Anticoagulation practices for continuous renal replacement therapy: a survey of physicians from the United States.

BACKGROUND: During continuous renal replacement therapy (CRRT), anticoagulants are recommended for patients at low risk of bleeding and not already receiving systemic anticoagulants. Current anticoagulants used in CRRT in the US are systemic heparins or regional citrate. To better understand use of anticoagulants for CRRT in the US, we surveyed nephrologists and critical care medicine (CCM) specialists. METHODS: The survey contained 30 questions. Respondents were board certified and worked in intensive care units of academic medical centers or community hospitals. RESULTS: 150 physicians (70 nephrologists and 80 CCM) completed the survey. Mean number of CRRT machines in use increased ∼30% from the pre-pandemic era to 2022. Unfractionated heparin was the most used anticoagulant (43% of estimated patients) followed by citrate (28%). Respondents reported 29% of patients received no anticoagulant. Risk of hypocalcemia (52%) and citrate safety (42%) were the predominant reasons given for using no anticoagulant instead of citrate in heparin-intolerant patients. 84% said filter clogging was a problem when no anticoagulant was used, and almost 25% said increased transfusions were necessary. Respondents using heparin (n = 131) considered it inexpensive and easily obtainable, although of moderate safety, citing concerns of heparin-induced thrombocytopenia and bleeding. Anticoagulant citrate dextrose solution was the most used citrate. Respondents estimated that 37% of patients receiving citrate develop hypocalcemia and 17% citrate lock. CONCLUSIONS: Given the increased use of CRRT and the lack of approved, safe, and effective anticoagulant choices for CRRT in the US, effective use of current and other anticoagulant options needs to be evaluated.

Pooled Dosing and Efficacy Analysis of the Sufentanil Sublingual Tablet 30 mcg Across Demographic Subgroups for the Management of Moderate-to-Severe Acute Pain.

PURPOSE: To aid nurses in dosing sufentanil sublingual tablet (SST) 30 mcg administered via a single-dose applicator, dosing requirements and efficacy of SST 30 mcg were analyzed across age, sex, race, and body mass index subgroups. DESIGN: Patient characteristics were pooled from three postoperative studies (two placebo-controlled and one open-label) and one open-label emergency department study. Drug dosing and efficacy data were pooled from the postoperative studies. METHODS: Efficacy was assessed through summed pain intensity difference to baseline during 12 hours across subgroups. FINDINGS: Mean (standard deviation) drug doses administered from 0 to 12 hours was 3.9 (2.0) for SST 30 mcg and was less frequent for older (≥65 years) versus younger patients. The summed pain intensity difference to baseline during 12 hours was superior with SST 30 mcg versus placebo across all subgroups. CONCLUSIONS: SST 30 mcg is a sublingual opioid analgesic with efficacy across demographic subgroups.

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.

An Open-Label Study of Sufentanil Sublingual Tablet 30 Mcg in Patients with Postoperative Pain.

Objective: To evaluate sufentanil sublingual tablet 30 mcg (SST 30 mcg) for postoperative pain in an older patient population with comorbidities. Design: Multicenter, open-label, single-arm study. Setting: Nine hospitals across the United States. Subjects: Adults aged ≥40 years who had undergone a surgical procedure. Methods: Patients with a postoperative pain intensity score ≥4 on an 11-point numeric rating scale (NRS) were allowed to enter the study and receive SST 30 mcg as requested for pain (minimum 60-minute redosing interval) over the 12-hour study period. Efficacy was assessed by patient reports of pain intensity on the NRS and a five-point pain relief scale. Safety was monitored throughout the study; plasma sufentanil concentrations were also measured. The primary efficacy endpoint was the time-weighted summed pain intensity difference (SPID) to baseline over 12 hours (SPID12). Results: Of the 140 patients enrolled, 69% were American Society of Anesthesiologists Physical Class II or III, 44% had a body mass index (BMI) ≥30 mg/kg2, and 29% had hepatic and/or renal impairment. Average age was 54.7 years (SD = 9.9 years), and average baseline pain intensity was 6.2 (SD = 1.9). The most common surgeries were abdominal (59%) and orthopedic (20%). The mean SPID12 was 36.0 (standard error of the mean = 2.2); mean scores were similar, regardless of age, sex, race, and BMI. From baseline, mean pain intensity decreased significantly starting 30 minutes postdose, and mean pain relief increased significantly starting 15 minutes postdose, remaining relatively stable through 12 hours (P < 0.001 at each time point). Four (3%) patients discontinued due to inadequate analgesia, and 45 (32%) patients had one or more adverse events that were considered possibly or probably related to the study drug. Mean plasma sufentanil concentrations were generally similar regardless of age, sex, BMI, or organ impairment status. Conclusions: SST 30 mcg was effective and well tolerated for the management of moderate-to-severe acute postoperative pain.

