The present Program Evaluation study examines sociodemographic characteristics of Veterans in the Phoenix VA Health Care System who have back pain, and specifically the likelihood of those characteristics being associated with a referral to the Chronic Pain Wellness Center (CPWC) in the year 2021. We examined the following characteristics: Race/ethnicity, gender, age, mental health diagnosis, substance use disorder diagnosis, and service-connected diagnosis.Our study used cross sectional data from the Corporate Data Warehouse for 2021. 13624 records had complete data for the variables of interest. Univariate and multivariate logistic regression was used to determine the likelihood of patients' being referred to the Chronic Pain Wellness Center.The multivariate model found under-referral to be significant for younger adults and for patients who identified as Hispanic/Latinx, Black/African American, or Native American/Alaskan. Those with depressive disorders and opioid use disorders, on the other hand, were found to be more likely to be referred to the pain clinic. Other sociodemographic characteristics were not found to be significant.Study limitations include the use of cross-sectional data, which cannot determine causality, and the inclusion of patients only if the ICD-10 codes of interest were recorded for an encounter in 2021 . In future efforts, we plan to examine, implement, and track the impact of interventions designed to mitigate these identified disparities in access to chronic pain specialty care. For almost twenty years, the Agency for Healthcare Research and Quality (AHRQ), part of the Department of Health and Human Services in the US, has been publishing National Healthcare Quality and Disparities Reports (NHQDR) to aid organizations that are working to reduce healthcare inequities. The 2021 NHQDR defines a healthcare disparity as “a difference between population groups in the way they access, experience, and receive healthcare.”  and inclDisparities in pain management due to race/ethnicity have long been documented. In 2012, Meghani et al. conducted a meta-analysis of research on disparities in pain treatment and reported that Black/African American individuals were the most disadvantaged racial/ethnic group and less likely than White counterparts to receive analgesic treatment for both traumatic/surgical pain and nontraumatic/nonsurgical pain. Hispanic/Latinx individuals received analgesic treatment comparable to White counterparts for traumatic/surgical pain but were less likely to receive comparable care for nontraumatic/nonsurgical pain . AnotherPain care is also influenced by gender biases. Samulowitz et al. conducted a literature review exploring gender norms and gender biases in the treatment of pain . In the Mental health and substance use disorders (SUD) also contribute to disparities in pain care. One study noted that providers who have stigmatized views of mental illness are more likely to lack confidence in patients' ability to adhere to pain treatment and subsequently offer those patients fewer pain treatment options . ResearcWhile age has been acknowledged as a factor greatly impacting a patient's overall healthcare and health outcomes , 27, ageWith awareness of both disparities in pain care and the significance of psychosocial determinants of health, a group of providers at the Phoenix VA Chronic Pain Wellness Center (CPWC) initiated a quality improvement project to explore potential disparities within our own system. This project examined referrals from primary care providers to the CPWC. Because of the ubiquity of back pain , we elecThis quality improvement initiative was designed for internal purposes in support of the VA mission and was given a determination of “not research” by the Phoenix VA Research Department. Therefore, this project did not require Institutional Review Board (IRB) review and approval. The data was obtained retrospectively from the VA's Corporate Data Warehouse (CDW) by a sequel (SQL) script as part of a Program Evaluation. The data was initially screened to include only those individuals who were treated for back pain within the last year. To meet criteria, a patient had to have an encounter in the year 2021 with one of the following ICD-10 codes: M54.1, M54.16, M54.17, M54.18, M54.3, M54.30, M54.32, M54.4, M54.40, M54.41, M54.42, M54.5, M54.50, M54.51, M54.59, or M54.8. Individuals who were not treated for back pain at some point in the year 2021 were excluded from the study. Patients were determined to have been referred to the CPWC if a Chronic Pain Consult was placed in the year 2021, and this was coded as a dichotomous variable. In general, consults to the CPWC are placed by a primary care provider (PCP) practicing within the Phoenix VA Health Care system. Usually these consults occur at a patient's request or if their PCP feels that they would benefit from additional treatment planning, consideration of multimodal pain rehabilitation, and/or medication management for chronic pain.The psychosocial variables of interest in this study were selected based on a literature review of factors that impact patients' access to chronic pain care. These were further limited by what archival data was available within the CDW. Psychosocial variables were defined for the analyses as follows:Six categories were available for race  and two for ethnicity (Hispanic/Latinx & non-Hispanic/Latinx) in patients' charts. The data was cleaned to exclude anyone who “declined to answer” race/ethnicity questions or had data that was classified as “unknown to patient.”Male, female, and gender diverse variables were all coded for this study. As the total number of gender diverse individuals in the sample was small, this group was not further divided into subcategories. Thus, our gender diverse category included the following: patients whose self-identified gender didn’t match the gender in their medical record, patients who self-identified as transgender, and patients who self-identified as “other” gender.The participants' medical record gender variable only allowed for the option of male or female; however, there was an additional option for individuals to self-identify their gender on their cover sheet. Of note, only about a fourth of individuals were found to have self-identified their gender. older adults, those 35–64 years old were classified as middle-aged adults, and those 18–34 years old were classified as younger adults.Patients' age was collapsed into three categories: Patients aged 65 and older were classified as anxiety , depression , somatization , trauma/post-traumatic stress disorder , or personality disorder  , opioid use disorder , cannabis use disorder , tobacco use disorder , and other substance use disorder . Patients were considered to have a substance use disorder if any of these ICD-10 codes were recorded for a clinical encounter during the year 2021.All substance use disorders were collapsed into five dichotomous categories, again based on ICD-10 codes: The presence of any service-connected diagnosis was treated as a dichotomous variable.p value <0.05. Univariate logistic regression analyses were conducted for each variable of interest in the study  in order to predict the likelihood of having a consult placed to CPWC. Subsequently, a single multivariate logistic regression model combining all the aforementioned variables was utilized to reduce experiment wide error and to account for multicollinearity.After the data was recoded, SPSS version 26 was utilized for data analysis. All the data was cleaned and screened; anyone with missing or incomplete data for variables of interest was excluded from the study. Nominal variables were dummy coded for the statistical analysis using White, non-Hispanic/Latinx, younger adults, and male as the reference groups.  