The journal of pain : official journal of the American Pain Society
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Mechanical sensitivity of muscle nociceptors was previously shown to increase 2 days after lengthening contractions (LC), but heat sensitivity was not different despite nerve growth factor (NGF) being upregulated in the muscle during delayed-onset muscle soreness (DOMS). The discrepancy of these results and lack of other reports drove us to assess heat sensitivity during DOMS in humans and to evaluate the effect of NGF on the heat response of muscle C-fibers. Pressure pain thresholds and pain intensity scores to intramuscular injection of isotonic saline at 48°C and capsaicin were recorded in humans after inducing DOMS. The response of single unmyelinated afferents to mechanical and heat stimulations applied to their receptive field was recorded from muscle-nerve preparations in vitro. In humans, pressure pain thresholds were reduced but heat and capsaicin pain responses were not increased during DOMS. In rats, the mechanical but not the heat sensitivity of muscle C-fibers was increased in the LC group. NGF applied to the receptive field facilitated the heat sensitivity relative to the control. The absence of facilitated heat sensitivity after LC, despite the NGF sensitization, may be explained if the NGF concentration produced after LC is not sufficient to sensitize nociceptor response to heat. ⋯ This article presents new findings on the basic mechanisms underlying hyperalgesia during DOMS, which is a useful model to study myofascial pain syndrome, and the role of NGF on muscular nociception. This might be useful in the search for new pharmacologic targets and therapeutic approaches.
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Levetiracetam is a novel anticonvulsant with antihyperalgesic efficacy in inflammatory pain. Nonsteroidal analgesics and caffeine, as analgesic adjuvant, are widely used against inflammatory pain. This study characterized the manner in which levetiracetam interacts with analgesics (ibuprofen, celecoxib, and paracetamol) and caffeine to suppress hyperalgesia in a model of localized inflammation. Rat paw inflammation was induced by intraplantar carrageenan (.1 mL, 1%). Hyperalgesia and antihyperalgesic effects of levetiracetam (orally), analgesics (orally), and caffeine (intraperitoneally) alone and 2-drug combinations of levetiracetam with analgesics or caffeine were examined by a modified paw pressure test. The type of interaction between components was determined by isobolographic analysis or by analysis of the log dose-response curves for drug combination and drugs alone. Levetiracetam (10-200 mg/kg), ibuprofen (12.5-100 mg/kg), celecoxib (3.75-30 mg/kg), paracetamol (50-200 mg/kg), caffeine (15-100 mg/kg), and 2-drug combinations of levetiracetam with analgesics/caffeine produced a significant, dose-dependent reduction of inflammatory hyperalgesia. Isobolographic analysis revealed that levetiracetam exerts a synergistic interaction with analgesics, with approximately 7-, 9-, and 11-fold reduction of doses of both drugs in combination of levetiracetam with paracetamol, celecoxib, and ibuprofen, respectively. Analysis of the log dose-response curves for levetiracetam (1-50 mg/kg) in the presence of caffeine (10 mg/kg) and levetiracetam applied alone also revealed a synergistic interaction. Levetiracetam's ED50 in the presence of caffeine was reduced approximately 11-fold. ⋯ The presented data suggest that 2-drug combinations of levetiracetam and nonsteroidal analgesics or caffeine could be useful in treatment of inflammatory pain. The efficacy and the adverse effects of those mixtures should be explored further in clinical settings.