Sufentanil sublingual tablet 30mcg for moderate-to-severe acute pain in the ED.

BACKGROUND: Pharmacological properties of the sufentanil sublingual tablet 30mcg (SST 30mcg) could offer potential analgesic advantages in settings requiring noninvasive, acute pain management. The feasibility of using SST 30mcg for moderate-to-severe pain management in the emergency department (ED) was evaluated. METHODS: This open-label, multicenter feasibility study included patients aged ≥18years who presented to the ED with moderate-to-severe pain (≥4 on the numeric rating scale of pain intensity (NRS); opioid-tolerant patients were excluded. Patients received a single SST 30-mcg dose (single-dose cohort) or, upon request, ≤3 additional doses ≥60min apart (multiple-dose cohort) and were evaluated over 1 or 2h. Effectiveness was assessed by patient-reported pain scores (11-point NRS; 5-point pain relief scale). Safety and tolerability were also assessed. RESULTS: Overall, 76 patients enrolled into the single-dose (n=40) and multiple-dose (n=36) cohorts. In the first hour (combined cohorts), mean pain intensity was significantly lower 15-min post-dosing (P<0.001; clinically meaningful within 30-minutes post-dosing) and continued to decrease during the first hour (P<0.001 for each 15-minute interval). Mean pain intensity (multiple-dose cohort) decreased from 7.6 at baseline to 4.5 at 1h and to 4.6 at 2h (P<0.001 for both); mean pain relief increased from baseline to 1.9 at 1h (P<0.001) and to 2.0 at 2h (P<0.001). Most (79%) patients had no adverse events (AEs), and there were no severe AEs. CONCLUSIONS: SST 30mcg was feasible for managing moderate-to-severe acute pain in an ED setting.

Sufentanil Sublingual Tablet 30 mcg for the Management of Pain Following Abdominal Surgery: A Randomized, Placebo-Controlled, Phase-3 Study.

BACKGROUND: Results from a phase-3, prospective, randomized, double-blind, placebo-controlled trial evaluating sufentanil sublingual tablet 30 mcg (SST) for the management of pain after ambulatory abdominal surgery are presented. METHODS: Adults with American Society of Anesthesiologists status 1 to 3 scheduled to undergo abdominoplasty, open tension-free inguinal hernioplasty, or laparoscopic abdominal surgery under general or spinal anesthesia that did not include intrathecal opioids during the operation were eligible. Opioid-tolerant patients were excluded. The primary endpoint was the time-weighted summed pain intensity difference to baseline (SPID) over 12 hours. Secondary endpoints included SPID over 24 and 48 hours, total pain relief, and patient and healthcare professional (HCP) global assessments. RESULTS: Overall, 161 patients were randomized to SST (N = 107) or placebo (N = 54); pain scores were recorded for up to 48 hours. SPID 12 was higher (greater pain intensity reduction from baseline) in the SST group compared with placebo (25.8 vs. 13.1; P < 0.001, with a difference of 12.7 [95% confidence interval 7.16, 18.23]). In the SST group, a greater proportion of patients and HCPs responded "good" or "excellent" on the global assessments compared with placebo (P < 0.001 for both). There was a numerically, but not statistically, higher incidence of nausea and headache in the SST group. CONCLUSIONS: In patients following abdominal surgery in an ambulatory care setting, SST was an effective opioid analgesic in postoperative pain management. In addition, SST was well tolerated with mild-to-moderate side effects, similar to those found in placebo-treated patients.

Evolution of Patient-Controlled Analgesia: From Intravenous to Sublingual Treatment.

