Preoperative Ketamine Has no Preemptive Analgesic Effect in Patients Undergoing Colon Surgery.

Study Overview
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Brief Summary
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The analgesic properties of ketamine are associated with its non-competitive antagonism of the N-methyl-D-aspartate receptor; these receptors exhibit an excitatory function on pain transmission and this binding seems to inhibit or reverse the central sensitization of pain. In the literature, the value of this anesthetic for preemptive analgesia in the control of postoperative pain is uncertain. The objective of this study was to ascertain whether preoperative low-dose ketamine reduces postoperative pain and morphine consumption in adults undergoing colon surgery. In a double-blind, randomized trial, 48 patients were studied. Patients in the ketamine group received 0.5 mg/kg intravenous ketamine before surgical incision, while the control group received normal saline. The postoperative analgesia was achieved with a continuous infusion of morphine at 0.015 mg∙kgˉ¹∙hˉ¹ with the possibility of 0.02 mg/kg bolus every 10 min. Pain was assessed using the Visual Analog Scale (VAS), morphine consumption, and hemodynamic parameters at 0, 1, 2, 4, 8, 12, 16, and 24 hours postoperatively. We quantified times to rescue analgesic (Paracetamol), adverse effects and patient satisfaction.

Detailed Description
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In spite of the techniques we have at our disposal and the elementary nature of incisional pain, optimal pain management remains a challenge. Because the severity of early postoperative pain relates to residual pain after some types of surgery, perioperative pain management can considerably influence the long-term quality of life in patients. Woolf, in 1983, first introduced the theory of preemptive analgesia to attenuate postoperative pain, confirming the presence of a central factor of post-injury pain hypersensitivity in experimental research. After this, experimental studies showed that various anti-nociceptive methods applied before injuries were more effective in reducing post-injury central sensitization in contrast to administration after injury. After activation of C-fibers by noxious stimuli, sensory neurons become more sensitive to peripheral inputs, a process called central sensitization. 'Wind up, another mechanism activating spinal sensory neurons, is seen after reiterated stimulation of C-fibers. These sensitizations produce c-fos expression in sensory neurons, and are related to the activation of N-methyl-D-aspartic acid (NMDA) and neurokinin receptors. These genes produce long-lasting changes in the pain-processing system, resulting in hyperexcitation. According to Wall, protection of sensory neurons against central sensitization may provide relief from pain after surgery. Based on this assumption, preemptive analgesia has been recommended as an effective aid to control postsurgical pain. NMDA antagonists have been demonstrated to block the induction of central sensitization and revoke the hypersensitivity once it is established. Ketamine is an old drug that is increasingly being considered for the treatment of acute and chronic pain. Its pharmacology and mechanism of action as an NMDA receptor antagonist are adequately known, but in clinical practice it presents irregular results. Since ketamine is an NMDA-receptor antagonist, it is supposed to avoid or revoke central sensitization, and thus to attenuate postoperative pain. This antihyperalgesic action can be achieved by smaller doses than those required for anesthesia. Small-dose ketamine has been specified as not more than 1 mg/kg when given as an iv bolus, and not higher than 20 µg∙kgˉ¹∙minˉ¹ when given as a constant infusion. Low-doses preemptive ketamine administered iv seem to reduce postoperative pain and/or analgesic consumption. According to one study, a single dose of ketamine 1 mg/kg, when administered in conjunction with local anesthetics, opioids or other anesthetics, provides good postoperative pain control. Regardless of the overwhelming effectiveness of preemptive ketamine in animal experiments, clinical reports are mixed; some authors have described positive effects while others have not. While early reviews of clinical findings were mostly contradictory, there is still conviction in the effectiveness of preemptive analgesia. To our knowledge, no prior controlled study has determined the effectiveness of preoperative low-dose iv ketamine as contrasted with placebo in adults after open colon surgery. Thus, this clinical trial was designed to examine the postoperative analgesic effectiveness and opioid-sparing effect of single low-dose iv ketamine in contrast with placebo administered preoperatively.

Official Title
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Preoperative Low-dose Ketamine Has no Preemptive Analgesic Effect in Opioid-naïve Patients Undergoing Colon Surgery When Nitrous Oxide is Used

Conditions
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Pain, Postoperative

Intervention / Treatment
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* Drug: Ketamine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: age between 18 and 75 years normal Body Mass Index (18.5 - 24.9) American Society of Anesthesiologists (ASA) class I, II or III elective surgery surgery time between 60-150 min understanding of the Visual Analog Scale (VAS) lack of allergies or intolerance to anesthetics absence of psychiatric illness Exclusion Criteria: cognitive deterioration inability to use the Patient-Controlled-Analgesia (PCA) device history of chronic pain syndromes chronic use of analgesics, sedatives, opioids or steroids liver or hematologic disease, history of drug or alcohol abuse intolerance to ketamine or Paracetamol.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Control<br>In the operating room, the anesthesiologist administered 50 mL of 0.9% saline intravenously to patients in the control group 30 minutes before surgical incision. | |
| Experimental: Ketamine<br>In the operating room, the anesthesiologist administered 0.5 mg/kg of ketamine chlorhydrate in 50 mL of 0.9 % saline intravenously to patients in the ketamine group 30 minutes before surgical incision. (a single dose). | Drug: Ketamine<br>* In the operating room, the anesthesiologist administered 0.5 mg/kg of ketamine chlorhydrate in 50 mL of 0.9 % saline intravenously to patients in the ketamine group 30 minutes before surgical incision (a single dose).<br>* Other names: ketamine chlorhydrate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Visual Analog Scale (VAS) score | The VAS represents a scale with the lowest value as 0 (no pain) and the highest value as 10 (worst imaginable pain). | at 0 hours postoperatively (arrival at recovery room) | 
| Visual Analog Scale (VAS) score | The VAS represents a scale with the lowest value as 0 (no pain) and the highest value as 10 (worst imaginable pain). | at 1 hour postoperatively | 
| Visual Analog Scale (VAS) score | The VAS represents a scale with the lowest value as 0 (no pain) and the highest value as 10 (worst imaginable pain). | at 2 hours postoperatively | 
| Visual Analog Scale (VAS) score | The VAS represents a scale with the lowest value as 0 (no pain) and the highest value as 10 (worst imaginable pain). | at 4 hours postoperatively | 
| Visual Analog Scale (VAS) score | The VAS represents a scale with the lowest value as 0 (no pain) and the highest value as 10 (worst imaginable pain). | at 8 hours postoperatively | 
| Visual Analog Scale (VAS) score | The VAS represents a scale with the lowest value as 0 (no pain) and the highest value as 10 (worst imaginable pain). | at 12 hours postoperatively | 
| Visual Analog Scale (VAS) score | The VAS represents a scale with the lowest value as 0 (no pain) and the highest value as 10 (worst imaginable pain). | at 16 hours postoperatively | 
| Visual Analog Scale (VAS) score | The VAS represents a scale with the lowest value as 0 (no pain) and the highest value as 10 (worst imaginable pain). | at 24 hours postoperatively | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| morphine consumption | The cumulative amounts of morphine (mg) administered through the Patient-Controlled-Analgesia (PCA) device as a basal infusion and the incremental supplemental bolus required by the patient were documented at these time points. | at 0, 1, 2, 4, 8, 12, 16, and 24 hours postoperatively | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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colon surgery, ketamine, patient-controlled-analgesia, preemptive analgesia