Research approaches for evaluating opioid sparing in clinical trials of acute and chronic pain treatments: Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials recommendations.

ABSTRACT: Randomized clinical trials have demonstrated the efficacy of opioid analgesics for the treatment of acute and chronic pain conditions, and for some patients, these medications may be the only effective treatment available. Unfortunately, opioid analgesics are also associated with major risks (eg, opioid use disorder) and adverse outcomes (eg, respiratory depression and falls). The risks and adverse outcomes associated with opioid analgesics have prompted efforts to reduce their use in the treatment of both acute and chronic pain. This article presents Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) consensus recommendations for the design of opioid-sparing clinical trials. The recommendations presented in this article are based on the following definition of an opioid-sparing intervention: any intervention that (1) prevents the initiation of treatment with opioid analgesics, (2) decreases the duration of such treatment, (3) reduces the total dosages of opioids that are prescribed for or used by patients, or (4) reduces opioid-related adverse outcomes (without increasing opioid dosages), all without causing an unacceptable increase in pain. These recommendations are based on the results of a background review, presentations and discussions at an IMMPACT consensus meeting, and iterative drafts of this article modified to accommodate input from the co-authors. We discuss opioid sparing definitions, study objectives, outcome measures, the assessment of opioid-related adverse events, incorporation of adequate pain control in trial design, interpretation of research findings, and future research priorities to inform opioid-sparing trial methods. The considerations and recommendations presented in this article are meant to help guide the design, conduct, analysis, and interpretation of future trials.

American Society for Enhanced Recovery and Perioperative Quality Initiative Joint Consensus Statement on Postoperative Delirium Prevention.

Postoperative delirium is a geriatric syndrome that manifests as changes in cognition, attention, and levels of consciousness after surgery. It occurs in up to 50% of patients after major surgery and is associated with adverse outcomes, including increased hospital length of stay, higher cost of care, higher rates of institutionalization after discharge, and higher rates of readmission. Furthermore, it is associated with functional decline and cognitive impairments after surgery. As the age and medical complexity of our surgical population increases, practitioners need the skills to identify and prevent delirium in this high-risk population. Because delirium is a common and consequential postoperative complication, there has been an abundance of recent research focused on delirium, conducted by clinicians from a variety of specialties. There have also been several reviews and recommendation statements; however, these have not been based on robust evidence. The Sixth Perioperative Quality Initiative (POQI-6) consensus conference brought together a team of multidisciplinary experts to formally survey and evaluate the literature on postoperative delirium prevention and provide evidence-based recommendations using an iterative Delphi process and Grading of Recommendations Assessment, Development and Evaluation (GRADE) Criteria for evaluating biomedical literature.

Resource use and costs associated with opioid-induced constipation following total hip or total knee replacement surgery.

PURPOSE: Constipation is a well-known complication of surgery that can be exacerbated by opioid analgesics. This study evaluated resource utilization and costs associated with opioid-induced constipation (OIC). PATIENTS AND METHODS: This retrospective, observational, and propensity-matched cohort study utilized the Premier Healthcare Database. The study included adults ≥18 years of age undergoing total hip or total knee replacement as inpatients who received an opioid analgesic and were discharged between January 1, 2012, and June 30, 2015. Diagnosis codes identified patients with OIC who were then matched 1:1 to patients without OIC. Generalized linear and logistic regression models were used to compare inpatient resource utilization, total hospital costs, inpatient mortality, and 30-day all-cause readmissions and emergency department visits. RESULTS: Of 788,448 eligible patients, 40,891 (5.2%) had OIC. Covariates were well balanced between matched patients with and without OIC (n=40,890 each). In adjusted analyses, patients with OIC had longer hospital lengths of stay (3.6 versus 3.3 days; p<0.001), higher total hospital costs (US$17,479 versus US$16,265; p<0.001), greater risk of intensive care unit admission (odds ratio [OR]=1.12, 95% CI: 1.01-1.24), and increased likelihood of 30-day hospital read-missions (OR=1.16, 95% CI: 1.11-1.22) and emergency department visits (OR=1.38, 95% CI: 1.07-1.79) than patients without OIC. No statistically significant difference was found with inpatient mortality (OR=0.89, 95% CI: 0.59-1.35). CONCLUSION: OIC was associated with greater resource utilization and hospital costs for patients undergoing primarily elective total hip or total knee replacement surgery. These results support OIC screening and management strategies as part of perioperative care management.

Association of Opioids and Sedatives with Increased Risk of In-Hospital Cardiopulmonary Arrest from an Administrative Database.

