Post-operative Analgesic Effect of Oral Nefopam (NefPO)

Postoperative Analgesic Effect of Orally Administrated Nefopam After a Total Knee Arthroplasty: a Randomized Controlled Trial

Primary knee arthroplasty by total prosthesis is a painful surgery, performed on patients with advanced gonarthrosis (stage III), thus already presenting hyperalgesia and hyperalgesia and allodynia. This terrain makes the risk of postoperative hyperalgesia but also of persistent postoperative risk of persistent post-surgical pain.

Nefopam is a non-opioid centrally acting analgesic drug used as a part of multimodal analgesia. The opioid-sparing effect of nefopam is still controversial across various surgical procedures. In France nefopam is only available as a parenteral formulation; however it is often administered orally. There is currently no study addressing the efficacy of oral nefopam for the postoperative pain management including pain prevention.

The investigators conduct a prospective, double-blinded randomized controlled study with the main objective to examine the effect of perioperative orally administered nefopam on postoperative pain after a total knee arthroplasty. Secondary objectives include the quantification of wound allodynia, analysis of adverse events, clinical outcomes, and a pharmacokinetic study of orally given nefopam (plasma and cerebrospinal fluid dosage).

Study Overview

• Status: Recruiting
• Conditions: Postoperative Pain After a Total Knee Arthroplasty
• Intervention / Treatment: Drug: Oral nefopam; Drug: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 40
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Frederic AUBRUN, MD/PHD; Phone Number: +33 4 72 07 26 11; Email: Frederic.aubrun@chu-lyon.fr
• Study Contact Backup: Name: Solene PANTEL; Phone Number: +33 4 26 73 27 25; Email: solene.pantel02@chu-lyon.fr

Study Locations

• France
  • Lyon, France, 69004
    • Recruiting
    • Département d'Anesthésie Réanimation, Groupement Hospitalier Nord, Hospices Civils de Lyon
    • Contact: Frédéric AUBRUN, MD-PhD; Phone Number: +33 04 72 07 26 11; Email: frederic.aubrun@chu-lyon.fr
    • Contact: Solène PANTEL; Phone Number: +33 04 26 73 27 25; Email: solene.pantel02@chu-lyon.fr
    • Sub-Investigator: Mikhail DZIADZKO, MD
    • Sub-Investigator: Thomas SCHULZ, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• adult patients scheduled for a total knee arthroplasty under spinal anesthesia at the Hopital de la Croix Rousse, Hospice Civils de Lyon, France.
• ASA (American Society of Anesthesiology) class between 1 et 3.
• written informed consent

Exclusion Criteria:

• any contraindication for nefopam (known hypersensitivity, past medical history of seizures, urinary retention, benign prostate hyperplasia, angle glaucoma, ischemic cardiomyopathy waiting for revascularization, atrial fibrillation)
• medical conditions known to influence the pharmacokinetics of nefopam (chronic kidney failure with Glomerular Filtration Rate (GFR) <30mL/min/1,73m2, liver failure, current treatment with rifampicin, carbamazepine, azoles fungicides, macrolides)
• current treatment with benzodiazepines, anxiolytics, antidepressants, histamine H1 antagonists, neuroleptics, baclofen, thalidomide, barbiturates
• medical history of gastric or esophageal surgery.
• phenylketonuria
• pregnancy or breastfeeding
• past use of oral nefopam

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: NEFOPAM 60mg PO/ 8 hours; Oral administration of nefopam 60mg 2 hours before the surgery following by 60mg each 8h for 24h.	Drug: Oral nefopam; Oral administration of nefopam 60mg 2 hours before the surgery following by 60mg each 8h for 24h. Oral nefopam is prepared ex-tempore from the intravenous formulation adding a taste masking compound by a non-caring nurse following detailed instructions.
Placebo Comparator: Placebo; Oral administration of a placebo 2 hours before the surgery following by one administration each 8h for 24h.	Drug: Placebo; Oral administration of a placebo 2 hours before the surgery following by one administration each 8h for 24h. Oral placebo is prepared ex-tempore with a taste masking compound by a non-charge nurse following detailed instructions

