Sufentanil Disposition and Pharmacokinetic Model-Based Dosage Regimen for Sufentanil in Ventilated Full-Term Neonates.

INTRODUCTION: Sufentanil is a potent synthetic opioid used for analgesia in neonates; however, data concerning drug disposition of sufentanil and dosage regimen are sparse in this population. Therefore, the aim of the study was to explore sufentanil disposition and to propose optimal loading and maintenance doses of sufentanil in ventilated full-term neonates. METHODS: Individual sufentanil pharmacokinetic parameters were calculated based on therapeutic drug monitoring data using a 2-compartmental model. Linear regression models were used to explore the covariates. RESULTS: The median (IQR) central volume of distribution (Vdc) and clearance (CL) for sufentanil were 4.7 (4.1-5.4) L/kg and 0.651 (0.433-0.751) L/h/kg, respectively. Linear regression models showed relationship between Vdc (L) and GA (r2 = 0.3436; p = 0.0452) as well as BW (r2 = 0.4019; p = 0.0268). Median optimal sufentanil LD and MD were 2.13 (95% CI: 1.78-2.48) µg/kg and 0.29 (95% CI: 0.22-0.37) µg/kg/h, respectively. Median daily COMFORT-B (IQR) scores ranged from 6 to 23 while no significant relationship between pharmacokinetic parameters and COMFORT-B scores was found. DISCUSSION/CONCLUSION: Body weight and gestational age were found as weak covariates for sufentanil distribution, and the dosage regimen was developed for a prospective trial.

Phenylpiperidine opioid effects on isoflurane minimum alveolar concentration in cats.

Different structurally related phenylpiperidine opioids exhibit different isoflurane-sparing effects in cats. Because minimum alveolar concentration (MAC) in cats is affected only by very high plasma concentrations of some phenylpiperidine opioids, we hypothesized these effects are caused by actions on nonopioid receptors. Using a prospective, randomized, crossover design, six cats were anesthetized with isoflurane, intubated, ventilated, and instrumented. Isoflurane MAC was measured in triplicate using a tail-clamp and bracketing technique. A computer-controlled intravenous infusion using prior pharmacokinetic models targeted plasma concentrations of 60 ng/ml fentanyl, 10 ng/ml sufentanil, or 500 ng/ml alfentanil, and isoflurane MAC was measured in duplicate. Next, naltrexone 0.6 mg/kg was administered to cats hourly during the opioid infusion, and isoflurane MAC was measured in duplicate. Blood was collected during MAC determinations to measure opioid concentrations. Responses were analyzed using repeated measures ANOVA with significance at p < .05. Alfentanil and sufentanil decreased isoflurane MAC by 16.4% and 6.4%, respectively, and these effects were completely reversed by naltrexone. Fentanyl had no significant effect on isoflurane MAC. Alfentanil and sufentanil modestly reduce isoflurane MAC via agonist effects on opioid receptors. However, these effects are too small to justify clinical use of phenylpiperidine opioids as single agents to reduce MAC in cats.

Malfunctioning sufentanil intrathecal pain pump: a case report.

BACKGROUND: Sufentanil is a potent opioid uncommonly used to manage pain and is rarely administered via an intrathecal pain pump system. CASE PRESENTATION: This case illustrates the use of intrathecal sufentanil in a 50-year-old Caucasian man for the management of chronic pain; however, the intrathecal drug delivery system experienced a malfunction which led to 1/100th output of the correct dosage. Interesting aspects of this case report include the uncommon choice of sufentanil use for an intrathecal drug delivery system, as well as the unusual pharmacokinetics of this drug. Specifically, this patient did not experience the major withdrawal that would be expected given significant under dosing of opioid, and this may be explained by the lipophilicity and context-sensitive half-times of sufentanil. CONCLUSIONS: Because of the absence of a clinically significant withdrawal in this case report, clinicians must be aware of relevant pharmacokinetic properties and unusual intrathecal drug delivery system technologies that influence a patient's response when device malfunction occurs.