BACKGROUND: While opioid use confers a known risk for respiratory depression, the incremental risk of in-hospital cardiopulmonary arrest, respiratory arrest, or cardiopulmonary resuscitation (CPRA) has not been studied. Our aim was to investigate the prevalence, outcomes, and risk profile of in-hospital CPRA for patients receiving opioids and medications with central nervous system sedating side effects (sedatives). METHODS: A retrospective analysis of adult inpatient discharges from 2008-2012 reported in the Premier Database. Patients were grouped into four mutually exclusive categories: (1) opioids and sedatives, (2) opioids only, (3) sedatives only, and (4) neither opioids nor sedatives. RESULTS: Among 21,276,691 inpatient discharges, 53% received opioids with or without sedatives. A total of 96,554 patients suffered CPRA (0.92 per 1000 hospital bed-days). Patients who received opioids and sedatives had an adjusted odds ratio for CPRA of 3.47 (95% CI: 3.40-3.54; p<0.0001) compared with patients not receiving opioids or sedatives. Opioids alone and sedatives alone were associated with a 1.81-fold and a 1.82-fold (p<0.0001 for both) increase in the odds of CPRA, respectively. In opioid patients, locations of CPRA were intensive care (54%), general care floor (25%), and stepdown units (15%). Only 42% of patients survived CPRA and only 22% were discharged home. Opioid patients with CPRA had mean increased hospital lengths of stay of 7.57 days and mean increased total hospital costs of $27,569. CONCLUSIONS: Opioids and sedatives are independent and additive risk factors for in-hospital CPRA. The impact of opioid sparing analgesia, reduced sedative use, and better monitoring on CPRA incidence deserves further study.

Perioperative clinical and economic outcomes associated with replacing first-generation high molecular weight hydroxyethyl starch (Hextend®) with low molecular weight hydroxyethyl starch (Voluven®) at a large medical center.

BACKGROUND: Several plasma volume expander alternatives exist to enhance intravascular volume status in patients undergoing surgery. The optimal intravascular volume expander in the perioperative setting is currently unknown. Low molecular weight hetastarch, Voluven® (130/0.4), may have a better safety profile than high molecular weight hetastarch, Hextend® (450/0.7). We examined the clinical and cost outcomes of converting from Hextend® to Voluven® in a large tertiary medical center. METHODS: Using a large electronic database, we retrospectively compared two different time periods (2009 and 2010) where the availability of semisynthetic colloids changed. Perioperative and postoperative outcomes including the use of red blood cells (RBC), platelets and coagulation factors, length of stay in the postoperative acute care unit (PACU), intensive care unit and hospital, as well as 30-day and 1-year mortality were compared. In addition, direct acquisition costs of all intraoperative and PACU colloids and crystalloid use were determined. RESULTS: A total of 4,888 adult subjects were compared of which 1,878 received Hextend® (pre-conversion) and 2,759 received Voluven® (post-conversion) during two separate 7-month periods within 1 year apart, with the remainder receiving Plasmanate. The patients were similar in terms of patient demographics, preoperative comorbidities, ASA status, emergency surgery, types of surgery, intraoperative, and PACU times. In unadjusted outcomes, patients in the Hextend® group received more lactated Ringer's than in the Voluven® group (2,220 + 1,312 vs. 1,946 ± 1,097 ml; P < 0.0001). The use of albumin (Plasmanate) was reduced from 10.5% of patients to 1.1% when Voluven® was substituted for Hextend®. Unadjusted outcomes were similar in each group including hospital LOS, percent change from baseline creatinine and receipt of intraoperative and PACU blood product administration. However, overall unadjusted total fluid costs were greater in the Voluven® compared to Hextend® group ($116.7 compared to $59.3; P < 0.001). CONCLUSIONS: Conversion from Hextend® to Voluven® in the perioperative period resulted in decreased albumin use and was not associated with changes in clinical outcomes and short- and long-term mortality. The conversion was associated with decreases in crystalloid use and an increase in colloid use and hence IV fluid acquisition costs in the Voluven® group.

Impact of postsurgical opioid use and ileus on economic outcomes in gastrointestinal surgeries.

