Philippe Richebé

BACKGROUND: Remifentanil-induced secondary hyperalgesia has been documented experimentally in both animals and healthy human volunteers, but never clinically. This study tested the hypotheses that increased pain sensitivity assessed by periincisional allodynia and hyperalgesia can occur after relatively large-dose intraoperative remifentanil and that small-dose ketamine prevents this hyperalgesia. METHODS: Seventy-five patients undergoing major abdominal surgery were randomly assigned to receive (1) intraoperative remifentanil at 0.05 microg x kg(-1) x min(-1) (small-dose remifentanil); (2) intraoperative remifentanil at 0.40 microg x kg(-1) x min(-1) (large-dose remifentanil); or (3) intraoperative remifentanil at 0.40 microg x kg(-1) x min(-1) and 0.5 mg/kg ketamine just after the induction, followed by an intraoperative infusion of 5 microg x kg(-1) x min(-1) until skin closure and then 2 microg x kg(-1) x min(-1) for 48 h (large-dose remifentanil-ketamine). Pain scores and morphine consumption were recorded for 48 postoperative hours. Quantitative sensory tests, peak expiratory flow measures, and cognitive tests were performed at 24 and 48 h. RESULTS: Hyperalgesia to von Frey hair stimulation adjacent to the surgical wound and morphine requirements were larger (P < 0.05) and allodynia to von Frey hair stimulation was greater (P < 0.01) in the large-dose remifentanil group compared with the other two groups, which were comparable. There were no significant differences in pain, pressure pain detection threshold with an algometer, peak flow, cognitive tests, or side effects. CONCLUSION: A relatively large dose of intraoperative remifentanil triggers postoperative secondary hyperalgesia. Remifentanil-induced hyperalgesia was prevented by small-dose ketamine, implicating an N-methyl-d-aspartate pain-facilitator process.

The development of chronic pain is considered a major complication after surgery. Basic science research in animal models helps us understand the transition from acute to chronic pain by identifying the numerous molecular and cellular changes that occur in the peripheral and central nervous systems. It is now well recognized that inflammation and nerve injury lead to long-term synaptic plasticity that amplifies and also maintains pain signaling, a phenomenon referred to as pain sensitization. In the context of surgery in humans, pain sensitization is both responsible for an increase in postoperative pain via the expression of wound hyperalgesia and considered a critical factor for the development of persistent postsurgical pain. Using specific drugs that block the processes of pain sensitization reduces postoperative pain and prevents the development of persistent postoperative pain. This narrative review of the literature describes clinical investigations evaluating different preventative pharmacologic strategies that are routinely used by anesthesiologists in their daily clinical practices for preventing persistent postoperative pain. Nevertheless, further efforts are needed in both basic and clinical science research to identify preclinical models and novel therapeutics targets. There remains a need for more patient numbers in clinical research, for more reliable data, and for the development of the safest and the most effective strategies to limit the incidence of persistent postoperative pain.

BACKGROUND: Although opioids are unsurpassed analgesics, experimental and clinical studies suggest that opioids activate N-methyl-d-aspartate pronociceptive systems leading to pain hypersensitivity and short-term tolerance. Because it is difficult in humans to differentiate pain from hyperalgesia during the postoperative period, the authors performed experimental studies with fentanyl using the rat incisional pain model for evaluating relations between hyperalgesia and short-term tolerance. Because N-methyl-d-aspartate receptor antagonists oppose both pain hypersensitivity and tolerance induced by opioids, the authors examined the capability of ketamine for improving exaggerated postoperative pain management. METHODS: During halothane anesthesia, a hind paw plantar incision was performed in rats receiving four fentanyl subcutaneous injections (100 microg/kg per injection, every 15 min). In some groups, three subcutaneous ketamine injections (10 mg/kg per injection, every 5 h) were performed in saline- or fentanyl-treated rats. One day after surgery, the analgesic effect of morphine (2 mg/kg subcutaneous) was tested. Analgesia, mechanical hyperalgesia, tactile allodynia, and pain score were assessed for several days using the paw pressure vocalization test, the von Frey application test, and the postural disequilibrium test. RESULTS: Fentanyl induced analgesia but also produced exaggerated postoperative pain as indicated by the enhancement of hyperalgesia, allodynia, and weight-bearing decrease after hind paw plantar incision. Ketamine pretreatment prevented such a fentanyl-induced enhancement of postoperative pain and improved its management by morphine. CONCLUSIONS: By opposing postoperative pain hypersensitivity and subsequent short-term tolerance induced by perioperative opioid use, ketamine not only improves exaggerated postoperative pain management but also provides better postoperative rehabilitation.

The pneumatic tourniquet is frequently used for upper and lower limb surgery to reduce bleeding, improve visualisation of important structures and expedite surgical procedures. Despite advances in technology, localised tissue damage secondary to cuff compression, ischaemia-reperfusion injuries and systemic complications still occur. The combination of these problems may affect outcome and contribute to prolonged hospitalisation. Use of the correct pneumatic tourniquet cuff size and a patient-specific cuff pressure with careful control of the duration of inflation may help reduce the incidence of these injuries. The efficacy of ischaemic preconditioning or postconditioning, and experimental treatments such as free radical scavenging, and use of nitric oxide synthetase inhibitors on endothelial dysfunction, systemic neutrophil activation and coagulation reactions needs to be established.