Pain
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The aim of the study was epidemiologically to evaluate the long-term effects of opioids on pain relief, quality of life and functional capacity in long-term/chronic non-cancer pain. The study was based on data from the 2000 Danish Health and Morbidity Survey. As part of a representative National random sample of 16,684 individuals (>16 years of age), 10,066 took part in an interview and completed a self-administered questionnaire. ⋯ Opioid usage was significantly associated with reporting of moderate/severe or very severe pain, poor self-rated health, not being engaged in employment, higher use of the health care system, and a negative influence on quality of life as registered in all items in SF-36. Because of the cross-sectional nature causative relationships cannot be ascertained. However, it is remarkable that opioid treatment of long-term/chronic non-cancer pain does not seem to fulfil any of the key outcome opioid treatment goals: pain relief, improved quality of life and improved functional capacity.
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Mechanisms of chronic pain, including neuropathic pain, are poorly understood. Upregulation of voltage-gated calcium channel (VGCC) alpha2delta1 subunit (Ca(v)alpha2delta1) in sensory neurons and dorsal spinal cord by peripheral nerve injury has been suggested to contribute to neuropathic pain. To investigate the mechanisms without the influence of other injury factors, we have created transgenic mice that constitutively overexpress Ca(v)alpha2delta1 in neuronal tissues. ⋯ In addition, gabapentin blocked VGCC currents concentration-dependently in transgenic, but not wild-type, sensory neurons. Thus, elevated neuronal Ca(v)alpha2delta1 contributes to specific pain states through a mechanism mediated at least partially by enhanced VGCC activity in sensory neurons and hyperexcitability in dorsal horn neurons in response to peripheral stimulation. Modulation of enhanced VGCC activity by gabapentin may underlie at least partially its antihyperalgesic actions.
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Gabapentin and pregabalin have been demonstrated, both in animal pain models and clinically, to be effective analgesics particularly for the treatment of neuropathic pain. The precise mechanism of action for these two drugs is unknown, but they are generally believed to function via initially binding to the alpha2delta subunit of voltage-gated Ca2+ channels. In this study, we used a pharmacological approach to test the hypothesis whether high affinity interactions with the alpha2delta subunit alone could lead to attenuation of neuropathic pain in rats. ⋯ In contrast, two ligands with comparable or superior alpha2delta binding affinities, m-chlorophenylglycine (Ki = 54 nM) and ABHCA (150 nM), exhibited no anti-allodynic effects at doses of 30-300 micromol/kg (p.o.), although these compounds achieved substantial brain levels. The data demonstrate that, at least in the rat spinal nerve ligation model of neuropathic pain, (L)-phenylglycine has an anti-allodynic effect, but two equally potent alpha2delta subunit ligands do not. These results suggest that additional mechanisms, besides alpha2delta interactions, may contribute to the effects of compounds like gabapentin, pregabalin and (L)-phenylglycine in neuropathic pain.