Pain Conditions Research Articles

Biphasic Hormetic-like Effect of Lebecetin, a C-type Lectin of Snake Venom, on Formalin-induced Inflammation in Mice.

Integrins, important extracellular matrix (ECM) receptor proteins, are affected by inflammation and can participate in the maintenance of many painful conditions. Although they are ubiquitous and changeable across all cell types, the roles of these cell adhesion molecules in pathological pain have not been fully explored. We evaluated the effects of the subcutaneous injection of lebecetin, a C-type lectin isolated from Macrovipera lebetina snake venom, previously reported to inhibit α5β1 and αv integrin activity, on different components of inflammation induced by the formalin administration in the hind paw of mice. The formalin-induced nocifensive behavior, edema, and histopathological changes in the hind paw associated with cytokine, iNOS, and COX2 expression, nociceptive-specific neuron activity, and microglial activation analysis in the spinal cord were evaluated in mice receiving vehicle or lebecetin pretreatment. Lebecetin inhibited the nocifensive responses in the formalin test, related edema, and cell infiltration in the injected paw in a biphasic, hormetic-like, and dose-dependent way. According to that hormetic trend, a reduction in pro-inflammatory cytokines IL-6, IL-8, and TNF-alpha and upregulation of the anti-inflammatory cytokine IL-10 in the spinal cord were found with the lowest doses of lebecetin. Moreover, COX2 and iNOS expression in serum and spinal cord followed the same biphasic pattern of cytokines. Finally, nociceptive neurons sensitization and activated microglia were normalized in the dorsal horn of the spinal cord by lebecetin. These findings implicate specific roles of integrins in inflammation and tonic pain, as well as in the related central nervous system sequelae.

Bioinformatics and systems biology approach to identify the pathogenetic link of neurological pain and major depressive disorder

Bioinformatics and systems biology approach to identify the pathogenetic link of neurological pain and major depressive disorder

The polymorphism Val158Met in the COMT gene: disrupted dopamine system in fibromyalgia patients?

The single-nucleotide polymorphism (SNP) rs4680 in the catechol-O-methyltransferase gene ( COMT ) is a missense variant (Val158Met) associated with altered activity of the COMT enzyme and suggested as a predictive feature for developing some chronic pain conditions. However, there are controversial results on its role in fibromyalgia (FM). Here, the SNP Val158Met was analyzed in 294 FM patients (without comorbidities) and 209 healthy controls (without chronic pain). The concurrent impact of Val158Met genotypes and FM comorbid disorders (depression and sleep impairment) on FM risk were tested. In addition, the genotypic distribution of FM patients in relation to pain intensity was evaluated. The G allele (Val) resulted in being more represented in the FM group (57.8%) compared with the control group (48.8%; P = 0.037). Logistic regression highlighted that having the G/G (Val/Val) homozygous genotype was associated with 2 times higher risk of having FM compared with the A/A (Met/Met) carriers ( P = 0.038), whereas depression and sleep impairment increased FM risk by 12 and 8 times, respectively ( P < 0.001). However, considering only the FM patient group, the A/A homozygous genotype was significantly associated with severe pain intensity ( P = 0.007). This study highlighted associations between the SNP Val158Met and both FM and pain intensity, suggesting a link between dopaminergic dysfunction and vulnerability to chronic pain. Further studies should explore this SNP in FM patients in conjunction with COMT enzymatic activity and other symptoms connected with the dopaminergic system such as depression or sleep impairment.

Methods for negating the impact of zinc contamination to allow characterization of positive allosteric modulators of glycine receptors

Zinc is a ubiquitous contaminant in many buffers, purified products and common labware that has previously been suggested to impact on the results of functional GlyR studies and may inadvertently cause the effectiveness of some GlyR modulators to be over-estimated. This could greatly impact the assessment of potential drug-candidates and contribute to the reduced effectiveness of compounds that reach clinical stages. This is especially true for GlyR modulators being developed for pain therapeutics due to the changes in spinal zinc concentrations that have been observed during chronic pain conditions. In this study we use two-electrode voltage clamp electrophysiology to evaluate the metal chelators tricine and Ca-EDTA, and show that tricine produces inhibitory effects at GlyRα1 that are not mediated by zinc. We also utilized the zinc insensitive W170S mutation as a tool to validate metal chelators and confirm that zinc contamination has not impacted the examination of lipid modulators previously developed by our lab. This study helps to further develop methods to negate the impact of contaminating zinc in functional studies of GlyRs which should be incorporated into future studies that seek to characterize the activity of novel modulators at GlyRs.