OBJECTIVES: To assess the incidence and economic impact of postoperative ileus (POI) following laparotomy (open) and laparoscopic procedures for colectomies and cholecystectomies in patients receiving postoperative pain management with opioids. METHODS: Using the Premier research database, we retrospectively identified adult inpatients discharged between 2008 and 2010 receiving postsurgical opioids following laparotomy and laparoscopic colectomy and cholecystectomy. POI was identified through ICD-9 diagnosis codes and postsurgical morphine equivalent dose (MED) determined. RESULTS: A total of 138,068 patients met criteria, and 10.3% had an ileus. Ileus occurred more frequently in colectomy than cholecystectomy and more often when performed by laparotomy. Ileus patients receiving opioids had an increased length of stay (LOS) ranging from 4.8 to 5.7 days, total cost from $9945 to $13,055 and 30 day all-cause readmission rate of 2.3 to 5.3% higher compared to patients without ileus. Patients with ileus received significantly greater MED than those without (median: 285 vs. 95 mg, p < 0.0001) and were twice as likely to have POI. MED above the median in ileus patients was associated with an increase in LOS (3.8 to 7.1 days), total cost ($8458 to $19,562), and readmission in laparoscopic surgeries (4.8 to 5.2%). Readmission rates were similar in ileus patients undergoing open procedures regardless of MED. CONCLUSIONS: Use of opioids in patients who develop ileus following abdominal surgeries is associated with prolonged hospitalization, greater costs, and increased readmissions. Furthermore, higher doses of opioids are associated with higher incidence of POI. Limitations are related to the retrospective design and the use of administrative data (including reliance on ICD-9 coding). Yet POI may not be coded and therefore underestimated in our study. Assessment of pre-existing disease and preoperative pain management was not assessed. Despite these limitations, strategies to reduce opioid consumption may improve healthcare outcomes and reduce the associated economic impact.

Cardiac output monitoring: a contemporary assessment and review.

OBJECTIVE: An increasing number of minimally or noninvasive devices are available to measure cardiac output in the critical care setting. This article reviews the underlying physical principles of these devices in addition to examining both animal and human comparative studies in an effort to allow clinicians to make informed decisions when selecting a device to measure cardiac output. DATA SOURCES: Peer-reviewed manuscripts indexed in PubMed. STUDY SELECTION: A systematic search of the PubMed database for articles describing the use of cardiac output monitors yielded 1,526 sources that were included in the analysis. DATA EXTRACTION: From all published cardiac output monitoring studies reviewed, the animal model, number of independent measurements, and correlation between techniques was extracted. DATA SYNTHESIS: Comparative studies in animals and humans between devices designed for measurement of cardiac output and experimental reference standards indicate thermodilution and Doppler-based techniques to have acceptable accuracy across a wide range of hemodynamic conditions, with bioimpedance techniques being less accurate. Thermodilution devices are marginally more accurate than Doppler-based devices but suffer from slower response time, increased invasiveness, and require stable core temperatures, good operator technique, and a competent tricuspid valve. Doppler-based techniques are less invasive and offer beat-to-beat measurements and excellent trending ability, but are dependent on accurate beam alignment and knowledge of aortic cross-sectional area. Studies of newer devices, such as pulse contour analysis, partial rebreathing, and pulse wave velocity, are far less in number and are primarily based on comparisons with thermodilution-based cardiac output measurements. Studies show widely ranging results. CONCLUSION: Thermodilution is relatively accurate for cardiac output measurements in both animals and humans when compared to experimental reference standards. Doppler-based techniques appear to have similar accuracy as thermodilution pulmonary artery catheters. Bioimpedance, pulse contour, partial rebreathing, and pulse wave velocity-based devices have not been studied as rigorously; however, the majority of studies included in this analysis point towards decreased accuracy.

Reduced length of hospital stay in colorectal surgery after implementation of an enhanced recovery protocol.

BACKGROUND: Enhanced recovery after surgery (ERAS) is a multimodal approach to perioperative care that combines a range of interventions to enable early mobilization and feeding after surgery. We investigated the feasibility, clinical effectiveness, and cost savings of an ERAS program at a major U. S. teaching hospital. METHODS: Data were collected from consecutive patients undergoing open or laparoscopic colorectal surgery during 2 time periods, before and after implementation of an ERAS protocol. Data collected included patient demographics, operative, and perioperative surgical and anesthesia data, need for analgesics, complications, inpatient medical costs, and 30-day readmission rates. RESULTS: There were 99 patients in the traditional care group, and 142 in the ERAS group. The median length of stay (LOS) was 5 days in the ERAS group compared with 7 days in the traditional group (P < 0.001). The reduction in LOS was significant for both open procedures (median 6 vs 7 days, P = 0.01), and laparoscopic procedures (4 vs 6 days, P < 0.0001). ERAS patients had fewer urinary tract infections (13% vs 24%, P = 0.03). Readmission rates were lower in ERAS patients (9.8% vs 20.2%, P = 0.02). DISCUSSION: Implementation of an enhanced recovery protocol for colorectal surgery at a tertiary medical center was associated with a significantly reduced LOS and incidence of urinary tract infection. This is consistent with that of other studies in the literature and suggests that enhanced recovery programs could be implemented successfully and should be considered in U.S. hospitals.

