The journal of pain : official journal of the American Pain Society
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Current fear-anxiety-avoidance models of chronic pain emphasize pain-related fear and anxiety as potential precursors for disabling chronic pain; however, anxiety and fear are often used interchangeably when discussing pain. Fear is a present-oriented emotive state associated with an imminent threat (eg, a patient about to receive an injection), whereas anxiety is a more general, future-oriented emotive state, that occurs in anticipation of threats without requiring an objective stimulus (eg, the possibility of receiving an injection). Theoretical and empirical evidence suggests pain-related fear and anxiety represent distinct cognitive constructs. Moreover, pain-related anxiety has been posited as a manifestation of anxiety sensitivity, which has implications for several theoretical models as well as treatment. The Fear of Pain Questionnaire and the Pain Anxiety Symptoms Scale-20 are popular measures, often used comparably, that were designed to measure pain-related fear and anxiety, respectively. These measures, along with the Anxiety Sensitivity Index, were administered to an undergraduate sample (N = 268; 66% women). Results of confirmatory factor analyses suggest each measure represents a related, but distinct, construct. Furthermore, correlations with anxiety sensitivity suggest that pain-related anxiety may be better conceptualized as a fundamental fear. Implications and directions for future research are discussed. ⋯ Fear-anxiety-avoidance models of chronic pain posit pain-related fear and anxiety as diatheses for disabling chronic pain. This research suggests theoretical and clinical distinctions between pain-related fear and anxiety. Moreover, pain-related anxiety appears more complex than a manifestation of anxiety sensitivity; pain-related anxiety may be better conceptualized as a fundamental fear.
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Inflammatory cytokines contribute to lumbar radiculopathy. Regulation of cytokines for transient cervical injuries, with or without longer-lasting inflammation, remains to be defined. The C7 root in the rat underwent compression (10gf), chromic gut suture exposure (chr), or their combination (10gf+chr). Ipsilateral C7 spinal cord and dorsal root ganglia (DRG) were harvested at 1 hour after injury for real-time PCR analysis of IL-1beta, IL-6, and TNF-alpha. Cytokine mRNA increased after all 3 injuries. TNF-alpha mRNA in the DRG was significantly increased over sham after 10gf+chr (P = .026). Spinal IL-1beta was significantly increased over sham after 10gf and 10gf+chr (P < .024); IL-6 was significantly increased after 10gf+chr (P < .024). In separate studies, the soluble TNF-alpha receptor was administered at injury and again at 6 hours in all injury paradigms. Allodynia was assessed and tissue samples were harvested for cytokine PCR. Allodynia significantly decreased with receptor administration for 10gf and 10gf+chr (P < .005). Treatment also significantly decreased IL-1beta and TNF-alpha mRNA in the DRG for 10gf+chr (P < .028) at day 1. Results indicate an acute, robust cytokine response in cervical nerve root injury with varying patterns, dependent on injury type, and that early increases in TNF-alpha mRNA in the DRG may drive pain-related signaling for transient cervical injuries. ⋯ Inflammatory cytokine mRNA in the DRG and spinal cord are defined after painful cervical nerve root injury. Studies describe a role for TNF-alpha in mediating behavioral sensitivity and inflammatory cytokines in transient painful radiculopathy. Results outline an early response of inflammatory cytokine upregulation in cervical pain.
