Abdominal Surgery, Postoperative Pain
Conditions
Keywords
Postoperative pain, Post-operative pain, Opioid, Laparoscopic surgery, Bupivacaine, Local anesthetic
Brief summary
This is a research study testing SABER-Bupivacaine (an experimental pain-relieving medication). SABER-Bupivacaine is designed to continuously deliver bupivacaine, a common local anesthetic, for a few days in order to treat local post-surgical pain. The purpose of this study is to investigate safety (side effects) associated with the use of SABER-Bupivacaine and how well it works in reducing pain and opioid-related side effects following various kinds of abdominal surgeries.
Interventions
Injectable Extended Release Solution; SABER-Bupivacaine /Once
DRUGBupivacaine HCl
Injectable Solution; Bupivacaine HCl /Once
DRUGSABER-Placebo
Injectable Solution; SABER-Placebo/Once
Sponsors
Nycomed
Hospira, now a wholly owned subsidiary of Pfizer
Durect
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients must be able to read and understand the consent form, provide written consent, complete trial-related procedures, and communicate with the trial staff * Males and females, 18 years of age and older scheduled to undergo elective general abdominal surgery * Patients must be healthy or have only mild systemic disease * BMI \< 45 * Patients must have ECG wave form within normal limits * Female and male patients must agree to use medically acceptable method of contraception throughout the entire trial period and for 1 week after the trial participation is completed
Exclusion criteria
* Patients who are pregnant or lactating * Patients undergoing emergency surgery (unless full consent is obtained and all screening procedures are completed prior to surgery) * Significant concomitant surgical procedure * History of multiple prior laparotomy procedures * Cancer with known metastases pre-operatively, which are suspected to impact post-operative recovery or pain * Planned formation of stoma during surgery or plans to undergo another laparotomy procedure within 30 days post-operatively * Pre-operative evidence of sepsis or septic shock * Pre-operative evaluation that suggests a surgery may preclude full closure of the incision(s) * Patients with current or regular use of systemic steroids, anticonvulsants, antiepileptics, antidepressants, or monoamine oxidase inhibitors, who cannot be withdrawn from these medications * Patients with current or regular use of drugs known to significantly prolong the QTc interval * Patients with known hypersensitivity to local anesthetic agents of the amide type (e.g. lidocaine, bupivacaine) * Patients with known hypersensitivity to morphine * Patients with conditions contraindicated for use of opioids * Patients with atrial fibrillation/flutter or other non-sinus rhythm (including paced rhythm); left bundle branch block (LBBB); or the following conditions: right bundle branch block (RBBB) in presence of a cardiac disease, significant cardiomyopathy, and myocardial infarction within last 6 months * Patients with a serum creatinine level two times more than the local laboratory normal limit * Patients who have received greater than 600 mg morphine equivalent daily dose for three or more days per week in the month prior to the surgical procedure * Patients who are currently being treated with methadone, or history of methadone use within the previous 6 months * Patients with known or suspected abuse of opioids or other illicit drugs * Patients with known or suspected alcohol abuse * Participation in another clinical trial at the same time or within 30 days of this trial * Patients who, in the Investigator's opinion, should not participate in the trial or may not be capable of following the trial schedule for any reason
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Pain Intensity on Movement | 0 to 72 hours post-dose | Mean pain intensity on movement AUC (time-normalized AUC) during the period 0 to 72 hours post-dose. Pain intensity was assessed with a standard 0 to 10 numeric rating scale (NRS), where no pain at all was rated as 0 and the worst pain imaginable was rated as 10. The AUC is computed for each patient using the standard trapezoidal rule and normalised by dividing by the time interval over which it is computed. This normalisation converts the AUC to the natural pain scale (NRS 0-10) to allow for better translation of the clinical treatment effect magnitude. |
