Unravelling the pathophysiology of complex regional pain syndrome: focus on sympathetically maintained pain.

1. In diseases such as complex regional pain syndrome (CRPS), where neuropathic pain is the primary concern, traditional pain classifications and lesion descriptors are of limited value. To obtain better treatment outcomes for patients, the underlying pathophysiological mechanisms of neuropathic pain need to be elucidated and analysed so that therapeutic targets can be identified and specific treatments developed. 2. In the present review, we examine the current literature on sympathetically maintained pain (SMP), a subset of neuropathic pain, within the context of CRPS. Evidence from both human and animal studies is presented and discussed in terms of its support for the existence of SMP and the mechanistic information it provides. 3. We discuss three current hypotheses that propose both a site and method for sympathetic-sensory coupling: (i) direct coupling between sympathetic and sensory neurons in the dorsal root ganglion; (ii) chemical coupling between sympathetic and nociceptive neuron terminals in skin; and (iii) the development of a-adrenoceptor-mediated supersensitivity in nociceptive fibres in skin in association with the release of inflammatory mediators. 4. Finally, we propose a new hypothesis that integrates the mechanisms of chemical coupling and a-adrenoceptor-mediated supersensitivity. This hypothesis is based on previously unpublished data from our laboratory showing that a histological substrate suitable for sympathetic-sensory coupling exists in normal subjects. In the diseased state, the nociceptive fibres implicated in this substrate may be activated by both endogenous and exogenous noradrenaline. The mediating a-adrenoceptors may be expressed on the nociceptive fibres or on closely associated support cells.