Evaluation of Nefopam and Sodium Chloride in Multimodal Analgesia Post-Total Hip Arthroplasty: A Randomized Controlled Trial

The primary objective of this study is to evaluate the **efficacy** of nefopam, administered either as a bolus or continuous infusion (IVSE), compared to placebo, in reducing the consumption of morphine within 24 hours following total hip arthroplasty. This is conducted within the framework of a multimodal analgesia regimen that includes at least paracetamol and a non-steroidal anti-inflammatory drug (NSAID). The clinical relevance of this objective lies in potentially minimizing opioid use, thereby reducing opioid-related side effects and improving postoperative recovery.

Secondary objectives include:

• Self-assessment of maximum pain using the Simplified Numerical Scale (ENS).
• Evaluating the efficacy of nefopam in bolus or IVSE versus placebo on early functional recovery.
• Assessing the efficacy of nefopam in continuous or intermittent infusion versus placebo on acute, chronic, and neuropathic pain scores six months post-surgery within a multimodal analgesia framework.
• Evaluating morphine analgesic consumption in the hospital.
• Assessing chronic pain at six months (at rest and during walking) using a standardized telephone questionnaire.
• Evaluating the tolerance profile of nefopam based on two commonly used administration modes: incidence of nausea, vomiting, malaise, flushing, and urinary catheterization between bolus and IVSE groups.
• Evaluating the adverse effects of morphine (nausea, vomiting, sedation, respiratory depression, respiratory complications, pruritus, constipation) in the presence or absence of nefopam, and according to the two commonly used administration modes: nefopam bolus versus IVSE versus placebo.
• Conducting a budget impact analysis of the generalization of the recommended strategy following the clinical study results over a five-year horizon, from the perspective of health insurance and hospital settings.

The clinical trial involves participants undergoing **total hip arthroplasty**. The sponsor has not provided information regarding the total number of participants. The study population includes both male and female subjects aged 18 years and older, who are in general good health and are scheduled for primary or secondary total hip replacement surgery. Participants are required to be fluent in French and must be receiving postoperative paracetamol and ketoprofen. The trial excludes vulnerable populations. Participants are selected based on their affiliation with a social security system and must provide informed consent. The study does not specify any particular lifestyle considerations such as diet or physical activity.

The clinical trial is designed to evaluate the efficacy of **nefopam** in reducing morphine consumption following total hip arthroplasty. This study is a randomized, double-blind, controlled trial, comparing nefopam administered either as a bolus or continuous infusion against a placebo. The trial is categorized as a low-intervention study and is expected to span from September 2023 to September 2026. Participants will be involved for a maximum of one day, with the primary endpoint being the cumulative morphine consumption within 24 hours post-surgery. Secondary endpoints include self-assessed pain levels, early functional recovery, and the safety profile of nefopam.

Study visits are structured as follows: an initial inclusion visit (screening) to confirm eligibility based on criteria such as age, language proficiency, and planned hip arthroplasty. Participants must provide informed consent and be scheduled for surgery under general or spinal anesthesia without intrathecal morphine. Follow-up visits will occur at 24 hours post-surgery to assess primary and secondary endpoints, including pain evaluation and functional recovery. An end-of-study visit will be conducted at the time of hospital discharge or on the fifth postoperative day, whichever comes first. A telephone follow-up at six months will assess long-term outcomes such as chronic pain and functional recovery.

Participants may be withdrawn from the study if they experience severe adverse events, such as convulsions or anaphylaxis, or if they withdraw consent. The trial aims to provide insights into the potential benefits of nefopam in multimodal analgesia, with implications for reducing opioid consumption and improving postoperative recovery in patients undergoing hip arthroplasty.

The clinical trial involves the administration of **nefopam**, marketed under the name ACUPAN 20 mg/2 mL, solution injectable. This medication is provided in the form of a **solution for injection** and is manufactured by BIOCODEX. The active substance, nefopam, is of chemical origin and is classified under the ATC code N02BG06. The maximum daily dose of nefopam is 120 mg, with a total maximum dose of 120 mg over the treatment period. The administration route is **intravenous perfusion**, and the trial includes both bolus and continuous infusion (IVSE) methods. The dosing schedule is adapted to the Marketing Authorization, with the IVSE method differing from the authorized bolus method, a common practice in clinical settings.

The comparator treatment in the trial is **sodium chloride**, marketed as CHLORURE DE SODIUM 0,9 % BAXTER, solution pour perfusion en poche. This product is a **solution for infusion** and is produced by BAXTER SAS. The active substance, sodium chloride, is also of chemical origin and is classified under the ATC code B05XA03. The maximum daily dose and total dose for sodium chloride are both 148 mL. The administration route is **intravenous perfusion**, and the solution is used as a standard-of-care therapy in the trial. The sodium chloride solution serves as a placebo in the context of evaluating the efficacy of nefopam in multimodal analgesia following total hip arthroplasty.

Efficacy in the clinical trial titled "NEFARTHRO - Effets précoces et tardifs du néfopam dans l'analgésie multimodale après arthroplastie totale de hanche" will be assessed using both primary and secondary endpoints. The primary endpoint is the cumulative consumption of morphine, measured in milligrams of intravenous morphine, within the first 24 hours post-surgery. This includes titration in the Post-Anesthesia Care Unit (PACU).

Secondary endpoints include several parameters: self-assessed maximum pain using the Simplified Numeric Scale (ENS) ranging from 0 (no pain) to 10 (maximum pain) at rest in the PACU, at rest and during walking between PACU discharge and 24 hours post-surgery, at 24 hours, and on the day of discharge. Functional recovery will be evaluated through the time to resume walking, leave the room, climb stairs, and the length of hospital stay, assessed using a standardized questionnaire at 24 hours and on day 5 or at discharge. Long-term functional recovery will be assessed by the time to abandon walking aids, evaluated via a standardized telephone questionnaire at 6 months.

Additional secondary endpoints include the consumption of opioid analgesics in the hospital between the first and fifth day or at discharge, chronic pain at 6 months (at rest and during walking) assessed via a standardized telephone questionnaire, and early and late **neuropathic pain** scores using the standardized DN2 score at 24 hours and 6 months. The safety profile of nefopam will be monitored by collecting all serious adverse events, such as seizures requiring anticonvulsants, confusion, or hallucinations, and anaphylaxis of grade II or higher during administration. Non-serious adverse events will also be recorded. The adverse effects of morphine, including nausea, vomiting, pruritus, urinary retention, and abnormal drowsiness, will be analyzed separately at 24 hours and on day 5 or at discharge. Lastly, the economic impact of the recommended strategy's generalization will be evaluated from the perspective of the health insurance system and hospitals over a 5-year horizon.