Population pharmacokinetics of intravenous sufentanil in critically ill patients supported with extracorporeal membrane oxygenation therapy.

BACKGROUND: Sufentanil is commonly used for analgesia and sedation during extracorporeal membrane oxygenation (ECMO). Both ECMO and the pathophysiological changes derived from critical illness have significant effects on the pharmacokinetics (PK) of drugs, yet reports of ECMO and sufentanil PK are scarce. Here, we aimed to develop a population PK model of sufentanil in ECMO patients and to suggest dosing recommendations. METHODS: This prospective cohort PK study included 20 patients who received sufentanil during venoarterial ECMO (VA-ECMO). Blood samples were collected for 96 h during infusion and 72 h after cessation of sufentanil. A population PK model was developed using nonlinear mixed effects modelling. Monte Carlo simulations were performed using the final PK parameters with two typical doses. RESULTS: A two-compartment model best described the PK of sufentanil. In our final model, increased volume of distribution and decreased values for clearance were reported compared with previous PK data from non-ECMO patients. Covariate analysis showed that body temperature and total plasma protein level correlated positively with systemic clearance (CL) and peripheral volume of distribution (V2), respectively, and improved the model. The parameter estimates of the final model were as follows: CL = 37.8 × EXP (0.207 × (temperature - 36.9)) L h-1, central volume of distribution (V1) = 229 L, V2 = 1640 × (total plasma protein/4.5)2.46 L, and intercompartmental clearance (Q) = 41 L h-1. Based on Monte Carlo simulation results, an infusion of 17.5 µg h-1 seems to reach target sufentanil concentration (0.3-0.6 µg L-1) in most ECMO patients except hypothermic patients (33 °C). In hypothermic patients, over-sedation, which could induce respiratory depression, needs to be monitored especially when their total plasma protein level is low. CONCLUSIONS: This is the first report on a population PK model of sufentanil in ECMO patients. Our results suggest that close monitoring of the body temperature and total plasma protein level is crucial in ECMO patients who receive sufentanil to provide effective analgesia and sedation and promote recovery. TRIAL REGISTRATION: Clinicaltrials.gov NCT02581280 , December 1st, 2014.

The optimal bolus dose of sufentanil for satisfactory laryngeal mask airway (LMA) insertion conditions in chinese pediatric patients: A prospective double-blind randomized controlled trial (CONSORT).

BACKGROUND: This study aimed to estimate the optimal dose of sufentanil, coadministered with 2.5 mg/kg propofol, for satisfactory laryngeal mask airway (LMA) insertion conditions in Chinese children and to determine the optimal bolus dose. METHODS: Seventy-five Chinese children aged 2 to 6 years with the American Society of Anesthesiologists physical status I or II, undergoing elective minor surgery were recruited. They were randomly divided into 5 different dosage groups (0, 0.05, 0.1, 0.15, 0.2 µg/kg). A predetermined sufentanil diluted with 5 mL saline was injected 30 s, 200 s later, followed by 2.5 mg/kg propofol over 10 s. After that the insertion conditions were assessed, using a 6-category score. The duration of apnea was recorded. A Probit analysis was performed to determine the ED50 and ED95 with 95% confidence interval for optimal conditions. RESULTS: There were less hemodynamic changes in all sufentanil groups than propofol-only group, with 0.2 µg/kg patients showing the most stable cardiovascular responses and best insertion conditions. However, the duration of apnea increased with the increasing dosage of sufentanil. From Probit analysis, the ED50 and ED95 of sufentanil for optimum score were 0.064 µg/kg and 0.177 µg/kg, respectively. CONCLUSION: In combination with propofol for anesthesia induction in Chinese children, sufentanil 0.2 µg/kg could prevent patients from dramatic hemodynamic change, providing satisfactory LMA insertion conditions.

Sufentanil pharmacokinetics in a full-term neonate treated with extracorporeal membrane oxygenation: a case report.

