Low Incidence of Opioid-Induced Respiratory Depression Observed with Oliceridine Regardless of Age or Body Mass Index: Exploratory Analysis from a Phase 3 Open-Label Trial in Postsurgical Pain.

INTRODUCTION: Advanced age and obesity are reported to increase the risk of opioid-induced respiratory depression (OIRD). Oliceridine, an intravenous opioid, is a G-protein-biased agonist at the µ-opioid receptor that may provide improved safety. The recent phase 3 ATHENA open-label, multicenter study evaluated postoperative use of oliceridine in patients with moderate-to-severe acute pain. This exploratory analysis of the ATHENA data examined the incidence of OIRD in older (≥ 65 years) and/or obese (BMI ≥ 30 kg/m2) patients and analyzed risk factors of OIRD. METHODS: Patients aged ≥ 18 years with a score ≥ 4 on an 11-point numeric pain rating scale (NPRS) received IV oliceridine as needed via bolus dosing and/or patient-controlled analgesia (PCA). OIRD occurring within 48 h of last dose of oliceridine was defined using two established definitions: (1) naloxone use, (2) respiratory rate < 10 breaths per minute and/or oxygen saturation < 90%. RESULTS: A total of 724 surgical patients with a mean age of 54.5 ± 15.9 years and a mean NRS score of 6.2 ± 2.1 were included in this analysis; 33.3% (241/724) were ≥ 65 years of age and 46.3% (335/724) had BMI (body mass index) ≥ 30 kg/m2. The overall OIRD incidence was 13.7% with no patients requiring naloxone. The OIRD incidence was similar in the elderly and younger adults' cohorts [10.8 vs. 15.1%, OR 0.68 (0.42, 1.1), p = 0.11], and in obese and non-obese groups [14.0 vs. 13.4%, OR 1.06 (0.69, 1.62), p = 0.80]. In patients that were both elderly and obese (n = 120), the incidence was 10.8%. The multivariate analysis identified baseline NRS ≥ 6 [OR 1.6 (1.0, 2.4), p = 0.0499], PCA administration [OR 1.9 (1.2, 3.1), p = 0.005], and concomitant use of benzodiazepines and/or gabapentinoids [OR 1.6 (1.0, 2.6), p = 0.045], as being associated with OIRD. CONCLUSIONS: Postoperative oliceridine use in patients with advanced age and/or increased BMI was not associated with increased risk of OIRD.

ATHENA: A Phase 3, Open-Label Study Of The Safety And Effectiveness Of Oliceridine (TRV130), A G-Protein Selective Agonist At The µ-Opioid Receptor, In Patients With Moderate To Severe Acute Pain Requiring Parenteral Opioid Therapy.

BACKGROUND: Pain management with conventional opioids can be challenging due to dose-limiting adverse events (AEs), some of which may be related to the simultaneous activation of ß-arrestin (a signaling pathway associated with opioid-related AEs) and G-protein pathways. The investigational analgesic oliceridine is a G-protein-selective agonist at the µ-opioid receptor with less recruitment of ß-arrestin. The objective of this phase 3, open-label, multi-center study was to evaluate the safety and tolerability, of IV oliceridine for moderate to severe acute pain in a broad, real-world patient population, including postoperative surgical patients and non-surgical patients with painful medical conditions. METHODS: Adult patients with a score ≥4 on 11-point NRS for pain intensity received IV oliceridine either by bolus or PCA; multimodal analgesia was permitted. Safety was assessed using AE reports, study discontinuations, clinical laboratory and vital sign measures. RESULTS: A total of 768 patients received oliceridine. The mean age (SD) was 54.1 (16.1) years, with 32% ≥65 years of age. Most patients were female (65%) and Caucasian (78%). Surgical patients comprised the majority of the study population (94%), most common being orthopedic (30%), colorectal (15%) or gynecologic (15%) procedures. Multimodal analgesia was administered to 84% of patients. Oliceridine provided a rapid reduction in NRS pain score by 2.2 ± 2.3 at 30 mins from a score of 6.3 ± 2.1 (at baseline) which was maintained to the end of treatment. No deaths or significant cardiorespiratory events were reported. The incidence of AEs leading to early discontinuation and serious AEs were 2% and 3%, respectively. Nausea (31%), constipation (11%), and vomiting (10%) were the most common AEs. AEs were mostly of mild (37%) or moderate (25%) severity and considered possibly or probably related to oliceridine in 33% of patients. CONCLUSION: Oliceridine IV for the management of moderate to severe acute pain was generally safe and well tolerated in the patients studied. CLINICALTRIALSGOV IDENTIFIER: NCT02656875.