Opioid administration delivered intravenously (IV) by patient-controlled analgesia (PCA) devices has been an important development in addressing insufficient management of acute pain in the postsurgical setting. However, IV PCA has several disadvantages, including operator error, risk of patient exposure to analgesic gaps, IV line patency issues, and risk of catheter-related infection, all of which contribute to the total cost of care. Morphine, the most commonly used opioid in IV PCA, has a relatively slow onset of analgesia, which may leave patients with inadequate initial pain control and at risk of opioid dose-stacking. Sufentanil is an opioid with no major active metabolites and a rapid onset of analgesia. The sufentanil sublingual tablet system (SSTS) with a 20-minute lockout and other safety features is a novel noninvasive PCA system in development for on-demand relief of moderate to severe acute pain in the hospital setting. Data from phase 3 trials of the use of SSTS after elective major open abdominal and orthopedic surgery show that analgesia is rapidly achieved, with a longer mean interdosing interval compared with IV PCA morphine (81 vs 47 minutes) and a high level of patient and nurse satisfaction. These data suggest that SSTS may also aid in the avoidance of some of the pitfalls inherent with IV PCA, which may help reduce hospital costs associated with IV PCA-related issues. This article describes the evolution, benefits, issues, and costs associated with IV PCA and reviews data from preclinical studies of sufentanil through SSTS phase 3 trials.

Sufentanil Sublingual Tablet System for the Management of Postoperative Pain after Knee or Hip Arthroplasty: A Randomized, Placebo-controlled Study.

BACKGROUND: Complications with IV patient-controlled analgesia include programming errors, invasive access, and impairment of mobility. This study evaluated an investigational sufentanil sublingual tablet system (SSTS) for the management of pain after knee or hip arthroplasty. METHODS: This prospective, randomized, parallel-arm, double-blind study randomized postoperative patients at 34 U.S. sites to receive SSTS 15 µg (n = 315) or an identical placebo system (n = 104) and pain scores were recorded for up to 72 h. Adult patients with American Society of Anesthesiologists status 1 to 3 after primary total unilateral knee or hip replacement under general anesthesia or with spinal anesthesia that did not include intrathecal opioids were eligible. Patients were excluded if they were opioid tolerant. The primary endpoint was the time-weighted summed pain intensity difference to baseline over 48 h. Secondary endpoints included total pain relief, patient and healthcare professional global assessments, and patient and nurse ease-of-care questionnaires. RESULTS: Summed pain intensity difference (standard error) was higher (better) in the SSTS group compared with placebo (76 [7] vs. -11 [11], difference 88 [95% CI, 66 to 109]; P < 0.001). In the SSTS group, more patients and nurses responded "good" or "excellent" on the global assessments compared with placebo (P < 0.001). Patient and nurse ease-of-care ratings for the system were high in both groups. There was a higher incidence of nausea and pruritus in the SSTS group. CONCLUSION: SSTS could be an effective patient-controlled pain management modality in patients after major orthopedic surgery and is easy to use by both patients and healthcare professionals.

Sufentanil sublingual tablet system vs. intravenous patient-controlled analgesia with morphine for postoperative pain control: a randomized, active-comparator trial.

BACKGROUND: Problems with intravenous patient-controlled analgesia (IV PCA) are well known, including invasive route of delivery and pump programming errors. The primary objective of this study was to evaluate patient satisfaction with a novel sublingual sufentanil PCA system (sufentanil sublingual tablet system 15 mcg with a 20-minute lockout interval; SSTS) to IV PCA morphine sulfate 1 mg with a 6-minute lockout interval (IV PCA MS) for the management of acute postoperative pain. METHODS: This was a randomized, open-label, 48-hour non-inferiority study with optional extension to 72 hours at 26 U.S. sites enrolling patients scheduled for elective major open abdominal or orthopedic (hip or knee replacement) surgery. The primary outcome measure was the proportion of patients who responded "good" or "excellent" (collectively "success") at the 48-hour timepoint on the Patient Global Assessment of method of pain control (PGA48). RESULTS: A total of 357 patients received study drug and 78.5% vs. 65.6% of patients achieved PGA48 "success" for SSTS vs. IV PCA MS, respectively, demonstrating non-inferiority (P < 0.001 using the one-side Z-test against the non-inferiority margin) as well as statistical superiority for treatment effect (P = 0.007). Patients using SSTS reported more rapid onset of analgesia and patient and nurse ease of care and satisfaction scores were higher than IV PCA MS. Adverse events were similar between the 2 groups; however, SSTS had fewer patients experiencing oxygen desaturations below 95% compared to IV PCA MS (P = 0.028). CONCLUSIONS: Sufentanil sublingual tablet system is a promising new analgesic technology that may address some of the concerns with IV PCA.

