Effects of pre-emptive pregabalin and multimodal anesthesia on postoperative opioid requirements in patients undergoing robot-assisted laparoscopic prostatectomy.

BACKGROUND: Previous findings indicate that pre-emptive pregabalin as part of multimodal anesthesia reduces opioid requirements compared to conventional anesthesia in patients undergoing robot-assisted laparoscopic prostatectomy (RALP). However, recent studies show contradictory evidence suggesting that pregabalin does not reduce postoperative pain or opioid consumption after surgeries. We conducted a register-based analysis on RALP patients treated over a 5-year period to evaluate postoperative opioid consumption between two multimodal anesthesia protocols. METHODS: We retrospectively evaluated patients undergoing RALP between years 2015 and 2019. Patients with American Society of Anesthesiologists status 1-3, age between 30 and 80 years and treated with standard multimodal anesthesia were included in the study. Pregabalin (PG) group received 150 mg of oral pregabalin as premedication before anesthesia induction, while the control (CTRL) group was treated conventionally. Postoperative opioid requirements were calculated as intravenous morphine equivalent doses for both groups. The impact of pregabalin on postoperative nausea and vomiting (PONV), and length of stay (LOS) was evaluated. RESULTS: We included 245 patients in the PG group and 103 in the CTRL group. Median (IQR) opioid consumption over 24 postoperative hours was 15 (8-24) and 17 (8-25) mg in PG and CTRL groups (p = 0.44). We found no difference in postoperative opioid requirement between the two groups in post anesthesia care unit, or within 12 h postoperatively (p = 0.16; p = 0.09). The length of post anesthesia care unit stay was same in each group and there was no difference in PONV Similarly, median postoperative LOS was 31 h in both groups. CONCLUSION: Patients undergoing RALP and receiving multimodal analgesia do not need significant amount of opioids postoperatively and can be discharged soon after the procedure. Pre-emptive administration of oral pregabalin does not reduce postoperative opioid consumption, PONV or LOS in these patients.

Feasibility of a transmucosal sublingual fentanyl tablet as a procedural pain treatment in colonoscopy patients: a prospective placebo-controlled randomized study.

Since patients often experience pain and unpleasantness during a colonoscopy, the present study aimed to evaluate the efficacy and safety of sublingually administered fentanyl tablets for pain treatment. Furthermore, since the use of intravenous drugs significantly increases colonoscopy costs, sublingual tablets could be a cost-effective alternative to intravenous sedation. We conducted a prospective placebo-controlled randomized study of 158 patients to evaluate the analgesic effect of a 100 µg dose of sublingual fentanyl administered before a colonoscopy. Pain, sedation, nausea, and satisfaction were assessed during the colonoscopy by the patients as well as the endoscopists and nurses. Respiratory rate and peripheral arteriolar oxygen saturation were monitored throughout the procedure. There were no differences between the fentanyl and placebo groups in any of the measured variables. The median pain intensity values, as measured using a numerical rating scale, were 4.5 in the fentanyl group and 5 in the placebo group. The sedation and oxygen saturation levels and the respiratory rate did not differ between the groups. The majority of the colonoscopies were completed.Our results indicate that a 100 µg dose of sublingual fentanyl is not beneficial compared to the placebo in the treatment of procedural pain during a colonoscopy.

Subcutaneously administered dexmedetomidine is efficiently absorbed and is associated with attenuated cardiovascular effects in healthy volunteers.

