Comparison of Low-Dose Esketamine Hydrochloride and Ketamine Hydrochloride for Severe Acute Pain in Emergency Departments: A Randomized Controlled Double-Blind Study

The primary objective of this randomized controlled double-blind study is to **compare** the proportion of patients experiencing at least one **psychodysleptic** effect in the control and active groups during the first hour of treatment. This is clinically relevant as it aims to evaluate the safety profile of low-dose **esketamine** versus low-dose **ketamine** in the management of severe acute pain in emergency departments, focusing on the potential adverse effects that could impact patient care and treatment decisions.

Secondary objectives include:

• Assessing the intensity of psychodysleptic effects as described by patients, which provides insight into the subjective experience and tolerability of the treatment.
• Comparing the analgesic efficacy of the two molecules during the first hour of treatment by evaluating the evolution of EN pain scores over time, the proportion of patients reporting relief (EN ≤3/10), and the rate of recourse to additional analgesia ("rescue analgesia"). This is crucial for determining the effectiveness of the treatments in providing pain relief.
• Defining the proportion of other possible adverse effects or abnormal vital constants measured every 15 minutes from t0 to t0 + 60 minutes, which is important for understanding the broader safety profile of the treatments.

The clinical trial involves **adult patients** aged 18 years and older, experiencing **severe acute pain**. The study population includes both male and female participants, with no vulnerable populations selected. Participants are required to have consulted the department for a medical or traumatic pathology responsible for acute pain, defined as pain less than 7 days old and rated 6 or higher on the EN pain scale. All participants must have provided free and informed consent and be affiliated with a social security scheme. The sponsor has not provided information regarding the total number of participants. The selection criteria ensure that the study population is representative of individuals experiencing significant acute pain, without specific lifestyle considerations such as diet or physical activity being highlighted.

The clinical trial is designed as a **randomized**, **controlled**, **double-blind** study to evaluate the effects of low-dose **esketamine** versus low-dose **ketamine** in patients experiencing severe acute pain in emergency departments. The primary objective is to compare the proportion of patients experiencing at least one psychodysleptic effect within the first hour of treatment. The trial will utilize the SERSDA scale to assess these effects every five minutes from the start of infusion to 60 minutes post-infusion. Secondary endpoints include assessing the intensity of psychodysleptic effects, comparing analgesic efficacy, and identifying other potential adverse effects or abnormal vital signs.

The trial is expected to commence recruitment on April 1, 2025, and conclude by September 1, 2027. Participants will be involved in the study for a maximum of one day, corresponding to the treatment period. The inclusion criteria specify that participants must be adults aged 18 or over, experiencing severe acute pain (pain score ≥6 on the EN scale), and must have provided informed consent. Exclusion criteria are not specified in the provided data.

Study visits will include an initial screening visit to confirm eligibility based on the inclusion criteria. During the treatment visit, participants will receive either ketamine at a dose of 0.3 mg/kg or esketamine at a dose of 0.15 mg/kg via **intravenous injection**. The primary and secondary endpoints will be assessed during this visit. The end-of-study visit will coincide with the completion of the treatment and assessment period. Participants may be terminated early from the study if they withdraw consent or if any adverse events necessitate discontinuation of treatment.

The clinical trial involves the administration of two experimental medications for the treatment of severe acute pain in emergency departments. The first medication is **KETAMINE RENAUDIN 50 mg/ml**, a solution for injection containing **ketamine hydrochloride** as the active substance. This pharmaceutical form is a solution injectable, and it is administered via **intravenous injection**. The maximum daily dose is 0.3 mg/kg, with a total dose not exceeding 0.3 mg/kg over a treatment period of one day. The product is manufactured by Laboratoire Renaudin and is not a paediatric formulation. The chemical origin of the active substance is confirmed, and the product is authorized for use in France.

The second medication is **ESKETAMINE IDD 25 mg/mL**, a solution for injection or infusion containing **esketamine hydrochloride**. This medication is also administered through **intravenous injection**. The maximum daily dose is 0.15 mg/kg, with a total dose not exceeding 0.15 mg/kg over a one-day treatment period. Manufactured by International Drug Development, this product is similarly not a paediatric formulation and is chemically derived. It holds authorization for use in France under the marketing authorization number 34009 550 737 8 9.

Both medications are used in a randomized controlled double-blind study to compare the proportion of patients experiencing psychodysleptic effects during the first hour of treatment. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment beyond the two investigational drugs. Participant compliance is monitored through adherence to the dosing schedules and administration routes specified for each medication.

Efficacy in this clinical trial will be assessed by evaluating the **psychodysleptic effects** experienced by patients receiving either ketamine or esketamine for severe acute pain in emergency departments. The primary endpoint is the proportion of patients experiencing at least one psychodysleptic effect in both the control group (ketamine IV 0.3 mg/kg) and the active group (esketamine IV 0.15 mg/kg). This will be measured using the SERSDA (Side Effects Rating Scale for Dissociate Anesthetics) scale, which includes 9 items. Patients will assess the presence of any of these items every 5 minutes from the start of infusion (t0) to 60 minutes post-infusion (t0 + 60 minutes).

Secondary endpoints include assessing the intensity of psychodysleptic effects as described by patients, comparing the analgesic efficacy of the two molecules during the first hour of treatment, and evaluating the evolution of EN pain scores over time. Additionally, the trial will measure the proportion of patients reporting pain relief (EN ≤ 3/10) and the rate of recourse to additional analgesia, known as "rescue analgesia." The trial will also define the proportion of other possible adverse effects or abnormal vital signs, which will be measured every 15 minutes from t0 to t0 + 60 minutes.