Improving refill adherence and hypertension control in black patients: Wisconsin TEAM trial.

OBJECTIVE: To assess the effectiveness and sustainability of a 6-month Team Education and Adherence Monitoring (TEAM) intervention for black patients with hypertension in community chain pharmacies. DESIGN: Cluster randomized trial. SETTING: 28 chain pharmacies (14 TEAM and 14 control) in five Wisconsin cities from December 2006 to February 2009. PARTICIPANTS: 576 black patients with hypertension. INTERVENTION: Trained pharmacist-technician teams implemented a 6-month intervention using scheduled visits, Brief Medication Questionnaires (BMQs), and novel toolkits for facilitating medication adherence and pharmacist feedback to patients and physicians. Control participants received patient information only. MAIN OUTCOME MEASURES: Refill adherence (≥80% days covered) and changes in systolic blood pressure (SBP), diastolic blood pressure, and blood pressure control using blinded assessments at 6 and 12 months. RESULTS: At baseline, all patients had blood pressure of 140/90 mm Hg or more. Of those eligible, 79% activated the intervention (mean 4.25 visits). Compared with control participants at 6 months, TEAM participants achieved greater improvements in refill adherence (60% vs. 34%, P < 0.001), SBP (-12.62 vs. -5.31 mm Hg, P < 0.001), and blood pressure control (50% vs. 36%, P = 0.01). Six months after intervention discontinuation, TEAM participants showed sustained improvements in refill adherence ( P < 0.001) and SBP ( P = 0.004), though the difference in blood pressure control was not significant ( P < 0.05) compared with control participants. Analysis of intervention fidelity showed that patients who received the full intervention during months 1 through 6 achieved significantly greater 6- and 12-month improvements in refill adherence and blood pressure control compared with control participants. CONCLUSION: A team-based intervention involving community chain pharmacists, pharmacy technicians, and novel toolkits led to significant and sustained improvements in refill adherence and SBP in black patients with hypertension.

Molecular and cellular mechanisms of the age-dependency of opioid analgesia and tolerance.

The age-dependency of opioid analgesia and tolerance has been noticed in both clinical observation and laboratory studies. Evidence shows that many molecular and cellular events that play essential roles in opioid analgesia and tolerance are actually age-dependent. For example, the expression and functions of endogenous opioid peptides, multiple types of opioid receptors, G protein subunits that couple to opioid receptors, and regulators of G protein signaling (RGS proteins) change with development and age. Other signaling systems that are critical to opioid tolerance development, such as N-methyl-D-aspartic acid (NMDA) receptors, also undergo age-related changes. It is plausible that the age-dependent expression and functions of molecules within and related to the opioid signaling pathways, as well as age-dependent cellular activity such as agonist-induced opioid receptor internalization and desensitization, eventually lead to significant age-dependent changes in opioid analgesia and tolerance development.

Virtual group-based mindfulness program for autistic women: A feasibility study.

BACKGROUND: Autistic women experience life differently than autistic men. For example, autistic women tend to be diagnosed significantly later than autistic men, they experience a higher number of traumas, and are at increased risk for mental health conditions. Given gender-specific life experiences, autistic women may benefit from gender-specific group-based supports. Virtual mindfulness has been shown to be helpful in improving well-being among autistic adults; however, limited research has explored the impact of virtual mindfulness when it is delivered to a group of autistic women only. OBJECTIVES: The aim of this article is to describe a preliminary evaluation of a virtual mindfulness group piloted for autistic women. Five key areas of feasibility were assessed in the current study: demand, implementation, acceptability, practicality, and limited efficacy testing. METHODS: Twenty-eight women participated in a 6-week virtual autism-informed mindfulness program and were asked to complete measures assessing psychological distress, self-compassion, and mindfulness at pre and post. Participants were also asked to complete a satisfaction survey after the program. RESULTS: Results showed that the program was feasible in terms of demand, implementation, practicality, and acceptability. While quantitative results showed there were no changes in psychological distress, self-compassion, and mindfulness from pre- to post-program, qualitative results showed some benefits. CONCLUSION: Given the unique challenges that some autistic women experience, offering groups to autistic women may have some value and it would be important to continue exploring this topic area.