PURPOSE: Palliative care patients often need sedation to alleviate intractable anxiety, stress, and pain. Dexmedetomidine is used for sedation of intensive care patients, but there is no prior information on its subcutaneous (SC) administration, a route that would be favored in palliative care. We compared the pharmacokinetics and cardiovascular, sympatholytic, and sedative effects of SC and intravenously (IV) administered dexmedetomidine in healthy volunteers. METHODS: An open two-period, cross-over design with balanced randomization was used. Ten male subjects were randomized to receive 1 µg/kg dexmedetomidine both IV and SC. Concentrations of dexmedetomidine and catecholamines in plasma were measured. Pharmacokinetic variables were calculated with non-compartmental methods. In addition, cardiovascular and sedative drug effects were monitored. RESULTS: Eight subjects completed both treatment periods. Peak concentrations of dexmedetomidine were observed 15 min after SC administration (median; range 15-240). The mean bioavailability of SC dexmedetomidine was 81% (AUC0-∞ ratio × 100%, range 49-97%). The mean (SD) peak concentration of dexmedetomidine in plasma was 0.3 (0.1) ng/ml, and plasma concentrations associated with sedative effects (i.e., > 0.2 ng/ml) were maintained for 4 h after SC dosing. Plasma noradrenaline concentrations were significantly lower (P < 0.001) within 3 h after IV than after SC administration. Subjective scores for vigilance and performance were significantly lower 0-60 min after IV than SC dosing (P < 0.001 for both). The onset of the cardiovascular, sympatholytic, and sedative effects of dexmedetomidine was clearly less abrupt after SC than IV administration. CONCLUSIONS: Dexmedetomidine is relatively rapidly and efficiently absorbed after SC administration. Subcutaneous dexmedetomidine may be a feasible alternative in palliative sedation, and causes attenuated cardiovascular effects compared to IV administration. CLINICALTRIALS. GOV IDENTIFIER: NCT02724098 . EUDRA CT number 2015-004698-34 .

Influence of intensive care treatment on the protein binding of sufentanil and hydromorphone during pain therapy in postoperative cardiac surgery patients.

BACKGROUND: Our objective was to evaluate the effect of intensive care treatment on the protein binding of sufentanil and hydromorphone in cardiac surgery patients during postoperative analgesia using a target-controlled infusion (TCI) and patient-controlled analgesia (PCA). METHODS: Fifty adult patients were enrolled in this prospective randomized study; of which, 49 completed the study (age range 40-81 yr). Sufentanil was administered as an analgesic intraoperatively, and hydromorphone was dosed after operation with TCI and PCA until 8 a.m. on the first postoperative day. Arterial plasma samples were collected for drug and protein concentration measurements up to 24 h after cardiac surgery. Corresponding patient data were collected from the electronic patient data system. After explorative data analysis with principal component analysis, multivariate regression analysis and non-linear mixed effects modelling was used to study the effect of treatment on protein binding. RESULTS: Data of 35 patients were analysed. The median protein binding of sufentanil and hydromorphone was 88.4% (IQ range 85.7-90.5%) and 11.6% (IQ range 9.5-14.3%), respectively. Free fraction of sufentanil increased towards the end of the study period, whereas hydromorphone free fraction remained nearly constant. The total sufentanil concentration and volume balance were identified as significant covariates for the protein binding of sufentanil. For the protein binding of hydromorphone, no significant covariate effects were found. CONCLUSIONS: Sufentanil protein binding was significantly dependent on changes in the total drug concentration and volume balance addressing the importance of adequate dosing and fluid-guided therapy. Hydromorphone protein binding was nearly constant throughout the study period. CLINICAL TRIAL REGISTRATION: EudraCT 2011-003648-31 and ClinicalTrials.gov: NCT01490268.

[Dexmedetomidine. Pharmacokinetics and pharmacodynamics]. / Dexmedetomidin. Pharmakokinetik und Pharmakodynamik.

Dexmedetomidine is a highly selective, potent α2-adrenoceptor agonist which was approved in 2011 by the European Medicines Agency for sedation of patients in intensive care units (ICU). Dexmedetomidine exhibits sedative as well as analgesic and anxiolytic effects. Recent studies suggest that dexmedetomidine may be an alternative to midazolam in long-term ICU sedation. This review summarizes the pharmacokinetics and pharmacodynamics of dexmedetomidine particularly in ICU patients and with special regard to covariate effects. Although dexmedetomidine is currently approved only for use in adults the pharmacokinetics and pharmacodynamics in children will also be addressed as there are numerous studies on this off-label use.

Changes in total and unbound concentrations of sufentanil during target controlled infusion for cardiac surgery with cardiopulmonary bypass.

