Analgesic Effects of Low-dose S-ketamine in Major Spine Fusion Surgery

Study Overview
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Brief Summary
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Despite opioid-based multimodal analgesia, moderate-to-severe pain remains a big problem in patients following multi-segment spinal fusion. As a N-methyl-D-aspartate receptor antagonist, S-ketamine has prominent analgesic effects through activating receptors both in the brain and in the spinal cord, inhibiting the excitatory postsynaptic potential, and thus blunting nociception transmission. This randomized controlled trial is designed to investigate whether perioperative S-ketamine infusion can decrease pain intensity after major spine fusion surgery.

Detailed Description
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Multi-segment spinal fusion usually lasts long and produces significant trauma. Patients following this surgery are at high risk of developing moderate-to-severe pain. In a large sample size cohort study investigating pain severity following 179 kinds of surgical procedures, multi-segment spinal fusion ranked the third with a median pain score of 6.6 (assessed with an 11-point scale, where 0=no pain and 10= the worst pain) and a median morphine consumption of 27 mg during the first postoperative day. High-dose opioids are associated with adverse effects including respiratory depression, sedation, nausea and vomiting, pruritus, and constipation, which are harmful for early postoperative recovery. A previous study showed that about 50% of patients are taking opioids for chronic pain at 3 months after spinal fusion surgery. Chronic pain is considered to be a result of poorly controlled acute postoperative pain. Thus, multimodal analgesia aiming at improving analgesia while decreasing opioid consumption is advocated to control acute postsurgical pain, in order to promote perioperative recovery and prevent chronic pain. Racemic ketamine, a commonly used N-methyl-D-aspartate receptor antagonist, is a mixture of equal parts of two optical isomers including R-(-)-ketamine and S-(+)-ketamine. It has prominent analgesic effects through activating receptors both in the brain and in the spinal cord, inhibiting the excitatory postsynaptic potential, and thus blunting nociception transmission. Additionally, studies also showed that, when used within the appropriate time, ketamine reduces pain-related sensitization that aggravates postoperative pain. Thus, ketamine is recommended as a part of a multimodal analgesia regimen in clinical practice, especially for patients undergoing major orthopedic surgery. However, the reported psychotropic side effects limit the clinical use of racemic ketamine. S-ketamine, an S-isomer of ketamine, is twice as potent as the racemic mixture in analgesia, and produces fewer side effects than the racemic ketamine. How, there are only a few studies exploring analgesic effect of S-ketamine in spine fusion surgery. In opioid-dependent patients, Nielsen et al. reported that intraoperative S-ketamine infusion reduced opioid consumption within 24 hours and relieved back pain intensity at 6 months, it also decreased the daily opioid use at 1 year after spinal surgery. On the other hand, the study of Brinck et al. did not found any superiority of intraoperative S-ketamine in reducing oxycodone consumption within 48 hours after lumbar fusion surgery in opioid-naive patients. Considering these inconsistent results, the effects of S-ketamine in spinal surgery require further clarification. This trial is designed to investigate the analgesic effect of S-ketamine infused both intraoperatively and postoperatively in patients undergoing multi-segment spine infusion surgery.

Official Title
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Analgesic Effects of Low-dose S-ketamine in Patients Undergoing Major Spine Fusion Surgery: A Double-blinded, Randomized Controlled Trial

Conditions
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S-ketamine, Postoperative Analgesia, Spine Fusion

