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Difelikefalin is a peripherally restricted and selective agonist of kappa opioid receptors that are considered to be important in modulating pruritus in conditions such as chronic kidney disease.
Learn More >Chronic widespread pain (CWP) has a negative impact on health status, but results have varied regarding gender-related differences and reported health status. The aim was to study the impact of CWP on health status in women and men aged 35-54 years in a sample of the general population. The aim was further to investigate lifestyle-related predictors of better health status in those with CWP in a 12- and 21-year perspective.
Learn More >Persistent post-traumatic headache (PTH) following mild traumatic brain injury (mTBI) is one of the most prominent and highly reported persistent post-concussion symptoms (PPCS). Non-pharmacologic treatments, including non-invasive neurostimulation technologies, have been proposed for use. Our objective was to evaluate headache characteristics at one-month following repetitive transcranial magnetic stimulation (rTMS) treatment in participants with PTH and PPCS. A double-blind, randomized, sham-controlled, pilot clinical trial was performed on twenty participants (18-65 years) with persistent PTH (ICHD-3) and PPCS (ICD-10). Ten sessions of rTMS therapy (10Hz, 600 pulses, 70% resting motor threshold amplitude) were delivered to the left dorsolateral prefrontal cortex (DLPFC). The primary outcome was a change in headache frequency or severity at one-month post-rTMS. Two-week long daily headache diaries and clinical questionnaires assessing function, PPCS, cognition, quality of life, and mood were completed at baseline, post-treatment, and at one-, three-, and six-months post-rTMS. A two-way (treatment x time) mixed ANOVA indicated a significant overall time effect for average headache severity [F(3,54)= 3.214, p=0.03] and a reduction in headache frequency at one-month post-treatment (#/two-weeks: REAL -5.2 (SD=5.8), SHAM -3.3 (SD=7.7). Secondary outcomes revealed an overall time interaction for headache impact, depression, post-concussion symptoms, and quality of life. There was a significant reduction in depression rating in the REAL group between baseline and one-month post-treatment, with no change in the SHAM group (PHQ-9; REAL -4.3 (SD=3.7, p=0.020), SHAM -0.7 (SD=4.7, p=1.0), Bonferroni corrected). In the REAL group, 60% returned to work while only 10% returned in the SHAM group (p=0.027). This pilot study demonstrates an overall time effect on headache severity, functional impact, depression, PPCS, and quality of life following rTMS treatment in participants with persistent PTH, however, findings were below clinical significance thresholds. There was a 100% response rate, no dropouts, and minimal adverse effects, warranting a larger phase II study.
Learn More >Painful diabetic neuropathy (PDN), a debilitating and progressive chronic pain condition that significantly impacts quality of life, is one of the common complications seen with long-standing diabetes mellitus. Neither pharmacological treatments nor low-frequency spinal cord stimulation (SCS) has provided significant and long-term pain relief for patients with PDN. This study aims to document the value of 10-kHz SCS in addition to conventional medical management (CMM) compared with CMM alone in patients with refractory PDN.
Learn More >Contemporary nonmalignant pain treatment algorithms commence with conservative non-invasive strategies, later progressing from minimally invasive interventions to invasive techniques or implantable devices. The most commonly used implantable devices are spinal cord stimulation (SCS) systems or targeted drug delivery (TDD) devices. Historically, SCS had been considered in advance of TDD, positioning TDD behind SCS failures. Following Institutional Review Board approval, data were extracted from electronic medical records of patients who underwent SCS trial in the Department of Pain Management at Cleveland Clinic from 1994 to 2013. The sample size was analyzed in two cohorts: those who succeeded with SCS and those who failed SCS and consequently proceeded to TDD. Univariate and multivariate analyses were performed and a predictive formula for successful outcomes was created. 945 patients were included in the cohort of which 119 (12.6%) subjects achieved adequate pain relief with TDD after failure of SCS. Gender, age, depression and primary pain diagnosis were significantly different in this subgroup. Males were 52% less likely to experience pain relief with SCS. The odds of SCS success decreased as age increased by 6% per year. Patients with comorbid depression, interestingly, were 63% more likely to succeed with SCS. A logistic model was created to predict SCS success which was used to create a predictive formula. Older male patients diagnosed with spine-related pain were more likely to benefit from TDD than SCS. This observation potentially identifies a subgroup in whom consideration for TDD in advance of SCS failure could prove more efficient and cost effective. These retrospective findings warrant prospective comparative studies to validate this derived predictive formula.
Learn More >Opioids are more commonly prescribed for chronic pain in rural settings in the USA, yet little is known about how the rural context influences efforts to improve opioid medication management.