Recovery of physical activity after cesarean delivery and its relationship with pain.

Pain and physical activity are tightly intertwined. Although their relationship has been explored in chronic pain conditions, we know little about the pattern of recovery in activity and its short- and long-term relationship with pain after surgery. We recruited 103 women undergoing elective cesarean delivery and acquired daily pain assessments and hourly steps in 98 of them for 2 months after surgery. Compliance was good, with 78% of subjects missing less than 7 days of activity. Study personnel required daily checking for compliance and 20 minutes per subject per week in study. Activity increased over the first 2 postoperative months in a log(time) manner. The slope of each modeled individual curve for activity was inversely correlated (r = -0.54; P < 0.0001) with worst daily pain. After removing these 2-month trends, pain and activity within an individual day were negatively associated with each point increase in pain being inversely associated with -119 steps (95% confidence interval [CI] = -214 to -25; P = 0.013). A patient's previous experience of pain was not associated with current activity as well as current activity was not associated with future pain scores. These data, although limited by the study of a single operation in a unique social circumstance with low risk of chronic postsurgical pain, demonstrate feasibility of measuring hourly activity for 2 months after surgery. Recovery from pain and inactivity are tightly correlated, and the negative relationship between within-day pain and activity without interday carryover relationships is in stark contrast to findings in chronic pain conditions.

Epidural Neostigmine versus Fentanyl to Decrease Bupivacaine Use in Patient-controlled Epidural Analgesia during Labor: A Randomized, Double-blind, Controlled Study.

BACKGROUND: The addition of opioids to epidural local anesthetic reduces local anesthetic consumption by 20% but at the expense of side effects and time spent for regulatory compliance paperwork. Epidural neostigmine also reduces local anesthetic use. The authors hypothesized that epidural bupivacaine with neostigmine would decrease total hourly bupivacaine use compared with epidural bupivacaine with fentanyl for patient-controlled epidural analgesia. METHODS: A total of 215 American Society of Anesthesiologists physical status II, laboring parturients requesting labor epidural analgesia consented to the study and were randomized to receive 0.125% bupivacaine with the addition of either fentanyl (2 µg/ml) or neostigmine (2, 4, or 8 µg/ml). The primary outcome was total hourly local anesthetic consumption, defined as total patient-controlled epidural analgesia use and top-ups (expressed as milliliters of 0.125% bupivacaine) divided by the infusion duration. A priori analysis determined a group size of 35 was needed to have 80% power at α = 0.05 to detect a 20% difference in the primary outcome. RESULTS: Of 215 subjects consented, 151 patients were evaluable. Demographics, maternal and fetal outcomes, and labor characteristics were similar among groups. Total hourly local anesthetic consumption did not differ among groups (P = 0.55). The total median hourly bupivacaine consumption in the fentanyl group was 16.0 ml/h compared with 15.3, 14.6, and 16.2 ml/h in the 2, 4, and 8 µg/ml neostigmine groups, respectively (P = 0.55). CONCLUSIONS: The data do not support any difference in bupivacaine requirements for labor patient-controlled epidural analgesia whether patients receive epidural bupivacaine with 2 to 8 µg/ml neostigmine or epidural bupivacaine with 2 µg/ml fentanyl.

Combined Spinal Epidural Technique for Labor Analgesia Does Not Delay Recognition of Epidural Catheter Failures: A Single-center Retrospective Cohort Survival Analysis.