All logistic regression analyses were two tailed with significance level set to a  = ±16.72) years. Additional demographic characteristics of the sample are presented in We identified 36,605 records as having at least one ICD-10 code for back pain in the year 2021. Of those records, 17,146 (46.8%) had an ICD-10 code for back pain as defined above. After cleaning and screening the data, 13,624 individuals with complete data for all variables of interest were identified and included in the analysis. The mean age of the sample was 58.32 (SDR2 = 0.001 (Cox & Snell), 0.003 (Nagelkerke), Model χ2(2) = 20.11, p < 0.001], race , ethnicity , anxiety disorder in 2021 , depressive disorder in 2021 , personality disorder in 2021 , opioid use disorder in 2021  cannabis use disorder in 2021  tobacco use disorder in 2021 . Other analyses were not found to be statistically significant, including those for gender, trauma/PTSD, somatization, alcohol use disorder, other substance use disorders, and presence of a service connected injury.Univariate analyses are presented in R2 = 0.012 (Cox & Snell), 0.027 (Nagelkerke), Model χ2(21) = 158.46, p < 0.001], and results are displayed in The multivariate analysis was significant [This quality improvement study presents information about back pain-related referrals to our subspecialty Chronic Pain Wellness Center (CPWC) in 2021 and also explores the relationship between those referrals and patients' psychosocial characteristics. Results reflect that 8% of patients with any back pain diagnosis  were referred to the CPWC, which is much higher than the 2% of chronic pain patients being managed by pain physicians as reported in a 2010 national survey . Of indiOur study also found that younger adults were less likely to be referred to CPWC. With the majority of the already limited research on ageism in pain treatment focused on disparities for older adults –36, it in = 292) of participants were identified as having a trauma/PTSD diagnosis compared to an estimated 11%–20% prevalence of PTSD diagnoses documented for the OEF/OIF Veteran cohort, 12% for the Gulf War/Desert Storm era, and 15% for the Vietnam Veteran population .Gender was not found to be a statistically significant factor in CPWC referrals, which appearsinconsistent with a long history of literature detailing disparities in pain care for females , 21, butLike gender, the presence or absence of a service-connected diagnosis was not found to be statistically significant. Veterans may apply for service connection if they became sick or injured during their military service or if military service worsened an existing condition . ServiceThere were cases in which the univariate and multivariate logistic regression analyses varied in their significance. For example, the univariate logistic regression analysis for tobacco use disorder was significant; however, when this variable was placed in the multivariate analysis, it was not a significant predictor. An explanation for this finding might be shared variance within the univariate variables and the multivariate analysis' reduced multicollinearity.Our quality improvement project has several limitations. The present study exclusively utilized cross-sectional data from 2021 that was pulled in 2022. Because of our reliance on ICD-10 codes, we may have miscategorized some patients due to inherent coding inaccuracies and inconsistencies . PatientAnother limitation of our study is the lack of nuanced information about why referrals were or were not placed. Providers' personal thresholds for placing a pain management consult, patient-provider dynamics during each appointment, and providers' implicit biases are not captured by our analyses in this context. Additionally, we operated under the assumption that the majority of the data was from patients with chronic lower back pain; it is possible that some acute or subacute back pain encounters were also included within our analysis. Unfortunately, there was no way for us to determine acute/subacute vs. chronic pain from the data available to us within the CDW. Speculation on how these factors might impact the referral process is beyond the current study.Finally, our study was conducted during the COVID-19 pandemic and in the year after many patients and providers experienced shelter-in-place orders that took a toll on physical and mental health. In 2021, we also saw the continuation of virtual healthcare delivery for many patients, which may have influenced referral patterns to specialty services such as CPWC. The pandemic may also have influenced systemic and interpersonally marginalizing interactions. The impact of COVID-19 on our project results is unclear. As we move forward with future iterations of this project, we may be able to gain more insight into what, if any, effects the pandemic had on referrals to CPWC.The current quality improvement project highlights several disparities in referrals to the CPWC based on various sociodemographic variables. However, it is not possible to conclude what factors might contribute to these disparities. As such, future research is needed to identify the mechanisms underlying the disparities. For example, it may be useful to explore other potentially moderating variables such as patients' socioeconomic status, service-connection rating, disability status, employment status, or education level. The amount of time a PCP spends with a patient or providers' educational background and demographics may also be found to have an impact on referral disparities. Future researchers might also consider assessing providers' self-reported competence in treating chronic pain or patients' self-reported experiences with marginalization in medical settings.As we continue to look for other factors that may be influencing referral disparities, we also hope to design and implement interventions that will begin to reduce disparities. We will explore methods of disseminating information to PCPs about populations that were underserved in this study and will also consider offering evidence-informed and thoughtfully designed training on reducing implicit bias –51. OtheIn this quality improvement project, we examined referrals to our Chronic Pain Wellness Center for back pain in the year 2021. We found that patients with depression and OUD were more likely whereas patients who were younger, Hispanic/Latinx, Black/African American, or Native American/Alaskan were less likely to be referred to our clinic. Our next step will be to design and implement an intervention that targets these disparities to improve pain care access for all Veterans who would benefit from it.