Patient and Healthcare Professional Satisfaction Ratings and Safety Profile of Sufentanil Sublingual Tablets for Treatment of Acute Pain: A Pooled Demographic Analysis.

OBJECTIVE: This analysis reports the healthcare professional global assessment (HPGA) and patient global assessment (PGA) scores and the adverse event (AE) profile by age, body mass index (BMI), sex, and race from the three Phase III registration studies for sufentanil sublingual tablet (SST) 30 mcg. METHODS: Global assessments and treatment-related AEs were analyzed from patients treated with SST 30 mcg for moderate-to-severe acute pain following surgery or in the emergency department (ED). Pooled data were analyzed across patient demographic subgroups. RESULTS: A total of 283 patients were included in the HPGA/PGA analyses. The majority underwent abdominal surgery, with the remaining patients undergoing orthopedic or "other" types of surgery. Overall, SST 30 mcg was highly rated by both healthcare professionals and patients across the demographic subgroups. A total of 323 patients were included in the safety evaluation. The majority of patients did not experience any SST-related AEs; however, those that did experienced common opioid-related side effects such as nausea, headache, dizziness, and vomiting. No patients experienced unexpected AEs or required the use of naloxone. CONCLUSION: SST 30 mcg was highly rated and well tolerated across demographic subgroups with the majority of patients not experiencing any adverse event related to SST 30 mcg. These findings support the use of sublingual sufentanil in all adult patients, regardless of age, BMI, sex, or race for the treatment of moderate-to-severe acute pain.

Research design considerations for chronic pain prevention clinical trials: IMMPACT recommendations.

Although certain risk factors can identify individuals who are most likely to develop chronic pain, few interventions to prevent chronic pain have been identified. To facilitate the identification of preventive interventions, an IMMPACT meeting was convened to discuss research design considerations for clinical trials investigating the prevention of chronic pain. We present general design considerations for prevention trials in populations that are at relatively high risk for developing chronic pain. Specific design considerations included subject identification, timing and duration of treatment, outcomes, timing of assessment, and adjusting for risk factors in the analyses. We provide a detailed examination of 4 models of chronic pain prevention (ie, chronic postsurgical pain, postherpetic neuralgia, chronic low back pain, and painful chemotherapy-induced peripheral neuropathy). The issues discussed can, in many instances, be extrapolated to other chronic pain conditions. These examples were selected because they are representative models of primary and secondary prevention, reflect persistent pain resulting from multiple insults (ie, surgery, viral infection, injury, and toxic or noxious element exposure), and are chronically painful conditions that are treated with a range of interventions. Improvements in the design of chronic pain prevention trials could improve assay sensitivity and thus accelerate the identification of efficacious interventions. Such interventions would have the potential to reduce the prevalence of chronic pain in the population. Additionally, standardization of outcomes in prevention clinical trials will facilitate meta-analyses and systematic reviews and improve detection of preventive strategies emerging from clinical trials.

Receptor mediation and nociceptin inhibition of bradykinin-induced plasma extravasation in the knee joint of the rat.

