Pre-operative Ketorolac Administration Has no Pre-emptive Analgesic Effect Following Total Abdominal Hysterectomy
Condition: Pain
Study type: Interventional
Phase: Phase 4

Summary: 
      Background: Experimental models using short duration noxious stimuli have led to the concept
      of pre-emptive analgesia. Ketorolac, a non-steroidal anti-inflammatory drug (NSAID), has been
      shown to have a post-operative narcotic sparing effect when given pre-operatively and
      alternatively to not have this effect. This study was undertaken to determine whether a
      single intravenous dose of ketorolac would result in decreased post-operative pain and
      narcotic requirements.

      Methods: In a double-blind, randomized controlled trial, 48 women undergoing abdominal
      hysterectomy were studied. Patients in the ketorolac group received 30 mg of intravenous
      ketorolac 30 minutes before surgical incision, while the control group received normal
      saline. The post-operative analgesia was performed with a continuous infusion of tramadol at
      12 mg/hour with the possibility of a 10 mg bolus every 10 minutes. Pain was assessed using
      the Visual Analog Scale (VAS), tramadol consumption and hemodynamic parameters at 0, 1, 2, 4,
      8, 12, 16 and 24 hours post-operatively. We quantified times to rescue analgesic (morphine),
      adverse effects and patient satisfaction.
    

Detailed description: 
      Damage to tissues has been shown to provoke a magnified reaction to noxious stimuli,
      peripherally by diminishing the threshold of nociceptive afferent nerve terminals and
      centrally by augmenting the excitability of second-order sensory neurons in the spinal cord;
      later resulting in an amplification and extension of postoperative pain after surgery. Hence,
      much research has focused on procedures to avoid these central neuroplastic changes through
      the usage of preemptive analgesia.

      Experimental models have conducted to the idea of 'preemptive analgesia' . The decrement of
      afferent nociceptive inputs to the spinal cord using analgesic techniques started before the
      initial painful stimulus avoids or attenuates the formation of spinal hyperexcitabilty and
      avoids the transformed processing of afferent input, leading to less postoperative pain.
      Whether such experimental models are applicable to the noxious circumstances occurring during
      surgery is controversial.

      Although preemptive analgesia with different agents have been successful in experimental
      animals, conclusions from human studies remain in conflict. A diversity of agents have been
      analyzed for their conceivable preemptive analgesic effects: local anesthetics, non-steroidal
      anti-inflammatory drugs (NSAIDs), paracetamol, opioids, magnesium, cytokine synthesis
      inhibitors, ketamine, and tricyclic antidepressants.

      Scientific research enabling an understanding of the molecular mechanisms of nociception has
      disclosed a considerable function of cytokines and prostaglandins (PG). Hyperexcitability
      also appears peripherally in nerve endings at the location of surgical tissue damage and is
      mediated in part by prostaglandins. Evidence is accumulating that products of the
      cyclooxygenase pathway may be engaged in the elaboration of central sensitization. Drugs that
      block the formation of prostaglandins such as NSAIDs might therefore be assumed to avoid or
      minimize the formation of this peripheral and central hyperexcitability. Their central
      analgesic actions are effected by averting spinal prostaglandin synthesis and attenuating
      liberation of neurotransmitters from the primary afferent terminals and spinal interneurons.

      Sporadic studies have established some considerable preemptive benefit of NSAIDs. As a
      result, the objective of this study was to ascertain the impact of a NSAID, ketorolac, on
      pain severity and analgesic requirement, in the early postoperative period.

      Ketorolac is a nonselective NSAID that blocks cyclooxygenase 1 (COX-1) and cyclooxygenase 2
      (COX-2) enzymes and as a result blocks the formation of prostaglandins attenuating the
      sensitization procedures. The antinociceptive and anti-inflammatory action of NSAIDs may be
      associated to the suppression of nitric oxide synthase activation, decreased generation of
      proinflammatory cytokines, and lipoxine activation. Consequently, this multidirectional
      activity indicates that there may be the probability of adjusting the nociception process by
      the employment of these drugs perioperatively.

      To our knowledge, no prior controlled study has determined the effectiveness of preoperative
      intravenous ketorolac compared to placebo in patients who underwent abdominal hysterectomies.
      Thus, this clinical trial was conceived to explore the postoperative analgesic efficiency and
      opioid-sparing action of a single dose of intravenous ketorolac in contrast with placebo
      administered preoperatively.
    

Intervention name(s): Ketorolac Tromethamine; Placebo
Intervention type(s): Drug; Other
Intervention description(s): In the operating room, the anesthesiologist administered ketorolac (30 mg) in 50 mL of 0.9 % saline intravenously to patients in the ketorolac group 30 minutes before surgical incision (a single dose).; 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
Other intervention name(s): ketorolac
Intervention MeSH terms: Ketorolac; Ketorolac Tromethamine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: preemptive analgesia; postoperative pain; NSAIDs; ketorolac; abdominal hysterectomy