Effect of opioid-related adverse events on outcomes in selected surgical patients.

PURPOSE: This retrospective study utilized a large, national hospital database to assess the impact of opioid-related adverse events (ORADE) on patient outcomes following selected surgical procedures known to require postoperative pain control. METHODS: Outcomes of patients with administratively documented ORADE were compared to those without. Multivariate regression determined differences in hospital costs; length of stay (LOS); odds of individuals being an outlier in total cost and LOS; and having a 30-day all-cause readmission. RESULTS: Among 319,898 surgeries of interest, 12.2% of patients experienced an ORADE. Patients had higher adjusted mean costs ($22,077 [95% CI 21,823-22,333] vs. $17,370 [95% CI 17,238-17,503]; p < 0.0001) and greater LOS (7.6 [95% CI 7.5-7.6] vs. 4.2 days [95% CI 4.2-4.2]; p <0.0001). Adjusted odds of being a total cost and LOS outlier were 2.8 (95% CI 2.7-2.8) and 3.2 (95% CI 3.1-3.3) times greater in the ORADE group. These patients were more likely to be readmitted (OR 1.06, 95% CI 1.02-1.09). CONCLUSIONS: Patients exhibiting a documented ORADE had greater overall costs, longer hospitalizations, and increased likelihood for readmission. These results highlight the economic impact associated with opioid use for postsurgical pain management.

How much are patients willing to pay to avoid postoperative muscle pain associated with succinylcholine?

STUDY OBJECTIVE: To determine how much money patients are willing to pay to avoid postoperative muscle pains associated with succinylcholine. DESIGN: Observational study with survey instrument. SETTING: University-affiliated metropolitan hospital. PATIENTS: Eighty-eight adult patients, 43 men and 45 women, who were scheduled to undergo surgery with general anesthesia and who completed a preoperative questionnaire (median age range, 41-50 y; median income, US$45,000-60,000). INTERVENTIONS AND MEASUREMENTS: Patients completed a computerized, interactive questionnaire preoperatively. They were asked about demographics and previous experiences with muscle pain and postoperative myalgia. With the use of the willingness-to-pay model, the value that they would be willing to pay for a hypothetical muscle relaxant that avoided postoperative myalgia was determined. MAIN RESULTS: Eighty-nine percent of patients considered avoiding postoperative myalgia as important. Patients were willing to pay a median (interquartile range) of $33 ($19-$50) out of pocket for a muscle relaxant that was not associated with postoperative myalgia, a figure that increased to $40 if the insurance company paid for the drug (P < 0.0001). Willingness to pay was influenced by patients' income but not by prior experience with postoperative myalgia. CONCLUSION: Patients consider avoidance of postoperative myalgia important and are willing to pay $33 out of pocket for a muscle relaxant that is not associated with this side effect.

Postoperative nausea and vomiting following inpatient surgeries in a teaching hospital: a retrospective database analysis.

OBJECTIVE: To report the incidence of postoperative nausea and vomiting (PONV), to describe the use of anti-emetics both for the prophylaxis and treatment of PONV, and to assess resource utilization and duration of post-anesthesia care unit (PACU) stay. RESEARCH DESIGN AND METHODS: We retrieved data from the Duke Anesthesia Peri-operative database. We included adult patients, who underwent inpatient surgery under general anesthesia with inhaled agents between January 2004 and February 2005, and had two or more risk factors for PONV documented preoperatively (female, previous history of PONV or motion sickness, non-smoker or use of postoperative opioid). Data on the use of prophylactic anti-emetics, the incidence of PONV, nausea scores, pain scores, and the use of rescue anti-emetics in PACU and in the period between PACU discharge and 24 h after surgery were recorded. Resource utilization and cost assessment was performed from the perspective of the hospital and included length and direct cost of PACU stay, as well as the acquisition costs of rescue anti-emetics in PACU. Descriptive statistics were used to summarize the demographic characteristics of patients. For group comparisons, data were analyzed with the t-test for continuous data, and the Chi-square test for categorical data. Multiple linear regression models were used to evaluate the association between PONV and PACU length of stay adjusting for confounding factors. RESULTS: A total of 3641 patients were included in the analysis. Of those, 2869 (79%) received prophylactic anti-emetics. In the PACU, nausea and vomiting were reported in 16% and 3% of the patients, respectively. Rescue anti-emetics were given to 26% of all patients. The incidence of vomiting was significantly less in patients who received PONV prophylaxis (p = 0.03). In multiple linear regression models, the duration of PACU stay was longer by a mean of 25 min in patients who experienced PONV or received rescue anti-emetics in PACU (p < 0.0001) despite the fact that the duration of surgery was shorter by a mean of 24 min in this group of patients (p < 0.0001). Following PACU discharge, 40% of patients reported nausea, vomiting or needed rescue anti-emetics. PONV was associated with significantly increased resource utilization and costs of PACU stay (p < 0.0001). Emesis was associated with greater incremental cost (138 US dollars) than nausea (85 US dollars), mainly from the longer duration of PACU stay. CONCLUSIONS: PONV remain a significant problem postoperatively and often persists beyond PACU discharge. The presence of PONV is associated with increased length of PACU stay and greater resource utilization and costs.