Validation of a questionnaire for Central nervous system Aspects of joint Pain: the CAP questionnaire.

Neuropathic-like pain, fatigue, cognitive difficulty, catastrophising, anxiety, sleep disturbance, depression, and widespread pain associate with a single factor in people with knee pain. We report the Central Aspects of Pain questionnaire (CAP) to characterise this across painful musculoskeletal conditions. CAP was derived from the 8 item CAP-Knee questionnaire, and completed by participants with joint pain in the Investigating Musculoskeletal Health and Wellbeing survey. Subgroups had osteoarthritis, back pain or fibromyalgia. Acceptability was evaluated by feedback and data missingness. Correlation coefficients informed widespread pain scoring threshold in relation to the other items, and evaluated associations with pain. Factor analysis assessed CAP structure. Intraclass Correlation Coefficient (ICC) between paper and electronic administration assessed reliability. Friedman test assessed score stability over 4 years in people reporting knee osteoarthritis. Data were from 3579 participants (58% female, median age; 71 years), including subgroups with osteoarthritis (n = 1158), back pain (n = 1292) or fibromyalgia (n = 177). Across the 3 subgroups, ≥10/26 painful sites on the manikin scored widespread pain. Reliability was high (ICC= 0.89 (95% CI: 0.84-0.92)) and CAP scores fit to 1 and 2 factor model, with a total CAP score that was associated with pain severity and quality (r = 0.50-0.72). In people with knee pain, CAP scores were stable over 4 years at the group level, but displayed significant temporal heterogeneity within individual participants. Central Aspects of Pain is reliably measured by the CAP questionnaire across a range of painful musculoskeletal conditions, and is a changeable state.

Prevalence and burden of pain across the entire spectrum of Huntington’s disease

BackgroundPain is an important symptom in Huntington’s disease (HD), however, not systematically studied and understood. The objective of the current study is to assess the prevalence of pain, pain interference...

(086) MEDICAL GASLIGHTING AND VULVOVAGINAL PAIN DISORDERS

Abstract Introduction Gaslighting is a form of epistemic injustice that involves testimonial injustice, in which patient’s experiences are discounted by others. The incidence of epistemic injustice has been described in a number of pain conditions including chronic fatigue syndrome and fibromyalgia, as well as in marginalized obstetric populations. Little research has been directed towards epistemic injustice in populations seeking treatment for benign gynecologic conditions or the unique context of vulvovaginal pain conditions. Additionally, little is known about the consequence of this type of injustice on patient’s perception of their care or willingness to seek care. Objective The purpose of this study was to develop a patient-validated instrument to measure patient experience of epistemic injustice in their past gynecologic care and to use the instrument to explore patient experiences in a vulvovaginal pain referral center. Methods An instrument was designed by the study team to quantify the incidence and distressed caused by gaslighting in patients seek care for vulvovaginal pain conditions. This was created based on common themes from written testimonials of patients available from National Vulvodynia Association. After construction, the instrument was submitted for feedback to officers from two vulvovaginal pain disorder patient societies. The survey was modified to include the feedback from these sources. The survey was then completed by patients establishing care with the clinic prior to their first appointment. Results 187 patients completed the survey in part or in full. Patients reported having seen an average of 5.7 providers prior to presentation. Patients felt supported by only 42% of past providers. Patients felt belittled by 27% of past providers. Patients felt 21% of past providers did not believe their symptoms. 45% of patients were told they “just needed to relax more”; 18% percent were recommended to drink alcohol to improve their condition; 55% considered giving up seeking care because they felt their concerns were not being addressed; 31% were told their symptoms were caused by high levels of anxiety; 22% were referred to psychiatry without other medical treatment for their symptoms; 19% felt unsafe during a medical encounter. 39% percent of patients were made to feel they were “crazy” and this was the most distressing of the questions asked (average 7.3/10 on a likert scale for distress for patients who had experienced this). Conclusions A survey based on patient concerns and validated by patients affected by vulvovaginal pain conditions has not been previously reported. This instrument was applied to a patient population at a large referral center for vulvovaginal pain conditions and the results showed that patients commonly experienced many forms of epistemic injustice, and greater than half of patients consider cessation of care for their condition because of these experiences. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Dr. Jill Krapf is a medical advisor for Evvy. Dr. Andrew Goldstein is a part time Employee of Daré Bioscience. He is a member of the board of directors of The Gynecologic Cancers Research Foundation. He is an advisor for: AbbVie, Incyte, and the National Vulvodynia Association. He has received research funding from Incyte.

