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Endometriosis is a common incurable inflammatory disorder that is associated with debilitating pelvic pain in women. Macrophages are central to the pathophysiology of endometriosis: they dictate the growth and vascularization of endometriosis lesions and more recently have been shown to promote lesion innervation. The aim of this study was to determine the mechanistic role of macrophages in producing pain associated with endometriosis. Herein, we show that macrophage depletion in a mouse model of endometriosis can reverse abnormal changes in pain behavior. We identified that disease-modified macrophages exhibit increased expression of IGF-1 in an model of endometriosis-associated macrophages and confirmed expression by lesion-resident macrophages in mice and women. Concentrations of IGF-1 were elevated in peritoneal fluid from women with endometriosis and positively correlate with their pain scores. Mechanistically, we demonstrate that macrophage-derived IGF-1 promotes sprouting neurogenesis and nerve sensitization . Finally, we show that the Igf-1 receptor inhibitor linsitinib reverses the pain behavior observed in mice with endometriosis. Our data support a role for macrophage-derived IGF-1 as a key neurotrophic and sensitizing factor in endometriosis, and we propose that therapies that modify macrophage phenotype may be attractive therapeutic options for the treatment of women with endometriosis-associated pain.-Forster, R., Sarginson, A., Velichkova, A., Hogg, C., Dorning, A., Horne, A. W., Saunders, P. T. K., Greaves, E. Macrophage-derived insulin-like growth factor-1 is a key neurotrophic and nerve-sensitizing factor in pain associated with endometriosis.
Learn More >Opioids are commonly prescribed to patients with painful and symptomatic degenerative joint disease preoperatively as a nonoperative intervention to reduce patients' symptoms and pain. The goal of total joint arthroplasty (TJA) is to reduce or eliminate the painful symptoms of degenerative joint disease. Due to the addictive property of opioid medications, some patients may develop a pattern of chronic opioid use after TJA.
Learn More >Children of chronic pain patients run greater risk for developing chronic pain themselves. Exposure to chronic pain of the parent might install cognitive (e.g., pain catastrophizing, interpretation and attentional bias) and affective (e.g., pain anxiety) vulnerability which increase the risk for the development of chronic pain complaints in offspring. This study examines whether pain-free offspring of parents with chronic pain complaints make more health-threatening interpretations and display a stronger pain-related attentional bias compared to the offspring of pain-free parents. We furthermore examined differences between both groups on pain catastrophizing, pain anxiety, and somatic symptoms, and explored the relations between parental pain catastrophizing and aforementioned pain vulnerability measures in offspring.
Learn More >People who are especially afraid of pain may display attention biases that increase their risk for developing chronic pain following an injury. However, specific neurophysiological mechanisms underlying associations between elevated trait fear of pain levels and environmental cues that signal potential pain experiences are not well understood. To address this gap, event-related potentials (ERPs) were recorded among 39 high pain-fearful (H-FOP) and 36 low pain-fearful (L-FOP) adults exposed to potentially painful somatosensory stimulation cued by sensory pain words versus non-painful stimulation cued by neutral words. H-FOP group members displayed slower reaction times in judging somatosensory stimulation and rated stimulation to be more intense than L-FOP group members did. H-FOP group members also exhibited comparatively earlier peak latencies of P2 and N2 components during word cue presentations as well as weaker P3 amplitudes in processing non-painful stimulation cued by sensory pain words. These findings suggested that, among the high trait pain-fearful, exposure to word cues signaling potential pain results in the allocation of fewer cognitive resources towards processing somatosensory stimuli that are not actually painful. This article is protected by copyright. All rights reserved.
Learn More >In previous studies that examined the impact of attention biases (ABs) on later pain outcomes, reaction times (RTs) in response to brief stimulus presentations had been used as measures of attention. Consequently, little is known about effects of ABs assessed during presentations of cues or biases in prolonged attention towards pain stimuli as influences on subsequent functioning. To address these gaps, 89 adults with chronic pain (68 women, 21 men) engaged in a baseline dot-probe task in which visual attention was tracked during injury-neutral (I-N) image pair presentations as well as a 6-month follow-up reassessing pain intensity and interference from pain. Neither RTs to probes after image pair offsets nor biases in initial orienting of gaze towards injury images predicted follow-up outcomes. However, participants who gazed at injury images for longer durations during I-N trials reported significantly more pain and interference at follow-up than did peers who gazed at injury images for less time, even after the impact of other significant baseline predictors had been controlled. In sum, results provided initial evidence for gaze biases reflecting prolonged vigilance towards pain-related information as a potential risk factor for relative elevations in pain and interference from chronic pain.