OBJECTIVE AND DESIGN: The aim was to investigate the signaling mechanisms and regulation of bradykinin (BK)-induced inflammation in rat knee joint. MATERIALS AND METHODS: Knee joints of anesthetized rats were perfused with BK (0.1-1.0 microM), and synovial plasma extravasation (PE) was evaluated by spectrophotometrical measurement of Evans Blue leakage. To examine the signaling pathway, B1 antagonist [des-Arg10]-HOE140 (0.1-1.0 microM) and B2 antagonist HOE140 (0.05-1.0 microM), calcitonin gene-related peptide (CGRP) antagonist CGRP8-37 (0.5-1.0 microM), prostaglandin E2 antagonist AH-6809 (0.1-1.0 microM), and histamine H1 antagonist mepyramine (0.1-1.0 microM) were used. Nociceptin (0.0001-1.0 microM) and antagonist J-113397 were tested for modulation of BK-induced PE. The analyses were compared side-by-side with 5-hydroxytryptamine-induced PE. RESULTS: BK perfusion dose-dependently induced PE, which was blocked by HOE140, CGRP8-37, AH-6809, and mepyramine. It was also inhibited by nociceptin, which could be reversed by antagonist J-113397. In contrast, 5-hydroxytryptamine-induced PE was biphasically regulated by nociceptin and was not antagonized by CGRP8-37. CONCLUSIONS: BK-induced PE is mediated by B2 receptors and may involve CGRP, prostaglandin, and histamine pathways. BK-induced PE is inhibited by nociceptin through the activation of ORL1 receptors. There are differences between BK- and 5-hydroxytryptamine-induced inflammation in signaling and modulation.

Pooled Phase III safety analysis of sufentanil sublingual tablets for short-term treatment of moderate-to-severe acute pain.

Aim: To evaluate the pooled safety of sufentanil sublingual tablets (SSTs) administered at 30-mcg dose equivalents over ≤72 h for moderate-to-severe acute pain management in medically supervised settings. Patients & methods: Safety data from SST 30 mcg Phase III studies were pooled with an additional patient subset from studies in which two SST 15 mcg were self-administered within 20-25 min (30-mcg dose-equivalent). Results: Analyses included 804 patients. Median (range) SST 30-mcg dosing over 24 h was 7.0 (1-15) tablets. Adverse events (AEs) were experienced by 60.5% (SST) and 61.4% (placebo) and treatment-related AEs by 43.8% (SST) and 33.5% (placebo; 10.3% difference; 95% CI: 2.0-18.6) of patients. No dose-dependent increase in oxygen desaturation was observed with SST. Conclusion: SST was well-tolerated, with most AEs considered mild or moderate in severity.

How regulators of G protein signaling achieve selective regulation.

The regulators of G protein signaling (RGS) are a family of cellular proteins that play an essential regulatory role in G protein-mediated signal transduction. There are multiple RGS subfamilies consisting of over 20 different RGS proteins. They are basically the guanosine triphosphatase (GTPase)-accelerating proteins that specifically interact with G protein alpha subunits. RGS proteins display remarkable selectivity and specificity in their regulation of receptors, ion channels, and other G protein-mediated physiological events. The molecular and cellular mechanisms underlying such selectivity are complex and cooperate at many different levels. Recent research data have provided strong evidence that the spatiotemporal-specific expression of RGS proteins and their target components, as well as the specific protein-protein recognition and interaction through their characteristic structural domains and functional motifs, are determinants for RGS selectivity and specificity. Other molecular mechanisms, such as alternative splicing and scaffold proteins, also significantly contribute to RGS selectivity. To pursue a thorough understanding of the mechanisms of RGS selective regulation will be of great significance for the advancement of our knowledge of molecular and cellular signal transduction.

Sublingual, transdermal and intravenous patient-controlled analgesia for acute post-operative pain: systematic literature review and mixed treatment comparison.

OBJECTIVE: To conduct a systematic literature review (SLR) and quantitative analysis to assess the comparative efficacy and safety of the sufentanil sublingual tablet system (SSTS) against other available patient controlled analgesia (PCA) options for post-operative analgesia. METHODS: An SLR was conducted for studies published between 2004 and 2016. Due to study heterogeneity, subgroup analyses were conducted controlling for differences in imputation methods for missing values, baseline pain severity, and type of surgery. Where sufficient data was available, a mixed treatment comparison (MTC) was performed. RESULTS: The MTC and subgroup analyses used 13 studies. In direct meta-analysis, there was a statistically significant difference in favor of SSTS compared with intravenous (IV) PCA (morphine) at 24 hours for the patient global assessment (PGA) scores of "good" or "excellent". For the Pain Intensity Score, there were numerical but not statistically significant differences in favor of the SSTS versus IV PCA (morphine) and the patient controlled transdermal system (PCTS) (fentanyl) in the MTC at 6 hours (standardized mean difference -0.27 [credible interval -2.78, 2.09] and -0.36 [-3.89, 3.03], respectively). The onset of pain relief was earlier with the SSTS versus IV PCA (morphine) as shown by the Pain Intensity Difference. Likewise, the onset was earlier compared with PCTS (fentanyl) where data was available. There was a significant difference in favor of SSTS compared with IV PCA (morphine) and with PCTS (fentanyl) for any adverse event, and numerical improvements for withdrawals due to adverse events. CONCLUSIONS: This meta-analysis shows that SSTS is an option for non-invasive management of moderate-to-severe post-operative pain which can be more effective, faster in onset and better tolerated than IV PCA (morphine) and PCTS (fentanyl).