At low doses, naltrexone (LDN) has been shown to modulate inflammation through the interruption of microglial cell activation within the central nervous system. One of the most likely contributors to centralized pain is changes in microglial cell processing. Therefore, it has been postulated that LDN can be used to manage patients with pain resulting from central sensitization due to this relationship. This scoping review aims to synthesize the relevant study data for LDN as a novel treatment strategy for various centralized pain conditions.A comprehensive literature search was conducted in PubMed, Embase, and Google Scholar, guided by the Scale for Assessment of Narrative Review Articles (SANRA) criteria.Forty-seven studies related to centralized pain conditions were identified. Many of the studies were case reports/series and narrative reviews, but a few randomized control trials have been conducted. Overall, the body of evidence revealed improvement in patient-reported pain severity and in outcomes related to hyperalgesia, physical function, quality of life, and sleep. Variability in dosing paradigms and the time to patient response was present in the reviewed studies.Evidence synthesized for this scoping review supports the ongoing use of LDN for the treatment of refractory pain in various centralized chronic pain conditions. Upon review of the currently available published studies, it is apparent that further high-quality, well-powered randomized control trials need to be conducted to establish efficacy, standardization for dosing, and response times. In summary, LDN continues to offer promising results in the management of pain and other distressing symptoms in patients with chronic centralized pain conditions. Naltrexone is an opioid antagonist that was first developed in 1963.Low-dose naltrexone (LDN) (4.5 mg), on the other hand, was first described in the 1980s as a treatment option to help with inflammation.Chronic pain affects an estimated 11% to 40% of the US populationAlthough the term “central sensitization” refers to specific changes in CNS neuronal response properties, central sensitization is characterized behaviorally by the presence of hyperalgesia and allodynia, defined as increased pain response to noxious and non-noxious stimuli, respectively.The goal of the present scoping review is to synthesize the available evidence related to LDN and its utility for various centralized pain conditions, as well as to highlight any knowledge gaps to guide development of well-designed randomized control trials (RCTs) and other research studies leading to evidence-based clinical practice guidelines.With the assistance of a professional librarian, a comprehensive literature review was conducted in PubMed, EMBASE, and Google Scholar, with publication dates ranging from January 1, 2000, to February 1, 2022. Article eligibility and inclusion criteria were limited to publications in the English language and studies pertaining to human subjects. Exclusion criteria included studies focusing on the use of full-dose naltrexone or the use of naltrexone for alcohol and opioid abuse, obesity, dermatological conditions, or other nonpainful disease processes . Studies involving cancer- or chemotherapy-induced neuropathy or pain were also excluded. All other studies reporting on patients using LDN for chronic pain were included. Keywords, Medical Subject Headings, and EMTREE subject headings were used to search for the concepts of LDN and chronic pain. Keywords included “low dose naltrexone” and “chronic pain”, “complex regional pain syndrome”, “inflammatory bowel disease”, “fibromyalgia”, “low back pain”, “rheumatoid arthritis”, “neuropathy”, and “migraines”. The numerical results from the literature search are represented in All search results were screened for eligibility and inclusion, starting with an initial title review, followed by an abstract and full-text review. To identify additional and missed pertinent studies after the initial review, the snowball strategy was used, in which all references and citations were reviewed. Publications not meeting the inclusion criteria were excluded from this review, and all duplicates were removed. Records meeting the inclusion criteria were further divided into categories by the specific condition being managed by LDN, as noted in Variables were tabulated, including study design, number of human subjects, follow-up duration, clinical outcomes, and adverse effects . For sysWith regard to the use of LDN for the treatment of CRPS, 2 systematic reviews, 4 narrative reviews, and 3 case reports were identified. CRPS is a complex pain condition, encompassing both neuropathic and nociplastic pathophysiology, that includes a variety of pain and sympathetically mediated symptoms arising after peripheral injury not related to specific damage to the nervous system  or arising from a specific peripheral nerve injury . The initial insult engages peripheral nervous system and CNS sensitization processes that have been shown to drive the autonomic and vasomotor symptoms and allodynia/hyperalgesia.The first case series documented by Chopra et al.In the second case report, Weinstock et al.Sturn et al.In the aforementioned case reports and series, none reported adverse effects while using LDN in these 4 patients with CRPS .On the topic of the use of LDN to treat pain and symptoms related to inflammatory bowel disease (IBD), 2 systematic and 3 narrative reviews were analyzed, along with 2 RCTs, 2 prospective cohorts, and 1 case report. Two of the included studies  evaluated IBD (including both ulcerative colitis [UC] and Crohn’s disease), whereas the remaining studies focused exclusively on Crohn’s. For the evaluation of disease severity in active Crohn’s, the Crohn’s Disease Activity Index (CDAI) score evaluates symptoms , weight, laboratory values, and extra-intestinal findings . A moderate to severe flare would score between 220 and 450, and remission is suggested at scores of <150.IBD is an umbrella term and includes both Crohn’s and UC. Crohn’s and UC share similar pathophysiology and symptoms, including abdominal pain, diarrhea, and hematochezia, but they differ in location and depth of inflammation within the enteric system.,,,The specific etiology of IBD remains unknown, but it is suspected to result from a combination of environmental and genetic risk factors. The pathogenesis, on the other hand, has been extensively studied and involves a dysregulation of the immune response toward host mucosal antigens or bacteria.P = .01), with 67% of patients achieving remission (P = .001). Health-related quality of life was found to be significantly improved compared with baseline. Adverse effects were minimal but were reported in a few patients; they included vivid dreams (n = 2) and insomnia (n = 5).The first prospective study, conducted by Smith et al., involved 17 subjects with chronic refractory active Crohn’s disease with symptoms including abdominal pain, hematochezia, malabsorption, and diarrhea. Eligible patients had histological and endoscopic evidence of active Crohn’s disease on the CDEIS.n = 16) or 4.5 mg LDN daily (n = 18). At 12 weeks, 88% of patients randomized to LDN had a 70-point decline in CDAI scores, compared with 40% of the placebo group (P = .009). Only 30% of the LDN group achieved