probe substrate for the in vitro study of CYP2D6 (Zanger et al. 2004). Tramadol, a synthetic opioid analgesic of the aminocyclohexanol type that has two chiral centers, is also used as a probe substrate for CYP2D6. (−)-Tramadol is metabolized to its O-desmethyltramadol (M1) largely by CYP2D6, as is (+)-tramadol but to a lesser extent (Paar et al. 1997; Subrahmanyam et al. 2001). Among the above five probe substrates of CYP2D6, dextromethorphan (O-demethylation) and bufuralol (1′-hydroxylation) are the two commonly used CYP2D6 probe substrates in vitro preferred by pharmaceutical industry investigators, where 60% used bufuralol as the probe substrate and 30% used dextromethorphan (Yuan et al. 2002).
Hepatotoxic effect of tramadol and O-desmethyltramadol in HepG2 cells and potential role of PI3K/AKT/mTOR
Published in Xenobiotica, 2021
Manar A. Helmy, Hussein Abdelaziz Abdalla, Heba Allah Abd El Rahman, Dalia Alsaied Moustafa Ahmed
Tramadol is centrally acting, synthetic opioid analgesics used as therapy for moderate to severe pain. It has proved multiple mechanisms of action, but it mainly acts through µ opioid receptor stimulation and inhibition of serotonin and noradrenaline reuptake (Barbosa et al. 2017). Tramadol is metabolized in the liver into five types of metabolites. O-desmethyltramadol or M1 metabolite of tramadol, product of CYP2D6 enzyme, is the one mainly pharmacologically active and 200 times more potent than the parent drug. CYD2D6 is highly polymorphic enzyme among populations and according to its activity and number of functional alleles; people can be divided into four different types of metabolism ultra-rapid, extensive, intermediate and slow metabolizers (Enggaard et al. 2006). Beside linking the therapeutic response to tramadol to CYP2D6 polymorphism, previous studies linked some tramadol-induced toxicities to higher M1 concentration in plasma (Ibrahim et al. 2016; Arafa and Atteia 2018) and recommended modulation of dose based on the type of metabolism.
Intrinsic clearance rate of O-desmethyltramadol (M1) by glucuronide conjugation and phase I metabolism by feline, canine and common brush-tailed possum microsomes
Published in Xenobiotica, 2020
Aaron M. Izes, Benjamin Kimble, Merran Govendir
Tramadol is a centrally acting analgesic used to minimise pain in people and cats (Pypendop & Ilkiw, 2008; Raffa, 1996). Its mechanism of action is mediated through interactions with opioid, adrenergic and serotonin receptors (Desmeules et al., 1996; Raffa et al., 1992). A significant portion of tramadol’s analgesic properties are reported to be derived from the actions of its main metabolite, O-DSMT (also referred to as M1), which has a 300-fold greater affinity for μ-opioid receptors than its parent compound (Gillen et al., 2000; Hennies et al., 1988). With respect to M1, the terms O-demethyltramadol and O-desmethyltramadol have been used interchangeably by authors (Gillen et al., 2000; Lee et al., 2019; Perez et al., 2016). Other frequently detected tramadol metabolites (M2–M4) are considered to have negligible pharmacological activity, although M5 has some reported activity (Gillen et al., 2000). The phase I metabolites in humans are mono-O-desmethyltramadol (M1), mono-N-desmethyltramadol (M2), di-N-desmethyltramadol (M3), tri-N,O-desmethyltramadol (M4) and di-N,O-desmethyltramadol (M5) (Gillen et al., 2000). A schematic representation of tramadol metabolism in the human liver cell is found at https://www.pharmgkb.org/pathway/ PA165946349 (Gong et al., 2014).
The human organic cation transporter OCT1 and its role as a target for drug responses
Published in Drug Metabolism Reviews, 2019
Nicolas Brosseau, Dindial Ramotar
On the basis of all the mutations identified so far, it is recommended by the International Transporter Consortium that the following non-synonymous SNPs of the OCT1 gene leading to the following five variants Arg61Cys, Cys88Arg, Gly401Ser, Met420del and Gly465Arg should be considered in pharmacogenomic studies. Table 2 summarizes the key polymorphisms, the effects on drug responses, and the allele frequencies using the data from the 1000 genomes (Yee et al. 2018). The five variants have been selected as they affect the pharmacokinetic properties of many drugs including the anti-migraine drug sumatriptan, the analgesic drug morphine and O-desmethyltramadol and the anti-nausea drug ondansetron (Tzvetkov et al. 2011, 2012, 2013; Matthaei et al. 2016). The consortium also recommended that studies must be focused on individuals with higher allele frequencies that result in reduced OCT1 function (Yee et al. 2018).