Pain Conditions Research Articles

Central sensitization symptoms in vulvodynia: exploring the role of temperament, personality traits, childhood adverse events, defense mechanisms, and mental pain on quality of life.

Vulvodynia is a chronic pain syndrome characterized by persistent vulvar pain, occurring without clinically identifiable disorders. Central sensitization (CS) is suggested to play a role in the pathophysiology of vulvodynia, as for other nociplastic pain conditions. This study delves into the complex interplay between psychosocial factors and CS burden in women with vulvodynia, aiming to identify potential predictors (temperament, personality traits, childhood adverse events, defense mechanisms, and mental pain) and understand their impact on quality of life (QoL). A cohort-based cross-sectional web survey of 357 women with vulvodynia. Outcomes included 8 self-report measures to assess the Central Sensitization Inventory (CSI) and psychological variables, including sensory processing sensitivity, traumatic experiences, personality traits, defense mechanisms, and mental pain. Hierarchical multiple regression analyses were conducted in study 1, revealing that the following predicted higher CSI scores in women with vulvodynia: higher emotional overexcitability, decreased low sensory threshold, increased bodily threat experiences, elevated psychoticism, greater use of immature and neurotic defense mechanisms, and heightened mental pain. The final regression model identified the following as the strongest predictors of CS: low sensory threshold (β = 0.316), bodily threat experiences (β = 0.145), neurotic defenses (β = 0.210), and mental pain (β = 0.269). In study 2, the model presented interactions among these psychological factors in predicting CSI values explaining 48.9% of the variance in CS, 30.3% in psychological QoL, and 57.1% in physical QoL. This model opens discussion for tailored psychological interventions aimed to improve overall QoL in women with vulvodynia. Strengths of the study include innovative insights into the interplay between psychological variables and the construct of CS and quality of life. As a limitation, the research was conducted as a cross-sectional study with self-reported measures. The study calls for comprehensive assessments that consider physical and mental aspects, paving the way for holistic health care approaches in the management of vulvodynia.

The effectiveness of stretching exercises in patients with fibromyalgia: A systematic review.

Fibromyalgia is one of the most prevalent chronic pain disorders. Fibromyalgia is characterised by generalised pain. In addition, patients with fibromyalgia often have co-morbidity. Since no cure is available, the treatment is based on symptom management, with physical exercise being the recommended first-line treatment. Different exercise modalities have been examined, including the practice of stretching exercises. The aim of the systematic review is to summarise the efficacy of stretching exercises on fibromyalgia symptoms and to study the content and the quality of the current evidence. The review followed the recommendations of the PRISMA statement. The search for articles was performed in April 2023. We searched on MEDLINE, PubMed, CINAHL, Web of Science, SCOPUS, AMED, PEDro, ClinicalTrials.gov and the Cochrane Collaboration Trials Register. The search was updated in March 2024. The protocol was registered in PROSPERO. Risk of Bias was assessed using the Cochrane Risk of Bias tool, and quality assessment was performed using the GRADE approach. In total, 2586 studies were found in the database searches, of which nine were included in the analysis. The primary outcome was pain. Secondary outcomes were self-reported quality of life, fatigue and physical and mental functioning. The available evidence shows that stretching exercises may improve pain, health-related quality of life and physical and mental functioning, but the level of evidence is low. The main limitation is due to issues with the heterogeneity of the interventions and small sample sizes. Trial registration: PROSPERO registration number CRD42023399614. Key Points •Stretching exercises show promise in the treatment of fibromyalgia. They may improve pain, health-related quality of life, physical functioning and mental health, but the level of evidence is low. •This study goes beyond previous research by presenting a more comprehensive and detailed analysis of the content and methodological quality of the current evidence. •Further research with clearly outlined protocols must be carried out to advance our understanding of the benefits of stretching exercises on fibromyalgia symptoms.