remission on the basis of CDAI scores, but the authors noted that the cohort’s baseline CDAI scores were very high, and remission is difficult in patients with high baseline CDAI scores. In addition to the CDAI outcome measures, CDEIS scores improved in 78% of patients in the LDN group, compared with 28% in the placebo group (P = .008), while complete remission was noted in 33% of the subjects who took LDN and 8% of the placebo group . Quality of life was clinically improved in the patients who took LDN compared with the placebo group, though this did not reach statistical significance (P = .3). Unique adverse effects reported in the LDN group included loss of appetite (n = 2) and constipation (n = 2), though these were not significantly different from placebo. Both groups experienced insomnia (n = 10), unusual dreams (n = 5), headache (n = 6), abdominal pain (n = 10), and nausea (n = 8).Smith et al. also conducted the first prospective double-blind single-center RCT study evaluating the effects of LDN in patients with Crohn’s disease.P = .005) for the LDN group. Because of the small sample size of the cohort, when LDN was compared with the effect of the placebo group, the difference between the CDAI scores did not reach statistical significance. Remission based on CDAI scores was achieved in only 25% of patients who took LDN, but quality of life significantly improved (P = .035) in patients who took LDN compared with placebo groups. Adverse events that were recorded included vivid dreams and nausea when patients were taking LDN as compared with placebo.In 2013, Smith et al. conducted a follow-up RCT with a crossover design, evaluating LDN in 12 children with moderate to severe Crohn’s disease.Shannon et al. wrote on a case report of a 14-year-old female patient with refractory Crohn’s disease showing erosions in the duodenum and biopsy consistent with duodenitis.Raknes et al. conducted an observational study evaluating LDN’s effect on the use of other medication for Crohn’s disease.n = 4, 2, and 1, respectively).The last 2 studies are the only ones that also included UC in their patient populations. Lie et al. conducted a prospective cohort study involving 47 patients with refractory IBD.n = 8) had IBD , the overall side effect profile of the study was relatively low, with 74 of the 121 subjects reporting mostly transient adverse effects, including headaches, anxiety, insomnia, muscle pain, vivid dreams, abdominal pain, and diarrhea, which resolved with extended use. However, 20 of the 74 discontinued LDN because of side effects. Of the patients with IBD, the average duration of treatment was 16.8 weeks. Of the 8 subjects with IBD, 2 had marked improvement, and 4 of the 8 subjects were unchanged (based on a patient-reported study-specific survey). It should be noted, however, that 2 of the 4 subjects with unchanged pain were in remission before they started LDN.Ploesser et al. conducted a retrospective chart review involving 121 subjects from a single gastroenterologist’s clinic who had various diagnoses, including irritable bowel syndrome, IBD, and chronic idiopathic constipation, and were prescribed LDN.With regard to the use of LDN for FM, 2 systematic reviews, 9 narrative reviews, 1 RCT, 3 prospective cohorts, 1 chart review, and 2 case reports have been published.,,FM is a chronic pain condition estimated to affect 1% to 6% of the general population and characterized by widespread musculoskeletal pain, hyperalgesia, and allodynia.P < .003), as well as significant reductions in daily pain, fatigue, and stress (P < .05) compared with placebo. Only 2 subjects reported adverse events in the form of vivid dreams, and 1 reported insomnia.Younger et al. were the first to report a positive impact of LDN on pain and pain-related symptoms in patients with refractory FM.P = .016), and the LDN group saw statistically significant improvement in mood (P = .039) compared with placebo. Successful response to treatment was defined as a significant reduction in self-reported pain severity and fatigue (defined as a reduction of >30% for each category). This was reported in 32% of the LDN treatment arm vs 11% of the placebo group (P = .05). In this study, the side effects of LDN included more frequent headaches and vivid dreams compared with placebo (P < .05).Subsequently, Younger completed a larger follow-up trial, a double-blind crossover RCT, in which 31 women with FM were evaluated.,Taking this further, in a single-blind crossover study in 8 women with FM, Parkitny et al. reported that FM was associated with increased release of various interleukins, proinflammatory cytokines, and growth factors.P = .003), their VAS scores improved from 6 out of 10 to 1 out of 10, and self-reported improvements were seen in fatigue, sleep, mood, and work capacity.Separately, Jackson et al. reported on a prospective cohort study involving 21 patients with FM. After 7 weeks of LDN treatment at 4.5 mg twice a day, their cold pressor test scores doubled  for both opioid users and patients with FM at 14, 26, and 30 weeks.Oaks et al. performed a retrospective review involving 254 patients with FM or opioid-induced hyperalgesia who were started on LDN.We found 1 systematic review analysis, 2 narrative reviews, and 1 case report discussing LDN and lower back pain.,The pathophysiology behind how LDN could be a therapeutic option for chronic low back pain is likely related to its effect on central sensitization and neural glial modulation, as central sensitization has been identified as being highly relevant in patients with chronic low back pain.P = .003). These included nonsteroidal anti-inflammatory drugs, disease-modifying antirheumatic drugs, tumor necrosis factor alpha inhibitors, corticosteroids, and opioids. In addition, a 47% (P < .001) reduction in opioids was seen.We found 1 retrospective study discussing rheumatoid arthritis and the use of LDN. Rheumatoid arthritis is a well-studied autoimmune disorder that results in chronic inflammation in multiple joints and a variety of other systemic manifestations. Rheumatoid arthritis is typically a peripheral joint disease, but, much like the other disease processes mentioned in the present review, continued inflammation and irritation of nociceptive receptors can lead to the centralization of pain over time.N-methyl-d-aspartate receptor expression, both of which enhance the excitation of neurons, specifically in lamina II.B receptors seen in diabetes, which has a close tie to the impaired inhibition of N-methyl-d-aspartate receptors.We found 1 systematic and 3 narrative reviews along with 1 RCT and 1 case report discussing LDN and diabetic neuropathy. It has been proposed that the pathophysiology of how diabetic neuropathy causes centralized pain involves the sensitization of primary afferents and dorsal horn neurons.Srinivasan et al. conducted an RCT comparing the efficacy of 2 mg LDN and 10 mg amitriptyline for painful diabetic peripheral neuropathy.Hota et al. presented the case reports on LDN and diabetic neuropathy.,,,,,,LDN is a relatively novel yet encouraging method for managing chronic centralized pain stemming from conditions such as FM, IBD, and CRPS. Development of new management strategies for these specific conditions is crucial, given the complex and unique challenges they pose to medical