Intervention / Treatment
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* Drug: S-ketamine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients aged between 18 and 80 years. Scheduled to undergo multi-segment (≥2) spine fusion surgery. Agreed to receive postoperative patient-controlled analgesia. Exclusion Criteria: Refused to participant in this trial. Poor blood pressure control in those with hypertension (BP >160/100 mmHg in the ward). Previous history of hyperthyroidism or pheochromocytoma. Previous history of schizophrenia, epilepsy or Parkinson disease. History of sick sinus syndrome, bradycardia (HR <50 beat per min), or atrioventricular block of grade II or higher without pacemaker. Severe heart dysfunction (New York Heart Association functional classification 4), hepatic insufficiency (Child-Pugh grade C), renal insufficiency (serum creatinine of 442 μmol/L or above, or requirement of renal replacement therapy), or ASA classification IV or above. Unable to complete preoperative assessment due to severe dementia or language barrier. Any other conditions that were considered unsuitable for the study participation.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: S-ketamine group<br>After anesthesia induction, a bolus of 0.15 mg/kg S-ketamine is injected intravenously about 30 min before incision; this is followed by a continuous infusion at a rate of 0.15 mg/kg/h until 1 hour before the end of surgery. After surgery, patient-controlled analgesia is provided. The pump is established with S-ketamine 25 mg, dexmedetomidine 100 microgram, and sufentanil 100 microgram, diluted with normal saline to 100 ml. The pump is programmed to deliver 2-ml boluses with a background infusion rate at 1 ml /h and a 10-min lockout interval. | Drug: S-ketamine<br>* After anesthesia induction, a bolus of 0.15 mg/kg S-ketamine is injected intravenously about 30 min before incision; this is followed by a continuous infusion at a rate of 0.15 mg/kg/h until 1 hour before the end of surgery. After surgery, patient-controlled analgesia is provided. The pump is established with S-ketamine 25 mg, dexmedetomidine 100 microgram, and sufentanil 100 microgram, diluted with normal saline to 100 ml. The pump is programmed to deliver 2-ml boluses with a background infusion rate at 1 ml /h and a 10-min lockout interval.<br>|
| Placebo Comparator: Control group<br>After anesthesia induction, a bolus of placebo (normal saline) in the same volume is injected intravenously about 30 min before incision; this is followed by a continuous infusion of placebo at the same rate until 1 hour before the end of surgery. After surgery, patient-controlled analgesia is provided. The pump is established with placebo, dexmedetomidine 100 microgram and sufentanil 100 microgram, diluted with normal saline to 100 ml. The pump is programmed to deliver 2-ml boluses with a background infusion rate at 1 ml /h and a 10-min lockout interval. | Drug: Placebo<br>* After anesthesia induction, a bolus of placebo (normal saline) in the same volume is injected intravenously about 30 min before incision; this is followed by a continuous infusion of placebo at the same rate until 1 hour before the end of surgery. After surgery, patient-controlled analgesia is provided. The pump is established with placebo, dexmedetomidine 100 microgram and sufentanil 100 microgram, diluted with normal saline to 100 ml. The pump is programmed to deliver 2-ml boluses with a background infusion rate at 1 ml /h and a 10-min lockout interval.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The percentage of patients with moderate-to-severe pain in the first 48 hours after surgery. | Moderate-to-severe pain is defined as a numeric rating scale (NRS; an 11-point scale where 0=no pain and 10=the worst pain) pain score ≥4. | Up to 48 hours after surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Opioid consumption during anesthesia | Opioid consumption in equivalent-dose of sufentanil | From induction to end of anesthesia | 
| Cumulative opioid consumption after surgery | Opioid consumption in equivalent-dose of sufentanil | From end of anesthesia to the 5th day after surgery | 
| NRS pain score at rest and with movement | Pain is assessed with a numeric rating scale (NRS; an 11-point scale where 0=no pain and 10=the worst pain) | Up to postoperative day 5 | 
| The percentage of using rescue analgesics | The percentage of using rescue analgesics | Up to postoperative day 5 | 
| Subjective sleep quality | Subjective sleep quality is assessed with NRS scale (0 indicates the best sleep and 10 indicates the worst sleep) | Up to postoperative day 5 | 
| Time to first ambulation | Time to first ambulation | Up to 30 days after surgery | 
| Quality of recover after surgery | Quality of recover is assessed with the Quality of Recovery scale, a 15-item Q-15 questionnaire with score ranges from 0 to 150, with higher score indicating better recovery. | On the third day after surgery | 
| Length of hospital stay after surgery | Length of hospital stay after surgery | Up to 30 days after surgery | 
| The percentage of taking oral analgesics | The percentage of taking oral analgesics | On the 30th day after surgery | 
| The severity of anxiety and depression | The severity of anxiety and depression is assessed with the Hospital Anxiety and Depression Scale, a 14-item questionnaire with scores range from 0 to 21 for either anxiety or depression. Higher score indicates more severe symptom. | On the 30th day after surgery | 
| The incidence of postoperative complications and mortality | The incidence of postoperative complications and mortality | Up to 30 days after surgery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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S-ketamine, Postoperative Analgesia, Spine Fusion