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

Pain, Postoperative Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02241278
• Other study ID #: MK334037
• Status: Completed
• Phase: Phase 4
• First received: September 11, 2014
• Last updated: September 15, 2014
• Start date: September 2001
• Est. completion date: June 2002

Study information

• Verified date: September 2014
• Source: Hospital Arquitecto Marcide
• Contact: n/a
• Is FDA regulated: No
• Health authority: Spain: Agencia Española de Medicamentos y Productos SanitariosSpain: Spanish Agency of Medicines
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 48
• Est. completion date: June 2002
• Est. primary completion date: June 2002
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 75 Years

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Prevention

Related Conditions & MeSH terms

• Pain, Postoperative

Intervention

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).

Locations

Country	Name	City	State
Spain	Hospital Arquitecto Marcide	Ferrol	A Coruna

Sponsors (2)

Lead Sponsor	Collaborator
Hospital Arquitecto Marcide	Complexo Hospitalario Universitario de A Coruña

Country where clinical trial is conducted

Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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	No
Other	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	No
Other	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.	No
Other	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.	No
Other	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.	No
Other	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	No
Other	Satisfaction score	Global patient satisfaction (0-3), regarding pain control, was measured 24 hours after the operation	24 hours postoperatively	No
Other	Side effects	Number of Participants with Serious and Non-Serious Adverse Events in the 24 hours postoperatively	24 hours postoperatively	Yes
Primary	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)	No
Primary	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	No
Primary	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	No
Primary	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	No
Primary	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	No
Primary	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	No
Primary	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	No
Primary	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	No
Secondary	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	No