(062) IMPLEMENTING A VALIDATED SEXUAL DYSFUNCTION SCREENING TOOL AT AN INNER-CITY WOMEN’S HEALTH CLINIC

Abstract Introduction The American College of Obstetricians and Gynecologists (ACOG) reports 43% of American women experience sexual health problems, including Female Sexual Interest and Arousal Disorder, Female Orgasmic Disorder, Genito–Pelvic Pain and Penetration Disorder, and Substance or Medication-Induced Sexual Dysfunction. Objective At Women’s Ambulatory Health Services (WAHS), an inner-city clinic associated with Hartford HealthCare, at which UConn Health ObGyn residents work, there is no routine screening in place for sexual dysfunction. This project aimed to implement the Female Sexual Function Index (FSFI) for screening for sexual dysfunction at this clinic to identify patients who may benefit from treatment. Methods We implemented the FSFI-short version, a six-question screening tool for sexual dysfunction that has been validated in English and Spanish and utilized in many countries on July 1st, 2022. Patients presenting for a new gynecologic visit or an annual gynecologic exam were asked to complete the screening tool. Patients who scored equal to or less than 18 on the FSFI-short version were identified as at risk for female sexual dysfunction and were offered referral to a health psychologist specializing in sexual dysfunction. We utilized the RE-AIM framework for implementation science to guide the implementation evaluation. We collected data on patients from July 1 through December 1, 2022. We collected patient demographics and implementation outcomes, including rate of survey completion, candidacy for referral and referral completion. Results 196 surveys were reviewed between July 1st and December 1st of 2022. 44 surveys were excluded for various reasons, including not meeting study inclusion criteria or invalid responses. 152 screening forms were included and 45 patients screened positive. Subjective patient barriers were gathered from comments written directly onto the paper survey as well as quotes documented by their providers in the visit note. These subjective barriers included hesitancy to discuss sexual health and lacking knowledge that the gynecologist provider offers assessment and management for these disorders. Conclusions The introduction of the FSFI-sv at WAHS has both expanded the resources offered to patients, enhanced the environment surrounding topics of women’s health both between staff members as well as within the patient-provider relationship, and has unearthed multiple opportunities for improving the screening process, referral selection and work flow for sexual dysfunction amongst the patient population. Disclosure No.

