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Co-prescription of opioids with other central nervous system (CNS) depressants is common but the combination may increase the risk for adverse events such as falls and fractures, particularly among older adults. We explored the risk of fall- or fracture-related hospital visits after opioid initiation among older adults with varying degrees of concomitant CNS depressant burden.
Learn More >Chronic migraine belongs to the "chronic long-duration headaches", and it is associated to high burden and significant economic impact. Treatment for both episodic (EM) and chronic migraine (CM) is based on the management of acute attacks and their prevention. For moderate/severe attacks, pharmacological therapies are triptans, dihydroergotamine nasal sprays or injections or neuroleptics, non-steroidal anti-inflammatory drugs, and corticosteroids. Chronic migraine belongs to the "chronic long-duration headaches", and it is associated to high burden and significant economic impact. Treatment for both episodic (EM) and chronic migraine (CM) is based on the management of acute attacks and their prevention. For moderate/severe attacks, pharmacological therapies are triptans, dihydroergotamine nasal sprays or injections or neuroleptics, non-steroidal anti-inflammatory drugs, and corticosteroids. The pathophysiology of CM is characterized by an abnormal activation of the trigemino-vascular system in the meninges causing a neurogenic inflammation, which explains the use of anti-inflammatory during attacks. It seems that the objective of the preventive therapy with the botulin toxin OnaBoNT-A consists in interrupting the release of CGRP and other neuropeptides as well as the activation of C-fiber nociceptor and of the nearby A-delta fibers. The protocol for migraine treatment with OnaBoNT-A injections consists of 31-39 pericranial injection sites involving seven muscle groups bilaterally in specific areas of the head and neck, with a total dose of between 155 and 195 units, every three months. The severe adverse events reported with high doses of botulin toxin for spasticity, have not been reported for CM treated with OnabotA at the labeled dose. The established improvement with onabotulinumtoxinA treatment in CM patients had a positive impact not only in reduction monthly headache days but also in improving quality of life, with reduction in both healthcare resource utilisation (HRU) and work impairment. Aim of this review was to give an overview on the use of BoNT-A in patients with CM, giving practical advices on the clinical indications.
Learn More >Persistent post-mastectomy pain after breast surgery is variable in duration and severity across patients, due in part to interindividual variability in pain processing. The Rapid OPPERA Algorithm (ROPA) empirically identified three clusters of patients with different risk of chronic pain based on four key psychophysical and psychosocial characteristics. We aimed to test this type of group-based clustering within in a perioperative cohort undergoing breast surgery to investigate differences in postsurgical pain outcomes. Women (N=228) scheduled for breast cancer surgery were prospectively enrolled in a longitudinal observational study. Pressure pain threshold (PPT), anxiety, depression, and somatization were assessed preoperatively. At 2-weeks, 3, 6, and 12-months after surgery, patients reported surgical area pain severity, impact of pain on cognitive/emotional and physical functioning, and pain catastrophizing. The ROPA clustering, which used patients' preoperative anxiety, depression, somatization, and PPT scores, assigned patients to three groups: Adaptive (low psychosocial scores, high PPT), Pain Sensitive (moderate psychosocial scores, low PPT), and Global Symptoms (high psychosocial scores, moderate PPT). The Global Symptoms cluster, compared to other clusters, reported significantly worse persistent pain outcomes following surgery. Findings suggest that patient characteristic-based clustering algorithms, like ROPA, may generalize across diverse diagnoses and clinical settings, indicating the importance of "person type" in understanding pain variability. Perspective: This article presents the practical translation of a previously developed patient clustering solution, based within a chronic pain cohort, to a perioperative cohort of women undergoing breast cancer surgery. Such preoperative characterization could potentially help clinicians apply personalized interventions based on predictions concerning postsurgical pain.
Learn More >Aging is a risk factor for the development of osteoarthritis (OA), a progressive joint disease leading to cartilage damage, pain, and loss of function. In a mouse model of OA, senolytic drugs to selectively clear senescent cells (SnCs) that accumulate with injury or aging yielded a chondroprotective effect; however, this therapeutic benefit was limited in aged mice. Due to inconsistency between cartilage destruction and pain-associated symptoms, we studied the therapeutic effect of senolytics on joint pain in spontaneous OA. We orally treated 21- and 22-month old mice with an ABT263 and Dasatinib and Quercetin (D+Q) drug combination. Selective elimination of the SnCs that accumulated in the articular cartilage and synovium by these two drugs did not alter cartilage degeneration and abnormal bone changes during spontaneous OA progression. Treatment reduced thermal and mechanical hyperalgesia associated with OA and peripheral sensitization through decreased expression of axon guidance proteins (nerve growth factor NGF/TrkA) and nociceptive neuron (calcitonin gene-related peptide, CGRP) projection to the synovium, subchondral bone marrow, and dorsal root ganglion, and knee joint angiogenesis. Selective removal of the SnCs from cultures of synovial cells from human OA patients also decreased expression of senescent markers, axonal growth-promoting factors, such as NGF, and angiogenesis markers. We suggest that systemic administration of ABT263 and D+Q is an exciting therapeutic approach to age-related OA pain.
Learn More >Diabetic peripheral neuropathy (DPN) is the most common complication of diabetes mellitus. Epalrestat, an aldose reductase inhibitor, has been approved for clinical therapy for diabetic peripheral neuropathic pain. In the present study, solid lipid-based nanoparticles are used for oral administration of epalrestat (E-SLN) and evaluated against diabetic neuropathic pain in a rat model.