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An upregulation of the endogenous opioid, dynorphin A, in the spinal cord is seen in multiple experimental models of chronic pain. Recent findings implicate a direct excitatory action of dynorphin A at bradykinin receptors to promote hyperalgesia in nerve injured rats, and its upregulation may promote, rather than counteract, enhanced nociceptive input due to injury. Here we examined a model of inflammatory pain by unilateral injection of complete Freund's adjuvant (CFA) into the rat hind paw. Rats exhibited tactile hypersensitivity and thermal hyperalgesia in the inflamed paw by 6 hours after CFA injection, whereas a significant elevation of prodynorphin transcripts in the lumbar spinal cord was seen at day 3 but not at 6 hours. Thermal hyperalgesia at day 3, but not at 6 hours, after CFA injection was blocked by intrathecal administration of anti-dynorphin antiserum or by bradykinin receptor antagonists. The antihyperalgesic effect of the latter was not due to de novo production of bradykinin or upregulation of spinal bradykinin receptors. These data suggest that elevated spinal dynorphin on peripheral inflammation mediates chronic inflammatory hyperalgesia. The antihyperalgesic effect of bradykinin receptor antagonists requires the presence of upregulated spinal dynorphin but not of de novo production of bradykinin, supporting our hypothesis that pathological levels of dynorphin may activate spinal bradykinin receptors to mediate inflammatory hyperalgesia. ⋯ This study shows that chronic peripheral inflammation induces a significant upregulation of the endogenous opioid peptide dynorphin. Elevated levels of spinal dynorphin and activation of spinal bradykinin receptors are essential to maintain inflammatory hyperalgesia. The results suggest that blockade of spinal bradykinin receptors may have therapeutic potential in chronic inflammatory pain.
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Randomized Controlled Trial Comparative Study
Effect of morphine and pregabalin compared with diphenhydramine hydrochloride and placebo on hyperalgesia and allodynia induced by intradermal capsaicin in healthy male subjects.
Intradermal (ID) capsaicin injection in humans induces spontaneous pain, flare, primary hyperalgesia, secondary hyperalgesia, and allodynia. Secondary hyperalgesia and allodynia are a reflection of central sensitization. The effect of treatment of single doses of (1) pregabalin, 300 mg single oral dose, and (2) morphine, 10 mg IV, on the area of secondary hyperalgesia induced by ID capsaicin injection was studied by using a randomized, double-blinded, placebo-controlled, 4-period, cross-over design in 20 healthy men. Compared with active placebo diphenhydramine (50 mg oral dose), pregabalin and morphine significantly reduced the area of secondary hyperalgesia over 15 to 240 minutes after capsaicin injection (approximately 25%, P = .002 and approximately 33%, P < .001, respectively). A smaller reduction was observed when pregabalin and morphine were compared with true placebo (approximately 13%, P = .081 and approximately 24%, P = .009, respectively). Diphenhydramine, on the other hand, increased the area of secondary hyperalgesia in comparison with true placebo (approximately 16%, P = .061). The relationship between the baseline area of hyperalgesia and assay sensitivity suggests that establishing minimum entry criteria for the baseline area of hyperalgesia requirement increases the sensitivity of the assay. ⋯ These results suggest that the minimally invasive intradermal capsaicin model, when it is compared with true placebo, can potentially be used for an early assessment of relevant pharmacology of novel analgesic compounds in healthy subjects. This platform may provide a means to rapidly assess new analgesics and enhance dose selection and decision-making during clinical development.
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In recent years, the National Institutes of Health (NIH) has experienced unprecedented reductions in its customary annual budget increases. Consequently, researchers, health care policy planners and others have a pressing need for accurate information on NIH funding patterns. We created a unique and objective system for compiling, classifying, and analyzing data on NIH grant awards and funding for research on pain, nausea, and dyspnea using naïve observers, cross-validation by multiple raters, and face validation by experts. We present results of our method and analyses for the period from 2003 to 2007. Following a 12% increase from 2003 to 2004, funding for pain research fell by 9.4% per year on average over the next 3 years. The percent of the total NIH budget going to support pain research increased to 0.78% in 2004 but fell to 0.61% in 2007. A piecewise regression model confirmed the declining trend represented a significant fit to the data (R(2)=0.98, p=0.024). Separate breakdowns by Institutes showed similar patterns. Analyses of nausea and dyspnea research support revealed small but steady increases over the same period. Declining support for pain research disproportionate to decreases in the NIH budget signals a need for measures to promote funding for meritorious applications. ⋯ Results of 5 year trends in numbers of grants and funding for research in pain, nausea, and dyspnea by the NIH show overall declines for pain but slight increases for nausea and dyspnea. Declining support for pain research that exceeds the reductions in the total NIH budget signals a need for measures to increase pain research funding.