(096) UNDERSTANDING THE RELATIONSHIP BETWEEN CHRONIC PAIN AND DEPRESSION IN LOCALIZED PROVOKED VULVODYNIA

Abstract Introduction Localized provoked vulvodynia (LPV) is a disease characterized by chronic pain in the vulva in response to touching the vulvar vestibular epithelium. As with other chronic pain disorders, vulvodynia is often found accompanied with depression, and depressive symptoms aggravate pain severity and persistence. While there is clear evidence of a connection between chronic vulvar pain and depression, the mechanism of this bidirectional relationship is largely unknown. Accumulating evidence suggests that inflammation plays a central role in depression. Since the pathophysiology of LPV also involves inflammation, we aim to better understand these relationships by pharmacologically inhibiting the enzyme that plays a key role in both inflammation and depression: soluble epoxide hydrolase (sEH). Objective To elucidate the role of sEH in localized provoked vulvodynia, which might be involved in the chronic pain and depression comorbidity prevalent in vulvodynia patients, and discuss the clinical significance of using sEH inhibitors, such as 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), for patients suffering from this condition. Methods Vulvar punch biopsies obtained from painful sites within the vulvar vestibule and non-painful sites within the external vulva of 6 LPV patients and 6 age/race-matched healthy controls were used to generate a library of primary fibroblast strains. Cells were treated with the inflammatory instigator interleukin-1β (IL-1β) and TPPU. Quantitative PCR, Western blotting, and enzyme-linked immunosorbent assays were used to assess the effects of sEH inhibition. Statistical analysis was performed using GraphPad Prism 10.0.2. Comparisons among groups were performed using the one-way analysis of variance (ANOVA) or two-way ANOVA, followed by post-hoc Tukey test. Results Vulvodynia patients produce increased levels of pro-inflammatory cytokines, namely interleukin-6 (IL-6) and prostaglandin E2 (PGE2), when compared with controls. Interestingly, mRNA (P = 0.0091) and protein (P = 0.0198) levels of sEH were significantly lower in the painful vestibule of these patients. When sEH was inhibited with TPPU, we observed a significant decrease in IL-6 levels (P = &amp;lt;0.0001), but not PGE2 (P = 0.6452). These preliminary findings are of fundamental importance as cytokines can directly contribute to the development of depressive symptoms. Conclusions Patients with vulvodynia are more likely to develop depressive symptoms than patients without vulvar pain. Likewise, patients with depression are more likely to develop vulvodynia than patients without depression. Our results suggest that sEH may play a role in this bidirectional mechanism, which could serve as a novel therapeutic target for chronic pain and depression comorbidity. Disclosure No.

(133) SELF-REPORTED EFFICACY OF PELVIC FLOOR PHYSICAL THERAPY AS A TREATMENT FOR PUDENDAL NEURALGIA: A CROSS-SECTIONAL STUDY

Abstract Introduction Pudendal neuralgia (PN) is a devastating sexual pain disorder characterized as pain of the genital and/or perineal regions and is often due to injury, irritation, or entrapment of the pudendal nerve. Pelvic floor physical therapy (PFPT) is a recommended treatment for PN despite the lack of clinical evidence supporting its use. Objective We aimed to understand the efficacy of PFPT for treating PN by evaluating self-reported efficacy from PN patients. Methods An online survey was conducted on PN patients who had participated in PFPT as a treatment for PN. Participants were asked to evaluate the efficacy of PFPT specifically regarding its effects on PN symptoms using a seven-point Patient Global Impression of Change (PGIC) scale: 1=very much worse, 2=much worse, 3=minimally worse, 4=no change, 5=minimally improved, 6=much improved, 7=very much improved. If lasting symptom improvement was achieved, participants were asked how many sessions before they first noticed an improvement in symptoms. Results The average PGIC score among participants was 4.6 ± 1.3 (n=144), indicating no to minimal improvement in symptoms. Twelve percent of participants scored 3 or lower, indicating worsening of symptoms, and only 22% scored 6 or 7, indicating much or very much improvement of symptoms. For those who had symptom improvement, 14.6% of participants reported improvement after only one PFPT session, and five was the median number of sessions before first noticing improvement. Conclusions PFPT is a minimally effective, and sometimes harmful, treatment for pudendal neuralgia. Better transparency should be provided to patients regarding PFPT’s lack of efficacy and potential harm for treating PN symptoms. Disclosure No.

