Pain
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One of the most commonly used experimental animal models for neuropathic pain is the chronic constriction injury (CCI) where four loose ligatures are tied around the sciatic nerve. One disadvantage of this model is the introduction of foreign material into the wound, which causes a local inflammatory reaction. Thus the distinction between the neuropathic and the inflammatory component of pain is difficult in this model. ⋯ In the epineurium the number of macrophages was strikingly increased after CCI compared with PST, indicating that the response of the immune system is different in a structural lesion with and without foreign material. In conclusion, PST is a pure nerve injury model without an epineurial inflammatory component due to foreign material and is therefore well suited for studying the role of local endoneurial processes in the development and maintenance of neuropathic pain. Also, the importance of regeneration in the termination of hyperalgesia can convincingly be shown in this model.
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Evidence from animal models and studies of human sensory nerves demonstrate that tetrodotoxin (TTX)-resistant Na(+) channels are present in sensory neurons and might play an important role in pain conduction and chronic pain. Recent investigations suggest that TTX-resistant Na(+) channels in the peripheral nervous system are less sensitive to local anesthetics than TTX-sensitive Na(+) channels. To test the effects of the clinically used local anesthetics lidocaine and bupivacaine on TTX-resistant action potentials (APs) in sensory neurons, we performed electrophysiological experiments on small dorsal root ganglion (DRG) neurons from young rats. ⋯ Time to peak and duration of TTX-resistant APs were prolonged by local anesthetics. Trains of APs could be elicited in some neurons by long-lasting current injections, and the half-maximal concentrations needed to suppress these trains were 30 microM lidocaine or 10 microM bupivacaine. We suggest that the reduction in firing frequency at low concentrations of local anesthetic may explain the phenomenon of paresthesia when sensory information is gradually suppressed during spinal anesthesia.
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Possible role of inflammatory mediators in tactile hypersensitivity in rat models of mononeuropathy.
Peripheral hypersensitivity (hyperalgesia and allodynia) are common phenomena both in inflammatory and in neuropathic pain conditions. Several rat models of mononeuropathy (Bennett, Seltzer and Gazelius models) display such symptoms following partial injury to the sciatic nerve. Using immunohistochemistry and behavioral tests, we investigated inflammatory cell and cytokine responses in the sciatic nerve 14 days after injury created in these different models as well as after axotomy. ⋯ Our findings indicate that the considerable increase in monocytes/macrophages induced by a nerve injury results in a very high release of IL-6 and TNF-alpha. This may relate to the generation of tactile allodynia/hyperalgesia, since there was a clear correlation between the number of ED-1 and IL-6-positive cells and the degree of allodynia. It is possible that measures to reduce monocyte/macrophage recruitment and the release of pro-inflammatory interleukins after nerve damage could influence the development of neuropathic pain.
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The inability of opioids to control pain over time may be influenced by different factors such as drug tolerance, hyperalgesia due to repeated morphine administration or progression of the original disease. In addition, chronic pain may alter morphine tolerance development. This study examined whether chronic morphine exposure differently affects mechanical and thermal stimulus evoked pain-related behaviour in non-operated, nerve-injured and sham-operated rats. ⋯ Following morphine pretreatment, acute i.v. morphine on day 16 remained effective against both mechanical and thermal stimuli in non-operated rats, but was strongly reduced in nerve-injured rats. Sham-operated rats displayed a tendency towards a reduced effect of i.v. morphine after morphine pretreatment in the mechanical but not in the thermal test. The results suggest that mechanical afferent systems may be more sensitive to hyperalgesia associated with repetitive morphine injections than thermal systems and that nerve injury facilitates the development of tolerance to morphine analgesia.
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Randomized Controlled Trial Clinical Trial
Defining the clinically important difference in pain outcome measures.
The purpose of this study was to determine the levels of change on standard pain scales that represent clinically important differences to patients. Data from analgesic studies are often difficult to interpret because the clinical importance of the results is not obvious. Differences between groups, as summarized by a change in mean values over time, can be difficult to apply to clinical care. ⋯ This study presents data-derived cut-off points for the changes in several pain scales, each reflecting the clinically important improvement for patients treating breakthrough cancer pain episodes with OTFC. Confirmation in other patient populations and different pain syndromes will be needed. The use of consistent clinically important cut-off points as the primary outcome in future pain therapy clinical trials will enhance their validity, comparability, and clinical applicability.