Coordination between midcingulate cortex and retrosplenial cortex in pain regulation

IntroductionThe cingulate cortex, with its subregions ACC, MCC, and RSC, is key in pain processing. However, the detailed interactions among these regions in modulating pain sensation have remained unclear.MethodsIn this study, chemogenetic tools were employed to selectively activate or inhibit neuronal activity in the MCC and RSC of rodents to elucidate their roles in pain regulation.Results: Our results showed that chemogenetic activation in both the RSC and MCC heightened pain sensitivity. Suppression of MCC activity disrupted the RSC’s regulation of both mechanical and thermal pain, while RSC inhibition specifically affected the MCC’s regulation of thermal pain.DiscussionThe findings indicate a complex interplay between the MCC and RSC, with the MCC potentially governing the RSC’s pain regulatory mechanisms. The RSC, in turn, is crucial for the MCC’s control over thermal sensation, revealing a collaborative mechanism in pain processing.ConclusionThis study provides evidence for the MCC and RSC’s collaborative roles in pain regulation, highlighting the importance of their interactions for thermal and mechanical pain sensitivity. Understanding these mechanisms could aid in developing targeted therapies for pain disorders.

Effectiveness of art therapy interventions for treating pain and anxiety in adolescents in the emergency department.

To evaluate the effectiveness of art therapy in reducing pain and anxiety in adolescents with painful conditions treated in the ED. We conducted a prospective pilot study of patients 12-18years old presenting with a painful condition to a tertiary-care children's hospital ED. Primary outcome was pain intensity measured using the Verbal Numerical Rating Scale (scored 0-10); a decrease of ≥ 20% was clinically significant. Anxiety was measured using the short-form six-item State-Trait Anxiety Inventory (scored 20-80: 20-40 = zero-low anxiety; 41-60 = moderate anxiety; 61-80 = high anxiety); a change from higher to lower category was clinically significant. Outcomes were measured at baseline, immediately after, and 1h after art therapy completion. A standardized interview was conducted immediately after art therapy completion. We enrolled a convenience sample of 50 patients. Mean duration of art therapy was 34.7min. Mean baseline pain was 6.2 and decreased by 23.2% (95% CI 14.9-31.5) and 28.6% (95% CI 9.2-48), immediately after and 1h after art therapy completion, respectively. Mean baseline anxiety was 48 (moderate) and decreased to 38 (low) and 43 (moderate) at the same time points, respectively. Forty-eight patients (96%) reported feelings of relaxation, decreased pain intensity, and/or empowerment (e.g., "Very relaxing"; "I didn't feel as much pain"; "Really showed my emotions"; "A way to explain to doctors what I'm feeling and what parts hurt"). Art therapy may be associated with clinically significant decreases and qualitative improvements in pain and anxiety in adolescents with painful conditions being treated in the ED. This novel treatment may improve the holistic care of adolescents with painful conditions in the ED.

Assessing how individuals conceptualize numeric pain ratings: validity and reliability of the Pain Schema Inventory (PSI–6) Short Form

BackgroundWhile numeric scales to represent pain intensity have been well validated, individuals use various conceptualizations when assigning a number to pain intensity, referred to as pain rating schema. The 18-item Pain Schema Inventory (PSI-18) quantifies pain rating schema by asking for numeric values for multiple mild, moderate or severe pain conditions. This study aimed to assess the validity and reliability of a shortened form of the PSI, using only 6 items (PSI-6).MethodsA secondary analysis was performed on two existing datasets. The first (n = 641) involved a community-based population that completed the PSI-18. The second (n = 182) included participants with chronic pain who completed the PSI-6 twice, one week apart. We assessed face validity, convergent validity, offset biases, test-retest reliability, and internal consistency of the PSI-6 compared to the PSI-18.ResultsBoth the PSI-18 and PSI-6 demonstrated excellent face validity. The PSI-6 demonstrated excellent convergent validity relative to the PSI-18, with correlations from r = 0.88 to 0.92. Bland-Altman plots revealed offset biases near zero (< 0.22 on 0–10 scale) across all categories of mild, moderate, severe and average pain. Internal consistency was excellent, with Cronbach's Alpha = 0.91 and 0.80, for PSI-18 and PSI-6 respectively. Test-retest reliability of the PSI-6 was high with correlations from r = 0.70–0.76.ConclusionThe PSI-6 is a valid and reliable tool to assess pain rating schema with reduced subject burden, to better interpret individuals’ pain ratings and adjust for inter-individual variability.