(025) DEVELOPING AND TESTING AN ONLINE PRIMARY CARE TOOLKIT FOR COMMUNITY MANAGEMENT OF VULVODYNIA

Abstract Introduction Vulvodynia is a chronic vulvar pain condition that affects 8-10% of women and people with vulvas. Despite its prevalence, healthcare providers (HCPs) often lack awareness, knowledge, and confidence in managing vulvodynia. This knowledge gap can lead to diagnostic delays, misdiagnoses, and reflex referrals to specialists. Moreover, research shows that patients feel invalidated in healthcare settings and perceive that their HCPs’ lack of vulvodynia awareness negatively impacts their care. Thus, there is a need for educational resources about vulvodynia that can be applied in healthcare settings. Specifically, community-based primary care providers could greatly benefit from vulvodynia resources because they are often a point of entry into the healthcare system. Objective To develop and test a new, online toolkit tailored to supporting community-based primary care providers with the assessment, diagnosis, and management of vulvodynia. In this pilot study, we sought to evaluate the adoption, acceptability, and preliminary efficacy of the vulvodynia toolkit in a pilot sample of community-based family physicians. Methods A working group of HCPs (family physicians, gynecologists, physiotherapist, psychologists) and patient partners with vulvodynia expertise developed the toolkit. The toolkit was designed in an online, modular format that could be integrated into short healthcare visits. A sample of 19 family physicians completed online surveys before and after piloting the toolkit in their community practice for 6 months. Adoption was measured in the post-toolkit survey by assessing the frequency and timing of toolkit use during the pilot period. Acceptability was measured in the post-toolkit survey by assessing physicians’ satisfaction with the toolkit content and quality. Preliminary efficacy was assessed by comparing physicians’ self-reported level of confidence with diagnosing, treating, and supporting patients with vulvodynia before and after the pilot period. Results Adoption. During the pilot period, physicians used the toolkit in advance of patient appointments (52.6%), during patient appointments (5.3%), or used a combination of both timepoints (42.1%). Over the 6-month pilot period, physicians used the toolkit an average of 2.61 times (SD = 1.50) in advance of seeing patients and 1.63 times (SD = 2.19) during patient appointments. Acceptability. Most physicians reported that they were satisfied or very satisfied with the toolkit overall (79.0%) and that it contained the right amount of information (68.4%). On average, the physicians rated their likelihood of recommending the toolkit to a colleague as 8/10 (SD = 1.75). Preliminary efficacy. Using repeated-measures MANOVAs, we found significant pre-toolkit to post-toolkit increases in physician’s confidence for diagnosing vulvodynia, p = .003, ηp 2 = .59, treating vulvodynia, p &amp;lt; .001, ηp2 = .72, and supporting patients with vulvodynia, p &amp;lt; .001, ηp2 = .73. Conclusions In this pilot study, we developed and tested an online vulvodynia toolkit tailored to educating community-based primary care providers. The toolkit demonstrated high acceptability and preliminary efficacy amongst a pilot group of family physicians, with large effect sizes. The results of this study exemplify the value of tailored education for improving physicians’ confidence with managing vulvodynia in community practice and lay the foundation for upscaling this tool to a wider population of HCPs. Disclosure No.

Are We Adding Pain-Free Years to Life? A Test of Compression Versus Expansion of Morbidity.

There has been debate regarding whether increases in longevity result in longer and healthier lives or more disease and suffering. To address the issue, this paper uses health expectancy methods and tests an expansion versus compression of morbidity with respect to pain. Data are from 1993 to 2018 Health and Retirement Study. Pain is categorized as no pain, non-limiting and limiting pain. Multistate life tables examine 77,996 wave-to-wave transitions across pain states or death using the Stochastic Population Analysis for Complex Events program. Results are presented as expected absolute and relative years of life for 70-, 80- and 90-year-old males and females. Confidence intervals assess significance of differences over time. Population- and status-based results are presented. For those 70 and 80 years old, relative and absolute life with non-limiting and limiting pain increased substantially for males and females, and despite variability on a wave-to-wave basis, results generally confirm an expanding pain morbidity trend. Results do not vary by baseline status, indicating those already in pain are just as likely to experience expansion of morbidity as those pain-free at baseline. Results are different for 90-year-olds who have not experienced expanding pain morbidity and do not show an increase in life expectancy. Findings are consistent with extant literature indicating increasing pain prevalence among older Americans and portend a need for attention on pain-coping resources, therapies, and prevention strategies.

