Pain, Postoperative
Conditions
Brief summary
The purpose of this study is to find out whether oral Naloxegol can reduce the side effects of opioid painkillers following surgery. This study aims to explore whether Naloxegol can similarly reduce opioid-induced side effects in post-surgical patients. About 130 surgery patients will participate in this study which is being conducted at Cleveland Clinic Main Campus.
Detailed description
Opioids are the gold standard for postoperative pain management, but they have been shown to produce uncomfortable side effects such as urinary retention (an inability to completely empty the bladder), constipation and nausea/vomiting. Clinical evidence demonstrates that Naloxegol can safely and effectively block these undesirable side effects while maintaining the painkilling effects of opioids in outpatients suffering from opioid-induced constipation.
Interventions
DRUGNaloxegol 25 MG
Oral Naloxegol 25 MG
DRUGPlacebo
matching oral placebo
Sponsors
The Cleveland Clinic
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Intervention model description
Effect of Naloxegol on reversing opioid-related side effects in patients recovering from elective primary hip surgery under spinal anesthesia who will be randomly assigned to oral Naloxegol or placebo for two postoperative days or until the date of discharge, whichever occurs earlier. The design will be a randomized, double-blind, placebo-controlled trial of oral Naloxegol in adults having elective primary hip or knee surgery under spinal anesthesia. The study will be performed at the Cleveland Clinic hospitals.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Provision of informed consent prior to any study specific procedures 2. Female or male aged at least 18 years 3. American Society of Anesthesiologists physical status 1-4; 4. Scheduled for elective primary hip or knee surgery under spinal anesthesia; 5. Expected to receive intravenous patient-controlled analgesia (IV PCA) 6. Expected to have significant postoperative pain 7. Negative pregnancy test
Exclusion criteria
1. Severe hepatic impairment, with/or twice the upper normal levels of liver enzymes 2. Severe renal impairment, or creatinine level \> 2.0 3. History of bladder cancer 4. Patients receiving perioperative regional anesthesia blocks 5. Presence of a sacral nerve stimulator 6. Medications (anticholinergic agents such as antihistamines, phenothiazines, antidepressants, antipsychotics), conditions or comorbidity causing urinary retention 7. Patient with requirement of urinary catheter insertion before or immediately post-surgery due to immobility 8. Urinary Tract Infections and other urogenital comorbidity (incontinence, cysto-ureteric reflux, known bladder retention) or conditions which can cause urinary retention 9. Severe peptic ulcer disease, diverticular disease, infiltrative gastrointestinal tract malignancies, or peritoneal metastases 10. Patients with known or suspected disruption of blood brain barrier, which may include but not limited to: Alzheimer's disease, stroke, poliomyelitis, cerebral palsy, multiple sclerosis, spinal lesions, and Parkinson's disease 11. Gastrointestinal obstruction/Gastrointestinal perforation 12. Strong CYP3A4 inhibitors (some antibiotics, antifungals, protease inhibitors, and antidepressants), Strong CYP3A4 inducers, Other opioid antagonists 13. Hypersensitivity to MOVANTIK (naloxegol) or any of its excipients
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Residual Urine Volume | from Postoperative days 1 to POD 2 or until day of discharge whichever occurs first | Residual urine volume in the bladder as assessed by bladder scan |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Side Effects of Naloxegol on Other Opioid Related Side Effects | Postoperative days 1-2 or until day of discharge whichever occurs first | Opioid-related Symptom Distress Scale (ORSDS) is a 4 point-scale that evaluates three symptom distress dimensions (frequency, severity, bothersomeness) for opioid-related side effects. The 12 elements of the ORSDS are nausea, vomiting, constipation, difficulty passing urine, difficulty concentrating, drowsiness, lightheaded, fatigue, feeling confused, itchiness, dry mouth, and headache. The ORSDS questionnaire was administered by a trained investigator on first and second postoperative days while patients remained hospitalized. We reported the average ORSDS score from all 12 elements, which ranged from 0 to 4 and higher scores represent worse outcome. |
| Need for Indwelling Urinary Catheterization | Postoperative days 1-2 or until day of discharge whichever occurs first | Number of patients receiving Naloxegol requiring indwelling urinary catheters |
| Quality of Recovery | Postoperative Days 2 or discharge day whichever was earlier | Quality of recovery is a validated scoring system that quantifies patients' early postoperative health status with range of 0-150 where higher score means better quality of recovery. We used the 15-question version, the QoR-15 |
Countries
United States
Participant flow
Recruitment details
of 508 patients screened, 136 patients meet all inclusion and exclusion criteria and gave consent to the study. 136 patients were randomized.