| Supplemental Opioid Use | 0-72 hours post dose | Total morphine-equivalent dose during 0-72 hours post dose. Median values were presented because data was not normally distributed. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion (Percent) of Patients Who Have Evidence of a Wound Infection | 0 to 14 days post-dose (Visits 3 and 4) | From Surgical Wound Healing and Local Tissue Condition Evaluation |
| Time-to-first Use of Opioid Rescue Medication | 0 to 14 days post-dose (Time from extubation until first opioid use) | — |
| Mean Pain Intensity on Movement | 0 to 48 hours post-dose | Mean pain intensity on movement AUC (time-normalized AUC) during the period 0 to 48 hours post-dose. Pain intensity was assessed with a standard 0 to 10 numeric rating scale (NRS), where no pain at all was rated as 0 and the worst pain imaginable was rated as 10. The AUC is computed for each patient using the standard trapezoidal rule and normalised by dividing by the time interval over which it is computed. This normalisation converts the AUC to the natural pain scale (NRS 0-10) to allow for better translation of the clinical treatment effect magnitude. |
| Pain Intensity at Rest AUC During 0-72 Hours Post Dose | 0-72 hours post dose | Mean pain intensity at rest AUC during the period 0 to 72 hours post-dose. Pain intensity was assessed with a standard 0 to 10 numeric rating scale (NRS), where no pain at all was rated as 0 and the worst pain imaginable was rated as 10. The AUC is computed for each patient using the standard trapezoidal rule and normalised by dividing by the time interval over which it is computed. This normalisation converts the AUC to the natural pain scale (NRS 0-10) to allow for better translation of the clinical treatment effect magnitude. |
| Mean Pain Intensity at Rest AUC During 0-48 Hours Post Dose | 0-48 hours post dose | Mean pain intensity at rest AUC during the period 0 to 48 hours post-dose. Pain intensity was assessed with a standard 0 to 10 numeric rating scale (NRS), where no pain at all was rated as 0 and the worst pain imaginable was rated as 10. The AUC is computed for each patient using the standard trapezoidal rule and normalised by dividing by the time interval over which it is computed. This normalisation converts the AUC to the natural pain scale (NRS 0-10) to allow for better translation of the clinical treatment effect magnitude. |
| Number (Incidence) of Participants With Opioid-related Side Effects | 0 to 30 days post-dose | AEs include: nausea, vomiting, constipation, dizziness, somnolence, urinary retention, respiratory depression |
| Total Morphine-equivalent Dose | 0-48 hours post dose | Total morphine-equivalent dose during 0-48 hours post dose. |
Countries
Australia, New Zealand, United States
Participant flow
Recruitment details
The trial was conducted at 15 sites in the US, 3 sites in Australia, and 1 site in New Zealand. The study was initiated on 21 December 2009 and completed on 30 September 2011.
Pre-assignment details
total of 393 patients were screened and 331 patients were randomized. There were 26 patients who were randomized but not treated. The reasons for not treating these patients included: conditions encountered during surgery necessitated procedures that did not meet protocol requirements, peri-operative epidural analgesia was administered, the test drug was not available, or the patient withdrew consent
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1-POSIMIR Open Laparotomy | 30 |
| Cohort 1-Bupivacaine HCl Open Laparotomy | 18 |
| Cohort 2-POSIMIR Laparoscopic Cholecystectomy | 30 |
| Cohort 2-Bupivacaine HCl Laparoscopic Cholecystectomy | 20 |
| Cohort 3-POSIMIR Laparoscopic Assisted Colectomy | 129 |
| Cohort 3-Placebo Laparoscopic Assisted Colectomy | 78 |
