Comparative metabolism of tramadol and tapentadol: a toxicological perspective

Abstract

Tramadol and tapentadol are centrally acting, synthetic opioid analgesics used in the treatment of moderate to severe pain. Main metabolic patterns for these drugs in humans are well characterized. Tramadol is mainly metabolized by cytochrome P450 CYP2D6 to O-desmethyltramadol (M1), its main active metabolite. M1 and tapentadol undergo mainly glucuronidation reactions. On the other hand, the pharmacokinetics of tramadol and tapentadol are dependent on multiple factors, such as the route of administration, genetic variability in pharmacokinetic components and concurrent consumption of other drugs. This review aims to comparatively discuss the metabolomics of tramadol and tapentadol, namely by presenting all their known metabolites. An exhaustive literature search was performed using textual and structural queries for tramadol and tapentadol, and associated known metabolizing enzymes and metabolites. A thorough knowledge about tramadol and tapentadol metabolomics is expected to provide additional insights to better understand the interindividual variability in their pharmacokinetics and dose-responsiveness, and contribute to the establishment of personalized therapeutic approaches, minimizing side effects and optimizing analgesic efficacy.

Cardiac Arrest Following Drug Abuse with Intravenous Tapentadol: Case Report and Literature Review

“…Both drugs have lower risks of respiratory depression, tolerance, and dependence. However, whereas tapentadol has no active metabolites and does not require metabolic activation to exert its analgesic effects, tramadol requires metabolism by the CYP450 complex to generate its active metabolite, O-desmethyl tramadol and this is required for tramadol to be completely effective [ 8 , 9 ]. Tapentadol is primarily and extensively (70%) metabolized via glucuronidation by the UGT1A9 and UGT2B7 enzymes, which transform it into the following inactive metabolites: N-desmethyl tapentadol (13%), resulting from metabolism by CYP2C9 and CYP2C19, and hydroxytapentadol (2%), resulting from metabolism by CYP2D6 [ 2 ].…”

Comparative pharmacology and toxicology of tramadol and tapentadol

“…Tramadol and tapentadol are two centrally acting, fully synthetic opioids with an atypical mechanism of action, as they combine μ‐opioid receptor (MOR) agonism with neurotransmitter (serotonin (5‐HT) and/or noradrenaline (NA) reuptake inhibition (Barbosa et al., ). They are two synthetic and structurally related opioids.…”

Oxidative stress/PERK/apoptotic pathways interaction contribute to tramadol neurotoxicity in rat cerebral and cerebellar cortex and thyme enhances the antioxidant defense system: histological, immunohistochemical and ultrastructural study

“…1,2 This dual action promotes an enhanced analgesia with a low incidence of side effects. Disturbance in ER homeostasis will result in ER stress with accumulation of unfolded/misfolded proteins inside its lumen.…”