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ISSUE NO 2 9 NEWS & REVIEWS Neuropathic pain: aetiology, symptoms, mechanisms, and management Woolf CJ, Mannion RJ The Lancet, 1999, 353:1959-1964 Neuropathic pain resulting from damage to the nervous system comprises a complex combination of negative symptoms or sensory deficits such as loss of sensation and positive symptoms including dysaethesia, parasaethesia and pain. This altered sensitivity is brought about by a change in the function, chemistry, and structure of neurons. There is no treatment to prevent the development of neuropathic pain, nor to adequately, predictably, and specifically control established neuropathic pain. Im- provements require targeting the mechanisms that produce the symptoms rather than the aetiology of the original insult to the nervous system. There is a wide range of mechanisms causing peripheral neuropathic pain including sodium channel imbalance, increased transmission, and α-receptor expression, all of which can cause spontaneous pain. Central sensitisation may result in hyperalgesia in response to stimulus. Sensitive and specific diagnostic tools are required to reveal the particular pathological processes that are responsible for the pain in an individual, but these will only be of value if the mechanisms can be adequately targeted with specific therapy. The responsibility will then be on the clinician to use the history, examination, investigation and diagnostic tools to identify the mechanisms operating in their patients and select the appropriate treatment. SUMMARY OF PUBLICATIONS Mechanism-based pain diagnosis – issues for analgesic drug development Woolf CJ, Mitchell BM, Max MD Anesthesiology, 2001, 95:241-249 Research to elucidate the mechanisms that contribute to the pathogenesis of pain has indicated that pain can be generated in multiple ways at a number of different sites that may coexist between and across diverse disease states. However, in clinical studies within conventional diagnostic groups of chronic pain patients there are subgroups with differing responses to drug treatment. Different aspects of pain are likely to be mediated by different input channels which represent the first anatomic target for treatment. The pain evoked by these input channels represents the operation of multiple mechanisms such as nociceptive transduction, peripheral sensitisation, altered sensory neuron excitability, central sensitisation, and synaptic reorganisation. At present there are no diagnostic tools that can unmistakably identify which mechanisms are present in a given patient so analysis is often based on symptom clusters such as spontaneous pain or stimulus-evoked pain rather than just on disease. Tissue type may provide a clue to mechanism due to differing inner- vation pattern and mix of neuro- transmitters. Also drug challenge can be used as a diagnostic test to guide treatment decision. A co-ordinated effort amongst research sectors is required to improve the knowledge on the impact of basic mechanistic insights on pain treatment. New approaches to the pharma- cotherapy of neuropathic pain Besson M, Piguet V, Dayer P, Desmeules J Expert Rev Clin Pharmacol, 2008, 1:683-693 As neuropathic pain is refractory to classical analgesics, and as our under- standing of the mechanisms generat- ing pain has increased, a mechanism- based approach to treatment has been advocated. However, clinical de- velopment has been disappointing due to the number and complexity of the pathophysiological mechanisms involved. Translating pain complaints and sensory findings into specific clin- ical mechanisms that have treatment implications requires further research. One mechanism may produce various symptoms, while on the other hand one symptom can be the result of a variety of mechanisms. Typically, clini- cal mechanism-based studies include fewer than 40 patients, are extremely labour intensive and require spe- cialised equipment for testing. Another element is the role of in- terindividual variability which can be environmentally or genetically related. Psychological factors and/or comor- bidities, as well as the social repercus- sions of pain, need to be taken into account in these mechanistic trials. Another emergent topic is the role of genetic polymorphisms in the in- terindividual variability in response to analgesic treatment. These may be a result of molecular differences at the level of drug-transport proteins or me- tabolism enzymes and drug targets. An evidence-based approach is essen- tial for testing the drugs in large pa- tient populations.