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total morphine consumption within 24h after the surgery.	Total dose of morphine consumed in 24h frame by a patient (PCA and/or additional morphine administration - parenteral or oral)	24 hours after the surgery.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hyperalgesia - Pressure Pain Threshold	The pressure pain threshold is determined using a Von Frey monofilaments on both (operated and contralateral) knees 24 hours after incision.	24 hours after the surgery
Hyperalgesia - Punctate Pain Intensity	The Punctuate pain intensity is determined using a Von Frey monofilament n°5,88 (60 g/mm2) and a pain scale (0 = no pain, 10 = the worst pain), on both the operated knee and the contralateral knee 24 hours after incision.	24 hours after the surgery
Hyperalgesia - Allodynia zone	The extension of allodynia around the wound is measured using a calibrated brush (100 mNewton) 24 hours after incision.	24 hours after the surgery
Pain intensity	Self-reported pain intensity at rest and while moving the operated leg. Each item is scored on a scale ranging from 0 to 10 (0 = no pain, 10 = the worst pain)	24 hours after the surgery and 3 months after the surgery
Self reported safety outcomes	Nausea and vomiting, unusual sweating, drowsiness, hallucinations, nightmares, palpitations, irritability	24 hours after the surgery
Measures Safety outcomes	The incidence of acute urinary retention, and mean cardiac frequency (calculated from the recorded cardiac frequency 3 times a day) are recorded, confusion, acute angle glaucoma.	24 hours after the surgery
Pharmacokinetics:Plasmatic and cerebrospinal fluid concentration of nefopam	Plasmatic and cerebrospinal fluid concentration of nefopam is measured.	2 hours after the first oral administration of nefopam or Placebo.
Pharmacokinetics:Plasmatic and cerebrospinal fluid concentration of nefopam-beta-D-glucuronide	Plasmatic and cerebrospinal fluid concentration of nefopam-beta-D-glucuronide is measured.	2 hours after the first oral administration of nefopam or Placebo.
Pharmacokinetics:Plasmatic and cerebrospinal fluid concentration of nefopam-N-oxyde	Plasmatic and cerebrospinal fluid concentration of nefopam-N-oxyde is measured.	2 hours after the first oral administration of nefopam or Placebo.
Pharmacokinetics:Plasmatic and cerebrospinal fluid concentration of nefopam-N-demethyl	Plasmatic and cerebrospinal fluid concentration of nefopam-N-demethyl is measured.	2 hours after the first oral administration of nefopam or Placebo.
Pharmacokinetics:Plasmatic and cerebrospinal fluid concentration of Nefopam hydrochloride	Plasmatic and cerebrospinal fluid concentration of Nefopam hydrochloride is measured.	2 hours after the first oral administration of nefopam or Placebo.
Persistent postoperative pain - DN4 (or DN2 by phone)	The DN4 questionnaire (or DN2 questionnaire if the visit is realized by phone) ("Douleurs Neuropathiques 4/2" = Neuropathic pain 4/2 in french) is recorded to investigate persistent postoperative pain defined as pain on the operated knee 3 months after the surgery.	3 months after the surgery
Persistent postoperative pain - DN4	The DN2 questionnaire ("Douleurs Neuropathiques 2" = Neuropathic pain 2 in french, abbreviated DN4 questionnaire) is recorded by phone if the 3 months visit is realized out of time. If the score is positive (>=3), the DN4 is recorded at hospital within 2 weeks post the 3 months visit.	4 months after the surgery

Collaborators and Investigators

• Sponsor: Hospices Civils de Lyon
• Investigators: Principal Investigator: Frederic AUBRUN, MD/PHD, Département d'Anesthésie Réanimation, Hopital de la Croix Rousse

Study record dates

Study Major Dates

• Study Start (Actual): June 29, 2021
• Primary Completion (Estimated): June 30, 2026
• Study Completion (Estimated): November 15, 2026

Study Registration Dates

• First Submitted: September 29, 2020
• First Submitted That Met QC Criteria: September 29, 2020
• First Posted (Actual): October 6, 2020

Study Record Updates

• Last Update Posted (Estimated): April 22, 2024
• Last Update Submitted That Met QC Criteria: April 19, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: total knee arthroplasty; Oral; postoperative pain; hyperalgesia; Nefopam; cerebrospinal fluid and plasma concentration
• Additional Relevant MeSH Terms: Pathologic Processes; Postoperative Complications; Pain; Neurologic Manifestations; Pain, Postoperative; Physiological Effects of Drugs; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Nefopam
• Other Study ID Numbers: 69HCL20_0111; 2020-002955-40 (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