| Total | 305 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Not treated | 2 | 5 | 0 | 0 | 11 | 8 |
| Overall Study | Other | 0 | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Physician Decision | 0 | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 1 | 0 | 0 | 3 | 1 |
Baseline characteristics
| Characteristic | Cohort 1-POSIMIR | Cohort 1-Bupivacaine HCl | Cohort 2-POSIMIR | Cohort 2-Bupivacaine HCl | Cohort 3-POSIMIR | Cohort 3-Placebo | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 56.8 years | 53.8 years | 44.2 years | 39.5 years | 60.2 years | 58.2 years | 56.1 years |
| BMI | 30.5 kg/m^2 | 27.0 kg/m^2 | 30.8 kg/m^2 | 31.9 kg/m^2 | 29.4 kg/m^2 | 27.5 kg/m^2 | 29.2 kg/m^2 |
| Sex: Female, Male Female | 18 Participants | 9 Participants | 20 Participants | 14 Participants | 70 Participants | 34 Participants | 165 Participants |
| Sex: Female, Male Male | 12 Participants | 9 Participants | 10 Participants | 6 Participants | 59 Participants | 44 Participants | 140 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 30 | 0 / 18 | 0 / 30 | 0 / 20 | 1 / 129 | 0 / 78 |
| other Total, other adverse events | 30 / 30 | 17 / 18 | 28 / 30 | 20 / 20 | 126 / 129 | 75 / 78 |
| serious Total, serious adverse events | 9 / 30 | 4 / 18 | 0 / 30 | 1 / 20 | 16 / 129 | 9 / 78 |
Outcome results
Primary
Mean Pain Intensity on Movement
Mean pain intensity on movement AUC (time-normalized AUC) during the period 0 to 72 hours post-dose. Pain intensity was assessed with a standard 0 to 10 numeric rating scale (NRS), where no pain at all was rated as 0 and the worst pain imaginable was rated as 10. The AUC is computed for each patient using the standard trapezoidal rule and normalised by dividing by the time interval over which it is computed. This normalisation converts the AUC to the natural pain scale (NRS 0-10) to allow for better translation of the clinical treatment effect magnitude.
Time frame: 0 to 72 hours post-dose
Population: ITT Population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Cohort 1-POSIMIR | Mean Pain Intensity on Movement | 4.9 score on a scale |
| Cohort 1-Bupivacaine HCl | Mean Pain Intensity on Movement | 5.0 score on a scale |
| Cohort 2-POSIMIR | Mean Pain Intensity on Movement | 2.8 score on a scale |
| Cohort 2-Bupivacaine HCl | Mean Pain Intensity on Movement | 3.9 score on a scale |
| Cohort 3-POSIMIR | Mean Pain Intensity on Movement | 4.8 score on a scale |
| Cohort 3-Placebo | Mean Pain Intensity on Movement | 5.1 score on a scale |
p-value: 0.147395% CI: [-2.11, 0.33]ANCOVA
p-value: 0.060195% CI: [-2.16, 0.05]ANCOVA
p-value: 0.148395% CI: [-0.8, 0.12]ANCOVA
Primary
Supplemental Opioid Use
Total morphine-equivalent dose during 0-72 hours post dose. Median values were presented because data was not normally distributed.
Time frame: 0-72 hours post dose
Population: ITT Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1-POSIMIR | Supplemental Opioid Use | 87.0 Milligram equivalents |
| Cohort 1-Bupivacaine HCl | Supplemental Opioid Use | 63.0 Milligram equivalents |
| Cohort 2-POSIMIR | Supplemental Opioid Use | 17.0 Milligram equivalents |
| Cohort 2-Bupivacaine HCl | Supplemental Opioid Use | 22.5 Milligram equivalents |
| Cohort 3-POSIMIR | Supplemental Opioid Use | 52.0 Milligram equivalents |
| Cohort 3-Placebo | Supplemental Opioid Use | 62.0 Milligram equivalents |
p-value: 0.990195% CI: [-54.5, 52]Wilcoxon (Mann-Whitney)
p-value: 0.20195% CI: [-14, 3.4]Wilcoxon Rank-Sum
p-value: 0.589795% CI: [-15, 8]Wilcoxon Rank-Sum
Secondary
Mean Pain Intensity at Rest AUC During 0-48 Hours Post Dose
Mean pain intensity at rest AUC during the period 0 to 48 hours post-dose. Pain intensity was assessed with a standard 0 to 10 numeric rating scale (NRS), where no pain at all was rated as 0 and the worst pain imaginable was rated as 10. The AUC is computed for each patient using the standard trapezoidal rule and normalised by dividing by the time interval over which it is computed. This normalisation converts the AUC to the natural pain scale (NRS 0-10) to allow for better translation of the clinical treatment effect magnitude.
