Non-opioid Analgesic Combination With Morphine for Postoperative Analgesia. (OCTOPUS)

Prospective, Controlled Versus Placebo, Randomized, Double-blind Study, Evaluating the Value of Non-opioid Analgesic Combination (Based on Paracetamol, Nefopam, Ketoprofen) for Postoperative Analgesia.

The combination of different analgesic drugs and/or analgesia techniques is part of the standard management of postoperative analgesia. The analysis of the literature reveals a lack of comparison of the associations of non-opioid analgesic (NOA) with morphine for postoperative analgesia.

The objectives of this study are :

• comparing the morphine sparing effect of different combination of 3 NOA (paracetamol, nefopam, ketoprofen) for postoperative analgesia.
• determining whether the morphine-sparing effect is associated with or without a reduction in the incidence of morphine side effects.
• evaluating the effects of NOA on postoperative hyperalgesia.

Study Overview

• Status: Terminated
• Conditions: Post Operative Analgesia
• Intervention / Treatment: Drug: Morphine; Drug: Paracetamol; Drug: Ketoprofen; Drug: Nefopam

Detailed Description

Since the description of the concept of balanced analgesia in the early 90's, the combination of different analgesic drugs and/or analgesia techniques is part of the standard management of postoperative analgesia. A recent survey conducted in France by Fletcher et al. showed that patients often received one or more NOA associated with an opioid. The benefit and risk of the use of opioids associated with NOA were recently reassessed as part of a formal recommendation of experts and detailed in a recent review. The analysis of the literature reveals a lack of comparison of the combinations of NOA with morphine for postoperative analgesia. For example, paracetamol and morphine in combination does not always allow a significant morphine-sparing effect compared with morphine alone and does not reduce the incidence of morphine side effects. A number of definitive answers has therefore yet to be found: Does NOA -morphine association allow an effective morphine-sparing effect? Is there an interest in prescribing several NOAs in association? If yes, what are the most interesting combinations in terms of morphine-sparing effect and safety?

Another question concerns the effects of NOA on postoperative hyperalgesia. This hyperalgesia, which results from surgery-related inflammation, is increased by consumption of morphine and not only contributes to the overall experience of postoperative pain but also to the chronicisation of postoperative pain. Since in clinical practice, hyperalgesia can be measured using specific tools (Von Frey filament type), our study will evaluate the anti-hyperalgesic effects of NOA on a subgroup of patients enrolled in the centers used to evaluate nociceptive thresholds.

The objectives of this study are :

• comparing the morphine sparing effect of different combination of 3 NOA (paracetamol, nefopam, ketoprofen) for postoperative analgesia.
• determining whether the morphine-sparing effect is associated with or without a reduction in the incidence of morphine side effects.
• evaluating the effects of NOA on postoperative hyperalgesia.

• Study Type: Interventional
• Enrollment (Actual): 223
• Phase: Phase 4

Contacts and Locations

Study Locations

• France
  • Bordeaux, France
    • Karine Nouette-Gaulain
  • Boulogne, France
    • Marcel Chauvin
  • Colombes, France
    • Hawa Keita-Meyer
  • Garches, France
    • Dominique Fletcher
  • Grenoble, France
    • Pierre Albaladejo
  • Lyon, France
    • Frédéric Aubrun
  • Montpellier, France
    • Xavier Capdevila
  • Nancy, France
    • Hervé Bouaziz
  • Nantes, France
    • Karim ASEHNOUNE
  • Nice, France
    • Marc Raucoules
  • Nîmes, France
    • Jacques Ripart
  • Paris, France
    • Anissa Belbachir
  • Paris, France
    • Emmanuel Marret
  • Paris, France
    • Jean-Xavier Mazoit
  • Paris, France
    • Marc Beaussier
  • Quincy sous Sénart, France
    • Sébastien Bloc
  • Reims, France
    • Jean-Marc Malinovsky
  • St Grégoire, France
    • Marc Gentili
  • Toulouse, France
    • Vincent Minville

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Adults older than 18 years
• Receiving scheduled surgery requiring the use of a PCA to treat postoperative pain
• Patients with a written informed consent
• Patients with a written informed consent for the sub-study on hyperalgesia (patients in the centers concerned)
• Affiliate to a social security system

Exclusion Criteria:

• Allergy to morphine, paracetamol, nefopam or ketoprofen or to any of their excipients
• Absorption of morphine and / or NOA within 24 hours before surgery
• Absorption of methadone within 48 hours before surgery
• History of epilepsy
• Renal insufficiency (creatinin clearance <30 ml / min MDRD)
• Hepatic insufficiency
• Severe respiratory insufficiency
• Pregnancy or breastfeeding women
• History of seizures
• Symptomatic urethroprostatic disorders
• Angle-closure glaucoma
• Gastrointestinal, cerebrovascular or other evolving bleedings
• Active peptic ulcer or active gastritis
• Severe heart failure
• History of asthma triggered by taking ketoprofen or similar substances
• Disable adult person under guardianship
• Use of nitrous oxide during anesthesia protocol

Study Plan

How is the study designed?