INTRODUCTION: Sufentanil is a potent analgesic drug used for pain management. A few studies describe the pharmacokinetics of sufentanil in neonates; however, no pharmacokinetic data about sufentanil during extracorporeal membrane oxygenation have been published yet. CASE REPORT: A 1-day-old neonate with moderate hypoxic-ischemic encephalopathy received veno-arterial extracorporeal membrane oxygenation support for refractory respiratory and circulatory failure. Sufentanil plasma concentrations were determined during both extracorporeal membrane oxygenation (n = 14) and non-extracorporeal membrane oxygenation (n = 17) period. Based on these measurements, individual sufentanil pharmacokinetic parameters were calculated. DISCUSSION: We observed increased sufentanil volume of distribution (11.6 vs 5.6 L/kg) and decreased sufentanil clearance (0.535 vs 0.746 L/h/kg) in extracorporeal membrane oxygenation period. The increment of volume of distribution was attributed to ECMO influence, while difference in clearance was probably due to drug interaction. CONCLUSIONS: This is the first description of sufentanil pharmacokinetics in neonate treated with extracorporeal membrane oxygenation. We observed considerably larger volume of distribution during extracorporeal membrane oxygenation period in comparison with non-extracorporeal membrane oxygenation period.

Effects of OPRM1 and ABCB1 gene polymorphisms on the analgesic effect and dose of sufentanil after thoracoscopic-assisted radical resection of lung cancer.

OBJECTIVE: To study the effects of single-nucleotide polymorphisms of the OPRM1 and ABCB1 genes on the analgesic effect and consumption of sufentanil after thoracoscopic-assisted radical resection of lung cancer. METHODS: A total of 225 Chinese Han nationality patients undergoing thoracoscopic-assisted radical resection of lung cancer were enrolled in the present study. Among them, 132 were males (58.67%) and 93 (41.33%) were females having American Society of Anesthesiologists statuses classified as grades I or II. The rs1799971, rs563649 and rs1323040 genotypes of the OPRM1 gene and rs2032582, rs1045642 and rs1128503 genotypes of the ABCB1 gene were detected by Sanger sequencing. The state anxiety index and pressure pain threshold were assessed preoperatively. Sufentanil was administered intravenously to maintain anesthesia. The doses and side effects of sufentanil consumed 6 h (T1), 24 h (T2) and 48 h (T3) after surgery were recorded. RESULTS: The sufentanil doses at T1, T2 and T3 were significantly higher in radical-operation lung cancer patients with mutant homozygous rs1799971 and rs1323040 loci in the OPRM1 gene and rs2032582 and rs1128503 loci in the ABCB1 gene. The doses of sufentanil consumed by mutant heterozygous lung cancer patients at T1, T2 and T3 were significantly higher than those consumed by patients without mutations, and the differences were statistically significant (P<0.05). There was no significant difference in sufentanil doses consumed by lung cancer patients with mutant homozygous, mutant heterozygous and wild-type rs563649 locus of the OPRM1 gene and rs1045642 locus of the ABCB1 gene at T1, T2 and T3 (P>0.05). There was no significant difference in the visual analog scale scores at T1, T2 and T3 for different genotypes of OPRM1 and ABCB1 genes in lung cancer patients (P>0.05). No significant difference was found between the adverse reactions of OPRM1 and ABCB1 genotypes in patients undergoing radical resection of lung cancer (P>0.05). CONCLUSION: The rs1799971 and rs1323040 polymorphisms of the OPRM1 gene and rs2032582 and rs1128503 polymorphisms of the ABCB1 gene are related to the analgesic effect and consumed dose of sufentanil in Chinese Han patients undergoing radical operation of lung cancer.

Altered Pharmacokinetics in Prolonged Infusions of Sedatives and Analgesics Among Adult Critically Ill Patients: A Systematic Review.