professionals. Although studies are limited mostly to case reports and narrative reviews, some RCTs have been completed. Promising results affecting pain and hyperalgesia have been shown in the RCTs and clinical trials, specifically for IBD and FM.LDN’s impact on centralized pain originates from the compound’s innate ability to modulate the CNS glial cells via TLR4.,,,,,,,In addition to improved pain, there were multiple reports of improved function,,,On the basis of the present review, LDN is generally well tolerated by most patients with chronic pain. Adverse effects were commonly reported but were minimal to mild at worst, with the most common being vivid dreams, diarrhea, and headaches.,,,,,,Throughout the investigated trials, there was significant variation in the timing of follow-up assessments, with study designs ranging from a day to a year, with the average follow-up time roughly 12 weeks.,Dosing varied among the studies, ranging from 0.2 mg to 9 mg daily, but 4.5 mg daily was the most used dosing regimen. Currently, it is well published that 4.5 mg daily is a feasible target dose for LDN. This is likely because of LDN’s paradoxical effect, in which doses up to 4.5 mg daily appear to enhance opioid signaling, whereas at higher doses this effect disappears and opioid antagonism begins.,,Multiple reviews have been published that have alluded to the direct benefit of LDN on chronic pain, quality of life, sleep, and anxiety.LDN is a novel therapeutic treatment option for patients with centralized chronic pain. Numerous small case reports and a few higher-quality trials support the use of LDN in chronic pain. Despite this, LDN is still used off label for many chronic pain conditions. It is imperative that higher-quality, well-designed, and controlled studies be conducted to expand and potentiate the application of LDN and its utility profile, as well as help with standardization of treatment regimens. Even though such studies are much needed, LDN still offers promising results in the current clinical management of refractory symptoms in patients with these chronic centralized pain conditions.


The exact mechanism involved in the development of postherpetic neuralgia (PHN) is not yet known. The objective of this study was to evaluate longitudinal functional connectivity (FC) changes in the neuroimaging case series of patients with acute herpes zoster (HZ). Cases: This study included five patients who had symptoms of HZ. Functional magnetic resonance imaging was conducted at enrollment and 3 months to determine FC changes. Of the five patients, three developed PHN. In the PHN subjects, the FC of the left superior frontal gyrus (SFG) and the right inferior frontal gyrus (IFG) were activated. The left SFG is known to contribute to higher cognitive functions and working memory. The right IFG is associated with pain processing and empathy for pain. Conclusions: Although only a few patients were enrolled in this study, the PHN could be affected by pain itself, as well as pain memory and psychological aspects such as empathy for pain. Herpes zoster (HZ) is a viral infection in the cranial nerve ganglia or dorsal root ganglia. It is associated with the reactivation of the varicella zoster virus (VZV). The clinical features of HZ include skin and neuropathic symptoms. Most skin symptoms are recovered within a few weeks. Pain also gets better as skin symptoms improve. However, in some cases, severe pain could be prolonged for a very long period, which is called postherpetic neuralgia (PHN). The exact mechanism of developing chronic pain is not yet known. Genetic mechanisms, priming effects on a cellular level, and brain functional connectivity (FC) changes are considered as factors contributing to chronic pain .Functional magnetic resonance image (fMRI) is a non-invasive, objective, and useful research tool to analyze the brain functionally and structurally . FC analThis case study included five patients diagnosed with HZ who visited the pain clinic at a university hospital from July 2018 through December 2018. They participated in the study for three months after enrollment. The Institutional Review Board of the Catholic University of Korea approved protocols for this study . This study was conducted in accordance with the Declaration of Helsinki. All patients provided written informed consent to participate in this study.p = 0.044).All subjects were adults aged more than 40 years. Their visits to the pain clinic were within 14 days after a manifestation of pain and skin symptoms, including rash, maculopapular, vesicle lesion, and so on, on the dermatome of the right chest or right abdomen . Before www.fil.ion.ucl.ac.uk/spm) with default parameters in the following order: head motion correction, co-registration, segmentation, normalization on to the Montreal Neurological Institute coordinates with a 2 mm isotropic voxel size, and spatial smoothing using an 8 mm isotropic full-width at half-maximum Gaussian kernel. Each voxel was assigned to the parcellation of regions of interest (ROIs) based on masks defined by an Automated Anatomical Labeling (AAL) [The fMRI study was conducted at a resting state without any experimental tasks to investigate the FC. The subjects underwent functional imaging using a 1.5 T MRI scanner . The functional images were acquired using a T2*-weighted single-shot echo-planar imaging (EPI) sequence that covered the whole brain  to obtain the blood-oxygen-level-dependent (BOLD) contrast. The total scan time was 10 min. Raw EPI data excluding the first five volumes  were preprocessed using SPM12 –postcentral gyrus (R) and the IFG (R) (opercular part)–IFG (R) (triangular part) were commonly activated FCs in the recovery group, while the SFG (L) –IFG (R)  was commonly activated in the PHN group.Jiang et al. found the FC in the dorsolateral prefrontal cortex (PFC) and precuneus/posterior cingulate cortex (PCC) is decreased in PHN patients . Fu et aBaliki et al. performed a whole-brain connectivity analysis in rodents exposed to neuropathic injury and observed changes in the FC between limbic systems and between the nociceptive network and limbic systems for up to 4 weeks . Bilbao In these case reports, commonly decreased FC did not exist among PHN patients. However, newly activated FC was commonly seen between the SFG (L)  and the IFG (R)  from the PHN group. The SFG (L) is known to contribute to higher cognitive functions, particularly working memory . IFG (R)In the previous studies, inter-hemispheric connectivity tends to be decreased in patients who have painful diseases such as PHN or traumatic axonal injury than in healthy controls . The posThis study has a few limitations. First, this study had a relatively small sample size. Thus, a larger sample is needed to confirm our results. Second, sticking to the concept of the modulation of the brain network and neuronal plasticity, the follow-up acquisition of fMRI for PHN patients could be useful for evaluating the effect of PHN on FC changes that might show another tendency. However, we did not have any further data in this study.The development of PHN could be affected by pain memory, psychological and emotional aspects such as empathy for pain, and working memory, as well as pain itself. Thus, prolonged pain conditions can jeopardize a patient’s recovery.


