Interplay between noxious heat sensitivity and temporal summation magnitude in patients with fibromyalgia and long-term opioid use

IntroductionIn chronic pain conditions such as fibromyalgia (FM), pain amplification within the central nervous system, or “central sensitization,” may contribute to the development and maintenance of chronic pain. Chronic pain treatments include opioid therapy, and opioid therapy may maladaptively increase central sensitization, particularly in patients who take opioids long-term. However, it has remained unknown how central sensitization is impacted in patients who use opioids long-term.MethodsTo investigate how long-term opioid therapy affects central sensitization, we used the validated measure of temporal summation. The temporal summation measurement consists of applying a series of noxious stimuli to a patient’s skin and then calculating changes in the patient’s pain rating to each stimulus. Using this measurement, we evaluated temporal summation in study participants with fibromyalgia who take opioids long-term (i.e., greater than 90 days duration; n = 24, opioid-FM). We compared opioid-FM responses to 2 control groups: participants with fibromyalgia who do not take opioids (n = 33, non-opioid FM), and healthy controls (n = 31). For the temporal summation measurement, we applied a series of 10 noxious heat stimuli (sensitivity-adjusted temperatures) to the ventral forearm (2s duration of each stimulus, applied once every 3 s). Additionally, we collected responses to standard pain and cognitive-affective questionnaires to assess pain severity and other factors.Results and discussionGroup differences in sensitivity-adjusted stimulus temperatures were observed, with only the non-opioid FM group requiring significantly lower stimulus temperatures (The opioid-FM group also required lower temperatures, but not significantly different from the control group). However, all 3 groups exhibited similar magnitudes of temporal summation. Across combined FM groups, temporal summation negatively correlated with pain severity (r = −0.31, p = 0.021). Within the opioid-FM group, higher pain sensitivity to heat (i.e., lower sensitivity-adjusted temperatures) showed a trend relationship with higher opioid dosage (r = −0.45, p = 0.036), potentially reflective of opioid-related hyperalgesia. Our findings also indicated that heightened pain severity may skew sensitivity-adjusted temporal summation, thereby limiting its utility for measuring central sensitization. Overall, in participants taking opioids, temporal summation may be influenced by hypersensitivity to heat pain, which appeared to vary with opioid dosage

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Data_Sheet_1_Interplay between noxious heat sensitivity and temporal summation magnitude in patients with fibromyalgia and long-term opioid use.PDF

IntroductionIn chronic pain conditions such as fibromyalgia (FM), pain amplification within the central nervous system, or “central sensitization,” may contribute to the development and maintenance of chronic pain. Chronic pain treatments include opioid therapy, and opioid therapy may maladaptively increase central sensitization, particularly in patients who take opioids long-term. However, it has remained unknown how central sensitization is impacted in patients who use opioids long-term.MethodsTo investigate how long-term opioid therapy affects central sensitization, we used the validated measure of temporal summation. The temporal summation measurement consists of applying a series of noxious stimuli to a patient’s skin and then calculating changes in the patient’s pain rating to each stimulus. Using this measurement, we evaluated temporal summation in study participants with fibromyalgia who take opioids long-term (i.e., greater than 90 days duration; n = 24, opioid-FM). We compared opioid-FM responses to 2 control groups: participants with fibromyalgia who do not take opioids (n = 33, non-opioid FM), and healthy controls (n = 31). For the temporal summation measurement, we applied a series of 10 noxious heat stimuli (sensitivity-adjusted temperatures) to the ventral forearm (2s duration of each stimulus, applied once every 3 s). Additionally, we collected responses to standard pain and cognitive-affective questionnaires to assess pain severity and other factors.Results and discussionGroup differences in sensitivity-adjusted stimulus temperatures were observed, with only the non-opioid FM group requiring significantly lower stimulus temperatures (The opioid-FM group also required lower temperatures, but not significantly different from the control group). However, all 3 groups exhibited similar magnitudes of temporal summation. Across combined FM groups, temporal summation negatively correlated with pain severity (r = −0.31, p = 0.021). Within the opioid-FM group, higher pain sensitivity to heat (i.e., lower sensitivity-adjusted temperatures) showed a trend relationship with higher opioid dosage (r = −0.45, p = 0.036), potentially reflective of opioid-related hyperalgesia. Our findings also indicated that heightened pain severity may skew sensitivity-adjusted temporal summation, thereby limiting its utility for measuring central sensitization. Overall, in participants taking opioids, temporal summation may be influenced by hypersensitivity to heat pain, which appeared to vary with opioid dosage.</p