Participants by arm
| Arm | Count |
|---|---|
| Treatment-Naloxegol Naloxegol 25 mg given once in the morning every day until Post-operative Day 3 or day of discharge whichever occurs first
Naloxegol 25 MG: Oral Naloxegol 25 MG | 67 |
| Placebo Arm Matching placebo given once in the morning every day until Post-operative Day 3 or day of discharge whichever occurs first
Placebo: matching oral placebo | 64 |
| Total | 131 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 2 |
Baseline characteristics
| Characteristic | Placebo Arm | Total | Treatment-Naloxegol |
|---|---|---|---|
| Age, Continuous | 62 years STANDARD_DEVIATION 11 | 63 years STANDARD_DEVIATION 12 | 64 years STANDARD_DEVIATION 13 |
| Anesthesia type General anesthesia | 45 Participants | 91 Participants | 46 Participants |
| Anesthesia type Spinal anesthesia | 18 Participants | 39 Participants | 21 Participants |
| Apfel PONV score | 2 units on a scale | 2 units on a scale | 2 units on a scale |
| ASA status 1 | 1 Participants | 2 Participants | 1 Participants |
| ASA status 2 | 15 Participants | 23 Participants | 8 Participants |
| ASA status 3 | 46 Participants | 98 Participants | 52 Participants |
| ASA status 4 | 2 Participants | 8 Participants | 6 Participants |
| Chronic opioid use | 32 Participants | 68 Participants | 36 Participants |
| Intraoperative colloids, ml | 0 ml | 0 ml | 0 ml |
| Intraoperative crystalloids | 1800 ml | 1900 ml | 2000 ml |
| Intraoperative opioid use | 20 mg | 20 mg | 20 mg |
| Intraoperative platelets | 0 cc | 0 cc | 0 cc |
| Intraoperative RBC | 0 cc | 0 cc | 0 cc |
| intraoperative Urine | 0 cc | 0 cc | 0 cc |
| Medical history alcohol abuse | 7 Participants | 17 Participants | 10 Participants |
| Medical history cancer | 6 Participants | 16 Participants | 10 Participants |
| Medical history chronic pain | 5 Participants | 6 Participants | 1 Participants |
| Medical history chronic pulmonary disease | 9 Participants | 18 Participants | 9 Participants |
| Medical history current smoker | 7 Participants | 16 Participants | 9 Participants |
| Medical history diabetes mellitus | 7 Participants | 14 Participants | 7 Participants |
| Medical history drug user | 5 Participants | 7 Participants | 2 Participants |
| Medical history Ischemic Heart Disease | 10 Participants | 24 Participants | 14 Participants |
| Medical history Kidney disease | 1 Participants | 5 Participants | 4 Participants |
| Medical history myocardial infarction | 4 Participants | 10 Participants | 6 Participants |
| Medical history neurological disease | 12 Participants | 19 Participants | 7 Participants |
| Medical history obstructive sleep apnea | 6 Participants | 15 Participants | 9 Participants |
| Race/Ethnicity, Customized African American | 5 Participants | 11 Participants | 6 Participants |
| Race/Ethnicity, Customized Caucasian | 57 Participants | 116 Participants | 59 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Unknown | 2 Participants | 3 Participants | 1 Participants |
| Sex: Female, Male Female | 32 Participants | 64 Participants | 32 Participants |
| Sex: Female, Male Male | 32 Participants | 67 Participants | 35 Participants |
| Surgery duration | 3.5 hours | 3.6 hours | 3.6 hours |
| Surgery type Hip | 64 Participants | 131 Participants | 67 Participants |
| Surgery type Knee | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 67 | 0 / 64 |
| other Total, other adverse events | 0 / 67 | 0 / 64 |
| serious Total, serious adverse events | 1 / 67 | 0 / 64 |
Outcome results
Primary
Residual Urine Volume
Residual urine volume in the bladder as assessed by bladder scan
Time frame: from Postoperative days 1 to POD 2 or until day of discharge whichever occurs first
