NefPO: Post-operative Analgesic Effect of Oral Nefopam

Sponsor

Hospices Civils de Lyon (Other)

Overall Status

Recruiting

CT.gov ID

NCT04576078

Collaborator

(none)

Enrollment

Location

Arms

28.6

Anticipated Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

High tibial osteotomy is a common procedure in orthopedic surgery; it is highly standardized (incision location and size, the volume of periosteal lesion, implanted material). It is associated with short recovery period but intense postoperative pain during first 24 hours. The surgical wound has a comprehensive innervation by saphenous and a terminal muscular branches of tibial nerve. These conditions allow reproducible measurements of analgesic drugs effects in postoperative period.

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 high tibial osteotomy. 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).

Condition or Disease	Intervention/Treatment	Phase
Postoperative Pain After a High Tibial Osteotomy	Drug: Oral nefopam Drug: Placebo	Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

58 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Triple (Participant, Care Provider, Investigator)

Masking Description:

Nefopam has a distinct bitter taste. A taste masking compound non interfering with chemical properties of the drug is used in both arms. Orally given mixture (nefopam or placebo) is prepared by an independent nurse in a separate location and given to a patient in patient's ward.

Primary Purpose:

Treatment

Official Title:

Postoperative Analgesic Effect of Orally Administrated Nefopam After a High Tibial Osteotomy : a Randomized Controlled Trial

Actual Study Start Date :

Jun 29, 2021

Anticipated Primary Completion Date :

Jul 30, 2023

Anticipated Study Completion Date :

Nov 15, 2023

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

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

Secondary Outcome Measures

Hyperalgesia - Pressure Pain Threshold [24 hours after the surgery]
The pressure pain threshold is determined using a Von Frey monofilaments on both (operated and contralateral) knees 24 hours after incision.
Hyperalgesia - Punctate Pain Intensity [24 hours after the surgery]
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.
Hyperalgesia - Allodynia zone [24 hours after the surgery]
The extension of allodynia around the wound is measured using a calibrated brush (100 mNewton) 24 hours after incision.
Pain intensity [24 hours after the surgery and 3 months after the surgery]
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)
Self reported safety outcomes [24 hours after the surgery]
Nausea and vomiting, unusual sweating, drowsiness, hallucinations, nightmares, palpitations, irritability
Measures Safety outcomes [24 hours after the surgery]
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.
Pharmacokinetics:Plasmatic and cerebrospinal fluid concentration of nefopam [2 hours after the first oral administration of nefopam or Placebo.]
Plasmatic and cerebrospinal fluid concentration of nefopam is measured.
Pharmacokinetics:Plasmatic and cerebrospinal fluid concentration of nefopam-beta-D-glucuronide [2 hours after the first oral administration of nefopam or Placebo.]
Plasmatic and cerebrospinal fluid concentration of nefopam-beta-D-glucuronide is measured.
Pharmacokinetics:Plasmatic and cerebrospinal fluid concentration of nefopam-N-oxyde [2 hours after the first oral administration of nefopam or Placebo.]
Plasmatic and cerebrospinal fluid concentration of nefopam-N-oxyde is measured.
Pharmacokinetics:Plasmatic and cerebrospinal fluid concentration of nefopam-N-demethyl [2 hours after the first oral administration of nefopam or Placebo.]
Plasmatic and cerebrospinal fluid concentration of nefopam-N-demethyl is measured.
Pharmacokinetics:Plasmatic and cerebrospinal fluid concentration of Nefopam hydrochloride [2 hours after the first oral administration of nefopam or Placebo.]
Plasmatic and cerebrospinal fluid concentration of Nefopam hydrochloride is measured.
Persistent postoperative pain - DN4 [3 months after the surgery]
The DN4 questionnaire ("Douleurs Neuropathiques 4" = Neuropathic pain 4 in french) is recorded to investigate persistent postoperative pain defined as pain on the operated knee 3 months after the surgery.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

adult patients scheduled for a high tibial osteotomy 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