BACKGROUND: It is unclear whether recognition of epidural catheter failures is delayed with combined spinal epidural technique (CSE) compared to traditional epidural technique (EPID) when used for labor analgesia. The authors hypothesized that recognition of failed catheters is not delayed by CSE. METHODS: Anesthetic, obstetric, and quality assurance records from 2,395 labor neuraxial procedures (1,440 CSE and 955 EPID) performed at Forsyth Medical Center (Winston-Salem, North Carolina) between June 30 and December 31, 2012, were retrospectively analyzed. The primary outcome was catheter survival (failure-free) time during labor analgesia. A proportional hazards model with the counting method was used to assess relationships between the techniques and survival (failure-free) time of catheters, while controlling for subjects' body mass index and providers' level of training in the final best-fit multivariable regression model. RESULTS: Cumulative incidence of epidural catheter failures was 6.6% for CSE and 11.6% for EPID (P = 0.001). In the multivariable regression model, catheters placed with CSE versus epidural were less likely to fail (hazard ratio, 0.58; 95% CI, 0.43 to 0.79; P = 0.0002) for labor analgesia. Among the catheters that failed, there was no overall difference in failure time course between the techniques (hazard ratio, 1.17; 95% CI, 0.89 to 1.54; P = 0.26) even though more failed catheters with CSE (48.4%) than with EPID (30.6%) were recognized within the first 30 min of placement (P = 0.009). CONCLUSIONS: In this cohort, CSE has a significantly lower risk of overall epidural catheter failures than EPID and does not delay recognition of epidural catheter failures. Choice of CSE versus EPID should be based on overall risk of failure, efficacy, and side effects.

A Randomized Controlled Trial Comparing Two Multimodal Analgesic Techniques in Patients Predicted to Have Severe Pain After Cesarean Delivery.

BACKGROUND: Improved pain control after cesarean delivery remains a challenging objective. Poorly treated acute pain following delivery is associated with an increased risk of chronic pain and depression. This study was conducted to determine whether the addition of systemic acetaminophen and an increased dose of intrathecal morphine would further reduce acute pain. The primary outcome was pain intensity with movement at 24 hours postoperatively. Secondary measures included persistent pain and depression at 8 weeks. METHODS: Seventy-four parturients scheduled for elective cesarean delivery under spinal anesthesia that were predicted to be above the 80th percentile for evoked pain intensity based on a 3-item preoperative screening questionnaire were enrolled. Patients in the intervention group received 300 mcg spinal morphine and 1 gram acetaminophen every 6 hours for 24 hours postoperatively. Patients in the control group received 150 mcg spinal morphine and placebo tablets. All patients received scheduled ibuprofen by mouth and IV morphine patient-controlled analgesia. At 24 hours, patients rated their pain intensity with movement, at rest, on average, and worst score using a visual analog scale for pain (100-mm unmarked line). The presence of persistent pain and depression was assessed at 8 weeks using the Edinburgh postpartum depression survey. RESULTS: Providing a higher dose of spinal morphine combined with systemic acetaminophen to patients predicted to be at high risk for severe post-cesarean delivery pain significantly reduced evoked pain scores with movement at 24 hours (mean ± SD: 46 ± 25 mm in control group versus 31 ±17 mm in intervention group, P = 0.009; 95% confidence interval for the difference between means: 4 mm, 26 mm). There was no difference in the incidence of persistent pain (13% (4/30) in control group versus 10% (3/30) in intervention group, P > 0.99), or depression at 8 weeks postoperatively (10% (3/30) in control group versus 13% (4/30) in intervention group, P > 0.99). CONCLUSIONS: Adding a higher dose of intrathecal morphine and oral acetaminophen to a multimodal pain regimen in patients predicted to be at risk for high acute postpartum pain after cesarean delivery results in a significant reduction of acute postoperative pain scores at 24 hours.

A randomized controlled comparison between combined spinal-epidural and single-shot spinal techniques in morbidly obese parturients undergoing cesarean delivery: time for initiation of anesthesia.