PURPOSE: The pharmacokinetic (PK) parameters of many drugs are altered as a consequence of the pathophysiological changes associated with critical illness. The critically ill population presents challenges when titrating infusions of sedatives and analgesics to maintain optimal sedation and pain levels. This systematic review examined the PK data in critically ill adult patients with prolonged infusions (>24 hours) of commonly used sedatives and analgesics to highlight possible altered PK parameters compared with noncritically ill patients. METHODS: A literature search of PK studies was performed by using MEDLINE (1946-December 2017) and EMBASE (1910-December 2017); we identified further studies by citation tracking (Web of Science) and checked references of retrieved studies and review articles. All studies were included that were published in English, Chinese, or German; conducted in critically ill adult patients receiving lorazepam, midazolam, propofol, dexmedetomidine, sufentanil, alfentanil, remifentanil, morphine, or fentanyl infusion for ≥24 hours; and reported PK parameters. When appropriate, we conducted a meta-analysis on volume of distribution at steady state (Vdss) (liters), clearance (Cl) (liters per hour), and elimination t1/2 (hours) by using a DerSimonian-Laird random effects model to estimate the summary mean and 95% CIs. Results were compared with commonly reported PK ranges in 70-kg noncritically ill patients. FINDINGS: Thirty-three randomized controlled trials and prospective cohort studies were identified involving 1803 adult critically ill patients with 35 drug treatment arms: fifteen midazolam (n = 906) studies, three dexmedetomidine (n = 561), nine propofol (n = 165), four lorazepam (n = 86), one morphine (n = 20), two remifentanil (n = 55), and one sufentanil (n = 10). Each study showed large variations in Vdss, Cl, and elimination t1/2 within and between individual participants. High clinical and methodical heterogeneity between the dexmedetomidine studies prevented the direct comparison of PK parameters between critically ill and noncritically ill patients. Use of midazolam, propofol, and lorazepam in critically ill patients was associated with at least a 2- to 4-fold increase in Vdss compared with noncritically ill patients; Cl decreased ∼2-fold for midazolam and 10-fold for morphine. Critically ill patients receiving prolonged infusions of midazolam, propofol, remifentanil, and sufentanil had at least 2-fold longer elimination or terminal t1/2 than noncritically ill patients. IMPLICATIONS: These findings show a marked difference in many PK parameters from those reported for noncritically ill patients. Initiatives to improve the delivery of prolonged sedatives and analgesic infusions should be informed by PK parameters (Vdss, context-sensitive t1/2, and elimination t1/2) and data derived from critically ill patients.

Influence of Cardiac Output on the Pharmacokinetics of Sufentanil in Anesthetized Pigs.

BACKGROUND: Sufentanil is used for general anesthesia and analgesia. The study aim was to determine the effect of pharmacologically induced changes in cardiac output on the pharmacokinetics of sufentanil in anesthetized pigs. METHODS: Twenty-four pigs were randomly assigned to low, high, and control cardiac output groups. Cardiac output was decreased or increased from baseline by at least 40%, or maintained within ± 10% of baseline, respectively. Sufentanil was administered as a bolus followed by a continuous infusion for 120 min. Timed arterial samples were drawn for sufentanil concentration measurements. RESULTS: Data from 20 animals were analyzed. The cardiac outputs (means ± SD) were 2.9 ± 0.7, 5.4 ± 0.7, and 9.6 ± 1.6 l/min in the low, control, and high cardiac output groups, respectively. The parameters of the two-compartment pharmacokinetic model for these cardiac outputs were: CL1: 0.9, 1.2, and 1.7 l/min; CL2: 0.9, 3.1, and 6.9 l/min; V1: 1.6, 2.9, and 5.2 l; and V2: 27.5, 47.0, and 79.8 l, respectively. Simulated sufentanil doses to maintain a target plasma concentration of 0.5 ng/ml for 3 h were 99.5, 128.6, and 157.6 µg for cardiac outputs of 3, 5, and 7 l/min, respectively. The context-sensitive half-times for these cardiac outputs increased from 3.1 to 19.9 and 25.9 min, respectively. CONCLUSIONS: Cardiac output influences the pharmacokinetics of sufentanil. Simulations suggest that in the case of increased cardiac output, the dose should be increased to avoid inadequate drug effect at the expense of prolonged recovery, whereas for low cardiac output the dose should be reduced, and a faster recovery may be expected.