Time frame: 0-48 hours post dose
Population: ITT Population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Cohort 1-POSIMIR | Mean Pain Intensity at Rest AUC During 0-48 Hours Post Dose | 3.6 score on a scale |
| Cohort 1-Bupivacaine HCl | Mean Pain Intensity at Rest AUC During 0-48 Hours Post Dose | 4.5 score on a scale |
| Cohort 2-POSIMIR | Mean Pain Intensity at Rest AUC During 0-48 Hours Post Dose | 2.0 score on a scale |
| Cohort 2-Bupivacaine HCl | Mean Pain Intensity at Rest AUC During 0-48 Hours Post Dose | 2.9 score on a scale |
| Cohort 3-POSIMIR | Mean Pain Intensity at Rest AUC During 0-48 Hours Post Dose | 3.4 score on a scale |
| Cohort 3-Placebo | Mean Pain Intensity at Rest AUC During 0-48 Hours Post Dose | 3.8 score on a scale |
Secondary
Mean Pain Intensity on Movement
Mean pain intensity on movement AUC (time-normalized AUC) during the period 0 to 48 hours post-dose. Pain intensity was assessed with a standard 0 to 10 numeric rating scale (NRS), where no pain at all was rated as 0 and the worst pain imaginable was rated as 10. The AUC is computed for each patient using the standard trapezoidal rule and normalised by dividing by the time interval over which it is computed. This normalisation converts the AUC to the natural pain scale (NRS 0-10) to allow for better translation of the clinical treatment effect magnitude.
Time frame: 0 to 48 hours post-dose
Population: ITT Population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Cohort 1-POSIMIR | Mean Pain Intensity on Movement | 5.2 score on a scale |
| Cohort 1-Bupivacaine HCl | Mean Pain Intensity on Movement | 6.0 score on a scale |
| Cohort 2-POSIMIR | Mean Pain Intensity on Movement | 3.2 score on a scale |
| Cohort 2-Bupivacaine HCl | Mean Pain Intensity on Movement | 4.4 score on a scale |
| Cohort 3-POSIMIR | Mean Pain Intensity on Movement | 5.2 score on a scale |
| Cohort 3-Placebo | Mean Pain Intensity on Movement | 5.5 score on a scale |
Secondary
Number (Incidence) of Participants With Opioid-related Side Effects
AEs include: nausea, vomiting, constipation, dizziness, somnolence, urinary retention, respiratory depression
Time frame: 0 to 30 days post-dose
Population: ITT Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1-POSIMIR | Number (Incidence) of Participants With Opioid-related Side Effects | 19 Participants |
| Cohort 1-Bupivacaine HCl | Number (Incidence) of Participants With Opioid-related Side Effects | 10 Participants |
| Cohort 2-POSIMIR | Number (Incidence) of Participants With Opioid-related Side Effects | 23 Participants |
| Cohort 2-Bupivacaine HCl | Number (Incidence) of Participants With Opioid-related Side Effects | 17 Participants |
| Cohort 3-POSIMIR | Number (Incidence) of Participants With Opioid-related Side Effects | 93 Participants |
| Cohort 3-Placebo | Number (Incidence) of Participants With Opioid-related Side Effects | 47 Participants |
Secondary
Pain Intensity at Rest AUC During 0-72 Hours Post Dose
Mean pain intensity at rest AUC during the period 0 to 72 hours post-dose. Pain intensity was assessed with a standard 0 to 10 numeric rating scale (NRS), where no pain at all was rated as 0 and the worst pain imaginable was rated as 10. The AUC is computed for each patient using the standard trapezoidal rule and normalised by dividing by the time interval over which it is computed. This normalisation converts the AUC to the natural pain scale (NRS 0-10) to allow for better translation of the clinical treatment effect magnitude.