BACKGROUND: There is no current consensus on the optimal technique for subarachnoid anesthesia in morbidly obese parturients even though some providers prefer the combined spinal-epidural (CSE) over single-shot spinal (SSS) technique. In this randomized controlled study, we compared the time required for initiation of subarachnoid anesthesia between SSS and CSE techniques in morbidly obese parturients undergoing elective cesarean delivery. METHODS: Morbidly obese parturients presenting for elective cesarean delivery were randomized to receive subarachnoid anesthesia performed either with a SSS or a CSE technique. The spinal procedure in the sitting position was attempted by an experienced resident for up to 10 minutes, and if unsuccessful, the attending obstetric anesthesiologist assumed control of the procedure. The primary outcome was the time it took from the insertion of the introducer needle (SSS group) or insertion of the epidural needle (CSE group) to the end of intrathecal injection of drugs (procedure time). RESULTS: Forty-four patients were enrolled and completed the study. Three were excluded due to protocol violations. Of the remaining, 21 patients were in the SSS group and 20 in the CSE group. Demographic variables and mean (SD) body mass index (48.7 ± 7.6 kg/m for SSS; 49.9 ± 8.6 kg/m for CSE) were not different between groups. The median [interquartile range] for procedure time was 210 [116-692] seconds and 180 [75-450] seconds for SSS and CSE groups, respectively (P = 0.36), while the 95% confidence interval (CI) of the difference was -80 to +180 seconds. The first operator completed the procedure in <10 minutes in 71% of subjects in the SSS group and 95% of those in the CSE group (P = 0.09) and the 95% CI of the difference was -2% to +45%. There were more attempts to successful completion of the procedure in the SSS group (P = 0.007) with its 95% CI of the difference being +1 to +6. CONCLUSION: Our results suggest that the CSE technique is noninferior to the SS technique in morbidly obese parturients for time of initiation of subarachnoid anesthesia and may be accomplished with fewer attempts than the SSS technique with experienced residents.

Predicting acute pain after cesarean delivery using three simple questions.

BACKGROUND: Interindividual variability in postoperative pain presents a clinical challenge. Preoperative quantitative sensory testing is useful but time consuming in predicting postoperative pain intensity. The current study was conducted to develop and validate a predictive model of acute postcesarean pain using a simple three-item preoperative questionnaire. METHODS: A total of 200 women scheduled for elective cesarean delivery under subarachnoid anesthesia were enrolled (192 subjects analyzed). Patients were asked to rate the intensity of loudness of audio tones, their level of anxiety and anticipated pain, and analgesic need from surgery. Postoperatively, patients reported the intensity of evoked pain. Regression analysis was performed to generate a predictive model for pain from these measures. A validation cohort of 151 women was enrolled to test the reliability of the model (131 subjects analyzed). RESULTS: Responses from each of the three preoperative questions correlated moderately with 24-h evoked pain intensity (r = 0.24-0.33, P < 0.001). Audio tone rating added uniquely, but minimally, to the model and was not included in the predictive model. The multiple regression analysis yielded a statistically significant model (R = 0.20, P < 0.001), whereas the validation cohort showed reliably a very similar regression line (R = 0.18). In predicting the upper 20th percentile of evoked pain scores, the optimal cut point was 46.9 (z =0.24) such that sensitivity of 0.68 and specificity of 0.67 were as balanced as possible. CONCLUSIONS: This simple three-item questionnaire is useful to help predict postcesarean evoked pain intensity, and could be applied to further research and clinical application to tailor analgesic therapy to those who need it most.

Success of spinal and epidural labor analgesia: comparison of loss of resistance technique using air versus saline in combined spinal-epidural labor analgesia technique.

BACKGROUND: Comparison of air versus saline for loss of resistance technique (LORT) in combined spinal epidural labor analgesia (CSE) has not been evaluated, and neither has the relation between CSE characteristics (the presence/absence of initial spontaneous clear fluid return or upon aspiration) and spinal/epidural analgesia outcomes. The authors hypothesized that there is no difference in the spinal analgesia success or epidural catheter efficacy between using air versus saline LORT for CSE. METHODS: A total of 360 patients were randomized to air or saline LORT for CSE. Primary outcome was spinal analgesia success as defined by verbal pain score of no more than 3 at 15 min after spinal dose administration. Secondary outcomes were CSE characteristics, catheter replacement, and average hourly epidural drug consumption. RESULTS: Results from 345 patients were analyzed. Spinal analgesia success, epidural catheter replacement, and drug consumption were not different between using air or saline LORT and were also independent of the presence/absence of fluid return on aspiration if initial spontaneous fluid returned to the spinal needle. However, epidural catheters inserted in absence of initial fluid return had a significantly higher catheter replacement rate (28.6%) than the 4.1% among those with initial fluid return (P < 0.03). CONCLUSIONS: Spinal analgesia success rate and epidural efficacy are independent of whether air or saline is used for LORT during CSE. Practice of aspiration for fluid after observing initial fluid return may be unnecessary because this practice does not alter spinal/epidural analgesia outcomes. However, epidural catheters inserted with the absence of initial fluid returned to spinal needle may pose a high failure risk.