Multistep Unified Models Using Prior Knowledge for the Prediction of Drug Clearance in Neonates and Infants.

Allometric approaches are widely used for interspecies scaling for the prediction of pharmacokinetic (PK) parameters during drug development. The concept of allometry can also be extended to predict PK parameters from adults to children. Three methods for extrapolating pediatric clearance were developed and evaluated using the clearance values of 4 drugs. The first method was established using a simple allometric (SA) model with estimated coefficient and exponent based on data ranging from children older than 2 years to adult. Then we developed a unified multistep single-exponent (MSE) and multistep body-weight-dependent exponent (MBDE) models. The major steps in these 2 new methods include generating pseudopredicted clearance for unobserved new populations such as preterm neonates, term neonates, and infants. Subsequent steps involve incorporating the pseudopredicted clearance with the actual PK data from older children and adults. All 3 models were then used to predict drug clearance in children ≤2 years old (N = 278). Drug clearance was predicted with mean absolute error of 29.6, 14.2, and 12.9 using SA, MSE, MBDE, respectively. The root mean square error was 65.9, 29.8, 24.7 for SA, MSE, MBDE, respectively. Approximately 41%, 72%, and 74% of the children's clearance data were within 0.5 to 1.5-fold of the observed values when drug clearance was extrapolated using SA, MSE, and MBDE models, respectively. The present multistep unified extrapolation approaches improved the prediction of clearance from preterm neonates to 2 years of age and may have practical use for first-in-pediatric dose selection.

Pharmacokinetic Properties of a Sufentanil Sublingual Tablet Intended to Treat Acute Pain.

BACKGROUND: Desirable product attributes for treatment of moderate-to-severe acute pain in many medically supervised settings are rapid onset and a route of administration not requiring intravenous access. The pharmacokinetic characteristics of sublingually administered tablets containing 15 or 30 µg of sufentanil are described. METHODS: Blood was sampled from healthy subjects (four studies, 122 subjects) and patients (seven studies, 944 patients). Studies in healthy subjects determined bioavailability, effect of inhibition of cytochrome P450 3A4, and the plasma concentration profile with single and hourly sublingual doses. Studies in patients evaluated effects of weight, age, sex, and organ impairment on apparent clearance. Noncompartmental and mixed-effect population methods were used. RESULTS: Bioavailability of a single sublingual tablet was 52%, decreasing to 35% with repeat dosing. Ketoconazole (CYP3A4 inhibitor) increased maximum plasma concentration 19% and increased the area under the curve 77%. After a single 30-µg dose, plasma concentrations reached the published sufentanil analgesic threshold (24 pg/ml) within 30 min, peaked at 1 h, and then decreased below therapeutic concentrations by ~3 h. With hourly administration, plasma concentrations plateaued by the fifth dose. Time for concentrations to decrease 50% from maximal values was similar after 1 dose (2.5 ± 0.85 h) and 12 doses (2.5 ± 0.72 h). Clearance increased with weight, decreased with age, and was not affected by renal or hepatic impairment. CONCLUSIONS: The time course of a single 30-µg dose was consistent with onset of analgesia and redosing frequency observed in clinical trials. Sublingual sufentanil tablets provide the opportunity to noninvasively and rapidly treat moderate-to-severe pain in a monitored setting.

Pharmacokinetics and pharmacodynamics of sublingual sufentanil for postoperative pain management.