Our objectives were to (1) determine whether a computerized clinical pharmacy approval and follow-up consult process for ordering new prescriptions for gabapentin for the treatment of neuropathic pain decreased the number of patients without documented treatment benefit while increasing follow-up and documentation of effectiveness, and (2) describe gabapentin use patterns at a Veterans Affairs (VA) Medical Center, including the use of first-line therapies prior to gabapentin therapy for neuropathic pain.The clinical pharmacy intervention included review of (1) the indication for gabapentin; (2) the required use and failure or contraindication of 3 first-line therapies: nonsteroidal anti-inflammatory drugs (NSAIDs), tricyclic anti-depressants (TCAs), and capsaicin cream; (3) the initial pain assessment; and (4) patient follow-up in 4 to 6 weeks, with repeat pain assessment. A retrospective chart review was performed for all patients who received a new prescription for gabapentin from October 2002 to April 2003 at the Portland VA Medical Center (PVAMC). The outcomes of interest for the provider group versus the clinical pharmacy managed group included follow-up at 6 weeks or less versus follow-up at more than 6 weeks, documentation of treatment benefit, how many of the 3 first-line therapies were tried before gabapentin, and whether the gabapentin therapy was discontinued.There were 237 patients who received a new prescription for gabapentin between October 2002 and April 2003. Of these gabapentin prescriptions, 61% (n=144) were prescribed for neuropathic pain. Of the new gabapentin prescriptions for neuropathic pain, 61% (n=88) were made from approved clinical pharmacy consults, 38% (n=54) were ordered without a clinical pharmacy consult, and 1% (n=2) were not included because the patient received the drug despite denial by the clinical pharmacy consult. The rate of follow-up to assess documentation of benefit of therapy with gabapentin was 87% (n=62) in the clinical pharmacy consult group compared with 51% (n=27) in the provider-managed group . Of the patients who were assessed by follow-up, 89% (n=55) of the clinical pharmacy consult group received follow-up within 6 weeks versus 52% (n=14) of the provider-managed group . Compared with the patients managed by clinical pharmacists, 43% (n=23) of the gabapentin patients in the provider-managed group had no evidence of prior use of any of the 3 agents required by the gabapentin neuropathic pain guideline, 55% (n=29) had evidence of prior use of 1 or 2 first-line agents, and only 2% (n=1) had evidence of prior use of all 3 required first-line agents, versus 100% (n=71) of the patients managed by clinical pharmacy consult. There was no difference in the rate of continuation of gabapentin therapy in the group of patients who received clinical pharmacy consults (65%) compared with the provider-managed group . Of the 148 pharmacy consults for new gabapentin prescriptions that were completed during the 7-month period from October 2002 through April 2003, 60 (40%) were denied, which resulted in the lack of gabapentin use in these 60 patients.A clinical pharmacy intervention as part of the management of a treatment guideline for appropriate gabapentin use promotes documentation of drug therapy effectiveness in neuropathic pain and prevention of gabapentin use prior to a trial with alternative first-line therapies.


