Mechanisms and Preventative Strategies for Persistent Pain following Knee and Hip Joint Replacement Surgery: A Narrative Review.

Chronic postsurgical pain (CPSP) following total knee arthroplasty (TKA) and total hip arthroplasty (THA) is a prevalent complication of joint replacement surgery which has the potential to decrease patient satisfaction, increase financial burden, and lead to long-term disability. The identification of risk factors for CPSP following TKA and THA is challenging but essential for targeted preventative therapy. Recent meta-analyses and individual studies highlight associations between elevated state anxiety, depression scores, preoperative pain, diabetes, sleep disturbances, and various other factors with an increased risk of CPSP, with differences observed in prevalence between TKA and THA. While the etiology of CPSP is not fully understood, several factors such as chronic inflammation and preoperative central sensitization have been identified. Other potential mechanisms include genetic factors (e.g., catechol-O-methyltransferase (COMT) and potassium inwardly rectifying channel subfamily J member 6 (KCNJ6) genes), lipid markers, and psychological risk factors (anxiety and depression). With regards to therapeutics and prevention, multimodal pharmacological analgesia, emphasizing nonopioid analgesics like acetaminophen and non-steroidal anti-inflammatory drugs (NSAIDs), has gained prominence over epidural analgesia. Nerve blocks and local infiltrative anesthesia have shown mixed results in preventing CPSP. Ketamine, an N-methyl-D-aspartate (NMDA)-receptor antagonist, exhibits antihyperalgesic properties, but its efficacy in reducing CPSP is inconclusive. Lidocaine, an amide-type local anesthetic, shows tentative positive effects on CPSP. Selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) have mixed results, while gabapentinoids, like gabapentin and pregabalin, present hopeful data but require further research, especially in the context of TKA and THA, to justify their use for CPSP prevention.

A mechanism of perhexiline's cytotoxicity in hepatic cells involves endoplasmic reticulum stress and p38 signaling pathway.

Perhexiline is a coronary vasodilator for angina treatment that was first developed in the 1960s. Perhexiline enjoyed worldwide success before reports of severe side effects, such as hepatotoxicity and neurotoxicity, caused its withdrawal from most of the markets. The underlying mechanism of the cytotoxicity of perhexiline, however, is not yet well understood. Here we demonstrated that perhexiline induced cellular damage in primary human hepatocytes, HepaRG cells and HepG2 cells. Analysis of gene and protein expression levels of endoplasmic reticulum (ER) stress markers showed that perhexiline caused ER stress in primary human hepatocytes and HepG2 cells. The splicing of XBP1 mRNA, a hallmark of ER stress, was observed upon perhexiline treatment. Using Gluc-Fluc-HepG2 cell line, we demonstrated that protein secretion was impaired upon perhexiline treatment, suggesting functional deficits in ER. Inhibition of ER stress using ER inhibitor 4-PBA or salubrinal attenuated the cytotoxicity of perhexiline. Directly knocking down ATF4 using siRNA also partially rescued HepG2 cells upon perhexiline exposure. In addition, inhibition of ER stress using either inhibitors or siRNA transfection attenuated perhexiline-induced increase in caspase 3/7 activity, indicating that ER stress contributed to perhexiline-induced apoptosis. Moreover, perhexiline treatment resulted in activation of p38 and JNK signaling pathways, two branches of MAPK cascade. Pre-treating HepG2 cells with p38 inhibitor SB239063 attenuated perhexiline-induced apoptosis and cell death. The inhibitor also prevented the activation of CHOP and ATF4. Overall, our study demonstrated that ER stress is one important mechanism underlying the hepatotoxicity of perhexiline, and p38 signaling pathway contributes to this process. Our finding shed light on the role of both ER stress and p38 signaling pathway in drug-induced liver injury.