Achieving successful treatment of postoperative pain remains a challenge. Recently, a sufentanil sublingual tablet system has been developed for treatment of moderate-to-severe postoperative pain. The phenylpiperidine sufentanil is a potent analgesic that rapidly crosses the blood-brain barrier and selectively activates central µ-opioid receptors. The system makes use of a hand-held dispenser system, which contains forty 15-µg sufentanil sublingual micro-tablets. The patient can release one tablet at 20-min intervals using a unique radiofrequency adhesive tag, which is wrapped around the patient's thumb. In this review, the authors discuss the pharmacology of sublingual sufentanil with reference to its suitability in the treatment of postoperative pain, the current evidence for the sublingual sufentanil system in postoperative pain treatment, and advantages and limitations of the sublingual system. We conclude that sufentanil is suited for the transmucosal route due to its pharmacokinetic profile, including rapid onset, absence of active metabolites and low tissue accumulation. The efficacy and safety of the sufentanil sublingual tablet system has been shown in over 600 patients in a limited set of studies; further independent studies are required to determine the position of the system among other forms of postoperative pain treatment. We conclude that the sublingual sufentanil tablet system allows effective pain relief, and allows patients to control their own pain relief and early postoperative mobility.

Predictive Performance of Physiologically Based Pharmacokinetic (PBPK) Modeling of Drugs Extensively Metabolized by Major Cytochrome P450s in Children.

The accuracy of physiologically based pharmacokinetic (PBPK) model prediction in children, especially those younger than 2 years old, has not been systematically evaluated. The aim of this study was to characterize the pediatric predictive performance of the PBPK approach for 10 drugs extensively metabolized by CYP1A2 (theophylline), CYP2C8 (desloratidine, montelukast), CYP2C9 (diclofenac), CYP2C19 (esomeprazole, lansoprazole), CYP2D6 (tramadol), and CYP3A4 (itraconazole, ondansetron, sufentanil). Model performance in children was evaluated by comparing simulated plasma concentration-time profiles with observed clinical results for each drug and age group. PBPK models reasonably predicted the pharmacokinetics of desloratadine, diclofenac, itraconazole, lansoprazole, montelukast, ondansetron, sufentanil, theophylline, and tramadol across all age groups. Collectively, 58 out of 67 predictions were within 2-fold and 43 out of 67 predictions within 1.5-fold of observed values. Developed PBPK models can reasonably predict exposure in children age 1 month and older for an array of predominantly CYP metabolized drugs.

Pharmacokinetics of Fentanyl and Its Derivatives in Children: A Comprehensive Review.

Fentanyl and its derivatives sufentanil, alfentanil, and remifentanil are potent opioids. A comprehensive review of the use of fentanyl and its derivatives in the pediatric population was performed using the National Library of Medicine PubMed. Studies were included if they contained original pharmacokinetic parameters or models using established routes of administration in patients younger than 18 years of age. Of 372 retrieved articles, 44 eligible pharmacokinetic studies contained data of 821 patients younger than 18 years of age, including more than 46 preterm infants, 64 full-term neonates, 115 infants/toddlers, 188 children, and 28 adolescents. Underlying diagnoses included congenital heart and pulmonary disease and abdominal disorders. Routes of drug administration were intravenous, epidural, oral-transmucosal, intranasal, and transdermal. Despite extensive use in daily clinical practice, few studies have been performed. Preterm and term infants have lower clearance and protein binding. Pharmacokinetics was not altered by chronic renal or hepatic disease. Analyses of the pooled individual patients' data revealed that clearance maturation relating to body weight could be best described by the Hill function for sufentanil (R 2 = 0.71, B max 876 mL/min, K 50 16.3 kg) and alfentanil (R 2 = 0.70, B max (fixed) 420 mL/min, K 50 28 kg). The allometric exponent for estimation of clearance of sufentanil was 0.99 and 0.75 for alfentanil clearance. Maturation of remifentanil clearance was described by linear regression to bodyweight (R 2 = 0.69). The allometric exponent for estimation of remifentanil clearance was 0.76. For fentanyl, linear regression showed only a weak correlation between clearance and bodyweight in preterm and term neonates (R 2 = 0.22) owing to a lack of data in older age groups. A large heterogeneity regarding study design, clinical setting, drug administration, laboratory assays, and pharmacokinetic estimation was observed between studies introducing bias into the analyses performed in this review. A limitation of this review is that pharmacokinetic data, based on different modes of administration, dosing schemes, and parameter estimation methods, were combined.