Indirect treatment comparison of two non-invasive patient-controlled analgesia treatments for acute post-operative pain management.

OBJECTIVES: To evaluate the relative clinical efficacy, safety, and tolerability associated with two non-invasive patient-controlled analgesia (PCA) treatments, sufentanil sublingual tablet system (SSTS) and fentanyl iontophoretic patient-controlled transdermal system (PCTS). These two treatments have recently been approved in the EU for the management of acute moderate-to-severe post-operative pain in adult patients. METHODS: As no head-to-head trials comparing SSTS and PCTS currently exist, indirect treatment comparison (ITC) analyses were conducted to evaluate SSTS or PCTS versus intravenous (IV) morphine PCA. RESULTS: Five studies, four assessing PCTS and one assessing SSTS, were included in this analysis. SSTS had statistical or numerical advantages over PCTS for both patient global assessment (PGA) and healthcare professional global assessment (HPGA) outcomes at all time points investigated. SSTS was also associated with greater patient ease of use (weighted mean difference [WMD]: 0.13; 95% confidence interval [CI]: -0.02-0.28) and a higher patient satisfaction score (WMD: 0.31; 95% CI: 0.05-0.57; p = .019) compared with PCTS. In terms of tolerability, all-cause withdrawals from treatment were reported to be less likely with SSTS (risk ratio: 0.65; 95% CI: 0.42-1.02). No significant differences were observed between SSTS and PCTS in terms of safety and adverse events. CONCLUSIONS: In the absence of direct head-to-head data, the combination of promising phase III trial results compared to IV morphine PCA, a SLR comparison against other opioid treatments, and the results of this exploratory analysis present a strong rationale in support of SSTS as a key option for management of post-operative pain.

Cost of Intravenous Analgesia for the Management of Acute Pain in the Emergency Department is Substantial in the United States.

Background: Pain is a leading cause of admission to the emergency department (ED) and moderate-to-severe acute pain in medically supervised settings is often treated with intravenous (IV) opioids. With novel noninvasive analgesic products in development for this indication, it is important to assess the costs associated with IV administration of opioids. Materials and Methods: A retrospective observational study of data derived from the Premier database was conducted. All ED encounters of adult patients treated with IV opioids during a 2-year time period, who were charged for at least one IV opioid administration in the ED were included. Hospital reported costs were used to estimate the costs to administer IV opioids. Results: Over a 24 month-period, 7.3 million encounters, which included the administration of IV opioids took place in 614 US EDs. The mean cost per encounter of IV administration of an initial dose of the three most frequently prescribed opioids were: morphine $145, hydromorphone $146, and fentanyl $147. The main driver of the total costs is the cost of nursing time and equipment cost to set up and maintain an IV infusion ($140 ± 60). Adding a second dose of opioid, brings the average costs to $151-$154. If costs associated with the management of opioid-related adverse events and IV-related complications are also added, the total costs can amount to $269-$273. Of these 7.3 million encounters, 4.3 million (58%) did not lead to hospital admission of the patient and, therefore, the patient may have only required an IV catheter for opioid administration. Conclusions: IV opioid use in the ED is indicated for moderate-to-severe pain but is associated with significant costs. In subjects who are discharged from the ED and may not have required an IV for reasons other than opioid administration, rapid-onset analgesics for moderate-to-severe pain that do not require IV administration could lead to direct cost reductions and improved care.