Neostigmine decreases bupivacaine use by patient-controlled epidural analgesia during labor: a randomized controlled study.

BACKGROUND: Intrathecal neostigmine not only produces analgesia but also severe nausea. In contrast, epidural neostigmine enhances opioid and local anesthetic analgesia without causing nausea. Previous studies examined only single epidural neostigmine bolus administration and did not assess the efficacy of continuous epidural infusion or several aspects of maternal and fetal safety. We therefore tested the hypothesis that epidural neostigmine in combination with bupivacaine by continuous infusion during labor would reduce the amount of bupivacaine required. METHODS: Twelve healthy women scheduled for elective cesarean delivery were assigned to receive epidural neostigmine, 40 microg (first six subjects) or 80 microg (second six subjects) as a single bolus, with fetal heart rate (FHR) and uterine contractions monitored for 20 min. In a subsequent experiment, 40 healthy laboring women were randomized to receive bupivacaine 1.25 mg/mL alone or with neostigmine 4 microg/mL by patient-controlled epidural analgesia. The primary outcome measure was hourly bupivacaine use. RESULTS: Epidural neostigmine bolus did not alter baseline FHR, induce contractions, or produce nausea. Epidural neostigmine infusion reduced bupivacaine requirement by 19% in all patients and 25% in those with >4 h of treatment (P < 0.05 for both) but might have contributed to the incidence of mild sedation. Mode of delivery, incidence of maternal nausea, and FHR abnormality were similar between groups. CONCLUSIONS: These data show that adding epidural neostigmine 4 microg/mL reduces the hourly bupivacaine requirement by 19%-25% with patient-controlled epidural analgesia during labor. Administered as a bolus and by continuous infusion at the studied doses, epidural neostigmine does not cause nausea and does not induce uterine contractions or FHR abnormalities, but mild sedation can occur.

Severity of acute pain after childbirth, but not type of delivery, predicts persistent pain and postpartum depression.

Cesarean delivery rates continue to increase, and surgery is associated with chronic pain, often co-existing with depression. Also, acute pain in the days after surgery is a strong predictor of chronic pain. Here we tested if mode of delivery or acute pain played a role in persistent pain and depression after childbirth. In this multicenter, prospective, longitudinal cohort study, 1288 women hospitalized for cesarean or vaginal delivery were enrolled. Data were obtained from patient interviews and medical record review within 36 h postpartum, then via telephone interviews 8 weeks later to assess persistent pain and postpartum depressive symptoms. The impact of delivery mode on acute postpartum pain, persistent pain and depressive symptoms and their interrelationships was assessed using regression analysis with propensity adjustment. The prevalence of severe acute pain within 36 h postpartum was 10.9%, while persistent pain and depression at 8 weeks postpartum were 9.8% and 11.2%, respectively. Severity of acute postpartum pain, but not mode of delivery, was independently related to the risk of persistent postpartum pain and depression. Women with severe acute postpartum pain had a 2.5-fold increased risk of persistent pain and a 3.0-fold increased risk of postpartum depression compared to those with mild postpartum pain. In summary, cesarean delivery does not increase the risk of persistent pain and postpartum depression. In contrast, the severity of the acute pain response to childbirth predicts persistent morbidity, suggesting the need to more carefully address pain treatment in the days following childbirth.

Antiemetic prophylaxis for postdischarge nausea and vomiting and impact on functional quality of living during recovery in patients with high emetic risks: a prospective, randomized, double-blind comparison of two prophylactic antiemetic regimens.

