Safety and Efficacy of Vocacapsaicin for Management of Postsurgical Pain: A Randomized Clinical Trial.

BACKGROUND: Nonopioid management of postsurgical pain remains a major unmet need. Few studies have evaluated TRPV1 agonists for analgesia after surgery. We studied intraoperative vocacapsaicin, a novel prodrug of the TRPV1 agonist capsaicin, in a validated model of postsurgical pain. METHODS: This was a triple-blinded, randomized, placebo-controlled, dose-ranging trial in patients undergoing bunionectomy. We randomized patients 1:1:1:1 to surgical site administration of 14 mL of placebo or one of three vocacapsaicin concentrations: 0.30, 0.15, or 0.05 mg/mL. The prespecified primary endpoint was the area-under-the-curve of the Numerical Rating Scale (NRS) pain score at rest through 96 hours for the 0.3 mg/mL group. Prespecified ordered, secondary endpoints for the 0.3 mg/mL group included percent of patients who did not require opioids from 0-96 hours, total opioid consumption through 96 hours, and the area-under-the-curve of the NRS pain score for the first week. RESULTS: We randomized 147 patients. During the first 96 hours, vocacapsaicin 0.30 mg/mL reduced pain at rest by 33% vs. placebo (primary endpoint, 95% CI [10%, 52%], effect size (Cohen's D) = 0.61, p = 0.005). Twenty-six percent of patients receiving vocacapsaicin 0.30 mg/mL did not require postoperative opioids for analgesia (p=0.025) vs. 5% of patients receiving placebo. Vocacapsaicin 0.30 mg/mL reduced opioid consumption over the first 96 hours by 50% vs. placebo (95% CI [26%, 67%], effect size = 0.76, p = 0.002). Vocacapsaicin 0.30 mg/mL reduced pain over the first week by 37% vs. placebo (95% CI [12%, 57%], effect size = 0.62, p = 0.004). Treatment effect persisted for at least 2 weeks. All study endpoints showed an administered concentration vs. response relationship. Vocacapsaicin was well-tolerated with no differences between groups in any safety parameter. CONCLUSIONS: A single, local administration of vocacapsaicin during surgery reduced pain and opioid consumption for at least 96 hours after surgery compared to control. TRIAL REGISTRATION: ClinicalTrials.gov NCT03599089.

Outpatient Treatment With Gabapentin in Women With Severe Acute Pain After Cesarean Delivery Is Ineffective: A Randomized, Double-Blind, Placebo-Controlled Trial.

BACKGROUND: Most of the 1.1 million women who deliver by cesarean in the United States each year have an uncomplicated recovery. However, severe pain resistant to standard multimodal therapy within the first days after surgery is associated with an increased risk for prolonged pain and opioid use. The best outpatient management for parturients with severe resistant early onset pain is not known. METHODS: We performed a prospective, double-blind, placebo-controlled, randomized trial of up to 12 weeks of outpatient treatment with gabapentin to evaluate its effectiveness to facilitate opioid cessation in women with at least 2 reports of severe pain during the immediate postpartum period resistant to standard multimodal pain management. Time to opioid cessation was the primary outcome. Time to pain resolution; time to discontinuation of gabapentin, acetaminophen, and ibuprofen; time to self-reported recovery; and National Institute of Health Patient-Reported Outcomes System (PROMIS) surveys for anxiety, depression, fatigue, and physical function were assessed as secondary outcomes. RESULTS: There was no difference in time to opioid cessation between patients who were randomly assigned to be treated with gabapentin (Kaplan-Meier estimated median of 2 [25th-75th percentiles of 1-3] weeks, n = 35) versus those who were treated with placebo (2 [1-3] weeks, n = 35). The hazard ratio was 1.1 (95% confidence interval [CI], 0.67-1.8), P = .65. There were no differences in any secondary end points between the study groups. CONCLUSIONS: Outpatient supplementation with gabapentin did not reduce time to opioid cessation, pain, anxiety, depression, fatigue, or improve physical function in women with severe pain after cesarean delivery. Gabapentin should not be routinely added to the standard outpatient multimodal regimen of ibuprofen, acetaminophen, and opioids.

The Effect of Night Float Rotation on Resident Sleep, Activity, and Well-Being.

BACKGROUND: Night float call systems are becoming increasingly common at training programs with the goal of reducing fatigue related to sleep deprivation and sleep disturbance. Previous studies have shown that trainees obtain less sleep during the night float rotation and have decreased sleep efficiency for several days after the rotation. The impact on physical and emotional well-being has not been documented. METHODS: Twenty-seven anesthesia residents were enrolled in a study using wearable sleep and activity trackers and National Institutes of Health Patient-Reported Outcome Measurement Information System (NIH PROMIS) surveys for sleep disturbance, fatigue, and positive affect to record data the week before ("baseline"), during ("night float"), and 1 week after ("recovery") their night float rotation. Each subject's data during the night float week and recovery week were compared to his or her own baseline week data using a paired, nonparametric analysis. The primary outcome variable was the change in average daily sleep hours during the night float week compared to the baseline week. Average daily rapid eye movement (REM) sleep, daily steps, and NIH PROMIS scores comparing night float and recovery weeks to baseline week were prespecified secondary outcomes. NIH PROMIS scores range from 0 to 100 with 50 as the national mean and more of the construct having a higher score. RESULTS: There was no difference in average daily sleep hours between the night float and the baseline weeks (6.7 [5.9-7.8] vs 6.7 [5.5-7.7] hours, median [interquartile range]; P = .20). Residents had less REM sleep during the night float compared to the baseline weeks (1.1 [0.7-1.5] vs 1.4 [1.1-1.9] hours, P = .002). NIH PROMIS fatigue scores were higher during the night float than the baseline week (58.8 [54.6-65.1] vs 48.6 [46.0-55.1], P = .0004) and did not return to baseline during the recovery week (51.0 [48.6-58.8], P = .029 compared to baseline). Sleep disturbance was not different among the weeks. Positive affect was reduced after night float compared to baseline (39.6 [35.0-43.5] vs 44.8 [40.1-49.6], P = .0009), but returned to baseline during the recovery week (43.6 [39.6-48.2], P = .38). CONCLUSIONS: The residents slept the same number of total hours during their night float week but had less REM sleep, were more fatigued, and had less positive affect. All of these resolved to baseline except fatigue, that was still greater than the baseline week. This methodology appears to robustly capture psychophysiological data that might be useful for quality initiatives.

