ADME and toxicity considerations for tramadol: from basic research to clinical implications

Doostmohammadi, Mohsen; Rahimi, Hamid Reza

doi:10.1080/17425255.2020.1776700

Cited by 21 publications

(14 citation statements)

References 122 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The cytochrome P450 2D6 (CYP2D6) enzyme plays an important role in the analgesic activity of tramadol. Previous studies demonstrated that CYP2D6 bioactivates tramadol to O‐desmethyltramadol (M1), which has approximately 300‐fold greater affinity for the µ‐opioid receptor in vitro than the parent compound 3,4 . In a recent clinical study, 20 mg desmetramadol (O‐desmethyl tramadol—M1) and 50 mg tramadol dosed every 6 h produced equivalent exposures of steady‐state (+)—M1 and analgesic effects, which indicated that tramadol acts as a prodrug and that the analgesic activity of tramadol is mainly derived from M1 5 .…”

Section: Introductionmentioning

confidence: 99%

Physiologically based pharmacokinetic modeling of tramadol to inform dose adjustment and drug‐drug interactions according to CYP2D6 phenotypes

Zheng

Zeng

et al. 2021

Pharmacotherapy

View full text Add to dashboard Cite

Objectives The objective of this study was to establish physiologically based pharmacokinetic (PBPK) models of tramadol and its active metabolite O‐desmethyltramadol (M1) and to explore the influence of CYP2D6 gene polymorphism on the pharmacokinetics of tramadol and M1. Furthermore, we used PBPK modeling to prospectively predict the extent of drug‐drug interactions (DDIs) in the presence of genetic polymorphisms when tramadol was co‐administered with the CYP2D6 inhibitors duloxetine and paroxetine. Methods Plasma concentrations of tramadol and M1 were used to adjust the turnover frequency (Kcat) of CYP2D6 for phenotype populations with different CYP2D6 genotypes. PBPK models were developed to capture the pharmacokinetics between CYP2D6 extensive metabolizers (EMs), intermediate metabolizers (IMs), poor metabolizers (PMs), and ultra‐rapid metabolizers (UMs). The validated models were then used to support dose adjustment in different CYP2D6 phenotypes and to predict the extent of CYP2D6‐mediated DDIs when tramadol was co‐administered with paroxetine or duloxetine. Results The PBPK models we built accurately describe tramadol and M1 exposure in the population with different CYP2D6 phenotypes. In our prediction, the area under the concentration‐time curve (AUCinf‐tDlast ) of M1 is 70% lower in PMs than in EMs, 27% lower in IMs, and 15% higher in UMs. Based on the models we built, we suggest that the oral dose of tramadol should be 50% higher for IMs and 25% lower for UMs to achieve an approximately equivalent plasma exposure of M1 as in EMs. When tramadol was co‐administered with paroxetine or duloxetine, the magnitude of the inhibitor‐substrate interaction was lowest in EMs (0.45), secondary in IMs (0.39), and highest in PMs (0.18) in terms of M1. Conclusion The current example uses the PBPK model to guide dose adjustment of tramadol and to predict the effect of CYP2D6 genetic polymorphisms on DDIs for rational clinical use of tramadol in the future.

show abstract

Section: Introductionmentioning

confidence: 99%

Physiologically based pharmacokinetic modeling of tramadol to inform dose adjustment and drug‐drug interactions according to CYP2D6 phenotypes

Zheng

Zeng

et al. 2021

Pharmacotherapy

View full text Add to dashboard Cite

show abstract

“…In order to evaluate the effects on oxidative status and putative oxidative damage, thiobarbituric acid reactive substances (TBARS), protein carbonyl groups, myeloperoxidase (MPO) activity and total antioxidant capacity were quantified in tissue and serum samples (Figure 1). antioxidants is suggested as a strategy to decrease tramadol-induced tissue damage [64]; prolonged dose interval or dose reductions are also suggested during chronic treatment [65]. Concerning tapentadol toxicity, Channell and Schug reported many adverse events, including neurological, respiratory, and cardiac function impairment [29].…”

Section: Repeated Exposure To Tramadol and Tapentadol Causes Oxidativmentioning

confidence: 99%

“…Besides histological changes, chronic tramadol administration in rodents was also associated with increased reactive oxygen species (ROS) and mitochondrial alterations in tissues such as brain and lung [58,59,63]. In fact, treatment with antioxidants is suggested as a strategy to decrease tramadol-induced tissue damage [64]; prolonged dose interval or dose reductions are also suggested during chronic treatment [65].…”