Multimodal pain therapy for patients with endometriosis: care structure in German pain centres

It is estimated that every tenth woman of childbearing age has endometriosis. That's around 1.7 million sufferers in Germany. There are around 40,000 new diagnoses every year (Diedrich et al. 2006). The most important leading symptom is severe pain during menstruation, but also abdominal pain independent of the period. The more severe the pain, the greater the reduction in quality of life (Facchin et al. 2015). Depending on the localisation of endometriosis lesions, other symptoms, functional complaints and accompanying symptoms may also occur. Endometriosis is a chronic pain disorder that often takes several years to be diagnosed. In addition, current therapies result in high recurrence rates and the cause of the disease remains unclear (Diedrich et al. 2006; AWMF 2020). The long-lasting pain leads to complex neurological changes that often cause the pain to become chronic (Ball and Khan 2020; Brawn et al. 2014). Pain is defined as chronic if it lasts for more than three months or is recurrent (Treede et al. 2019).

The efficacy of evening primrose seed oil supplements on ART outcomes: A triple-blinded randomized placebo-controlled clinical trial

BackgroundEvening primrose oil (EPO) has been extensively documented for its potential benefits in various medical conditions, including gestational diabetes, inflammatory diseases, cyclic breast pain, cancer, premenstrual syndrome, menopausal syndrome, and female reproductive disorders. ObjectivesThe aim of this study was to investigate the impact of evening primrose oil (EPO) supplementation on the outcomes of assisted reproductive technology (ART). MethodsA randomized, triple-blinded, placebo-controlled clinical trial was conducted. A total of 84 infertile women who were candidates for intracytoplasmic sperm injection (ICSI) were randomly assigned to either the EPO supplementation group or the placebo (p) group with a 1:1 ratio. The EPO capsule was given from day 1–2 of the ART cycle at a dosage of 1000 mg every eight hours for two weeks. Finally, the ART outcomes parameters as well as the treatment side effects were evaluated. ResultsThe results illustrated no statistically significant disparities between the groups in terms of the number of oocytes retrieved, ovarian sensitivity index (OSI), rate of fertilization, and number and quality of embryos (p>0.05). However, a notably enhanced incidence of pregnancy and implantation rates in the EPO group was observed when compared to the P group (42.9 % vs. 17.4 % and 23±30.5 % vs. 10.87±26 %, respectively). Moreover, none of the patients experienced side effects from the intervention. ConclusionsEPO consumption for two weeks could improve ART outcomes by increasing implantation and pregnancy rates without significantly affecting the number of mature oocytes, rate of fertilization, and the quantity and quality of embryos. These findings highlight the significance of a maternal preconception diet.

Evaluation of the feasibility and acceptability of a home-based supervised exercise programme in individuals with spinal cord injuries: SCI-HOME-ACTIVE study protocol

Physical activity is essential to a healthy lifestyle for adults with spinal cord injuries (SCI). Although exercise is recognised as an important tool for improving the well-being and independence of...

The Analgesic Effects of Botulinum Neurotoxin by Modulating Pain-Related Receptors; A Literature Review.

Botulinum neurotoxins (BoNTs), produced by Clostridium botulinum, have been used for the treatment of various central and peripheral neurological conditions. Recent studies have suggested that BoNTs may also have a beneficial effect on pain conditions. It has been hypothesized that one of the mechanisms underlying BoNTs' analgesic effects is the inhibition of pain-related receptors' transmission to the neuronal cell membrane. BoNT application disrupts the integration of synaptic vesicles with the cellular membrane, which is responsible for transporting various receptors, including pain receptors such as TRP channels, calcium channels, sodium channels, purinergic receptors, neurokinin-1 receptors, and glutamate receptors. BoNT also modulates the opioidergic system and the GABAergic system, both of which are involved in the pain process. Understanding the cellular and molecular mechanisms underlying these effects can provide valuable insights for the development of novel therapeutic approaches for pain management. This review aims to summarize the experimental evidence of the analgesic functions of BoNTs and discuss the cellular and molecular mechanisms by which they can act on pain conditions by inhibiting the transmission of pain-related receptors.