BACKGROUND: Target controlled infusion (TCI) with sufentanil is usually performed using the Gepts model, which was derived from patients undergoing general surgery. It is, however, known that pharmacokinetics of sufentanil can be changed during cardiopulmonary bypass (CPB). We tested whether TCI during coronary artery bypass surgery with CPB produces constant total, unbound sufentanil concentration-time course or both. METHODS: After IRB approval, written informed consent was obtained from 38 male patients (48-74 yr) undergoing coronary artery bypass surgery. Anaesthesia was managed with propofol and TCI of sufentanil, using the Gepts model, targeting plasma concentrations of 0.4 (n=18) or 0.8 ng ml(-1) (n=20). Arterial blood samples were taken before, during, and after CPB. Total and unbound sufentanil concentrations were measured by HPLC with tandem mass spectrometry. The accuracy of the TCI model was assessed by the prediction error, and a pharmacokinetic model was determined by population analysis. RESULTS: The median prediction error of the TCI with the Gepts model before, during, and after CPB was 59.6, 3.9, and -10.4%, respectively. The unbound sufentanil concentrations increased significantly during CPB. Pharmacokinetic modelling showed an increase in elimination and intercompartmental clearance after initiation of CPB. CONCLUSIONS: Neither total nor unbound sufentanil concentrations remained constant when performing a TCI with the Gepts model in coronary artery bypass surgery with CPB. A pharmacokinetic model derived from patients undergoing cardiac surgery with CPB might improve the performance of TCI in this population.

Oxycodone clearance is markedly reduced with advancing age: a population pharmacokinetic study.

BACKGROUND: Oxycodone is a µ-opioid receptor agonist, the global use of which has increased vigorously during the past decade. The pharmacokinetic data of oxycodone available for elderly are limited, and there appear to be only little data on the population pharmacokinetics of oxycodone. METHODS: We analysed 1272 plasma oxycodone samples of 77 individuals (range of age 19-89 yr) with non-linear mixed effect modelling. Inter- and intra-individual variability of the model was estimated for clearances and distribution volumes. The effect of covariates was studied with simulations. RESULTS: Data were best described with a two-compartment linear model. Lean body mass and age were found to be significant covariates for elimination clearance and the volume of the central compartment. The population estimates of elimination clearance, volume of the central compartment, and the volume of distribution at steady state for a reference individual (male 35 yr, 70 kg, 170 cm) were 51.0 litre h(-1), 134, and 258 litres, respectively. The elimination half-life of oxycodone showed an age-dependent increase. The context-sensitive half-time at steady state increased from 3.8 to 4.6 h between the age of 25 and 85 yr, respectively. Simulations of repetitive bolus dosing showed a 20% increase in oxycodone concentration in the elderly. CONCLUSIONS: Age was found to be a significant covariate for oxycodone pharmacokinetics. In elderly patients, dosing should therefore be reduced and carefully titrated to avoid considerable accumulation of oxycodone and potentially hazardous side-effects.

Exposure to oral S-ketamine is unaffected by itraconazole but greatly increased by ticlopidine.

This study examined drug-drug interactions of oral S-ketamine with the cytochrome P450 (CYP) 2B6 inhibitor ticlopidine and the CYP3A inhibitor itraconazole. In this randomized, blinded, crossover study, 11 healthy volunteers ingested 0.2 mg/kg S-ketamine after pretreatments with oral ticlopidine (250 mg twice daily), itraconazole (200 mg once daily), or placebo in 6-day treatment periods at intervals of 4 weeks. Ticlopidine treatment increased the mean area under the plasma concentration-time curve extrapolated to infinity (AUC(0-∞)) of oral ketamine by 2.4-fold (P < 0.001), whereas itraconazole treatment did not increase the exposure to S-ketamine. The ratio of norketamine AUC(0-∞) to ketamine AUC(0-∞) was significantly decreased in the ticlopidine (P < 0.001) and itraconazole phases (P = 0.006) as compared to placebo. In the ticlopidine and itraconazole phases, the areas under the effect-time curves (self-reported drowsiness and performance) were significantly higher than those in the placebo phase (P < 0.05). The findings suggest that the dosage of S-ketamine should be reduced in patients receiving ticlopidine.