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Endomorphin 2 (EM2) is the predominant endogenous mu-opioid receptor (MOR) ligand in the spinal cord. Given its endogenous presence, antinociceptive responsiveness to the intrathecal application of EM2 most likely reflects its ability to modulate nociception when released in situ. In order to explore the physiological pliability of sex-dependent differences in spinal MOR-mediated antinociception, we investigated the antinociception produced by intrathecal EM2 in male, proestrus female, and diestrus female rats. Antinociception was reflected by changes in tail flick latency to radiant heat. In females, the spinal EM2 antinociceptive system oscillated between analgesically active and inactive states. During diestrus, when circulating estrogens are low, spinal EM2 antinociceptive responsiveness was minimal. In contrast, during proestrus, when circulating estrogens are high, spinal EM2 antinociception was robust and comparable in magnitude to that manifest by males. Furthermore, in proestrus females, spinal EM2 antinociception required spinal dynorphin and kappa-opioid receptor activation, concomitant with MOR activation. This is required for neither spinal EM2 antinociception in males nor the antinociception elicited in proestrus females by spinal sufentanil or [d-Ala(2),N-methyl-Phe(4),Gly-ol(5)]-enkephalin, which are prototypic MOR-selective nonpeptide and peptide agonists, respectively. These results reveal that spinal EM2 antinociception and the signaling mechanisms used to produce it fundamentally differ in males and females. ⋯ The inability to mount spinal EM2 antinociception during defined stages of the estrus (and presumably menstrual) cycle and impaired transition from spinal EM2 analgesically nonresponsive to responsive physiological states could be causally associated with the well-documented greater severity and frequency of chronic intractable pain syndromes in women vs men.
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Review Meta Analysis
The relation between pain-related fear and disability: a meta-analysis.
Within a biopsychosocial framework, psychological factors are thought to play an important role in the onset and progression of chronic pain. The cognitive-behavioral fear-avoidance model of chronic pain suggests that pain-related fear contributes to the development and maintenance of pain-related disability. However, investigations of the relation between pain-related fear and disability have demonstrated considerable between-study variation. The main goal of the current meta-analysis was to synthesize findings of studies investigating cross-sectional associations between pain-related fear and disability in order to estimate the magnitude of this relation. We also tested potential moderators, including type of measure used, demographic characteristics, and relevant pain characteristics. Searches in PubMed and PsycINFO yielded a total of 46 independent samples (N = 9,579) that reported correlations between pain-related fear and disability among persons experiencing acute or chronic pain. Effect size estimates were generated using a random-effects model and artifact distribution method. The positive relation between pain-related fear and disability was observed to be moderate to large in magnitude, and stable across demographic and pain characteristics. Although some variability was observed across pain-related fear measures, results were largely consistent with the fear-avoidance model of chronic pain. ⋯ Results of this meta-analysis indicate a robust, positive association between pain-related fear and disability, which can be classified as moderate to large in magnitude. Consistent with the fear-avoidance model of chronic pain, these findings suggest that pain-related fear may be an important target for treatments intended to reduce pain-related disability.
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Randomized Controlled Trial
Developmental data supporting simplification of self-report pain scales for preschool-age children.
Claims regarding the ability of preschool-age children to provide accurate self-reports using standard pain scales are not well supported by age-specific evidence. Responses of children younger than 5 years are often idiosyncratic and subject to biases. Simplifying the task of self-report of pain would make it more developmentally appropriate for 3- to 5-year-olds. A binary question is asked: "Does it hurt?" or an equivalent. If yes, a simplified scale is presented, comprising 3 categories representing low, medium, and high pain severity. Children aged 3 to 5 years (N = 184) were recruited from preschools and day care centers. Following parental consent and child assent, children were randomly assigned to use either the Faces Pain Scale-Revised or a 3-face scale preceded by a yes-no question to rate pain in 9 picture stories from the Charleston Pediatric Pain Pictures portraying no pain, moderate pain, and severe pain. The simplified pain rating task made no difference for 5-year-olds, whose mean scores were nearly identical using the 2 approaches. However, discrimination of the 3 levels of Charleston Pediatric Pain Pictures items was significantly better in 3- and 4-year-olds with the simplified task than with the Faces Pain Scale-Revised. Simplifying the task improved preschool-age children's ability to estimate pain intensity. ⋯ Standard self-report pain scales with 6 faces are confusing for many 3- and 4-year-olds. In basic preparatory research for future development of a preschool self-report pain scale, we simplified the task. This simplification made no difference for 5-year-olds but improved the performance of 3- and 4-year-olds.