Evidence-based management of postoperative nausea and vomiting: a review.

PURPOSE: To provide evidence-based guidelines for the prophylaxis and treatment of postoperative nausea and vomiting (PONV). SOURCE: Literature from randomized controlled trials, systematic reviews, logistic regression analyses and expert opinion in the management of PONV. PRINCIPAL FINDINGS: The etiology of PONV is multifactorial. Patient, anesthesia, and surgery related risk factors have been identified. Universal PONV prophylaxis is not cost-effective. Identification of patients at high-risk of PONV allows targeting prophylaxis to those who will benefit most from it. No prophylaxis is needed for patients at low risk for PONV. For patients at moderate risk for PONV, prophylaxis using a single antiemetic or a combination of two agents should be considered. Double and triple antiemetic combinations should be considered for patients at high risk for PONV. Furthermore, a multimodal approach should be adopted incorporating steps to keep the baseline risk of PONV low. The optimum cost-effective approach to the management of PONV will differ between an ambulatory centre and an inpatient hospital setting. For the treatment of established PONV in patients who failed prophylaxis, patients should not receive a repeat dose of the prophylactic antiemetic. Rather, a drug acting at a different receptor should be used. Beyond six hours after surgery, patients can be treated with any of the agents used for prophylaxis, except dexamethasone and transdermal scopolamine. CONCLUSION: PONV are common after anesthesia and surgery. We provided evidence-based guidelines for the management of this problem based on the available literature.

Pharmacotherapy of postoperative nausea and vomiting.

Postoperative nausea and vomiting (PONV) are two of the most common and unpleasant side effects following anaesthesia and surgery. Despite the development of new anti-emetics and a vast amount of published research, PONV continues to be a problem, especially in high-risk patients. Recent interest has focused on the use of a combination of agents, acting on different receptors and the adoption of a multimodal approach to tackle this problem. The search for the most cost-effective strategy has also been a major goal. This article will discuss the risk factors and physiology of PONV, currently available therapies, the use of a multimodal approach and the cost-effectiveness of PONV management. Finally, recommendations for the prophylaxis and treatment of PONV will be discussed.

How much are patients willing to pay to avoid intraoperative awareness?

STUDY OBJECTIVE: To determine how much patients are willing to pay to avoid intraoperative awareness? DESIGN: Observational study SETTING: University-affiliated metropolitan hospital. PATIENTS: 60 patients who completed a questionnaire (39 F, 21 M). The mean age was 43 years and the median household income range of 45,000-60,000 US dollars. INTERVENTIONS: Patients completed an interactive computer-generated questionnaire on the value of preventing intraoperative awareness and their willingness to pay for a "depth of anesthesia" monitor. Their willingness to pay for the prevention of postoperative pain, nausea and vomiting, postoperative grogginess, and sleepiness was also determined as a means of comparison. MEASUREMENTS AND MAIN RESULTS: Patients were willing to pay (WTP) 34 US dollars, 10 US dollars to 42 US dollars (median, interquartile range) for a monitor that would assist an anesthesia care provider assess the depth of anesthesia in an effort to avoid awareness. This increased to 43 US dollars, 20 US dollars to 77 US dollars (p < 0.0,001) (median, interquartile range), if the insurance company was making the payment and the WTP value only decreased minimally to 33 US dollars if the incidence of awareness was reduced 10-fold. CONCLUSION: The incidence of intraoperative awareness and WTP value for monitoring awareness have a nonlinear relationship (a risk averse utility function), which suggests that patients assign an intrinsic base value for a rare or very rare possibility of an event. Other healthcare economic analyses (such as cost effectiveness) do not take this factor into account and assume a linear value relationship (i.e., if something occurs ten times less frequently, it has ten times less value). IMPLICATION: The median value for patients' WTP for a monitor that might prevent awareness under anesthesia was 34 US dollars given an incidence of 5/1,000 cases. The incidence of awareness and WTP value have a nonlinear relationship suggesting that patients assign an intrinsic base value for the possibility of awareness.