Design of Clinical Trials Evaluating Sedation in Critically Ill Adults Undergoing Mechanical Ventilation: Recommendations From Sedation Consortium on Endpoints and Procedures for Treatment, Education, and Research (SCEPTER) Recommendation III.

OBJECTIVES: Clinical trials evaluating the safety and effectiveness of sedative medication use in critically ill adults undergoing mechanical ventilation differ considerably in their methodological approach. This heterogeneity impedes the ability to compare results across studies. The Sedation Consortium on Endpoints and Procedures for Treatment, Education, and Research Recommendations convened a meeting of multidisciplinary experts to develop recommendations for key methodologic elements of sedation trials in the ICU to help guide academic and industry clinical investigators. DESIGN: A 2-day in-person meeting was held in Washington, DC, on March 28-29, 2019, followed by a three-round, online modified Delphi consensus process. PARTICIPANTS: Thirty-six participants from academia, industry, and the Food and Drug Administration with expertise in relevant content areas, including two former ICU patients attended the in-person meeting, and the majority completed an online follow-up survey and participated in the modified Delphi process. MEASUREMENTS AND MAIN RESULTS: The final recommendations were iteratively refined based on the survey results, participants' reactions to those results, summaries written by panel moderators, and a review of the meeting transcripts made from audio recordings. Fifteen recommendations were developed for study design and conduct, subject enrollment, outcomes, and measurement instruments. Consensus recommendations included obtaining input from ICU survivors and/or their families, ensuring adequate training for personnel using validated instruments for assessments of sedation, pain, and delirium in the ICU environment, and the need for methodological standardization. CONCLUSIONS: These recommendations are intended to assist researchers in the design, conduct, selection of endpoints, and reporting of clinical trials involving sedative medications and/or sedation protocols for adult ICU patients who require mechanical ventilation. These recommendations should be viewed as a starting point to improve clinical trials and help reduce methodological heterogeneity in future clinical trials.

Non-steady State Modeling of the Ventilatory Depressant Effect of Remifentanil in Awake Patients Experiencing Moderate-to-severe Obstructive Sleep Apnea.

BACKGROUND: Evidence suggests that obstructive sleep apnea promotes postoperative pulmonary complications by enhancing vulnerability to opioid-induced ventilatory depression. We hypothesized that patients with moderate-to-severe obstructive sleep apnea are more sensitive to remifentanil-induced ventilatory depression than controls. METHODS: After institutional approval and written informed consent, patients received a brief remifentanil infusion during continuous monitoring of ventilation. We compared minute ventilation in 30 patients with moderate-to-severe obstructive sleep apnea diagnosed by polysomnography and 20 controls with no to mild obstructive sleep apnea per polysomnography. Effect site concentrations were estimated by a published pharmacologic model. We modeled minute ventilation as a function of effect site concentration and the estimated carbon dioxide. Obstructive sleep apnea status, body mass index, sex, age, use of continuous positive airway pressure, apnea/hypopnea events per hour of sleep, and minimum nocturnal oxygen saturation measured by pulse oximetry in polysomnography were tested as covariates for remifentanil effect site concentration at half-maximal depression of minute ventilation (Ce50) and included in the model if a threshold of 6.63 (P < 0.01) in the reduction of objective function was reached and improved model fit. RESULTS: Our model described the observed minute ventilation with reasonable accuracy (22% median absolute error). We estimated a remifentanil Ce50 of 2.20 ng · ml (95% CI, 2.09 to 2.33). The estimated value for Ce50 was 2.1 ng · ml (95% CI, 1.9 to 2.3) in patients without obstructive sleep apnea and 2.3 ng · ml (95% CI, 2.2 to 2.5) in patients with obstructive sleep apnea, a statistically nonsignificant difference (P = 0.081). None of the tested covariates demonstrated a significant effect on Ce50. Likelihood profiling with the model including obstructive sleep apnea suggested that the effect of obstructive sleep apnea on remifentanil Ce50 was less than 5%. CONCLUSIONS: Obstructive sleep apnea status, apnea/hypopnea events per hour of sleep, or minimum nocturnal oxygen saturation measured by pulse oximetry did not influence the sensitivity to remifentanil-induced ventilatory depression in awake patients receiving a remifentanil infusion of 0.2 µg · kg of ideal body weight per minute.