The journal of pain : official journal of the American Pain Society
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Human and animal studies suggest that estrogens are involved in the processing of nociceptive sensory information and analgesic responses in the central nervous system. Rapid pronociceptive estrogenic effects have been reported, some of which likely involve G protein-coupled estrogen receptor (GPER) activation. Membrane depolarization and increases in cytosolic calcium and reactive oxygen species (ROS) levels are markers of neuronal activation, underlying pain sensitization in the spinal cord. Using behavioral, electrophysiological, and fluorescent imaging studies, we evaluated GPER involvement in spinal nociceptive processing. Intrathecal challenging of mice with the GPER agonist G-1 results in pain-related behaviors. GPER antagonism with G15 reduces the G-1-induced response. Electrophysiological recordings from superficial dorsal horn neurons indicate neuronal membrane depolarization with G-1 application, which is G15 sensitive. In cultured spinal sensory neurons, G-1 increases intracellular calcium concentration and induces mitochondrial and cytosolic ROS accumulation. In the presence of G15, G-1 does not elicit the calcium and ROS responses, confirming specific GPER involvement in this process. Cytosolic calcium concentration elevates faster and with higher amplitude following G-1 intracellular microinjections compared to extracellular exposure, suggesting subcellular GPER functionality. Thus, GPER activation results in spinal nociception, and the downstream mechanisms involve cytosolic calcium increase, ROS accumulation, and neuronal membrane depolarization. ⋯ Our results suggest that GPER modulates pain processing in spinal sensory neurons via cytosolic calcium increase and ROS accumulation. These findings extend the current knowledge on GPER involvement in physiology and disease, providing the first evidence of its pronociceptive effects at central levels and characterizing some of the underlying mechanisms.
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Randomized Controlled Trial Multicenter Study Comparative Study
Comparative responsiveness of pain measures in cancer patients.
Brief measures to assess and monitor pain in cancer patients are available, but few head-to-head psychometric comparisons of different measures have been reported. Baseline and 3-month data were analyzed from 274 patients enrolled in the Indiana Cancer Pain and Depression (INCPAD) trial. Participants completed the Brief Pain Inventory (BPI), the PEG (a 3-item abbreviated version of the BPI), the short form (SF)-36 pain scale, and a pain global rating of change measure. The global rating was used as the criterion for standardized response mean and receiver operating characteristic curve analyses. To assess responsiveness to the trial intervention, we evaluated standardized effect size statistics stratified by trial arm. All measures were responsive to global improvement, discriminated between participants with and without improvement, and detected a significant intervention treatment effect. Short and longer measures were similarly responsive. Also, composite measures that combined pain severity and interference into a single score (BPI total, PEG, SF-36 pain) performed comparably to separate measures of each domain (BPI severity and BPI interference). ⋯ Pain measures as brief as 2 or 3 items that provide a single score are responsive in patients with cancer-related pain. Ultra-brief measures offer a valid and efficient means of assessing and monitoring pain for the clinical management as well as research of cancer-related pain.
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Randomized Controlled Trial
Tanezumab reduces osteoarthritic knee pain: results of a randomized, double-blind, placebo-controlled phase III trial.
The objective of this study was to compare the analgesic efficacy of tanezumab versus placebo in patients with osteoarthritis (OA) of the knee. This was a 32-week, randomized, double-blind, placebo-controlled phase III trial (NCT00733902). The patient criteria included diagnosis of OA; Western Ontario and McMaster Universities OA Index (WOMAC) Pain and Physical Function subscale scores of ≥5 and ≥4, respectively; Patient's Global Assessment of Osteoarthritis (PGA) ≥3; and failure of nonopiate pain medications or candidacy for invasive interventions. Patients received 3 intravenous doses of tanezumab (2.5, 5, or 10 mg) or placebo. The co-primary efficacy end points were changes in WOMAC subscales and PGA at week 16. Adverse events were monitored throughout. Overall, 690 patients (61% female) were randomized and treated. Those treated with tanezumab showed significant improvement in the 3 co-primary end points (P ≤ .015 for all). The incidence of adverse events was 55 to 60% for tanezumab-treated patients versus 48% for placebo-treated patients. Joint replacement was reported in 4 patients, 1 in each treatment group; a total of 5 joints were replaced (1 index knee and 4 hips). The tanezumab OA clinical program is currently on clinical hold due to potential adverse reactions leading to joint replacement. ⋯ This is the first phase III randomized, controlled trial to demonstrate that nerve growth factor blockade by tanezumab has superior analgesic efficacy in OA of the knee compared with placebo. Tanezumab was well tolerated, and reports of worsening OA and/or joint replacement were evenly distributed across the treatment groups.
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Multiple abnormalities in pain processing have been reported in patients with chronic musculoskeletal pain syndromes. These changes include mechanical and thermal hyperalgesia, decreased thresholds to mechanical and thermal stimuli (allodynia), and central sensitization, all of which are fundamental to the generation of clinical pain. Therefore, we hypothesized that quantitative sensory tests may provide useful predictors of clinical pain intensity of such patients. Our previous studies of fibromyalgia (FM) patients have shown statistically significant correlations of quantitative sensory test results with clinical pain intensity, including mechanical spatial summation, number of pain areas, wind-up, and wind-up aftersensations. Although these tests predicted up to 59% of the variance in FM clinical pain intensity, their expense and technical complexities limited widespread use in clinical practice and trials. Thus, we developed practical tests of primary (mechanical) and secondary (heat) hyperalgesia that also strongly predict clinical pain intensity in patients with chronic musculoskeletal pain disorders. Thirty-six individuals with FM, 24 with local musculoskeletal pain, and 23 normal controls underwent testing of mechanical and heat hyperalgesia at the shoulders and hands. All subjects rated experimental pains using an electronic visual analog scale. Using either heat or pressure pain ratings as well as tender point counts and negative affect as predictors, up to 49.4% of the patients' variance of clinical pain intensity could be estimated. Results of this study emphasize the important contributions of peripheral and central factors to both local and widespread chronic pain. Overall, measures of mechanical and heat hyperalgesia in combination with tender point and negative affect provided powerful predictors of clinical pain intensity in chronic musculoskeletal pain patients that can be readily used in clinical practice and trials. ⋯ Simple tests of mechanical and heat hyperalgesia can predict large proportions of the variance in clinical pain intensity of chronic musculoskeletal pain patients and thus are feasible to be included in clinical practice and clinical trials.
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Sexual assault (SA) is common, but the epidemiology of acute pain after SA has not previously been reported. We evaluated the severity and distribution of pain symptoms in the early aftermath of SA among women receiving Sexual Assault Nurse Examiner (SANE) care, and the treatment of pain by SANE nurses. Severe pain (≥7 on a 0-10 numeric rating scale) was reported by 53/83 women sexual assault survivors (64% [95% CI, 53-74%]) at the time of SANE evaluation and 43/83 women (52% [95% CI, 41-63%]) 1 week later. Pain in 4 or more body regions was reported by 44/83 women (53% [95% CI, 42-64%]) at the time of initial evaluation and 49/83 women (59% [95% CI, 48-70%]) at 1 week follow-up. Among survivors with severe pain at the time of initial postassault evaluation, only 7/53 (13% [95% CI, 6-26%]) received any pain medication at the time of initial SANE treatment. These findings suggest that pain is common in SA survivors in the early postassault period, but rarely treated. ⋯ Acute pain is common after sexual assault. Practice guidelines for SANE nurses and others who provide care to sexual assault survivors in the early aftermath of assault should include specific recommendations for pain evaluation and treatment. Prospective longitudinal studies of pain outcomes among sexual assault survivors are needed.