Preliminary structural MRI based brain classification of chronic pelvic pain: A MAPP network study

Neuroimaging studies have shown that changes in brain morphology often accompany chronic pain conditions. However, brain biomarkers that are sensitive and specific to chronic pelvic pain (CPP) have not yet been adequately identified. Using data from the Trans-MAPP Research Network, we examined the changes in brain morphology associated with CPP. We used a multivariate pattern classification approach to detect these changes and to identify patterns that could be used to distinguish participants with CPP from age-matched healthy controls. In particular, we used a linear support vector machine (SVM) algorithm to differentiate gray matter images from the 2 groups. Regions of positive SVM weight included several regions within the primary somatosensory cortex, pre-supplementary motor area, hippocampus, and amygdala were identified as important drivers of the classification with 73% overall accuracy. Thus, we have identified a preliminary classifier based on brain structure that is able to predict the presence of CPP with a good degree of predictive power. Our regional findings suggest that in individuals with CPP, greater gray matter density may be found in the identified distributed brain regions, which are consistent with some previous investigations in visceral pain syndromes. Future studies are needed to improve upon our identified preliminary classifier with integration of additional variables and to assess whether the observed differences in brain structure are unique to CPP or generalizable to other chronic pain conditions

Brain white matter changes associated with urological chronic pelvic pain syndrome: multisite neuroimaging from a MAPP case-control study.

Clinical phenotyping of urological chronic pelvic pain syndromes (UCPPSs) in men and women have focused on end organ abnormalities to identify putative clinical subtypes. Initial evidence of abnormal brain function and structure in male pelvic pain has necessitated large-scale, multisite investigations into potential UCPPS brain biomarkers. We present the first evidence of regional white matter (axonal) abnormalities in men and women with UCPPS, compared with positive (irritable bowel syndrome, IBS) and healthy controls. Epidemiological and neuroimaging data were collected from participants with UCPPS (n = 52), IBS (n = 39), and healthy sex- and age-matched controls (n = 61). White matter microstructure, measured as fractional anisotropy (FA), was examined by diffusion tensor imaging. Group differences in regional FA positively correlated with pain severity, including segments of the right corticospinal tract and right anterior thalamic radiation. Increased corticospinal FA was specific and sensitive to UCPPS, positively correlated with pain severity, and reflected sensory (not affective) features of pain. Reduced anterior thalamic radiation FA distinguished patients with IBS from those with UCPPS and controls, suggesting greater microstructural divergence from normal tract organization. Findings confirm that regional white matter abnormalities characterize UCPPS and can distinguish between visceral diagnoses, suggesting that regional axonal microstructure is either altered with ongoing pain or predisposes its development

The posterior medial cortex in urologic chronic pelvic pain syndrome

Altered resting-state (RS) brain activity, as a measure of functional connectivity (FC), is commonly observed in chronic pain. Identifying a reliable signature pattern of altered RS activity for chronic pain could provide strong mechanistic insights and serve as a highly beneficial neuroimaging-based diagnostic tool. We collected and analyzed RS functional magnetic resonance imaging data from female patients with urologic chronic pelvic pain syndrome (N = 45) and matched healthy participants (N = 45) as part of an NIDDK-funded multicenter project (www.mappnetwork.org). Using dual regression and seed-based analyses, we observed significantly decreased FC of the default mode network to 2 regions in the posterior medial cortex (PMC): the posterior cingulate cortex (PCC) and the left precuneus (threshold-free cluster enhancement, family-wise error corrected P &lt; 0.05). Further investigation revealed that patients demonstrated increased FC between the PCC and several brain regions implicated in pain, sensory, motor, and emotion regulation processes (eg, insular cortex, dorsolateral prefrontal cortex, thalamus, globus pallidus, putamen, amygdala, hippocampus). The left precuneus demonstrated decreased FC to several regions of pain processing, reward, and higher executive functioning within the prefrontal (orbitofrontal, anterior cingulate, ventromedial prefrontal) and parietal cortices (angular gyrus, superior and inferior parietal lobules). The altered PMC connectivity was associated with several phenotype measures, including pain and urologic symptom intensity, depression, anxiety, quality of relationships, and self-esteem levels in patients. Collectively, these findings indicate that in patients with urologic chronic pelvic pain syndrome, regions of the PMC are detached from the default mode network, whereas neurological processes of self-referential thought and introspection may be joined to pain and emotion regulatory processes