Evaluation of Perioperative Intravenous Esketamine on Postoperative Craniotomy Pain in Drug-Resistant Temporal Lobe Epilepsy: A Randomized Controlled Trial

The primary objective of this study is to evaluate the effect of adding **s-ketamine** to a multimodal pain management regimen, which includes acetaminophen and opioids, compared to a placebo with the same regimen, on total opioid consumption following craniotomy in patients with drug-resistant temporal lobe epilepsy. The total opioid consumption will be assessed five times within the first seven days post-operation. This is clinically relevant as it aims to reduce opioid use, which is associated with significant side effects and dependency risks, thereby potentially improving postoperative pain management and patient outcomes.

Secondary objectives include assessing postoperative pain scores using the Visual Analogue Scale (VAS) and Numeric Rating Scale (NRS) during the first seven days post-operation and at three and six months. Additionally, the study will evaluate the length of hospital stay, various psychological parameters, patient health-related quality of life, and the incidence of adverse events. These secondary endpoints provide a comprehensive understanding of the broader impacts of s-ketamine on recovery and quality of life following craniotomy.

The clinical trial focuses on patients experiencing **post-craniotomy headache** following elective resective surgery for drug-resistant temporal lobe epilepsy. The study population includes both male and female participants over the age of 18, who have been diagnosed with drug-resistant epilepsy characterized by chronic, focal epilepsy, and are not seizure-free with antiepileptic medication, with no further medication options due to adverse effects. Participants have provided signed informed consent for trial participation. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed to evaluate the effect of **esketamine** on acute and chronic postoperative pain following craniotomy in patients with drug-resistant temporal lobe epilepsy. This study is a prospective, randomized, double-blind, placebo-controlled trial. Participants will be randomly assigned to receive either esketamine or a placebo, both administered via **intravenous infusion**. The trial will span a period of approximately seven years, with an estimated recruitment start date of August 14, 2018, and an estimated end date of December 31, 2025.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age over 18 years, undergoing elective resective surgery for drug-resistant temporal lobe epilepsy, and providing signed informed consent. The primary endpoint is the total postoperative opioid consumption measured on the 7th postoperative day, with interim assessments at 24, 48, 72, and 96 hours postoperatively. Secondary endpoints include the length of hospital stay, patient health-related quality of life, psychological parameters, adverse events, and postoperative pain scores during the first seven postoperative days.

The expected length of participant involvement is up to seven days post-surgery, with the possibility of early termination from the study if adverse events occur or if the participant withdraws consent. The trial aims to provide insights into the efficacy of esketamine as part of a multimodal pain management approach, potentially reducing opioid consumption and improving postoperative outcomes for patients undergoing craniotomy.

The clinical trial involves the administration of **esketamine**, a chemical active substance, as the experimental medication. Esketamine is provided in the form of a solution for injection or infusion. The administration route is via **intravenous infusion**. The dosing regimen specifies a maximum daily dose of 2.4 mg/kg and a maximum total dose of 5.05 mg/kg over a treatment period of up to 2 days. The trial aims to evaluate the effect of esketamine on postoperative pain management in patients undergoing craniotomy for drug-resistant temporal lobe epilepsy. Participant compliance with the dosing schedule will be monitored throughout the study.

The study also includes the use of **sodium chloride** as a non-experimental treatment, serving as a placebo comparator. Sodium chloride is similarly provided as a solution for injection or infusion and is administered via intravenous infusion. The dosing parameters for sodium chloride mirror those of esketamine, with a maximum daily dose of 2.4 mg/kg and a maximum total dose of 5.05 mg/kg over a 2-day period. This placebo is used to assess the efficacy of esketamine in reducing opioid consumption when added to a multimodal pain management approach, which includes acetaminophen and opioids.

Efficacy in this clinical trial will be assessed by evaluating the effect of adding **s-ketamine** to a multimodal pain management approach on total opioid consumption after craniotomy in patients with drug-resistant temporal lobe epilepsy. The primary endpoint is the total postoperative opioid consumption measured on the 7th postoperative day, with interim measurements at 24, 48, 72, and 96 hours postoperatively. This will provide a comprehensive assessment of opioid use over the first week following surgery.

Secondary endpoints include the length of hospital stay, patient health-related quality of life assessed using the RAND SF-36 questionnaire, psychological parameters evaluated through specific questionnaires, adverse events, and postoperative pain scores measured using the Visual Analog Scale (VAS) and Numeric Rating Scale (NRS) during the first 7 postoperative days. These secondary endpoints will offer additional insights into the broader impact of the treatment on patient recovery and well-being.