Design Details

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

Number of Arms

8

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Control group C: Placebo; All patients will receive treatment intraoperatively (IV) in 30 minutes, 60 minutes before the end of the intervention, then postoperatively every 6 hours for 48 hours.	Drug: Morphine; Other Names: All patients will receive morphine postoperatively (titration, then PCA).
Experimental: Group P: Paracetamol; All patients will receive treatment intraoperatively (IV) in 30 minutes, 60 minutes before the end of the intervention, then postoperatively every 6 hours for 48 hours.	Drug: Morphine; Other Names: All patients will receive morphine postoperatively (titration, then PCA).; Drug: Paracetamol
Experimental: Group N: Nefopam; All patients will receive treatment intraoperatively (IV) in 30 minutes, 60 minutes before the end of the intervention, then postoperatively every 6 hours for 48 hours.	Drug: Morphine; Other Names: All patients will receive morphine postoperatively (titration, then PCA).; Drug: Nefopam
Experimental: Group K: Ketoprofen; All patients will receive treatment intraoperatively (IV) in 30 minutes, 60 minutes before the end of the intervention, then postoperatively every 6 hours for 48 hours.	Drug: Morphine; Other Names: All patients will receive morphine postoperatively (titration, then PCA).; Drug: Ketoprofen
Experimental: Group PN: paracetamol and nefopam; All patients will receive treatment intraoperatively (IV) in 30 minutes, 60 minutes before the end of the intervention, then postoperatively every 6 hours for 48 hours.	Drug: Morphine; Other Names: All patients will receive morphine postoperatively (titration, then PCA).; Drug: Paracetamol; Drug: Nefopam
Experimental: Group PK: paracetamol and ketoprofen; All patients will receive treatment intraoperatively (IV) in 30 minutes, 60 minutes before the end of the intervention, then postoperatively every 6 hours for 48 hours.	Drug: Morphine; Other Names: All patients will receive morphine postoperatively (titration, then PCA).; Drug: Paracetamol; Drug: Ketoprofen
Experimental: Group NK: nefopam and ketoprofen; All patients will receive treatment intraoperatively (IV) in 30 minutes, 60 minutes before the end of the intervention, then postoperatively every 6 hours for 48 hours.	Drug: Morphine; Other Names: All patients will receive morphine postoperatively (titration, then PCA).; Drug: Ketoprofen; Drug: Nefopam
Experimental: Group PNK: paracetamol, nefopam and ketoprofen; All patients will receive treatment intraoperatively (IV) in 30 minutes, 60 minutes before the end of the intervention, then postoperatively every 6 hours for 48 hours.	Drug: Morphine; Other Names: All patients will receive morphine postoperatively (titration, then PCA).; Drug: Paracetamol; Drug: Ketoprofen; Drug: Nefopam

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Morphine consumption (mg), accumulated over 24 hours, measured by patient controlled analgesia (PCA).	Day 1

Secondary Outcome Measures

Outcome Measure	Time Frame
Morphine consumption (mg) measured by patient controlled analgesia (PCA).	Day 2, day 3
Incidence of side effects associated with morphine: nausea, vomiting, sedation, urinary retention, pruritus.	Day 3
Area of hyperalgesia measured using a von Frey filament expressed in cm2, 48 hours after surgery (sub-study in 3 centers).	Day 2
Incidence of chronic pain assessed by a telephone questionnaire 3 months after surgery (sub-study in 3 centers).	Month 3
Global satisfaction (measured after treatment)	Day 3

Collaborators and Investigators

• Sponsor: Rennes University Hospital
• Investigators: Study Chair: ERIC BELLISSANT, Rennes University Hospital

Publications and helpful links

General Publications

• Beloeil H, Albaladejo P, Sion A, Durand M, Martinez V, Lasocki S, Futier E, Verzili D, Minville V, Fessenmeyer C, Belbachir A, Aubrun F, Renault A, Bellissant E; OCTOPUS group. Multicentre, prospective, double-blind, randomised controlled clinical trial comparing different non-opioid analgesic combinations with morphine for postoperative analgesia: the OCTOPUS study. Br J Anaesth. 2019 Jun;122(6):e98-e106. doi: 10.1016/j.bja.2018.10.058. Epub 2018 Dec 29.

Study record dates

Study Major Dates

• Study Start (Actual): July 23, 2013
• Primary Completion (Actual): January 16, 2016
• Study Completion (Actual): January 16, 2016

Study Registration Dates

• First Submitted: June 18, 2013
• First Submitted That Met QC Criteria: June 18, 2013
• First Posted (Estimate): June 20, 2013

Study Record Updates

• Last Update Posted (Actual): February 6, 2018
• Last Update Submitted That Met QC Criteria: February 2, 2018
• Last Verified: February 1, 2018

More Information

Terms related to this study

• Keywords: Morphine; Post operative analgesia ;; Paracetamol ;; Ketoprofen ;; Nefopam
• Additional Relevant MeSH Terms: Nervous System Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Perceptual Disorders; Agnosia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Antipyretics; Analgesics, Opioid; Narcotics; Acetaminophen; Morphine; Ketoprofen; Nefopam
• Other Study ID Numbers: 130505A-32