Learn More >Epigenetics is a process that alters gene activity or phenotype without any changes in the underlying DNA sequence or genotype. These biological changes may have deleterious effects and can lead to various human diseases. Ongoing research is continuing to illuminate the role of epigenetics in a variety of pathophysiologic processes. Several categories of epigenetic mechanisms have been studied including chromatin remodeling, DNA methylation, histone modification, and non-coding RNA mechanisms. These epigenetic changes can have a long-term effect on gene expression without any underlying changes in the DNA sequences. The underlying pathophysiology of disorders of brain-gut interaction and stress-induced visceral pain are not fully understood and the role of epigenetic mechanisms in these disorders are starting to be better understood. Current work is underway to determine how epigenetics plays a role in the neurobiology of patients with chronic visceral pain and heightened visceral nociception. More recently, both animal models and human studies have shown how epigenetic regulation modulates stress-induced visceral pain. While much more work is needed to fully delineate the mechanistic role of epigenetics in the neurobiology of chronic visceral nociception, the current study by Louwies et al., in Neurogastroenterology and Motility provides additional evidence supporting the involvement of epigenetic alterations in the central nucleus of the amygdala in stress-induced visceral hypersensitivity in rodents.
Learn More >The pathogenesis of chronic migraine remains unresolved. Recent studies have affirmed the contribution of GLUA1-containing AMPA receptors to chronic migraine. The dopamine D2 receptor, a member of G protein-coupled receptor superfamily, has been proven to have an analgesic effect on pathological headaches. The present work investigated the exact role of the dopamine D2 receptor in chronic migraine and its effect on GLUA1-containing AMPA receptor trafficking.
Learn More >A reciprocity between the stress and the pain system is recognized; however, the manner by which sex affects this reciprocity is unclear. Understanding the interactions of stress, pain, and sex may shed light on the apparent women's vulnerability to chronic pain, which often co-exists with increased distress, and to affective disorders, which often co-exist with chronic pain. The study's aim was to examine the effect of acute, validated, psychosocial stress on pain perception and modulation of women and men in a controlled manner. Participants were 82 women and 66 men. Heat-pain threshold, heat-pain tolerance and pain modulation by temporal summation of pain (TSP), and pain adaptation, were measured before and after exposure to the Montreal Imaging Stress Task (MIST) or to a sham task. The stress response was verified by perceived ratings of stress and anxiety, autonomic variables, and salivary cortisol. A significant stress response was obtained by the MIST among both sexes; however, women displayed a greater increase in perceived distress, and men displayed a greater increase in cortisol. Among women, TSP decreased and pain adaptation increased following the MIST, responses that were predicted by perceived distress levels. Among men, TSP increased following the MIST but was not predicted by the stress variables. In conclusion, acute stress manipulation seems to differentially affect both stress and pain responses of women and men: Women exhibited stress-induced antinociception, and men exhibited stress-induced pronociception. Higher perceived stress levels among women may trigger a temporary increase in pain inhibition mechanisms to serve evolutionary purposes.
Learn More >Despite a preponderance of pain-related attentional bias research, little is known about how these biases arise and change over time. We tested whether the degree of attentional bias malleability, that is, ability to acquire and relinquish patterns of selective attention towards pain information, predicts daily pain interference. Individuals with chronic pain (N = 66) completed a novel attentional bias malleability procedure based on a modified dot-probe paradigm. Participants received a contingency that encouraged an attentional preference toward and away from pain words across two counterbalanced blocks, and attentional bias was assessed before and after each contingency block. Participants then completed a daily diary for 7 days, including PROMIS-29 pain severity and interference. Multilevel modelling was conducted to predict daily pain interference from attentional bias malleability constructs, controlling for pain severity and demographic factors. Greater attentional bias (F1,391 = 3.97, p = .047), greater readiness to acquire an attentional bias (F1,389) = 4.92, p = .027), and less readiness to lose an acquired attentional bias toward pain (F1,354 = 5.18, p = .024) all predicted less pain interference. There was also an interaction between pain severity and overall attentional bias malleability (F1,62 = 5.48, p = .023), such that as pain severity increased, those who showed greater attentional bias malleability showed less corresponding increase in their pain interference, than those who showed less attentional bias malleability. This study adds new thinking to the dynamic nature of attentional bias, and how such biases might arise and influence pain outcomes.
Learn More >We described trends in pelvic pain characteristics over two years of follow-up among adolescents and adults with and without endometriosis participating in the longitudinal observational cohort of the Women's Health Study: From Adolescence to Adulthood (A2A), utilizing data reported at baseline and at years one and two of follow-up. Participants completed a questionnaire at baseline (between November 2012-May 2019) and annually thereafter that included validated measures of severity, frequency, and life interference of dysmenorrhea, acyclic pelvic pain, and dyspareunia. Our study population included 620 participants with surgically-confirmed endometriosis (rASRM stage I/II=95%) and 671 community and hospital-based controls; median age=19 and 24 years, respectively. The proportion reporting hormone use varied across the three years ranging from 88%-92% for cases and 56%-58% for controls. At baseline, endometriosis cases were more likely to report severe, frequent, and life interfering dysmenorrhea, acyclic pelvic pain, and dyspareunia compared to controls. Among cases, frequency and severity of dysmenorrhea and dyspareunia were relatively static across two years. However, acyclic pelvic pain improved. Severe acyclic pain decreased from 69% at baseline to 46% at Year 2. Daily pain decreased from 28% to 14%, and life interference from 68% to 38%. Trends among controls remained fairly stable across 2 years. Among endometriosis cases who completed the questionnaire at all three time points, 18% reported persistent, severe acyclic pelvic pain at all three time-points. Over time, different trends were observed by pelvic pain type among endometriosis cases and controls, supporting the importance of assessing multi-dimensional features of pelvic pain.
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