Comparison of Morphine and Endomorphin Analog ZH853 for Tolerance and Immunomodulation in a Rat Model of Neuropathic Pain

µ-Opioid receptor agonists, the gold standard for analgesia, come with significant side effects when used chronically. Tolerance, defined as the decrease in analgesic activity after repeated use, remains a vital therapeutic obstacle as it increases the likelihood of dose escalation and potentially lethal side effects like respiratory depression. Previous experiments have indicated that the endomorphin-1 analog, ZH853, is a specific µ-opioid receptor agonist with reduced side effects like tolerance and glial activation following chronic central administration in pain-naïve animals. Here we investigated the effects of chronic, peripheral administration of µ-opioid receptor agonists following neuropathic injury. Though µ-opioids are effective at reducing neuropathic pain, they are not recommended for 1st line treatment due to negative side effects. Compared to chronic morphine, chronic ZH853 treatment led to decreased tolerance and reduced glial activation. Following twice daily intravenous injections, morphine was less potent and had a shorter duration of antinociception compared to ZH853. Chronic morphine, but not chronic ZH853, elevated markers of activation/inflammation of astrocytes (GFAP), microglia (Iba1), the proinflammatory cytokine TNFα and phosphorylated MAP kinase pp38. By contrast, chronic ZH853 reduced Iba1 and TNFα relative to both morphine and vehicle, suggesting anti-inflammatory properties with respect to these markers. GFAP and pp38 were not significantly different from vehicle but were significantly lower than morphine. This study demonstrates the effectiveness of chronic ZH853 for providing analgesia in a neuropathic pain state with reduced tolerance compared to morphine, potentially due to reductions in spinal glial activation. PerspectiveNeuropathic pain is generally undertreated, resistant to available medications, and opioid treatment is limited by side-effects. Here, we show that, compared to an equiantinociceptive dose of a stereotypical µ-opioid receptor agonist, morphine, chronic intravenous administration of endomorphin analog ZH853 led to prolonged antiallodynia, reduced tolerance, and inhibition of spinal cord neuroinflammation in male spared nerve-injured rats.

Comorbid Chronic Pain and Post-traumatic Stress Disorder: Current Rates and Psychiatric Comorbidities Among U.S. Military Veterans.

This study reports rates of comorbid chronic pain and post-traumatic stress disorder (PTSD) among U.S. military veterans and rates of psychiatric comorbidities among those with both chronic pain and PTSD. This study utilized National Veterans Affairs (VA) administrative data to identify all veterans treated for chronic pain or PTSD in 2023. Multivariable logistic regression models determined the likelihood of each psychiatric comorbidity for those with chronic pain and PTSD relative to those with chronic pain only and separately to those with PTSD only, after adjusting for demographic variables and all other psychiatric comorbidities. Of the 5,846,453 service users of the VA in 2023, a total of 2,091,391 (35.8%) met the criteria for chronic pain and 850,191 (14.5%) met the criteria for PTSD. Furthermore, 21.6% of those with chronic pain also had PTSD and over half (53.2%) of those with PTSD also met the criteria for chronic pain (n = 452,113). Veterans with chronic pain and PTSD were significantly more likely to be women, Black or African American, Hispanic or Latina, and urban dwelling. Veterans with chronic pain and PTSD had significantly higher rates of all selected comorbidities relative to veterans with chronic pain only. Patients with comorbid chronic pain and PTSD may benefit from tailored treatments to address the additive impact of these conditions.

Association between Socioeconomic Inequalities in Pain and All-cause Mortality in China: Evidence from the China Health and Retirement Longitudinal Study.

Fewer studies focus on the equality of pain, and the relationship between pain and death is inconclusive. Investigating the distribution of pain and potential mortality risks is crucial for ameliorating painful conditions and devising targeted intervention measures. Our study aimed to investigate the association between inequalities in pain and all-cause mortality in China. Longitudinal cohort data from the China Health and Retirement Longitudinal Study (CHARLS) 2011-2013 (waves 1, wave 2) were used in this study. Pain was self-reported at baseline, and death information was obtained from the 2013 follow-up survey. The concentration index and its decomposition were used to explain the inequity of pain, and the association between pain and death was analyzed by cox proportional risk model. A total of 16747 participants were included, with an average age of 59.57±9.82 years old. The prevalence of pain was 32.54% (8196/16747). The main pain type was moderate pain (36.36%), and the common pain locations were waist (19.30%), leg (14.78%), and head (13.44%). We found that the prevalence of pain was concentrated in participant with poor economic status (concentration index: -0.066, 95%CI: -0.078, -0.054), and educational level (36.49%), location (36.87%) and economic status (25.05%) contributed significantly to the inequality of pain. In addition, cox regression found that participants with pain was associated with an increased risk of all-cause mortality (HR=1.30, 95%CI: 1.06, 1.61). The prevalence of pain in Chinese adults is concentrated among participants with poor economic conditions, and pain increases the risk of all-cause death. Our results highlight the importance of socioeconomic factors to reduce deaths due to pain inequities by implementing targeted interventions to reduce pain inequities.