Learn More >The United States is experiencing an epidemic of opioid use disorder (OUD) and overdose-related deaths. However, the genetic basis for the ability to discontinue opioid use has not been investigated. We performed a genome-wide association study (GWAS) of opioid cessation (defined as abstinence from illicit opioids for >1 year or <6 months before the interview date) in 1130 African American (AA) and 2919 European ancestry (EA) participants recruited for genetic studies of substance use disorders and who met lifetime Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria for OUD. Association tests performed separately within each ethnic group were combined by meta-analysis with results obtained from the Comorbidity and Trauma Study. Although there were no genome-wide significant associations, we found suggestive associations with nine independent loci, including three which are biologically relevant: rs4740988 in ( = 2.24 × 10), rs36098404 in ( = 2.24 × 10), and rs592026 in ( = 6.53 × 10). Significant pathways identified in persons of European ancestry (EA) are related to vitamin D metabolism ( = 3.79 × 10) and fibroblast growth factor (FGF) signaling ( = 2.39 × 10). UK Biobank traits including smoking and drinking cessation and chronic back pain were significantly associated with opioid cessation using GWAS-derived polygenic risk scores. These results provide evidence for genetic influences on opioid cessation, suggest genetic overlap with other relevant traits, and may indicate potential novel therapeutic targets for OUD.
Learn More >Expectation interacting with nociceptive input can shape the perception of pain. It has been suggested that reward-related expectations are associated with the activation of the ventral tegmental area (VTA), which projects to the striatum (e.g., nucleus accumbens [NAc]) and prefrontal cortex (e.g., rostral anterior cingulate cortex [rACC]). However, the role of these projection pathways in encoding expectancy effects on pain remains unclear. In this study, we leveraged a visual cue conditioning paradigm with a long pain anticipation period and collected magnetic resonance imaging (MRI) data from 30 healthy human subjects (14 females). At the within-subject level, whole brain functional connectivity (FC) analyses showed that the mesocortical pathway (VTA-rACC FC) and the mesolimbic pathway (VTA-NAc FC) were enhanced with positive expectation but inhibited with negative expectation during pain anticipation period. Mediation analyses revealed that cue-based expectancy effects on pain were mainly mediated by the VTA-NAc FC, and structural equation modeling showed that VTA-based FC influenced pain perception by modulating pain-evoked brain responses. At the between-subject level, multivariate pattern analyses demonstrated that gray matter volumes in the VTA, NAc, and rACC were able to predict the magnitudes of conditioned pain responses associated with positive and/or negative expectations across subjects. Our results therefore advance the current understanding of how the reward system is linked to the interaction between expectation and pain. Furthermore, they provide precise functional and structural information on mesocorticolimibic pathways that encode within-subject and between-subject variability of expectancy effects on pain.Studies have suggested that reward-related expectation is associated with the activation of the ventral tegmental area (VTA), which projects to the striatum and prefrontal cortex. However, the role of these projection pathways in encoding expectancy effects on pain remains unclear. Using multi-modality MRI and a visual cue conditioning paradigm, we found that the functional connectivity and gray matter volumes in key regions (the VTA, nucleus accumbens, and rostral anterior cingulate cortex) within the mesocorticolimbic pathways encoded expectancy effects on pain. Our results advance the current understanding of how the reward system is linked to the interaction between expectation and pain, and provide precise functional and structural information on mesocorticolimbic pathways that encode expectancy effects on pain.
Learn More >: Prurigo nodularis (PN) is an intensely pruritic skin condition of considerable morbidity. However, the pathogenesis of PN and its association with underlying neuropathy is unclear. : We sought to investigate the association between PN and etiologies of peripheral neuropathy. : A cross-sectional analysis of adult patients (≥18-year-old) with PN, AD, and Psoriasis at the Johns Hopkins Health System over a six-year period (January 2013-January 2019) was performed. The strength of association with etiologies of peripheral neuropathy were compared to a control cohort of individuals without PN, as well as those with AD or psoriasis. : A total of 1122 patients with PN were compared to 10,390 AD patients, 15,056 patients with psoriasis, and a control cohort of 4,949,017 individuals without PN, with respect to 25 comorbidities associated with peripheral neuropathies. : Comparisons between peripheral neuropathies and PN represent associations but are not causal relationships. : Prurigo nodularis is strongly associated with peripheral neuropathies, suggesting a role for neural dysregulation in pathogenesis.
Learn More >In the emergency room, distinguishing between a migraine with aura and a transient ischemic attack (TIA) is often not straightforward and mistakes can be harmful to both the patient and to society. To account for this difficulty, the third edition of the International Classification of Headache disorders (ICHD-3) changed the diagnostic criteria of migraine with aura.
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