Background The Pain Monitoring Device (PMD) monitor (Medasense Biometrics Ltd., Ramat Gan, Israel) uses the Nociception Level (NOL) index, a multiple parameterderived index that has recently shown a good sensitivity and specificity to detect noxious stimuli. The aim of this study was to assess the latest version of the device (PMD200 TM) on variations of the NOL response after standardized tetanic stimuli to study the correlation between remifentanil doses and NOL. Methods Data from 26 patients undergoing midline laparotomy and receiving a desflurane-remifentanil-based anesthetic coupled with low thoracic epidural analgesia were analyzed. A standardized tetanic stimulus was applied to the forearm of the patients at different remifentanil infusion rates. The primary aim was to evaluate the correlation between post-tetanic stimulation NOL values from the PMD200 and remifentanil doses. The NOL index variations after experimental and clinical stimuli were also compared with heart rate (HR), mean arterial pressure (MAP), and Bispectral Index TM (BIS). Results A correlation between post-tetanic stimulation NOL values and remifentanil doses was found (r =-0.56; 95% confidence interval [CI],-0.70 to-0.44; P\0.001). The NOL discriminated noxious from non-noxious states with the maximal Youden's index value of the NOL receiver operating characteristic (ROC) curve showing a specificity of 88% (95% CI, 69.0 to 100) and sensitivity of 79.1% (95% CI, 56.2 to 95.5). The area under the NOL ROC curve (AUC, 0.9; 95% CI, 0.84 to 0.95) was significantly different from the other variables (P \ 0.001 vs HR; P \ 0.001 vs MAP; P \ 0.001 vs BIS). Conclusions The NOL value after noxious stimulus decreased with incremental remifentanil doses, showing a significant inverse correlation between the NOL index and opioid doses. The sensitivity and specificity of NOL to discriminate between noxious and non-noxious stimuli suggests its interesting potential as a monitor of nociception intensity during anesthesia.

Various diseases such as type 2 diabetes (T2D) may alter drug clearance. The objective of this study was to evaluate the effects of T2D on CYP450 expressions and activities using high-fat diet (HFD) as a model of obesity-dependent diabetes in C57BL6 mice. The cyp450 mRNA expression levels for 15 different isoforms were determined in the liver and extra-hepatic tissues (kidneys, lungs and heart) of HFD-treated animals (n = 45). Modulation of cyp450 metabolic activities by HFD was assessed using eight known substrates for specific human ortholog CYP450 isoforms: in vitro incubations were conducted with liver and extra-hepatic microsomes. Expression levels of cyp3a11 and cyp3a25 mRNA were decreased in the liver (>2–14-fold) and kidneys (>2-fold) of HFD groups which correlated with a significant reduction in midazolam metabolism (by 21- and 5-fold in hepatic and kidney microsomes, respectively, p < 0.001). HFD was associated with decreased activities of cyp2b and cyp2c subfamilies in all organs tested except in the kidneys (for tolbutamide). Other cyp450 hepatic activities were minimally or not affected by HFD. Taken together, our data suggest that substrate-dependent and tissue-dependent modulation of cyp450 metabolic capacities by early phases of T2D are observed, which could modulate drug disposition and pharmacological effects in various tissues.