Systematic Structure-Activity Relationship Study of Nalfurafine Analogues toward Development of Potentially Nonaddictive Pain Management Treatments.

Despite the availability of numerous pain medications, the current array of Food and Drug Administration-approved options falls short in adequately addressing pain states for numerous patients and consequently worsens the opioid crisis. Thus, it is imperative for basic research to develop novel and nonaddictive pain medications. Toward addressing this clinical goal, nalfurafine (NLF) was chosen as a lead and its structure-activity relationship (SAR) systematically studied through design, syntheses, and in vivo characterization of 24 analogues. Two analogues, 21 and 23, showed longer durations of action than NLF in a warm-water tail immersion assay, produced in vivo effects primarily mediated by KOR and DOR, penetrated the blood-brain barrier, and did not function as reinforcers. Additionally, 21 produced fewer sedative effects than NLF. Taken together, these results aid the understanding of NLF SAR and provide insights for future endeavors in developing novel nonaddictive therapeutics to treat pain.

Studying Health and Illness Experience using Linked Data (SHIELD): Empowering customers to donate shopping data for chronic pain research

Introduction &amp; BackgroundChronic pain is considered a priority in healthcare and a threat to well-being across the globe, it is thus crucial to accurately measure the national levels of pain conditions and their impacts on workplace productivity and well-being. Chronic pain has traditionally been studied in isolation with either self-reported survey data or standalone shopping records. The former are limited in scale and can be marred by response biases, while the latter lack ‘ground truths’: what research teams can measure are usually the purchase patterns of pain relief products, but neither the severity nor types of pain conditions. Objectives &amp; ApproachData donation tools offer a novel approach to study chronic pain by linking the two aspects and establish statistical relationships between medicine consumptions and the multiple facets of pain experience. In a survey, we asked participants (N = 953) to share their loyalty card data with us, which is made possible with the data portability tool provided by Tesco (i.e., the largest supermarket chain in the United Kingdom) as part of the General Data Protection Regulation (GDPR). Based on questions adopted from popular inventories used in health research (e.g., EQ5D Health States, ONS4 Well-being, WEMWBS scales), we also asked participants to report the details of their pain conditions, hours of employment, and both general and mental health states. This allowed us to associate chronic pain - both subjective and objective (i.e., reflected by medicine consumption) - with its economic and personal consequences. Data collection was conducted via research panel providers, thus should approximate national representativeness. Relevance to Digital FootprintsThis work links digital footprints data donated by individuals to self-reported survey data, also develops an infrastructure for these data to be collected and safely stored. Conclusions &amp; ImplicationsOne key value of this project is to pioneer a measure of chronic pain that can be applied to transactional records that are much bigger in scale in future analytic works. Our research team has access to an array of different digital footprints data, including longitudinal transactional data provided by a major pharmacy chain (~20 million customers and ~429 million baskets). In order to utilise these data to associate them with regional workplace productivity measures and well-being data released by the Office for National Statistics, a metric must be defined to extract the prevalence of chronic pain from shopping data, which is informed by the patterns found by the data donation project.