Mechanisms of sensory adaptation and inhibition of the cold and menthol receptor TRPM8.

Our sensory adaptation to cold and chemically induced coolness is mediated by the intrinsic property of TRPM8 channels to desensitize. TRPM8 is also implicated in cold-evoked pain disorders and migraine, highlighting its inhibitors as an avenue for pain relief. Despite the importance, the mechanisms of TRPM8 desensitization and inhibition remained unclear. We found, using cryo-electron microscopy, electrophysiology, and molecular dynamics simulations, that TRPM8 inhibitors bind selectively to the desensitized state of the channel. These inhibitors were used to reveal the overlapping mechanisms of desensitization and inhibition and that cold and cooling agonists share a common desensitization pathway. Furthermore, we identified the structural determinants crucial for the conformational change in TRPM8 desensitization. Our study illustrates how receptor-level conformational changes alter cold sensation, providing insights into therapeutic development.

Understanding the Kynurenine Pathway: A Narrative Review on its Impact across Chronic Pain Conditions.

Chronic pain is a debilitating symptom with a significant negative impact on the quality of life and socioeconomic status, particularly among adults and the elderly. Major Depressive Disorder (MDD) stands out as one of the most important comorbid disorders accompanying chronic pain. The kynurenine pathway serves as the primary route for tryptophan degradation and holds critical significance in various biological processes, including the regulation of neurotransmitters, immune responses, cancer development, metabolism, and inflammation. This review encompasses key research studies related to the kynurenine pathway in the context of headache, neuropathic pain, gastrointestinal disorders, fibromyalgia, chronic fatigue syndrome, and MDD. Various metabolites produced in the kynurenine pathway, such as kynurenic acid and quinolinic acid, exhibit neuroprotective and neurotoxic effects, respectively. Recent studies have highlighted the significant involvement of kynurenine and its metabolites in the pathophysiology of pain. Moreover, pharmacological interventions targeting the regulation of the kynurenine pathway have shown therapeutic promise in pain management. Understanding the underlying mechanisms of this pathway presents an opportunity for developing personalized, innovative, and non-opioid approaches to pain treatment. Therefore, this narrative review explores the role of the kynurenine pathway in various chronic pain disorders and its association with depression and chronic pain.

A preliminary study exploring the effects of transcutaneous spinal cord stimulation on spinal excitability and phantom limb pain in people with a transtibial amputation.

Phantom limb pain (PLP) is debilitating and affects over 70% of people with lower-limb amputation. Other neuropathic pain conditions correspond with increased spinal excitability, which can be measured using reflexes and F-waves. Spinal cord neuromodulation can be used to reduce neuropathic pain in a variety of conditions and may affect spinal excitability, but has not been extensively used for treating phantom limb pain. Here, we propose using a non-invasive neuromodulation method, transcutaneous spinal cord stimulation (tSCS), to reduce PLP and modulate spinal excitability after transtibial amputation.&#xD;Approach: We recruited three participants, two males (5- and 9-years post-amputation, traumatic and alcohol-induced neuropathy) and one female (3 months post-amputation, diabetic neuropathy) for this 5-day study. We measured pain using the McGill Pain Questionnaire, visual analog scale (VAS), and pain pressure threshold test. We measured spinal reflex and motoneuron excitability using posterior root-muscle (PRM) reflexes and F-waves, respectively. We delivered tSCS for 30 minutes/day for 5 days. &#xD;Main Results: After 5 days of tSCS, McGill Pain Questionnaire scores decreased by clinically-meaningful amounts for all participants from 34.0±7.0 to 18.3±6.8; however, there were no clinically-significant decreases in VAS scores. Two participants had increased pain pressure thresholds across the residual limb (Day 1: 5.4±1.6 lbf; Day 5: 11.4±1.0 lbf). F-waves had normal latencies but small amplitudes. PRM reflexes had high thresholds (59.5±6.1 µC) and low amplitudes, suggesting that in PLP, the spinal cord is hypoexcitable. After 5 days of tSCS, reflex thresholds decreased significantly (38.6±12.2 µC; p<0.001).&#xD;Significance: These preliminary results in this non-placebo-controlled study suggest that, overall, limb amputation and PLP may be associated with reduced spinal excitability and tSCS can increase spinal excitability and reduce PLP.