Time frame: 0-72 hours post dose
Population: ITT Population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Cohort 1-POSIMIR | Pain Intensity at Rest AUC During 0-72 Hours Post Dose | 3.4 score on a scale |
| Cohort 1-Bupivacaine HCl | Pain Intensity at Rest AUC During 0-72 Hours Post Dose | 4.2 score on a scale |
| Cohort 2-POSIMIR | Pain Intensity at Rest AUC During 0-72 Hours Post Dose | 1.7 score on a scale |
| Cohort 2-Bupivacaine HCl | Pain Intensity at Rest AUC During 0-72 Hours Post Dose | 2.5 score on a scale |
| Cohort 3-POSIMIR | Pain Intensity at Rest AUC During 0-72 Hours Post Dose | 3.1 score on a scale |
| Cohort 3-Placebo | Pain Intensity at Rest AUC During 0-72 Hours Post Dose | 3.5 score on a scale |
Secondary
Proportion (Percent) of Patients Who Have Evidence of a Wound Infection
From Surgical Wound Healing and Local Tissue Condition Evaluation
Time frame: 0 to 14 days post-dose (Visits 3 and 4)
Population: ITT Population
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Cohort 1-POSIMIR | Proportion (Percent) of Patients Who Have Evidence of a Wound Infection | Patients with Wound Infection at Visit 3 (Day 7) | yes | 2 Participants |
| Cohort 1-POSIMIR | Proportion (Percent) of Patients Who Have Evidence of a Wound Infection | Patients with Wound Infection at Visit 4 (Day 14) | yes | 1 Participants |
| Cohort 1-POSIMIR | Proportion (Percent) of Patients Who Have Evidence of a Wound Infection | Patients with Wound Infection at Visit 3 (Day 7) | no | 23 Participants |
| Cohort 1-POSIMIR | Proportion (Percent) of Patients Who Have Evidence of a Wound Infection | Patients with Wound Infection at Visit 4 (Day 14) | no | 23 Participants |
| Cohort 1-Bupivacaine HCl | Proportion (Percent) of Patients Who Have Evidence of a Wound Infection | Patients with Wound Infection at Visit 4 (Day 14) | no | 14 Participants |
| Cohort 1-Bupivacaine HCl | Proportion (Percent) of Patients Who Have Evidence of a Wound Infection | Patients with Wound Infection at Visit 3 (Day 7) | yes | 1 Participants |
| Cohort 1-Bupivacaine HCl | Proportion (Percent) of Patients Who Have Evidence of a Wound Infection | Patients with Wound Infection at Visit 3 (Day 7) | no | 14 Participants |
| Cohort 1-Bupivacaine HCl | Proportion (Percent) of Patients Who Have Evidence of a Wound Infection | Patients with Wound Infection at Visit 4 (Day 14) | yes | 2 Participants |
| Cohort 2-POSIMIR | Proportion (Percent) of Patients Who Have Evidence of a Wound Infection | Patients with Wound Infection at Visit 3 (Day 7) | yes | 0 Participants |
| Cohort 2-POSIMIR | Proportion (Percent) of Patients Who Have Evidence of a Wound Infection | Patients with Wound Infection at Visit 3 (Day 7) | no | 30 Participants |
| Cohort 2-POSIMIR | Proportion (Percent) of Patients Who Have Evidence of a Wound Infection | Patients with Wound Infection at Visit 4 (Day 14) | no | 30 Participants |
| Cohort 2-POSIMIR | Proportion (Percent) of Patients Who Have Evidence of a Wound Infection | Patients with Wound Infection at Visit 4 (Day 14) | yes | 0 Participants |
| Cohort 2-Bupivacaine HCl | Proportion (Percent) of Patients Who Have Evidence of a Wound Infection | Patients with Wound Infection at Visit 3 (Day 7) | yes | 0 Participants |
