The journal of pain : official journal of the American Pain Society
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Chronic sleep disturbance-induced stress is known to increase basal pain sensitivity. However, most surgical patients frequently report short-term sleep disturbance/deprivation during the pre- and postoperation periods and have normal pain perception presurgery. Whether this short-term sleep disturbance affects postsurgical pain is elusive. Here, we report that pre- or postexposure to rapid eye movement sleep disturbance (REMSD) for 6 hours daily for 3 consecutive days did not alter basal responses to mechanical, heat, and cold stimuli, but did delay recovery in incision-induced reductions in paw withdrawal threshold to mechanical stimulation and paw withdrawal latencies to heat and cold stimuli on the ipsilateral side of male or female rats. This short-term REMSD led to stress shown by an increase in swim immobility time, a decrease in sucrose consumption, and an increase in the level of corticosterone in serum. Blocking this stress via intrathecal RU38486 or bilateral adrenalectomy abolished REMSD-caused delay in recovery of incision-induced reductions in behavioral responses to mechanical, heat, and cold stimuli. Moreover, this short-term REMSD produced significant reductions in the levels of mu opioid receptor and kappa opioid receptor, but not Kv1.2, in the ipsilateral L4/5 spinal cord and dorsal root ganglia on day 9 after incision (but not after sham surgery). ⋯ Our findings show that short-term sleep disturbance either pre- or postsurgery does not alter basal pain perception, but does exacerbate postsurgical pain hypersensitivity. The latter may be related to the reductions of mu and kappa opioid receptors in the spinal cord and dorsal root ganglia caused by REMSD plus incision. Prevention of short-term sleep disturbance may help recovery from postsurgical pain in patients.
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Interactions between exogenous and endogenous opioids are not commonly investigated as a basis for sexually dimorphic opioid analgesia. We investigated the influence of spinal endomorphin 2 (EM2), an endogenous mu-opioid receptor (MOR) ligand, on the spinal antinociception produced by intrathecally administered opioids. Activation of spinal MORs facilitated spinal EM2 release. This effect was sexually dimorphic, occurring in males but not in females. Although activational effects of testosterone were required for opioid facilitation of spinal EM2 release in males, the absence of this facilitation in females did not result from either insufficient levels of testosterone or mitigating effects of estrogens. Strikingly, in males, the contribution of spinal EM2 to the analgesia produced by intrathecally applied MOR agonists depended on their analgesic efficacy relative to that of EM2. Spinal EM2 released by the higher efficacy MOR agonist sufentanil diminished sufentanil's analgesic effect, whereas EM2 released by the lower efficacy morphine had the opposite effect on spinal morphine antinociception. Understanding antithetical contributions of endogenous EM2 to intrathecal opioid antinociception not only enlightens the selection of opioid medications for pain management but also helps to explain variable sex dependence of the antinociception produced by different opioids, facilitating the acceptance of sexually dimorphic antinociception as a basic tenet. ⋯ The male-specific MOR-coupled enhancement of spinal EM2 release implies a parallel ability to harness endogenous EM2 antinociception. The inferred diminished ability of females to utilize the spinal EM2 antinociceptive system could contribute to their greater frequency and severity of chronic pain syndromes.
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There is little information regarding changes in placebo responsiveness with age, although first predictors of placebo responders such as psychological and physiological processes have been identified. Reviews and meta-analyses indicate that placebo response rates in randomized controlled trials (RCTs) are higher in children and adolescents compared with adults. As these studies cannot control for age-dependent differences in the natural course of the disease, biases might contribute to different placebo rates in RCTs. To avoid these biases, this study investigated age-related differences in placebo responsiveness between children and adults in a well-established experimental model of placebo analgesia combining classic conditioning and expectation. Our data confirm placebo analgesic responses in children, which did not differ in magnitude from those of adults. The influence of previous experience on subsequent treatment outcome was stronger in children than in adults, indicating an increased relevance of learning processes for treatment outcomes in children. Further studies are needed to understand the influence of treatment-related learning processes in children and adolescents, which might critically determine treatment responsiveness during adulthood. ⋯ This study is the first to experimentally explore placebo analgesia and influences of previous experience on placebo responses in children compared with adults. We found comparable placebo responses in both groups and an increased relevance of learning processes for treatment outcomes in children.
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Validation of the Hospital Anxiety and Depression Scale (HADS) in Patients with Acute Low Back Pain.
The Hospital Anxiety and Depression Scale (HADS) is a self-report instrument used to evaluate depression and anxiety in clinical research. The HADS has advantages over other assessments of anxiety and depression; it is efficient in assessing both anxiety and depression with a total of 14 items, and it was originally developed on a general medical rather than psychiatric sample. However, the HADS has not been evaluated specifically for use in clinical trials of acute pain. Validation analyses were conducted on data from a randomized, double-blind, parallel-group study of tapentadol immediate release vs oxycodone immediate release for acute low back pain (N = 666). Analyses of psychometric properties, internal consistency, convergent validity, assessments of bias, and confirmatory factor analysis were conducted on pretreatment data. Additional analyses were performed to test the responsiveness and predictive validity of the HADS. Both the Anxiety and Depression subscales (1) showed good psychometric properties, (2) had high internal consistency, (3) displayed good convergent validity, (4) had no unexpected biases, (5) fit the a priori factor structure, and (6) were highly sensitive to changes as a result of analgesic treatment. We conclude that the HADS is a valid instrument for efficient, low-burden assessment of anxiety and depression in clinical trials with an acute low back pain population. ⋯ Considered together with the results of other recent studies, the data suggest that the HADS can provide a valid, responsive, and efficient assessment of anxiety and depression in acute low back pain for clinical trials and other clinical research examining acute pain populations.
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Data on the tolerability of opioids in patients with cancer-related pain are limited. Here, we report a systematic review that includes all published prospective studies reporting adverse events (AEs) of morphine, oxycodone, fentanyl, methadone, or hydromorphone for cancer-related pain in patients naive for these opioids. We included 25 studies describing 31 treatment cohorts, made an overview of study characteristics, and reported rates of AEs per type of opioid. The frequency of the most commonly reported AEs varied widely: nausea from 3 to 85%, vomiting from 4 to 50%, constipation from 5 to 97%, drowsiness from 3 to 88%, and dry mouth from 1 to 94%. There was a large heterogeneity among included studies, especially regarding the assessment and reporting of AEs. We describe how differences in assessment and reporting influence outcome rates. Although AEs are an important issue in daily clinical practice, realistic incidence rates of AEs per type of opioid are unknown because of the immense heterogeneity among studies. ⋯ Although opioid-related adverse events are an important issue when treating cancer-related pain, realistic rates of adverse events per type of opioid are unknown because of immense heterogeneity among studies and lack of systematic assessment and reporting. There is an urgent need for studies with standardized outcome measures and reporting.