Flip-Flop Phenomenon in Epidural Sufentanil Pharmacokinetics: A Population Study in Children and Infants.

The aims of this study were to develop a population pharmacokinetic model of sufentanil coadministered with 0.2% ropivacaine as an epidural infusion in infants and describe the sufentanil absorption profile from epidural space. Data from 2 previously published studies were merged for analysis-20 infants aged 3-36 months receiving sufentanil as an epidural infusion and 41 children 0-17 years old receiving sufentanil as a long-term intravenous infusion. A population nonlinear mixed-effects model was built in NONMEM. Sufentanil pharmacokinetics were described by a 2-compartment model with first-order absorption. The effect of body size on all volume and clearance parameters was included in the model according to allometric scaling with theoretical exponents. The maturation process of metabolic clearance was described by the Hill model. During the model-building process the population was divided into 2 fractions with different typical values of metabolic clearance (CL1 and CL2). The typical values of systemic clearance scaled to a 70-kg patient for the 2 subpopulations were CL1 = 52.6 L/h and CL2 = 158 L/h. The parameters of the Hill function were 54.9 weeks for the postmenstrual age of 50% clearance maturation and 0.802 for the Hill coefficient. The typical values of distribution clearance and volumes of the central and peripheral compartments for a patient with a weight of 70 kg were Q = 40.5 L/h, VC = 7.63 L, and VT = 473 L, respectively. The value of the absorption rate constant from the epidural space was 0.0459/h, which suggests flip-flop pharmacokinetics of sufentanil after epidural administration.

Sufentanil sublingual tablet system for the management of postoperative pain.

INTRODUCTION: Intravenous patient-controlled opioid analgesia has been an important improvement in addressing insufficient management of acute postoperative pain for over 40 years. However, there are number of weaknesses for intravenous patient-controlled analgesia, including operator and device error, intravenous line patency issues, and risk of catheter-related infection, all of which contribute to the complications and increase in cost of care. The sublingual sufentanil tablet system is a major evolution in both drug and technological management of postoperative pain. Areas covered: We reviewed the use of the sublingual sufentanil tablet system in management of moderate to severe postoperative pain in hospitalized patients, with a particular focus on the pharmacological properties of sufentanil and clinical use in different surgical patients. Expert opinion: The sublingual sufentanil tablet system can decrease intravenous opioid based patient-controlled analgesia related complications and safety issues. Current clinical studies have demonstrated this noninvasive-novel system to be safe and effective in management of acute pain in the postsurgical setting. Researchers should focus on comparing it with other available patient controlled analgesia modalities and evaluating the efficiency and cost effectiveness of the sublingual sufentanil tablet system.

Preparing Drugs for Infusion Via Syringe Pump: A Key Step to Ensure Homogeneous Concentration.

OBJECTIVE: Preparation of drug solutions used with electronic syringe infusion pumps plays a crucial role in the delivery of an accurate drug concentration. Is there a correlation between drug concentrations during syringe pump infusion and preparation protocols? METHOD: Norepinephrine, insulin, and sufentanil were prepared in 3 different ways: (1) the drug was taken from the vial, then the solvent was added followed by an air bubble, and mixing was performed by turning the syringe top-to-bottom in a 180° shaking movement 5 consecutive times; (2) the drug was taken from the vial, then the solvent was added and not mixed; and (3) the solvent was taken from a stock solution, then the drug was added and not mixed. Concentrations of drugs were determined at different times during administration by reverse-phase high-performance liquid chromatography with ultraviolet detection. All analyses were performed in triplicate and were based on measurement of peak areas. RESULTS: With no shaking of the syringe, the concentration of the injected drugs varies widely. In any case, mixing of the syringe contents by turning the syringe in a top-to-bottom 180° shaking movement 5 times with an air bubble would ensure administration of the drug at a constant concentration. CONCLUSIONS: Without mixing, the concentrations of all drug solutions varied widely when administered via an electronic syringe infusion pump. Mixing syringe contents should be made part of the compulsory curriculum for administering medications at all levels of medical education. (Critical Care Nurse. 2016;36[4]:36-45).