Section: Introductionmentioning

confidence: 99%

Repeated Administration of Clinically Relevant Doses of the Prescription Opioids Tramadol and Tapentadol Causes Lung, Cardiac, and Brain Toxicity in Wistar Rats

et al. 2021

View full text Add to dashboard Cite

Tramadol and tapentadol, two structurally related synthetic opioid analgesics, are widely prescribed due to the enhanced therapeutic profiles resulting from the synergistic combination between μ-opioid receptor (MOR) activation and monoamine reuptake inhibition. However, the number of adverse reactions has been growing along with their increasing use and misuse. The potential toxicological mechanisms for these drugs are not completely understood, especially for tapentadol, owing to its shorter market history. Therefore, in the present study, we aimed to comparatively assess the putative lung, cardiac, and brain cortex toxicological damage elicited by the repeated exposure to therapeutic doses of both prescription opioids. To this purpose, male Wistar rats were intraperitoneally injected with single daily doses of 10, 25, and 50 mg/kg tramadol or tapentadol, corresponding to a standard analgesic dose, an intermediate dose, and the maximum recommended daily dose, respectively, for 14 consecutive days. Such treatment was found to lead mainly to lipid peroxidation and inflammation in lung and brain cortex tissues, as shown through augmented thiobarbituric acid reactive substances (TBARS), as well as to increased serum inflammation biomarkers, such as C reactive protein (CRP) and tumor necrosis factor-α (TNF-α). Cardiomyocyte integrity was also shown to be affected, since both opioids incremented serum lactate dehydrogenase (LDH) and α-hydroxybutyrate dehydrogenase (α-HBDH) activities, while tapentadol was associated with increased serum creatine kinase muscle brain (CK-MB) isoform activity. In turn, the analysis of metabolic parameters in brain cortex tissue revealed increased lactate concentration upon exposure to both drugs, as well as augmented LDH and creatine kinase (CK) activities following tapentadol treatment. In addition, pneumo- and cardiotoxicity biomarkers were quantified at the gene level, while neurotoxicity biomarkers were quantified both at the gene and protein levels; changes in their expression correlate with the oxidative stress, inflammatory, metabolic, and histopathological changes that were detected. Hematoxylin and eosin (H & E) staining revealed several histopathological alterations, including alveolar collapse and destruction in lung sections, inflammatory infiltrates, altered cardiomyocytes and loss of striation in heart sections, degenerated neurons, and accumulation of glial and microglial cells in brain cortex sections. In turn, Masson’s trichrome staining confirmed fibrous tissue deposition in cardiac tissue. Taken as a whole, these results show that the repeated administration of both prescription opioids extends the dose range for which toxicological injury is observed to lower therapeutic doses. They also reinforce previous assumptions that tramadol and tapentadol are not devoid of toxicological risk even at clinical doses.

show abstract

“…This has led to an increase in the number of cases of poisoning, side effects and deaths [1]. Several cases of toxicity and abuse caused by this drug have been reported in the medical literature [2,3]. Tramadol is an effective pharmaceutical drug for moderate to severe pain relief that affects the transmission of pain impulses through the μ-opioid receptor and inhibits norepinephrine and serotonin reuptake [4].…”

Section: Introductionmentioning

confidence: 99%

Effects of naloxone and diazepam on blood glucose levels in tramadol overdose using generalized estimating equation (GEE) model; (an experimental study)

et al. 2021

View full text Add to dashboard Cite

Background Tramadol is a synthetic opioid and poisoning is increasing around the world day by day. Various treatments are applied for tramadol poisoning. Due to the unknown effects of tramadol poisoning and some of its treatments on blood glucose levels, this study was conducted to investigate the overdose of tramadol and its common treatments (naloxone, diazepam), and their combination on blood glucose levels in male rats. Methods This study was conducted in 45 male Wistar rats. The animals were randomly divided into five groups of 9. They received a 75 mg/kg dose of tramadol alone with naloxone, diazepam, and a combination of both of these two drugs. On the last day, animals’ tail vein blood glucose levels (BGL) were measured using a glucometer at different times, including before the tramadol injection (baseline) and 1 hour, 3 hours, and 6 hours after wards. The rats were anesthetized and sacrificed 24 h after the last injection. Blood samples were then taken, and the serum obtained was used to verify the fasting glucose concentration. Data were analyzed using SPSS software at a significance level of 0.05 using a one-way analysis of variance (ANOVA) and a generalized estimating equation (GEE). Results According to the GEE model results, the diazepam-tramadol and naloxone-diazepam-tramadol groups showed blood glucose levels five units higher than the tramadol group (p < 0.05). The diazepam-tramadol group had significantly higher blood glucose levels than the naloxone-tramadol group (p < 0.05). The mean blood glucose levels before the intervention, 3 hours and 6 hours after the injection of tramadol did not differ between the groups, but the blood glucose levels 1 hour after the injection of tramadol in the group of naloxone-tramadol were significantly lower than in the control group (p < 0.05). Blood glucose levels did not differ between the groups 24 h after injection of tramadol. Conclusion The results of the present study showed tramadol overdose does not affect blood glucose levels. The diazepam-tramadol combination and the diazepam-naloxone-tramadol combination caused an increase in blood glucose levels.

show abstract

ADME and toxicity considerations for tramadol: from basic research to clinical implications

Cited by 21 publications

References 122 publications

Physiologically based pharmacokinetic modeling of tramadol to inform dose adjustment and drug‐drug interactions according to CYP2D6 phenotypes

Physiologically based pharmacokinetic modeling of tramadol to inform dose adjustment and drug‐drug interactions according to CYP2D6 phenotypes

Repeated Administration of Clinically Relevant Doses of the Prescription Opioids Tramadol and Tapentadol Causes Lung, Cardiac, and Brain Toxicity in Wistar Rats

Effects of naloxone and diazepam on blood glucose levels in tramadol overdose using generalized estimating equation (GEE) model; (an experimental study)

Contact Info

Product

Resources

About