Postoperative pain at buccal mucosal graft (BMG) harvest site hinders the resumption of food intake. We aim to study the effect of inferior-alveolar nerve block plus buccal nerve block (IANB + BNB) on pain scores.This was a retrospective case–control study performed in a single center from July 2021 to July 2022 . We performed IANB + BNB with a mixture of 5 mL each of 1% lignocaine and 0.25% bupivacaine and 4 mg dexamethasone, in addition to local infiltration of 2% lignocaine and (1:100 000) epinephrine combination before harvesting BMG. We retrospectively compared the recorded postoperative pain scores using the visual analog scale (VAS) among patients who received and did not receive IANB + BNB. The time for resumption of pain-free diets and postoperative analgesic requirements was compared.P= .043], 6 hours , 12 hours , and 24 hours  were better in the intervention arm. However, the pain beyond the second day was similar. The IANB + BNB group resumed solid food quicker, and the cumulative paracetamol dose required was less . Fewer patients required opioids.The study groups included 20 patients each and were similar in age and graft size. The VAS scores at 0 hours [1.0 (1.25) vs. 2.5 (3.5); Patients who received IANB + BNB had better pain scores during the first 24 hours following surgery and tolerated solid diet quicker. The inferior alveolar plus buccal nerve block decreases postoperative pain at the buccal mucosal graft harvest site.The effect of better pain scores lasts for at least the first 24 hours following the surgery.Patients who received the block had lesser postoperative analgesic requirements and opioid consumption.Patients who received the block resumed pain-free solid diets quicker by 1 day.2 Postoperative pain at the BMG harvest site often hinders the resumption of food intake.3Buccal mucosal graft (BMG) is the most common and versatile graft used for various techniques of urological reconstruction. The BMG harvest for various kinds of urethroplasties, which is a simple and commonly performed procedure world over, is not without its own complications.8 With regard to primary wound closure, which is the most commonly used and most extensively studied technique, the existing literature shows contradicting outcomes in terms of patients’ postoperative morbidity. Hence, no clear-cut, proven strategy to tackle this issue is available at the current date.Various strategies to alleviate pain, like infiltration of the donor site with various types of local anesthetics and primary closure of the donor wound, have been tried in the past.Patients undergoing BMG harvest at our center often report that the pain at the harvest site is more bothersome than at the surgical site. Pain, in turn, hampers oral intake post-harvest. There have been instances where the patient’s postoperative hospital stay has been extended for this same reason. We explored possible ways to help our patients and enhance their postoperative course. 10 The inferior alveolar nerve supplies buccal mucosa over the first premolar, canine, and lower incisors. The buccal nerve innervates the buccal mucosa over the second premolar, lower molars, and gingiva. This block can potentially alleviate pain after buccal nerve harvest. Upon trying this procedure on a couple of patients after consent, we found positive results. We started adopting this approach as a common practice at our institute. To our knowledge, the application of the combined IANB + BNB for BMG harvest is yet to be studied. We aim to study the effect of IANB + BNB on postoperative pain scores at the BMG harvest site.The combined inferior alveolar and buccal nerve block (IANB + BNB), which is commonly used in lower jaw dental procedures, covers the area of interest of BMG.This case–control study was performed in the department of urology at a single tertiary care center in India. Informed consent was obtained from all the study participants. An institutional ethical committee approval  was obtained (Reference number: T/IM-NF/Urology/23/27). The study duration was from July 2021 to July 2022. All the patients who underwent BMG harvesting were considered for the study from July 2021 to July 2022. The patients who underwent BMG harvest between July 2021 and December 2021 underwent the procedure without any nerve blocks. From January 2022 to July 2022, all the patients underwent the procedure after IANB + BNB. Patients with additional labial/lingual mucosal graft harvest, a history of tobacco consumption, previous history of BMG harvest, active dental infections, and poor oral hygiene, and patients with missing data were excluded. The flowchart of the study is shown in All the patients were preoperatively instructed on twice-daily brushing and chlorhexidine mouthwash thrice-daily, along with oral hygiene. All the surgical steps were standardized. All the patients underwent nasal intubation to facilitate BMG harvesting.After painting and draping, the oral cavity of the patient was opened and held in position using a Doyen’s mouth gag. The desired length of BMG to be harvested was marked on the cheek after identifying and excluding Stenson’s duct opening. In the study arm, IANB + BNB was performed. A mixture of 5 mL of 1% lignocaine, 5 mL of 0.25% bupivacaine, and 4 mg of dexamethasone were prepared. A 24-gauge needle with a syringe was taken. For IANB, the needle was inserted parallel and about 1 cm above the mandibular occlusion plane toward the pterygomandibular raphe until the ramus was hit. Then, the needle was withdrawn slightly for about a millimeter and aspirated to rule out intravascular placement. Then 4-5 mL of the block were injected. For BNB, the needle is withdrawn and reinserted just lateral and anterior to the edge of the ramus at the level of occlusion of the posteriormost molar. The needle was advanced for 3-5 mm, and about 4 mL of the block were injected. Following this, local infiltration with a 1:1 combination of 2% lignocaine and (1:100 000) epinephrine was injected submucosally. This was used to hydro-dissect and lift the mucosa to facilitate harvest. The size of the graft required depended on the type of procedure and the index case. Once the required size of BMG was harvested, the harvest site was left to heal by secondary intention, and no wound closure was performed. The harvest site was packed with gauze soaked with 1:100 000 epinephrine immediately after the harvest for 6-8 hours. The pack removal was performed on postoperative day (POD) 1, along with cold water irrigation. Any bleeders were checked visually. The control arm comprised patients who did not receive any nerve block between July 2021 and December 2021. It is because we changed our practice to incorporate performing the IANB + BNB in patients requiring BMG from January 2022. The graft was harvested after injecting a 1:1 combination of 2% lignocaine and (1:100 000) epinephrine. This was injected in a plane beneath the mucosa. The remaining procedure was similar to the study arm. Oral rehabilitation of the patients started once the pack was removed, and the patients were encouraged to resume cold liquids initially, followed by a solid diet as tolerated. Intravenous paracetamol was used as the postoperative analgesic, and opioids in the form of tramadol 100 mg were used for breakthrough pain. common practice in our department. The time of resumption of pain-free liquid and solid diet intake was also recorded. Initial baseline and demographic factors were recorded using a prespecified case record proforma. Postoperative pain scores at the harvest site were recorded using the visual analog scale (VAS). The values were recorded at intervals of 0 hours, 6 hours, 12 hours, 24 hours, 48 hours, and every 24 hours until POD 5 or discharge, as a P-value of <.05 was considered significant. For comparing parametric data, the independent samples t-test was used, and for non-parametric