| Cohort 2-Bupivacaine HCl | Proportion (Percent) of Patients Who Have Evidence of a Wound Infection | Patients with Wound Infection at Visit 3 (Day 7) | no | 19 Participants |
| Cohort 2-Bupivacaine HCl | Proportion (Percent) of Patients Who Have Evidence of a Wound Infection | Patients with Wound Infection at Visit 4 (Day 14) | no | 18 Participants |
| Cohort 2-Bupivacaine HCl | Proportion (Percent) of Patients Who Have Evidence of a Wound Infection | Patients with Wound Infection at Visit 4 (Day 14) | yes | 1 Participants |
| Cohort 3-POSIMIR | Proportion (Percent) of Patients Who Have Evidence of a Wound Infection | Patients with Wound Infection at Visit 3 (Day 7) | yes | 6 Participants |
| Cohort 3-POSIMIR | Proportion (Percent) of Patients Who Have Evidence of a Wound Infection | Patients with Wound Infection at Visit 4 (Day 14) | yes | 4 Participants |
| Cohort 3-POSIMIR | Proportion (Percent) of Patients Who Have Evidence of a Wound Infection | Patients with Wound Infection at Visit 4 (Day 14) | no | 119 Participants |
| Cohort 3-POSIMIR | Proportion (Percent) of Patients Who Have Evidence of a Wound Infection | Patients with Wound Infection at Visit 3 (Day 7) | no | 116 Participants |
| Cohort 3-Placebo | Proportion (Percent) of Patients Who Have Evidence of a Wound Infection | Patients with Wound Infection at Visit 3 (Day 7) | no | 73 Participants |
| Cohort 3-Placebo | Proportion (Percent) of Patients Who Have Evidence of a Wound Infection | Patients with Wound Infection at Visit 3 (Day 7) | yes | 0 Participants |
| Cohort 3-Placebo | Proportion (Percent) of Patients Who Have Evidence of a Wound Infection | Patients with Wound Infection at Visit 4 (Day 14) | yes | 0 Participants |
| Cohort 3-Placebo | Proportion (Percent) of Patients Who Have Evidence of a Wound Infection | Patients with Wound Infection at Visit 4 (Day 14) | no | 77 Participants |
Secondary
Time-to-first Use of Opioid Rescue Medication
Time frame: 0 to 14 days post-dose (Time from extubation until first opioid use)
Population: ITT Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1-POSIMIR | Time-to-first Use of Opioid Rescue Medication | 0.6 Hours |
| Cohort 1-Bupivacaine HCl | Time-to-first Use of Opioid Rescue Medication | 0.5 Hours |
| Cohort 2-POSIMIR | Time-to-first Use of Opioid Rescue Medication | 0.6 Hours |
| Cohort 2-Bupivacaine HCl | Time-to-first Use of Opioid Rescue Medication | 0.5 Hours |
| Cohort 3-POSIMIR | Time-to-first Use of Opioid Rescue Medication | 0.6 Hours |
| Cohort 3-Placebo | Time-to-first Use of Opioid Rescue Medication | 0.5 Hours |
Secondary
Total Morphine-equivalent Dose
Total morphine-equivalent dose during 0-48 hours post dose.
Time frame: 0-48 hours post dose
Population: ITT Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1-POSIMIR | Total Morphine-equivalent Dose | 69.5 mg IV Morphine equivalents |
| Cohort 1-Bupivacaine HCl | Total Morphine-equivalent Dose | 52.0 mg IV Morphine equivalents |
| Cohort 2-POSIMIR | Total Morphine-equivalent Dose | 15.0 mg IV Morphine equivalents |
| Cohort 2-Bupivacaine HCl | Total Morphine-equivalent Dose | 19.7 mg IV Morphine equivalents |
| Cohort 3-POSIMIR | Total Morphine-equivalent Dose | 41.5 mg IV Morphine equivalents |
| Cohort 3-Placebo | Total Morphine-equivalent Dose | 43.0 mg IV Morphine equivalents |