Yoga and Physical Therapy for Chronic Pain and Opioid Use Disorder Onsite in an Opioid Treatment Program: A Randomized Controlled Trial.

There is a lack of integrated treatment for chronic pain and opioid use disorder (OUD). Yoga and physical therapy (PT) may improve pain and physical function of people living with (PLW) chronic low back pain (CLBP) and may also reduce opioid craving and use, but PLW with OUD face barriers to accessing these interventions. We hypothesize that compared to treatment as usual (TAU), providing yoga and PT onsite at opioid treatment programs (OTPs) will be effective at improving pain, opioid use, and quality of life among people with CLBP and OUD, and will be cost-effective. In this hybrid type-1 effectiveness-implementation study, we will randomly assign 345 PLW CLBP and OUD from OTPs in the Bronx, NY, to 12 weeks of onsite yoga, onsite PT, or TAU. Primary outcomes are pain intensity, opioid use, and cost-effectiveness. Secondary outcomes include physical function and overall well-being. This trial tests an innovative, patient-centered approach to combined management for pain and OUD in real-world settings. We rigorously examine the efficacy of yoga and PT onsite at OTPs as nonpharmacologic, cost-effective treatments among people with CLBP and OUD who face barriers to integrated care.

User Experience in Immersive Virtual Reality-Induced Hypoalgesia in Adults and Children Suffering from Pain Conditions

User Experience in Immersive Virtual Reality-Induced Hypoalgesia in Adults and Children Suffering from Pain Conditions

D2-like dopamine receptors blockade within the dentate gyrus shows a greater effect on stress-induced analgesia in the tail-flick test compared to D1-like dopamine receptors.

Acute stress, as a protective mechanism to respond to an aversive stimulus, can often be accompanied by suppressing pain perception via promoting consistent burst firing of dopamine neurons. Besides, sensitive and advanced research techniques led to the recognition of the mesohippocampal dopaminergic terminals, particularly in the hippocampal dentate gyrus (DG). Moreover, previous studies have shown that dopamine receptors within the hippocampal DG play a critical role in induced antinociceptive responses by forced swim stress (FSS) in the presence of inflammatory pain. Since different pain states can trigger various mechanisms and transmitter systems, the present experiments aimed to investigate whether dopaminergic receptors within the DG have the same role in the presence of acute thermal pain. Ninety-seven adult male albino Wistar rats underwent stereotaxic surgery, and a stainless steel guide cannula was unilaterally implanted 1 mm above the DG. Different doses of SCH23390 or sulpiride as D1- and D2-like dopamine receptor antagonists were microinjected into the DG 5-10 min before exposure to FSS, and 5 min after FSS exposure, the tail-flick test evaluated the effect of stress on the nociceptive response at the time-set intervals. The results demonstrated that exposure to FSS could significantly increase the acute pain perception threshold, while intra-DG administration of SCH23390 and sulpiride reduced the antinociceptive effect of FSS in the tail-flick test. Additionally, it seems the D2-like dopamine receptor within the DG plays a more prominent role in FSS-induced analgesia in the acute pain model.

