An Efficacy and Safety Study to Compare Morphine 6-glucuronide (M6G) and Morphine in Patients Suffering With Post-Operative Pain for at Least 24 Hours

Study Overview
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Brief Summary
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To compare the incidence and severity of nausea in the study treatment groups, during the 18-hour period starting 6 hours after titration to pain relief; following confirmation of the assumption of non-inferiority between the two groups of pain relief over the 24 hour post-operative period. Pain relief and nausea will be determined by measuring the areas under the curves of pain intensity and nausea verbal rating scale scores.

Official Title
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A Randomised Double-blind Study to Compare the Analgesic Efficacy and Safety Profiles of M6G and Morphine, as a Loading Dose Followed by PCA, in Patients Suffering Moderate to Severe Post-operative Pain Requiring PCA for at Least 24 Hours

Conditions
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Postoperative Pain

Intervention / Treatment
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* Drug: Morphine 6-glucuronide
* Drug: Morphine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients undergoing any of the following elective surgical procedures that, in the Investigator's opinion, would have required the use of post-operative patient controlled analgesia for a minimum of 24 hours: Abdominal hysterectomy with the exception of laparoscopic procedures. Bowel / gastrointestinal (GI) surgery Major urological surgery Aged ≥ 18 years American Society of Anesthesiologists (ASA) grades I to III If female, the patient had to be post-menopausal (last menstruation > 1 year previously), or surgically sterile (e.g. full hysterectomy or tubal ligation). If neither of these was the case, she had to use adequate contraception (i.e. hormonal contraceptive, intrauterine device (IUD), or a double barrier method) and to have a negative urine pregnancy test during the 24-hours prior to surgery. Provide written informed consent to participate in the trial prior to surgery. Exclusion Criteria: The patient was pregnant or lactating. Had a known sensitivity to morphine or other opiates, or a medical condition such that opiates were contraindicated. Had a known sensitivity to paracetamol, or a medical condition such that paracetamol was contraindicated. Had received any investigational drug within the 90 days prior to the start of the study, or was scheduled to receive one during the study period. Had been involved in any previous M6G study. Had a documented history or current evidence of alcohol or drug abuse within the year prior to screening. Had clinically significant findings on pre-treatment evaluations (e.g. laboratory results, electrocardiograms, medical history, physical examination) that, in the Investigator's opinion, should have excluded them from the study. Had a concurrent disorder that resulted in excessive pain that, in the Investigator's opinion, would have interfered with the pain assessments during the study (e.g.severe rheumatoid arthritis, muscle dystrophy or neuropathic pain). Had a blood clotting disorder or other blood dyscrasias. Had requested the use of epidural or intrathecal anaesthesia techniques. Required the use of a local anaesthetic block and/or infiltration of wound sites. Required the concomitant use of opioids or non-steroidal anti-inflammatory drugs(NSAIDs) during the study due to an existing concurrent condition. Had a history of Left Ventricular Failure or compromised cardiovascular function, defined as New York Heart Association (NYHA) level 3. Had a history of severe renal impairment or a creatinine level > 3 times the upper limit of normal. Was having surgery that would have prevented the use of oral or rectal paracetamol(iv administration of paracetamol was not allowed). Was expected to require prolonged ventilation after surgery. Was opioid tolerant or had a history of chronic opioid use. Had cognitive impairment that would, in the Investigator's opinion, have precluded participation or compliance with protocol defined procedures (i.e. use of PCA).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: M6G<br>An initial slow bolus injection up to 60 min prior to end of surgery. If required, two additional slow bolus injections to achieve baseline pain relief. Continuing on PCA for a minimum of 24 hours. | Drug: Morphine 6-glucuronide<br> <br> |
| Active Comparator: Morphine<br>An initial slow bolus injection up to 60 min prior to end of surgery. If required, two additional slow bolus injections to achieve baseline pain relief. Continuing on PCA for a minimum of 24 hours. | Drug: Morphine<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and severity of nausea | To compare the incidence and severity of nausea in the study treatment groups, during the 18-hour period starting 6 hours after titration to pain relief; following confirmation of the assumption of non-inferiority between the two groups of pain relief over the 24-hour post-operative period. Pain relief and nausea were determined by measuring the areas under the curves of pain intensity and nausea verbal rating scale scores. | The 6-18 hour period after titration to pain relief | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Analgesic effect | To compare the analgesic effect of the study treatments using an Investigator- and patient-administered VRS-11 scale of pain intensity over the following time periods following achievement of baseline pain relief. 0-12 hours (AUCbaseline-12) 0-48 hours (AUCbaseline - 48) 12-24 hours (AUC12 - 24) 24-48 hours (AUC24 - 48) Pain levels will be compared using the AUC from baseline. | 0-48 hours after titration to pain relief | 
| The incidence and severity of nausea | To compare the incidence and severity of nausea in the study treatment groups over the following time periods following achievement of baseline pain relief: 0-12 hours, 0-24 hours, 0-48 hours, 12-24 hours, 24-48 hours. | 0-48 hours | 
| The incidence and severity of vomiting | To compare the incidence and severity of vomiting in the study treatment groups over the following time periods following achievement of baseline pain relief: 0-12 hours, 0-24 hours, 0-48 hours, 12-24 hours, 24-48 hours | 0-48 hours | 
| The amounts of study drug required to achieve a baseline pain severity score of ≤ 3 | To compare the amounts of study drug required to achieve a baseline pain severity score of ≤ 3 | 60-30mins before close of surgery to time 0. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Morphine 6-glucuronide, Morphine, Patient Controlled Analgesia, Post Operative Nausea and Vomiting