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As activation of the NMDA receptor plays an important role in central sensitisation, many
studies have focussed on the ability of NMDA receptor antagonists to produce pre‐emptive or
preventive analgesic effects. A qualitative systematic review of NMDA receptor antagonists
showed that ketamine and dextromethorphan produced a significant preventive analgesic
benefit; in all positive preventive studies, a direct analgesic benefit of the drug also occurred in
the early postoperative period; no positive effect was seen in four studies using magnesium
(McCartney et al, 2004 Level I). The addition of low‐dose IV ketamine to thoracic epidural
analgesia reduced the severity and need for treatment of post‐thoracotomy pain at 1 and
3 months postoperatively (Suzuki et al, 2006 Level II). However, in a later study of thoracic
surgery patients, when single dose intrapleural ropivacaine and intravenous analgesia was
combined with either perioperative ketamine or saline, no difference in chronic pain up to
4 months was noted (Duale et al, 2009 Level II).
In a study of multimodal analgesia (local anaesthetic, opioid, ketamine and clonidine) in four
groups of patients having colonic resection, a clear preventive effect on the development of
residual pain up to 1 year after surgery was demonstrated with continuous perioperative CHAPTER 1
epidural analgesia; residual pain at 1 year was lowest in patients who received intraoperative
versus postoperative epidural analgesia (Lavand'homme et al, 2005 Level II).
Key messages
1. The timing of a single analgesic intervention (preincisional rather than postincisional),
defined as pre‐emptive analgesia, has a significant effect on postoperative pain relief with
epidural analgesia (R) (Level I).
2. There is evidence that some analgesic interventions have an effect on postoperative pain
and/or analgesic consumption that exceeds the expected duration of action of the drug,
defined as preventive analgesia (U) (Level I).
3. NMDA receptor antagonist drugs in particular show preventive analgesic effects (U)
(Level I).
4. Perioperative epidural analgesia combined with ketamine intravenously decreases
hyperalgesia and long‐term pain up to 1 year after colonic surgery compared with
intravenous analgesia alone (N) (Level II).
1.5 ADVERSE PHYSIOLOGICAL AND PSYCHOLOGICAL
EFFECTS OF ACUTE PAIN
1.5.1 Acute pain and the injury response
Acute pain is one of the activators of the complex neurohumoral and immune response to
injury (Figure 1.2), and both peripheral and central injury responses have a major influence on
acute pain mechanisms. Thus acute pain and injury of various types are inevitably interrelated
and if severe and prolonged, the injury response becomes counterproductive and can have
adverse effects on outcome (Kehlet & Dahl, 2003; Chapman et al, 2008).
Although published data relate to the combination of surgery or trauma and the associated
acute pain, some data have been obtained with experimental pain in the absence of injury.
Electrical stimulation of the abdominal wall results in a painful experience (visual analogue
scale [VAS] 8/10) and an associated hormonal/metabolic response, which includes increased
cortisol, catecholamines and glucagon, and a decrease in insulin sensitivity (Greisen et al, 2001).
Although acute pain is only one of the important triggers of the ‘injury response’ (Figure 1.2),
Acute pain management: scientific evidence 15
