Post-operative Analgesic Effect of Oral Nefopam

Study Overview
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Brief Summary
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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).

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

Conditions
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Postoperative Pain After a Total Knee Arthroplasty

Intervention / Treatment
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* Drug: Oral nefopam
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NEFOPAM 60mg PO/ 8 hours<br>Oral administration of nefopam 60mg 2 hours before the surgery following by 60mg each 8h for 24h. | Drug: Oral nefopam<br>* 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.<br>|
| Placebo Comparator: Placebo<br>Oral administration of a placebo 2 hours before the surgery following by one administration each 8h for 24h. | Drug: Placebo<br>* 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<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Nefopam, Oral, postoperative pain, hyperalgesia, cerebrospinal fluid and plasma concentration, total knee arthroplasty