Procedures for pediatric pain management
Harald Breivik, William I Campbell, Michael K Nicholas in Clinical Pain Management, 2008
Tramadol is a moderate potency analgesic, usually classified as an opioid, but with both opioid and nonopioid modes of action.20 It has become popular in pediatric practice, mainly in Europe, because opioid side effects may be less prominent.21[II],22[II] The opioid effects of tramadol are mediated through direct but weak μ-agonist activity, and more potent (× 2–300) μ-agonist effects by an active metabolite O-desmethyltramadol. Tramadol also appears to act through serotonergic and noradrenergic mechanisms.20 As the active metabolite of tramadol is produced by the cytochrome P450 enzyme CYP2D6 (see above under Codeine), unanswered questions arise regarding the effects of genetic polymorphisms and development on the efficacy of tramadol.23 Nevertheless, tramadol has been used widely in children, including in the neonate. Tramadol pharmacokinetics have been investigated; clearance is reduced in the neonatal period but reaches 44 percent of the mature value by one month and is similar to adults by one year.24
Substrates of Human CYP2D6
Shufeng Zhou in 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).
Information on level of drugs into breastmilk
Wendy Jones in Breastfeeding and Medication, 2018
In 2015 the FDA recommended that tramadol is not used in breastfeeding mothers. When tramadol is taken, it is changed in the liver to O-desmethyltramadol (known as M1). Both tramadol and M1 relieve pain and are responsible for side effects that some people may experience, but M1 has stronger opioid effects than the tramadol. Tramadol is metabolised in the liver by enzyme cytochrome P450 isoenzyme 2D6 (CYP2D6). Some people have a variation of this enzyme that changes codeine to morphine and tramadol to M1 faster and to a greater extent than in other people. These individuals are called CYP2D6 ultra-rapid metabolisers. Just as in codeine, this can produce an accumulation of the drug in breastmilk. This genotype is present in up to 10% of the white population in Europe and North America, but only 4% of black African Americans (FDA 2015).
Co-crystal of tramadol-celecoxib: preclinical and clinical evaluation of a novel analgesic
Published in Expert Opinion on Investigational Drugs, 2019
Neus Gascon, Carmen Almansa, Manuel Merlos, José Miguel Vela, Gregorio Encina, Adelaida Morte, Kevin Smith, Carlos Plata-Salamán
In the single-dose study, the PK of tramadol and celecoxib was modified by CTC administration (Table 1; Figure 2c–d). Tramadol from CTC had a similar area under the plasma concentration–time curve (AUCt) (90% CI of the LS means ratios within 80.00–125.00%) but absorption was delayed showing a lower maximum plasma concentration (Cmax decreases by 24%) and slight prolongation of time to maximum plasma concentration (Tmax from 1.8 h to 2.7 h; p < 0.001), when compared with IR tramadol administered individually (90% CI: 72.11–79.79%) or in free combination with celecoxib (90% CI: 72.58–80.32%). Results were similar for O-desmethyltramadol, the main active metabolite of tramadol. Celecoxib from CTC exhibited a faster Tmax compared with celecoxib alone (Tmax from 2.3 h to 1.5 h; p < 0.01) or in free combination with IR tramadol (Tmax from 3.0 h to 1.5 h; p < 0.001). The Cmax of celecoxib from CTC was increased by 10% relative to free combination (90% CI: 105.15–131.89%) and decreased by 30% relative to celecoxib alone (90% CI: 64.16–80.44%), possibly indicating that, in free combination but not when co-crystalized, tramadol decreases the dissolution and absorption of celecoxib. The AUCt of celecoxib from CTC was decreased by 29% compared with celecoxib alone (90% CI: 68.45–74.76%) or by 24% in free combination with IR tramadol (90% CI: 75.56–82.53%) [25]. Both the single-dose and multiple-dose phase I studies described here were performed with EU drug formulations.
Changes in CYP2D enzyme activity following induction of type 2 diabetes, and administration of cinnamon and metformin: an experimental animal study
Published in Xenobiotica, 2018
Ali Taheri, Hoda Lavasani, Sara Kasirzadeh, Behjat Sheikholeslami, Yalda H. Ardakani, Mohammad-Reza Rouini
Tramadol hydrochloride (T) is a centrally acting opioid being used as a pain reliever in diabetic neuropathy. The drug undergoes hepatic phase-1 and phase-2 biotransformation with subsequent excretion by the kidney. O-desmethyltramadol (M1), the product of CYP2D6-mediated O-demethylation of tramadol, is the main pharmacologically active metabolite with an affinity to μ-opioid receptors that is approximately 200 times greater than that of tramadol itself. M1 is being used in drug metabolism studies as a model drug of phase I oxidative biotransformation (Harati et al., 2000; Pedersen et al., 2005; Smith, 2009). CYP2D6 is a human CYP isoform. CYP2D isoforms in rats are CYP2D1, CYP2D2, CYP2D3, CYP2D4 and CYP2D5. The rat CYP2D isoform(s), which catalyze tramadol metabolism, has not probably yet been determined; therefore CYP2D is used throughout the article (Zuber 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.
Related Knowledge Centers
- Active Metabolite
- Cyp2D6
- Codeine
- Liver
- Opioid
- Analgesic
- Tramadol
- Μ-Opioid Receptor
- Agonist
- Δ-Opioid Receptor