Sublingual sufentanil, a new opportunity for the improvement of postoperative pain management in Italy.

Despite the availability of national and international guidelines, adequate postoperative pain (POP) management is still a challenge in Italy. One of the potential reasons for the high incidence of surgical patients complaining moderate to severe pain is the difficult application of the currently recommended analgesic techniques in clinical practice. In particular, morphine, the most commonly used systemic opioid in the POP treatment, has some unfavorable pharmacodynamic and pharmacokinetic characteristics for POP management, suggesting a potential relevant improvement by using different opioids. Many of sufentanil properties make it particularly suitable for POP control: a high affinity for the µ opioid receptor, the highest therapeutic index compared to any other opioid used in clinical practice and the absence of clinically relevant active metabolites. The elevated potency, together with the high lipophilicity of sufentanil, allow the preparation of a nanotablet, 3 mm of diameter and 0.75 mm of thickness, containing 15 µg of active drug. The sublingual route allows a longer time of drug plasmatic permanence in comparison to IV route, overcoming the need for continuous dosing. The patient-controlled system, considered in the present review, is preprogrammed to deliver one sublingual tablet of sufentanil with a 20-minute lockout period with a radiofrequency identification thumb tag allowing only the patient to activate the on demand button. Phase II and III studies have assessed the efficacy of this system in POP management, showing that it was considered more satisfactory than the IV PCA morphine system by both patients and nurses. The introduction of this simple and innovative system of patient-controlled analgesic administration could represent an opportunity for Italy to update the current practice in POP management.

Pharmacokinetic and pharmacodynamic evaluation of sublingual sufentanil in the treatment of post-operative pain.

INTRODUCTION: Intravenous patient-controlled analgesia using opioids is frequently used to provide perioperative analgesia. However, there are a number of drawbacks for intravenous patient-controlled analgesia. The sufentanil sublingual tablet system is a major evolution in technology and drug development for postoperative pain management. AREAS COVERED: We reviewed the use of sublingual sufentanil in postoperative pain management, with a focus on chemistry, pharmacokinetics and clinical use in different surgical patients. EXPERT OPINION: The sufentanil sublingual tablet system can decrease intravenous patient-controlled analgesia-related safety issues. Current clinical studies have demonstrated this novel system to be safe and effective in postoperative pain management.

Pharmacokinetics of sufentanil during long-term infusion in critically ill pediatric patients.

The aim of this study was to develop a population pharmacokinetic model of sufentanil and to assess the influence of covariates in critically ill children admitted to a pediatric intensive care unit. After institutional approval, 41 children were enrolled in the study. Blood samples for pharmacokinetic (PK) assessment were collected from routinely placed arterial catheters during and after discontinuation of infusion. Population nonlinear mixed-effects modeling was performed using NONMEM. A 2-compartment model described sufentanil PK sufficiently. Typical values of the central and peripheral volume of distribution and the metabolic and intercompartmental clearance for a theoretical patient weighing 70 kg were VC = 7.90 l, VT = 481 L, Cl = 5.3 L/h, and Q = 38.3 L/h, respectively. High interindividual variability of all PK parameters was noted. Allometric/isometric principles to scale sufentanil PK revealed that to achieve the same steady-state sufentanil concentrations in plasma for pediatric patients of different body weights, the infusion rate should follow the formula (infusion rate for a 70-kg adult patient, µg/h) × (body weight/70 kg)(0.75). Severity of illness described by PRISM score, the monitored physiological and laboratory parameters, and coadministered drugs such as vasopressors were not found to be significant covariates.