Experimental pre-emptive analgesia: what value for the clinician?

writing yet another editorial on pre-emptive analgesia when extensive editorials and reviews1–4 have been published within less than a year, and even in this Journal.5 In fact, pre-emptive analgesia is such a complex and controversial topic that it can be viewed from many different aspects. I would like to consider the significance of experimental results, like the ones reported by Nakamura and Takasaki in this issue,6 which are overall very encouraging, and the clinical application of pre-emptive analgesia which seems less glorious. What does it mean to the clinical anesthesiologist? There has been considerable interest in pre-emptive analgesia since Wall7 raised the possibility that pain after surgery might be reduced by preventing intra-operative nociceptive impulses from reaching the spinal cord. Such an approach, in addition to the obvious immediate benefit of protecting the patient at the time of surgical trauma, will also prevent the development of specific central neural changes, i.e., central sensitization which is a more general phenomenon whereby sensory neurons lower their response thresholds, expand their receptive fields and fire spontaneously after noxious peripheral stimulation.8 The discovery of the changes associated with the phenomenon of central sensitization has led to attempts to prevent these changes from occurring. It has been demonstrated that early postoperative pain is a significant predictor of long-term pain.9 It was hoped that steps which would reduce or abolish noxious input to the spinal cord during surgery would reduce or minimize spinal cord changes and thereby lead to reduced pain postoperatively and in the long term. It would be expected that an intervention which pre-empts central sensitization and seeks to prevent it from occurring, rather than attempts to treat it after it has occurred, would be more successful.10 In this issue of the Journal, Nakamura and Takasaki6 have investigated the expression of Fos, the protein product of the immediate early gene c-fos (cellular-fos), following intrathecal administration of fentanyl at different concentrations and times, using the formalin test in the rat. They show that fentanyl in pre-treatment and early post-treatment groups suppresses Fos activity compared to vehicle. Furthermore, they show that Fos activity suppression in these groups is different between superficial and deep laminae of the spinal cord. The authors conclude that intrathecal fentanyl is likely to be an effective pre-emptive analgesic. Before discussing their results, let us first consider the significance of Fos expression in the spinal cord and, subsequently, the value of the formalin test in this context. Immediate early genes such as v-fos (viral-fos) were the first shown to be capable of inducing cell proliferation and became known as proto-oncogenes. When the same gene was then described in cells it was termed cfos (cellular-fos).11 More than 100 immediate early genes are now known and have fundamental roles in cell proliferation, differentiation and programmed cell death. The protein products of proto-oncogenes are generated in the cell membrane, cytosol and, importantly, in the nucleus; thus they are ideally located for the regulation of gene expression. c-fos form a heterodimer and bind to the activating protein-1 site of DNA and transactivate gene transcription.12 At the level of the spinal cord the basal expression of c-fos is negligible and animal handling or injection of saline does not induce the expression of c-fos protein.13 Hunt et al. were the first to demonstrate that a variety of noxious stimuli result in induction of Fos-like proteins in the dorsal horn of the spinal cord.14 c-fos is one of the first immediate early genes to be induced, the half-life of which is relatively short, and the level of c-fos follows closely the intensity/duration of the noxious stimulation. Indeed, analgesic drugs, such as opioids, given before the injury reduce the extent of c-fos expression in a dose-dependent manner.15 Histochemical studies in the rat central nervous system suggest that expression of the c-fos proto-oncogene, as measured by Fos protein 946 EDITORIAL