Prevalence and predictors of fibromyalgia among Egyptian physicians: a cross-sectional study

BackgroundFibromyalgia is a chronic, disabling disorder of widespread musculoskeletal pain. It is generally considered a stress-related syndrome. Healthcare workers are prone to mental and physical stress due to due to excessive work burdens, long working hours, and a lack of balance between work and social life.ObjectiveThe aim of this study was to examine the prevalence of fibromyalgia and its predictors among Egyptian physicians.MethodsSix hundred and ninety-one Egyptian physicians completed an online survey which included a self-reported fibromyalgia rapid screening tool (FiRST) as well as demographic (sex and age), health-related (chronic illnesses if any), and employment data (workday length, specialty, and employer). Logistic regression was performed to explore possible predictors of fibromyalgia.ResultsFibromyalgia was observed in 13.2% of participants, with a female to male ratio of 3.8:1. Predictors of FM in this cohort included the following: female sex (odds ratio (OR) 2.2, 95% confidence interval (CI) 1.2–3.9, p = 0.014), age 41–50 years (OR 3.8, 95% CI 1.5–9.6, p = 0.005), concomitant chronic illness: endocrinopathies (other than diabetes mellitus) (OR 2.69, 95% CI 1.09–6.64, p = 0.035), musculoskeletal disorders (OR 5.60, 95% CI 2.96–10.6, p < 0.001), autoimmune disorders (OR 3.61, 95% CI 1.69–7.73, p = 0.002), employment at a Ministry of Health Healthcare Facility (OR 1.8, 95% CI 1.1–3.1, p = 0.013), and a workday length of ≥ 13 h (OR 2.4, 95% CI 1.1–5.3, p = 0.038). Physicians in surgical specialties were less likely to suffer from FM (OR 0.47, 95% CI 0.24–0.94, p = 0.033).ConclusionEgyptian physicians have higher fibromyalgia prevalence than the general population. Demographic, health-related, and professional predictors of FM were identified in this cohort.

Study Protocol for the Opioid and Pain Treatment in Indigenous Communities Trial: A Systems Level Intervention for Enhanced Screening and Brief Intervention and Referral for Co-Occurring Chronic Pain and Opioid Use Disorder.

American Indian/Alaska Native (AI/AN) individuals have the highest rates of opioid overdose mortality and chronic pain (CP) compared to other racial/ethnic groups in the United States. These individuals also report higher rates of pain anxiety and pain catastrophizing, which are both associated with poorer outcomes and risk for opioid misuse (OM) and opioid use disorder (OUD) among individuals with CP. Yet, no prior studies have examined rates of comorbid pain and OUD among AI/AN adults. This commentary describes an implementation research partnership of 3 AI/AN-serving clinics and a university team that utilizes an implementation hybrid type III design to examine the impact of implementation strategies on adoption and sustainability of evidence-based screening and brief intervention for CP and OM/OUD among AI/AN clients. As part of our community-engaged approach, we embrace both AI/AN models and Western models, and a collaborative board of 10 individuals guided the research throughout. We hypothesize that our culturally centered approach will increase rates of screening and brief intervention and improve identification of and outcomes among AI/AN clients with CP and OUD who receive treatment at participating sites. Each site convenes a workgroup to evaluate and set goals to culturally center screening and brief interventions for CP and OM/OUD. Data collected include deidentified electronic health records to track screening and brief interventions and rates of CP and OUD; provider and staff surveys beginning prior to implementation and every 6 months for 2 years; and a subset of clients will be recruited (N = 225) and assessed at baseline, 6, and 12 months to examine biopsychosocial and spiritual factors and their experiences with culturally centered screening and brief intervention. Cultural adaptations to the measures and screening and brief intervention as well as barriers and facilitators will be addressed. Recommendations for successful Tribal health clinic-university partnerships are offered.

Quantitative sensory testing in notalgia paresthetica reveals small fiber-type-specific differences in non-pruritic sensitivity: a pilot study.