Population: 17 patients were completely missing on urine residual. Multiple imputation was used solely for estimating the treatment effect on urinal residual. The summary statistics of urine residual for each day was reported based on original data.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Treatment-Naloxegol | Residual Urine Volume | Day 1 AM | 62 ml |
| Treatment-Naloxegol | Residual Urine Volume | Day 2 AM | 32 ml |
| Treatment-Naloxegol | Residual Urine Volume | Day 2 PM | 0 ml |
| Treatment-Naloxegol | Residual Urine Volume | Day 1 PM | 48 ml |
| Placebo Arm | Residual Urine Volume | Day 2 PM | 28 ml |
| Placebo Arm | Residual Urine Volume | Day 1 AM | 114 ml |
| Placebo Arm | Residual Urine Volume | Day 1 PM | 31 ml |
| Placebo Arm | Residual Urine Volume | Day 2 AM | 28 ml |
p-value: 0.8495% CI: [0.32, 2.55]Mixed Models Analysis
p-value: 0.7395% CI: [0.26, 2.56]Mixed Models Analysis
Secondary
Need for Indwelling Urinary Catheterization
Number of patients receiving Naloxegol requiring indwelling urinary catheters
Time frame: Postoperative days 1-2 or until day of discharge whichever occurs first
Population: Our final analyzed study population had 131 patients since 5 patients did not complete (due to withdrawal or not receiving any treatment) the study thus were removed from the final analysis. Among 131 patients, 4 patients were missing from this analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment-Naloxegol | Need for Indwelling Urinary Catheterization | 19 Participants |
| Placebo Arm | Need for Indwelling Urinary Catheterization | 7 Participants |
p-value: 0.01298.3% CI: [0.98, 6.8]Chi-squared
Secondary
Quality of Recovery
Quality of recovery is a validated scoring system that quantifies patients' early postoperative health status with range of 0-150 where higher score means better quality of recovery. We used the 15-question version, the QoR-15
Time frame: Postoperative Days 2 or discharge day whichever was earlier
Population: We only had a total of 131 patients in our final analysis since 5 patients were removed from the final analysis due to not completing the study (withdrawal or not receiving any treatment). Among 131 patients, 9 patients were missing from this analysis
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment-Naloxegol | Quality of Recovery | 119 units on a scale |
| Placebo Arm | Quality of Recovery | 123 units on a scale |
p-value: 0.0898.3% CI: [-12, 2]Wilcoxon (Mann-Whitney)
Secondary
Side Effects of Naloxegol on Other Opioid Related Side Effects
Opioid-related Symptom Distress Scale (ORSDS) is a 4 point-scale that evaluates three symptom distress dimensions (frequency, severity, bothersomeness) for opioid-related side effects. The 12 elements of the ORSDS are nausea, vomiting, constipation, difficulty passing urine, difficulty concentrating, drowsiness, lightheaded, fatigue, feeling confused, itchiness, dry mouth, and headache. The ORSDS questionnaire was administered by a trained investigator on first and second postoperative days while patients remained hospitalized. We reported the average ORSDS score from all 12 elements, which ranged from 0 to 4 and higher scores represent worse outcome.
Time frame: Postoperative days 1-2 or until day of discharge whichever occurs first
Population: some patients were missing on this outcome at repeated measurements. A mixed effects model assuming auto-regressive correlation structure and the outcome was log-transformed
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Treatment-Naloxegol | Side Effects of Naloxegol on Other Opioid Related Side Effects | Day 1 | 0.53 log(score on a scale) |
| Treatment-Naloxegol | Side Effects of Naloxegol on Other Opioid Related Side Effects | Day 2 | 0.34 log(score on a scale) |
| Placebo Arm | Side Effects of Naloxegol on Other Opioid Related Side Effects | Day 1 | 0.45 log(score on a scale) |
| Placebo Arm | Side Effects of Naloxegol on Other Opioid Related Side Effects | Day 2 | 0.34 log(score on a scale) |
p-value: 0.9198.3% CI: [0.63, 1.67]Mixed Models Analysis