Learn More >The Pain Sensitivity Questionnaire (PSQ) is a self-rating instrument developed as a time- and cost-saving alternative to quantitative sensory testing (QST). The aims of the study were to assess 1) the associations between PSQ scores and QST in women with persistent pelvic pain and in pain-free controls, and 2) to what extent demographic variables and psychological distress influenced PSQ scores.
Learn More >Pain and physical activity are tightly intertwined. Although their relationship has been explored in chronic pain conditions, we know little about the pattern of recovery in activity and its short- and long-term relationship with pain after surgery. We recruited 103 women undergoing elective cesarean delivery and acquired daily pain assessments and hourly steps in 98 of them for 2 months after surgery. Compliance was good, with 78% of subjects missing less than 7 days of activity. Study personnel required daily checking for compliance and 20 minutes per subject per week in study. Activity increased over the first 2 postoperative months in a log(time) manner. The slope of each modeled individual curve for activity was inversely correlated (r=-0.54; p<0.0001) with worst daily pain. After removing these 2 month trends, pain and activity within an individual day were negatively associated with each point increase in pain being inversely associated with -119 steps (95% CI: -214 to -25; p=0.013). A patient's previous experience of pain was not associated with current activity as well as current activity was not associated with future pain scores. These data, although limited by the study of a single operation in a unique social circumstance with low risk of chronic postsurgical pain, demonstrate feasibility of measuring hourly activity for 2 months after surgery. Recovery from pain and inactivity are tightly correlated, and the negative relationship between within day pain and activity without inter-day carry-over relationships are in stark contrast to findings in chronic pain conditions.
Learn More >Cancer and its surgical treatment are among the most important triggering events for persistent pain, but additional factors need to be present for the clinical manifestation, such as variants in pain-relevant genes. In a cohort of 140 women undergoing breast cancer surgery, assigned based on a three-year follow-up to either a persistent or non-persistent pain phenotype, next generation sequencing was performed for 77 genes selected for known functional involvement in persistent pain. Applying machine learning and item categorization techniques, 21 variants in 13 different genes were found to be relevant to the assignment of a patient to either the persistent pain or the non-persistent pain phenotype group. In descending order of importance for correct group assignment, the relevant genes comprised DRD1, FAAH, GCH1, GPR132, OPRM1, DRD3, RELN, GABRA5, NF1, COMT, TRPA1, ABHD6, and DRD4, of which one in the DRD4 gene was a novel discovery. Particularly relevant variants were found in the DRD1 and GPR132 genes, or in a cis-eCTL position of the OPRM1 gene. Supervised machine learning based classifiers, trained with 2/3 of the data, identified the correct pain phenotype group in the remaining 1/3 of the patients at accuracies and areas under the receiver operator characteristic curves of 65 – 72 %. When using conservative classical statistical approaches, none of the variants passed α-corrected testing. The present data analysis approach, using machine learning and training artificial intelligences, provided biologically plausible results and outperformed classical approaches to genotype phenotype association.
Learn More >To determine if the perioperative administration of valproic acid reduces the incidence of chronic pain three months after amputation or revision surgery.
Learn More >Patient beliefs and perceptions about the causes and meaning of their chronic pain are related to their psychosocial functioning. Beliefs and perceptions about chronic pain held by spouses may also be related to patient functioning. We used a laboratory procedure to evaluate whether spouse beliefs about and perceptions of chronic pain were related to spouse negative responses toward patients with chronic low back pain during a conflictual discussion and to their attributions about patient pain behavior during a subsequent pain-induction task. Patients (n = 71) and their spouses (n = 71) participated in a 10-minute discussion followed by the patient undergoing a 10-minute structured pain behavior task. Findings were that a) spouse perceptions that patient's pain was a mystery were significantly related to greater patient perceived spouse critical/invalidating responses toward the patient during the discussion; and b) spouse perceptions that patient's pain was a mystery were related to internal and negative attributions spouses made while observing patients display pain behaviors during the structured pain behavior task. Inasmuch as both spouse critical/invalidating speech toward patients and negative attributions regarding the cause of patient behavior are related to poor patient functioning, spouse uncertainty about the source and potential legitimacy of their partner's pain may play crucial roles in affecting patient well-being. PERSPECTIVE: Spouse beliefs about and perceptions of patient chronic pain were related to spouse behavior toward patients during a discussion and to attributions explaining patient pain during physical activity. If spouse confusion and doubt about patient pain is related to negative behavior and attributions, then modifying these perceptions may be a fundamental intervention target.
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