Preoperative Ketamine Has no Preemptive Analgesic Effect in Patients Undergoing Colon Surgery.
Condition: Pain, Postoperative
MeSH terms: Pain, Postoperative
Study type: Interventional
Phase: Phase 4

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.
    

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.
    

Intervention name(s): Ketamine
Intervention type(s): Drug
Intervention description(s): 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 intervention name(s): ketamine chlorhydrate
Intervention MeSH terms: Ketamine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: colon surgery; ketamine; patient-controlled-analgesia; preemptive analgesia