BACKGROUND: We compared two antiemetic prophylaxis regimens, their efficacy for preventing postdischarge nausea and vomiting, and their impact on quality of living, during recovery. METHODS: Sixty-four women undergoing outpatient gynecological surgery and at high risk for emesis were randomized into one of two groups. The study group received intraoperative IV dexamethasone 8 mg and ondansetron 4 mg, followed with an 8 mg oral disintegrating ondansetron tablet, to be taken on discharge and in the morning of postoperative days 1 and 2. The control group received only the IV ondansetron 4 mg intraoperatively. The incidence and severity of emetic symptoms and pain were assessed while patients were in the recovery room and via telephone and patient diary for 5 days after discharge. A modified functional living index of emesis was used to assess the impact on quality of living during recovery. RESULTS: Sixty patients, 30 in each group, completed the study. The incidences for postdischarge nausea were 57% and 20%, and for postdischarge vomiting 20% and 3% in the control and study groups, respectively, for the period between the 8th and 120th hours postanesthesia (P < 0.05). Thirty-three percent of the study and 60% of the control group reported that emetic symptoms negatively affected their quality of living (P < 0.05). CONCLUSIONS: When compared with a single dose of intraoperative IV ondansetron prophylaxis, our study regimen of additional intraoperative dexamethasone and once a day ondansetron significantly reduced the incidence of postdischarge nausea and vomiting and its negative impact on quality of living during the first 5 days of recovery.

Multifactorial preoperative predictors for postcesarean section pain and analgesic requirement.

BACKGROUND: The study aimed to determine predictive factors for postcesarean pain and analgesia using an assessment of pain threshold and suprathreshold thermal stimuli as well as degree of somatization and anxiety. METHODS: Thirty-four healthy parturients scheduled for cesarean delivery under subarachnoid anesthesia were enrolled. Preoperative thermal pain threshold, intensity, and unpleasantness to heat stimuli applied to arm and lower back, State Trait Anxiety Inventory, and patient expectation for postoperative pain and need for analgesia were assessed. After surgery, overall, resting, and movement pain and analgesic consumption were recorded. Prediction of pain and analgesic use outcomes was made by principal component factor analysis, followed by stepwise linear regression. RESULTS: Resting pain was predicted by two factors, thermal pain and unpleasantness and patient expectation (r2 = 0.26, P < 0.01), evoked pain by thermal pain threshold in the back (r2= 0.20, P < 0.009), composite pain by thermal pain and unpleasantness and preoperative blood pressure (r2 = 0.28, P < 0.008), intraoperative analgesic need by preexisting pain (r2 = 0.22, P < 0.006), recovery room analgesia by thermal pain threshold and State Trait Anxiety Inventory (r2 = 0.27, P < 0.01), and total analgesic need by State Trait Anxiety Inventory (r2 = 0.22, P < 0.01). These models predicted the upper twentieth percentile of composite pain scores and analgesic requirement with sensitivity of 0.71 to 0.80 and specificity of 0.76 to 0.80. CONCLUSIONS: The authors' results suggest a meaningful combination of preoperative patient responses from physical and psychological tests yields a valid multifactorial predictive model for postoperative pain and analgesic requirement with significant improvements over individual predictive variables.

Dural puncture with a 27-gauge Whitacre needle as part of a combined spinal-epidural technique does not improve labor epidural catheter function.

BACKGROUND: This prospective, double-blind, randomized study was designed to examine whether the combined spinal-epidural technique without subarachnoid drug administration improved epidural catheter function when compared with the traditional epidural technique. METHODS: After institutional review board approval and informed consent, 251 healthy laboring parturients were randomly assigned to either group DP (combined spinal-epidural technique with 27-gauge Whitacre needle dural puncture but without subarachnoid drug administration) or group NoDP (traditional epidural technique). Patient-controlled epidural analgesia was initiated with 0.11% bupivacaine and 2 microg/ml fentanyl. Top-up doses in 5-ml increments of 0.25% bupivacaine were administered if needed. Previous power analysis revealed that a sample size of 108 patients/group was needed to show a clinically useful reduction of the catheter manipulation rate from 32% to 15%. RESULTS: In groups DP and NoDP, 107 and 123 evaluable patients, respectively, completed the study. Demographics and outcome variables measured, including epidural catheter manipulation and replacement rate, sacral sparing, unilateral block, number of top-up doses, average hourly epidural drug usage, highest sensory blockade level, and labor analgesia quality, were not different between groups. A subgroup of 18 patients without cerebral spinal fluid return during dural puncture had a higher catheter replacement rate than those of groups DP and NoDP, but it did not reach statistical significance. CONCLUSIONS: Dural puncture with a 27-gauge Whitacre needle without subarachnoid drug administration during combined spinal-epidural labor analgesia did not improve epidural labor analgesia quality or reduce catheter manipulation or replacement rate when compared with a traditional epidural technique.