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

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

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.

Study Overview

• Status: Completed
• Conditions: Postoperative Pain
• Intervention / Treatment: Drug: Morphine; Drug: Morphine 6-glucuronide

• Study Type: Interventional
• Enrollment (Actual): 517
• Phase: Phase 3

Contacts and Locations

Study Locations

• Czechia
  • Prague, Czechia, 180 00
    • Teaching Hospital Bulovka, Department of Urology
• France
  • Cedex 20
    • Paris, Cedex 20, France, 75970
      • Anaesthetisia - Resuscitation Department, Tenon Hospital
• Germany
  • Bonn, Germany, 53105
    • Universitätsklinikum Bonn, Klinik und Poliklinik f. Anaesthesiologie
• Netherlands
  • Leiden, Netherlands, 2300 RC
    • Department of Anaesthesiology, Leiden University Medical Centre
• Poland
  • Lublin, Poland, 20-081
    • Ii Klinika Anestezjologii i It
• United Kingdom
  • Renfrewshire
    • Glasgow, Renfrewshire, United Kingdom, G11 6NT
      • Intensive Care Unit, Level 5, Western Infirmary,
  • West Lothian
    • Livingston, West Lothian, United Kingdom, EH54 6PP
      • St John's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: M6G; 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
Active Comparator: Morphine; 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

What is the study measuring?

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.

Collaborators and Investigators

• Sponsor: Paion UK Ltd.
• Collaborators: Chiltern International Ltd.; HFL Ltd.
• Investigators: Principal Investigator: Alexander Binning, M.D., Intensive Care Unit, Level 5, Western Infirmary, Glasgow, G11 6NT; Study Director: James Lees, B.Sc., Paion UK Ltd.

Study record dates

Study Major Dates

• Study Start: November 1, 2005
• Primary Completion (Actual): November 1, 2006
• Study Completion (Actual): December 1, 2006

Study Registration Dates

• First Submitted: March 5, 2010
• First Submitted That Met QC Criteria: March 5, 2010
• First Posted (Estimated): March 8, 2010

Study Record Updates

• Last Update Posted (Actual): August 29, 2023
• Last Update Submitted That Met QC Criteria: August 28, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: Morphine 6-glucuronide; Morphine; Patient Controlled Analgesia; Post Operative Nausea and Vomiting
• Additional Relevant MeSH Terms: Pathologic Processes; Postoperative Complications; Pain; Neurologic Manifestations; Pain, Postoperative; Physiological Effects of Drugs; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Opioid; Narcotics; Morphine
• Other Study ID Numbers: M6G022; 2005-001690-99 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No