Tapentadol Hydrochloride

Tapentadol (TAP) is a centrally acting analgesic which is broadly used in the management of moderate to severe pain. The current study was conducted to examine the dose-dependent hepatotoxic effects of TAP via evaluating molecular, biochemical, and histopathological parameters. Thirty-two Sprague Dawley rats were divided into four groups i.e., control, TAP (10 mg/kg), TAP (25 mg/kg), and TAP (50 mg/kg) treated group. Our results showed that TAP intoxication upregulated the gene expression of Yes-associated protein 1 (YAP1) while downregulating the gene expression of tumor suppressor kinase 1 (LATS1), mammalian sterile 20-like kinase 1 (MST1), farnesoid X receptor (FXR), small heterodimer partner (SHP) and bile salt export pump (BSEP), thereby suggesting a compromise Hippo-YAP signaling and bile acid homeostasis. TAP exposure suppressed the activities of glutathione reductase (GSR), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), hemeoxygenase-1 (HO-1), as well as glutathione S-transferase (GST) coupled with glutathione (GSH) contents while significantly augmented the levels of malondialdehyde (MDA) and reactive oxygen species (ROS). Furthermore, TAP intoxication elevated the levels of cholic acid, chenodeoxycholic acid, deoxycholic acid, taurocholic acid, glycocholic acid, alkaline phosphatase (ALP), alanine transaminase (ALT), aspartate aminotransferase (AST), and Gamma-glutamyltransferase (GGT) while downregulating total protein and albumin. Moreover, TAP induced strong inflammatory and apoptotic responses, which were characterized by an increase in nuclear factor-κB (NF-κB), tumor necrosis factor-alpha (TNF-α), interleukin-1-beta (IL-1β), interleukin-6 (IL-6), cyclooxygenase-2 (COX-2), Bcl-2 associated X protein (Bax), cysteine-aspartic acid protease-3 (caspase-3), and cysteine-aspartic acid protease-9 (caspase-9) while inhibition of B cell lymphoma-2 (Bcl-2). Similarly, TAP administration induced severe histopathological alterations including hepatic degeneration, sinusoidal dilation, inflammation, and necrosis. Our findings are further supported by in-silico analysis that showed strong binding affinity of TAP with key regulatory genes. Collectively, these findings suggest that TAP is a hepatotoxic agent and warrant further clinical trials to evaluate its effects in humans.

This systematic review aims to evaluate the efficacy, safety, and tolerability of oral tapentadol in the management of cancer-related pain in adults. It updates the 2015 Cochrane review on the same topic by including newer trials up to March 2024.

A systematic search of Medline (via PubMed), the Cochrane Central Register of Controlled Trials, and references from the previous review was conducted. Randomized controlled trials comparing oral tapentadol with placebo or other opioids (e.g., morphine, oxycodone, tramadol/paracetamol) in adults with chronic cancer pain were included. The main outcomes assessed were pain reduction, need and dose of rescue medication, adverse events, treatment discontinuation, and patient-reported global impression of change. Risk of bias was evaluated using the Cochrane tool. Meta-analyses were performed using a random-effects model.

Five randomized controlled trials comprising 1152 patients were included. Across all outcomes evaluated, there was no significant difference between tapentadol and comparator opioids. Pain reduction was comparable (MD=-0.06; 95% CI: [-0.44, 0.31]), as were adverse effects (RR=0.98; 95% CI: [0.90, 1.08]), need for rescue medication (RR=1.07; 95% CI: [0.93, 1.22]), and dropout rates (RR=1.10; 95% CI: [0.87, 1.40]). All outcomes were rated as inconclusive due to overlapping confidence intervals with the null effect. The overall risk of bias was high in three studies and unclear in two.

Tapentadol demonstrated similar efficacy and safety compared to other opioids for cancer-related pain, with no evidence of superiority. Given the limited number and methodological quality of studies, further high-quality trials are needed to establish more robust conclusions.