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Pain Management Research Institute, University of Sydney, Royal North Shore Hospital, St. Leonards, NSW, Australia
Address correspondence and reprint requests to Dr. Philip J. Siddall, Pain Management Research Institute, University of Sydney, Royal North Shore Hospital, St. Leonards, NSW, Australia. Address e-mail to phils{at}med.usyd.edu.au
The article by Decosterd et al. (1) published in this issue of Anesthesia & Analgesia highlights differences between two rat models of peripheral neuropathic pain in response to systemic drug administration. The first model was a unilateral crush injury of the sciatic nerve, and the sensory abnormality found at 2 weeks after the injury was, at each testing session, a progressive decrease in the threshold to elicit leg flexor withdrawal from application of von Frey hairs, a phenomenon the authors call "progressive tactile hyperalgesia." The second model involved unilaterally dividing the common peroneal and tibial nerves but not the sural nerve (they call this a "spared nerve injury model"). These rats showed reduced thresholds for flexor withdrawal to von Frey hair application and prolonged leg withdrawal to pinprick of sural nerve-innervated skin areas, but progressive tactile hyperalgesia was not present. Thus the two models differed in the test measures used, and the recent paper shows further differences by pharmacological means. The progressive tactile hyperalgesia associated with the nerve crush model was reduced by systemic morphine, gabapentin, the N-methyl-D-aspartic (NMDA) acid antagonist MK801, and amitriptyline, but comparable doses of these drugs had little effect on the changes produced by the spared nerve model. The authors draw attention to the likely differing peripheral and central mechanisms involved in generating the dysesthesia in the two models and attribute the different drug responses to such different mechanisms. They state the need "to identify in which models and in which patients particular pain mechanisms are expressed and what outcome measures can detect these." They also suggest that the spared nerve model with its poor response to drugs may involve mechanisms relevant to patients with neuropathic pain resistant to drug therapy.
We agree with the conclusion that there is heterogeneity in neuropathic pain mechanisms even when considering only those with peripheral nerve damage. The complexity of neuropathic pain is increased when that of central origin is included. Pain after spinal cord injury and poststroke pain are likely to involve mechanisms partly or wholly different from those involved in pain associated with peripheral nerve damage.
Classifying any physiological or pathological process by underlying mechanisms is a logical and well-used approach, and Woolf et al. (2) have emphasized the need to apply this to pain. It is an attractive hypothesis that modifying specific mechanisms involved in pain perception will result in better management. The difficulties in the implementation of this approach, however, are significant, and they have not received sufficient attention. These caveats fall into two groups: 1) the difficulty in assessing the contribution of a mechanism discovered in animal experiments to perceived pain in humans, and 2) the relative selectivity of the proposed mechanism for the nociceptive/pain system. We shall illustrate this with examples.
When peripheral inflammation develops there is good evidence from animal experiments that peripheral nociceptors sensitize (they may fire impulses to normally innocuous stimuli) and that the firing of spinal neurons to incoming nociceptive impulses is heightened (central sensitization). On the basis of the clinical efficacy of nonsteroidal analgesics, peripheral sensitization contributes significantly to pain associated with peripheral inflammation in humans. The contribution of central sensitization to perceived pain in a clinical context, however, is basically unknown. The unsensitized system may be quite capable of resulting in severe pain when dealing with a barrage of impulses from the inflamed periphery. The centrally sensitized system may be more important in pain being felt in response to minimal inputs, but we do not know.
Selectivity of a mechanism or structure for the nociceptive/pain system appears to be rare, both peripherally and centrally. Although endogenous opioids are not widely used neurotransmitters in the central nervous system, there are opiate receptors in several areas of the brain not related to nociception/pain, and hence opiates are not only analgesics. Experimentally, wind-up of responses of spinal neurons to peripheral nerve stimulation is readily reduced by NMDA antagonists, but these receptors for the excitatory transmitter L-glutamate are widely distributed in the central nervous system. NMDA antagonists have been used as ancillary drugs in some forms of pain control, but unacceptable sedation and dysphoria are common accompaniments. An attractive approach to selectivity is the possibility that an enzyme/receptor may be expressed only under particular conditions. The peripheral induction of the enzyme COX-2 with peripheral inflammation is an example, but COX-2 inhibitors have not been the panacea that theory predicted. The point we are making is that even if an experimental mechanism can be shown to be relevant to clinical pain, it does not necessarily follow that management will improve. But of course we have to try.
How do we improve our ability to identify underlying mechanisms in the clinic? Accurate identification of mechanisms is probably best achieved by accurate identification of clusters of information on the basis of a combination of findings from history, examination, and other investigations. It may mean greater use of existing assessment techniques such as quantitative sensory testing. It almost certainly means the development of new clinical diagnostic techniques that can reliably detect the pathophysiology that basic scientists have worked so hard to uncover.
Among pain practitioners, there is a concern that a purely biological approach, no matter how accurately it identifies a pathophysiological mechanism, cannot adequately address the multiplicity of psychological and social factors that in all of us contribute to the perception and expression of pain. For many who have embraced the biopsychosocial concept of pain, a move toward attempting to identify specific biological mechanisms is seen as reductionist and even futile. It is clear that pain perception is multifactorial and many processes contribute to our experience of pain. A concerted effort to identify and address biological contributors should not result in our being unaware or dismissive of these psychosocial factors. To ignore the latter would result in both assessment and treatment being incomplete and unsatisfactory. We believe that a synthesis of these divergent approaches, with accurate identification of the specific biological, psychological, and social contributors and application of efficacious treatments linked to specific mechanisms, will provide the best outcomes for our patients.
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