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

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

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.

Study Overview

• Status: Completed
• Conditions: Pain, Postoperative
• Intervention / Treatment: Drug: Ketamine

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 48
• Phase: Phase 4

Contacts and Locations

Study Locations

• Spain
  • A Coruna
    • Ferrol, A Coruna, Spain, 15405
      • Hospital Arquitecto Marcide

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Control; 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; 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; 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).; Other Names: ketamine chlorhydrate

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Blood Pressure (BP) systolic	Measured in mm Hg. We evaluated these hemodynamic parameters as an indirect measure of pain.	at 0, 1, 2, 4, 8, 12, 16, and 24 hours postoperatively
Blood Pressure (BP) diastolic	Measured in mm Hg. We evaluated these hemodynamic parameters as an indirect measure of pain	at 0, 1, 2, 4, 8, 12, 16, and 24 hours postoperatively
Heart rate	We evaluated these hemodynamic parameters as an indirect measure of pain	at 0, 1, 2, 4, 8, 12, 16, and 24 hours postoperatively.
Respiratory rate	We evaluated these hemodynamic parameters as an indirect measure of pain.	at 0, 1, 2, 4, 8, 12, 16, and 24 hours postoperatively.
Time for the first demand of analgesia	The time interval to first solicited rescue analgesia in the 24 h postoperatively (in minutes). This rescue analgesia was administered if the established analgesic treatment was not sufficient to alleviate pain.	24 h postoperatively.
Number of rescue doses	The number of times a rescue analgesic dose was administered as a supplement in the first postoperative 24 hours.	24 h postoperatively
Satisfaction score	Global patient satisfaction (0-3), regarding pain control, was measured 24 hours after the operation	24 hours postoperatively
Side effects	Number of Participants with Serious and Non-Serious Adverse Events in the 24 hours postoperatively	24 hours postoperatively

Collaborators and Investigators

• Sponsor: Hospital Arquitecto Marcide
• Collaborators: Complexo Hospitalario Universitario de A Coruña
• Investigators: Study Chair: Manuel Camba Rodriguez, M.D., Hospital Arquitecto Marcide; Principal Investigator: Beatriz Nistal Nuno, M.D., Complexo Hospitalario Universitario A Coruña; Study Director: Enrique Freire-Vila, M.D., Complexo Hospitalario Universitario A Coruña; Principal Investigator: Francisco Castro Seoane, M.D., Hospital Arquitecto Marcide

Study record dates

Study Major Dates

• Study Start: September 1, 2001
• Primary Completion (Actual): June 1, 2002
• Study Completion (Actual): June 1, 2002

Study Registration Dates

• First Submitted: September 11, 2014
• First Submitted That Met QC Criteria: September 15, 2014
• First Posted (Estimate): September 16, 2014

Study Record Updates

• Last Update Posted (Estimate): September 16, 2014
• Last Update Submitted That Met QC Criteria: September 15, 2014
• Last Verified: September 1, 2014

More Information

Terms related to this study

• Keywords: preemptive analgesia; ketamine; colon surgery; patient-controlled-analgesia
• Additional Relevant MeSH Terms: Pathologic Processes; Postoperative Complications; Pain; Neurologic Manifestations; Pain, Postoperative; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, Dissociative; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Ketamine
• Other Study ID Numbers: MK334037