Notalgia paresthetica (NP) is a chronic condition characterized by pruritus and other unpleasant dysesthetic sensations unilaterally on the subscapular back. Its specific underlying mechanisms are largely unknown, though hypothesized to be neuropathic. Determination of possible somatosensory contributors to the condition could pave the way for novel treatments. Given the potential involvement of non-pruritic mechanisms in NP, our objective was to broadly characterize the somatosensory function in NP-affected and unaffected skin using methods that have been standardized in pain-free controls and painful neuropathic disorders. We hypothesized that if NP is caused by neuropathic mechanisms not targeted directly to pruritoceptors in the skin, somatosensory abnormalities would not be itchspecific. Second, given the lack of symptoms on the contralateral side of the back, we hypothesized that this region would be normally sensitive. In this study, quantitative sensory testing (QST) was used to comprehensively assess the somatosensory function in 15 adult patients with NP. Standardized QST metrics were performed in the NP-affected region and compared with the contralateral asymptomatic skin and itch-free individuals using an age, gender, and site-matched reference data set. There were no significant differences in sensitivity between symptomatic and asymptomatic skin, except for increased mechanical-evoked itch on the itchy side. However, reference data set comparisons revealed bilateral hyposensitivity to innocuous cold and noxious pinprick and higher temporal summation of pain in patients with NP. In addition, compared with reference data, patients with NP demonstrated decreased sensitivity to cold and pinprick, presence of paradoxical heat sensations, and increased wind-up of pain. These results suggest a role for Aδ fiber pathways and central sensitization in NP-associated itch. More research is needed to determine whether sensory differences extend beyond the NP-affected dermatomal level and what might cause neuropathy specifically targeting Aδ fibers.

Discovery of Novel, Selective, and Nonbasic Agonists for the Kappa-Opioid Receptor Determined by Salvinorin A-Based Virtual Screening.

Modulating the kappa-opioid receptor (KOR) is a promising strategy for treating various human diseases. KOR agonists show potential for treating pain, pruritus, and epilepsy, while KOR antagonists show potential for treating depression, anxiety, and addiction. The diterpenoid Salvinorin A (SalA), a secondary metabolite of Salvia divinorum, is a potent and selective KOR agonist. Unlike typical opioids, SalA lacks a basic nitrogen, which encouraged us to search for nonbasic KOR ligands. Through structure-based virtual screening using 3D pharmacophore models based on the binding mode of SalA, we identified novel, nonbasic, potent, and selective KOR agonists. In vitro studies confirmed two virtual hits, SalA-VS-07 and SalA-VS-08, as highly selective for the KOR and showing G protein-biased KOR agonist activity. Both KOR ligands share a novel spiro-moiety and a nonbasic scaffold. Our findings provide novel starting points for developing therapeutics aimed at treating pain and other conditions in which KOR is a central player.

Relationships between Applied Mindfulness Practice, Chronic Pain, and Pain-Related Functioning in Veterans

Mindfulness-based interventions (MBIs) have been shown to improve chronic pain and associated conditions like depression, anxiety, and sleep disorders. However, there is limited research on how Veterans with chronic pain apply mindfulness skills to manage pain in daily life. This cross-sectional study examined the association between applied mindfulness practice, pain, and several pain-related conditions among 1,737 Veterans with chronic pain prior to enrollment in a trial of two MBIs. Applied mindfulness practice was assessed using the Applied Mindfulness Process Scale (AMPS). Outcomes included pain interference, pain intensity, pain catastrophizing, fatigue, sleep disturbance, anxiety, depression, PTSD, physical function, and social participation. Higher overall AMPS scores, as well as the positive and negative emotional regulation subscales of the AMPS, were associated with less pain interference and catastrophizing, as well as better outcomes for all pain-related conditions. The positive emotional regulation subscale had the strongest associations with outcomes. There was no significant association between the AMPS and pain intensity. Results suggest applied mindfulness practice, especially positive emotional regulation, may improve pain and functioning. In addition, the AMPS shows promise as a process measure of mindfulness skills applied in daily life. Additional research is needed to examine different aspects of mindfulness in the context of MBIs. PerspectiveThis article describes the relationship between applied mindfulness practice and pain-related outcomes, prior to a mindfulness-based intervention, using a novel measure of mindfulness practice. These findings underscore the importance of measuring applied mindfulness practice prior to and during clinical interventions to treat chronic pain.