Astaxanthin alleviates fibromyalgia pain and depression via NLRP3 inflammasome inhibition

Fibromyalgia is characterised by widespread chronic pain and is often accompanied by comorbidities such as sleep disorders, anxiety, and depression. Because it is often accompanied by many adverse symptoms and lack of effective treatment, it is important to search for the pathogenesis and treatment of fibromyalgia. Astaxanthin, a carotenoid pigment known for its anti-inflammatory and antioxidant properties, has demonstrated effective analgesic effects in neuropathic pain. However, its impact on fibromyalgia remains unclear. Therefore, in this study, we constructed a mouse model of fibromyalgia and investigated the effect of astaxanthin on chronic pain and associated symptoms through multiple intragastrical injections. We conducted behavioural assessments to detect pain and depression-like states in mice, recorded electroencephalograms to monitor sleep stages, examined c-Fos activation in the anterior cingulate cortex, measured activation of spinal glial cells, and assessed levels of inflammatory factors in the brain and spinal cord, including interleukin (IL)-1β, IL-6, and tumour necrosis factor- α(TNF-α).Additionally, we analysed the expression levels of IL-6, IL-10, NOD-like receptor thermal protein domain associated protein 3 (NLRP3), Apoptosis-associated speck-like protein containing CARD, and Caspase-1 proteins. The findings revealed that astaxanthin significantly ameliorated mechanical and thermal pain in mice with fibromyalgia and mitigated sleep disorders and depressive-like symptoms induced by pain. A potential mechanism underlying these effects is the anti-inflammatory action of astaxanthin, likely mediated through the inhibition of the NLRP3 inflammasome, which could be one of the pathways through which astaxanthin alleviates fibromyalgia. In conclusion, our study suggests that astaxanthin holds promise as a potential analgesic medication for managing fibromyalgia and its associated symptoms.

Spectrophotometric determination of celecoxib and tramadol in the new approved formulated dosage form using principle component regression assistive model

Celecoxib and tramadol have been combined in a novel FDA-approved medication to address acute pain disorders requiring opioid treatment when other analgesics proved either intolerable or ineffective. The absorbance spectra of celecoxib and tramadol exhibit significant overlap, posing challenges for their individual quantification. This study introduces a spectrophotometric quantification approach for celecoxib and tramadol using a principle component regression assistive model to assist resolving the overlapped spectra and quantifying both drugs in their binary mixture. The model was constructed by establishing calibration and validation sets for the celecoxib and tramadol mixture, employing a five-level, two-factor experimental design, resulting in 25 samples. Spectral data from these mixtures were measured and preprocessed to eliminate noise in the 200–210 nm range and zero absorbance values in the 290–400 nm range. Consequently, the dataset was streamlined to 81 variables. The predicted concentrations were compared with the known concentrations of celecoxib and tramadol, and the errors in the predictions were evidenced calculating root mean square error of cross-validation and root mean square error of prediction. Validation results demonstrate the efficacy of the models in predicting outcomes; recovery rates approaching 100 % are demonstrated with relative root mean square error of prediction (RRMSEP) values of 0.052 and 0.164 for tramadol and celecoxib, respectively. The selectivity was further evaluated by quantifying celecoxib and tramadol in the presence of potentially interfering drugs. The model demonstrated success in quantifying celecoxib and tramadol in laboratory-prepared tablets, producing metrics consistent with those reported in previously established spectrophotometric methods.

Translation, cross-cultural adaptation, and measurement properties of the Arabic version of the fear avoidance components scale

Purpose This study aimed to translate, validate, and cross-culturally adapt the original FACS into the Arabic language. Methods The English version of the FACS was translated and culturally adapted into Arabic following international guidelines. The psychometric properties of the final version of the FACS-Arabic (FACS-A) were tested among 119 patients with different musculoskeletal (MSK) pain disorders. Results The Cronbach’s α for the FACS-A was 0.86. The test-retest reliability, measured with intraclass correlation coefficient, was 0.80. The FACS-A showed positive significant correlations with other psychological patient-reported measures, including the pain catastrophizing scale (PCS) (r = 0.545); p ≤ 0.01), Brief Pain Inventory (BPI)-pain score (r = 0.546; p ≤ 0.01), BPI-pain interference score (r = 0.511; p ≤ 0.01), and Hospital Anxiety and Depression Scale (HADS) (r = 0.451, 0.336, respectively; p ≤ 0.01). Confirmatory factor analysis of the FACS-A confirmed the two-factor structure found in the original English version. Conclusion This study determined the FACS-A to be a reliable and valid tool for the assessment of the fear-avoidance beliefs in Arabic-speaking individuals with MSK pain disorders.