data, the Mann–Whitney test was used. All the statistical functions were performed using the software Statistical Package for Social Sciences version 29.0 . The categorical data were expressed using proportions. The continuous data were expressed using mean (standard deviation) or median (interquartile range) based on the normalcy of the data. We analyzed the pain scores, time of resumption of food, and analgesic requirements. A A total of 42 patients had BMG harvests between January 2022 and July 2022, and all of them underwent the BMG harvest using IANB + BNB. Thirty-eight patients underwent BMG harvest between July 2021 and December 2021 without any block. Among both groups, after exclusion  vs. 2.5 (3.5); P= .85] (About 80% of patients (n = 16) in the study arm and 70% (n = 14) of patients in the control arm were male. In the study arm, 40% of patients underwent the procedure for male urethral stricture disease and hypospadias repair, while 20% of patients were females with urethral stricture. In the control arm, 60% (n = 12) were males with urethral stricture disease, 30% (n = 6) were females with urethral stricture, and 2 patients had a hypospadias repair. Both study groups did not differ in terms of age  .P= .04], 6 hours , 12 hours , and 24 hours  were significantly less in patients who received IANB + BNB than those who did not receive a block. However, VAS scores at 48 hours on POD 3 and POD 5 were not significantly different. On comparing the postoperative pain scores , it was P= .009]. The paracetamol dose consumed during the first 5 days of surgery was significantly less in patients who received IANB + . About 30% of patients required at least 1 dose of opioid for breakthrough analgesia as opposed to 50% of patients who did not receive a block.Both the study groups were able to resume normal liquid diet by the second POD, while the patients receiving IANB + BNB were able to resume normal solid diet quicker [2.5 (1.25) vs. 3.5 (1.25) days; 2 Important morbidities of this procedure are postoperative pain at the harvest site, scarring, contracture, and difficulty in mouth opening.11 There is a rare chance of hematoma formation if the wrong plane is entered and hemostasis is not done properly.12 Perioral numbness is an additional complication if the mental nerve is injured while harvesting labial mucosa.14 In contrast, perioral numbness following BMG harvest was also reported in 68% of patients by Wood et al.3 The authors have commented that this was a consequence of the excision of the mucosa and is unavoidable. Persistent changes in salivary secretion have been reported in 11% of patients in the same study. Donor site morbidities following BMG harvest have been studied previously.3 In a study by Dublin and Stewart,1 out of 35 patients who have undergone BMG harvest, more than 64% of patients reported being in pain at the donor site even 48 hours following the graft harvest. Various strategies to alleviate pain have been tried with variable success. Significant postoperative pain often hinders the resumption of a normal oral diet. As many as 83% of the patients considered BMG harvest painful, and more than half of them thought that the pain at the harvest site was worse than expected.3 In a randomized controlled trial (RCT) by Muruganandam et al,4 a total of 50 patients were randomized 1:1 to either undergo wound closure or non-closure. They found that donor site pain was significantly less in patients with non-closure on POD 1 and 2. In a similar RCT by Rourke et al5 in 2012, a total of 50 patients were randomized to either wound closure or non-closure. They found that the non-closure group had better pain scores till POD 3, following which the pain slightly worsened compared to the closure group. The non-closure group also had an earlier return to a regular solid diet (70.8% vs. 19.2% on POD 1) and full mouth opening (79.1% vs. 15.3%). The authors postulated that wound closure under tension causes more pain owing to edema incited by wound closure. Barbagli et al15 have postulated that an ovoid shape of the graft may aid in tension-free wound closure as opposed to a rectangular-shaped graft. They further commented that increased postoperative pain might be more so because of the rectangular shape of the graft rather than closure or non-closure. Similar results were seen in another RCT by Soave et al6 in 2018, where 135 patients were included. They concluded that wound non-closure was non-inferior to the primary closure of the donor site in terms of postoperative pain and morbidity. Contrary to the earlier findings, an RCT by Wong et al,7 comprising 34 patients, found that the pain scores were comparable, but the closure group could tolerate a regular diet earlier. In the same retrospective analysis, primary wound closure after graft harvest was found to be more painful, especially until POD 5.8 in 2020 published an RCT investigating a new strategy. They randomized 50 patients to either receive 2% lignocaine with epinephrine as hydro dissection (control arm) or an additional injection of 20 mL 1.3% liposomal bupivacaine injection at the muscle bed and mucosal edges (intervention arm). They found out that postoperative pain scores at the donor site were comparable. Still, narcotic use in the first 24 hours of surgery decreased in the intervention arm, though the difference did not persist at 48 hours. Chua et al16 have tried the applicability of nerve block in urethroplasties for the first time. They found infraorbital nerve block superior to no block in terms of postoperative pain scores and early resumption of diet. In this RCT comprising 30 patients, pain scores were better in patients who received block, though the exact duration of how long the effect lasted was not mentioned. Moreover, we feel that the denervation of the infraorbital nerve does not completely cover the area of interest of a BMG. Its effect has previously been studied in cleft lip repair, nasal, and transsphenoidal surgeries.19Jonnavithula et al9 The buccal nerve innervates the buccal mucosa over the second premolar and lower molars and the gingiva.10 The procedure of applying the IANB + BNB is relatively straightforward once the surgeon becomes familiar with the regional anatomy.20The combined IANB + BNB, commonly used in lower jaw dental procedures, covers the area of interest of BMG but has not been studied in this setting to our knowledge. The inferior alveolar nerve, which arises from the mandibular nerve, supplies sensory innervation to the ipsilateral half of the mandible, the buccal mucosa over the first premolar, canine, and lower incisors, and the skin over the chin and ipsilateral lower lip.In our study, we found that patients receiving IANB + BNB had better pain scores during the first 24 hours of the block and could resume solid diet intake quicker by about 1 day. It was also seen that postoperative analgesic use and the requirement for opioid analgesics have decreased. However, some patients required prolonged analgesics to control pain at the operation site rather than the pain at the donor site.This study is the first of its kind where the usage of IANB + BNB has been studied in the setting of reconstructive urology, especially where BMG harvest is required. To our knowledge, no such study has been done in the existing literature.This study, though encouraging, has its limitations. There was no formal sample size calculation done. This was a retrospective study, and all the required data was unavailable for all the patients, resulting in the exclusion of a few patients. A prospective randomized study with a larger sample size would have better eliminated the biases regarding the type of surgery for which the BMG was harvested and other unknown confounding factors. Other morbidities at the donor site were not assessed completely due to the lack of complete data availability. Patients who received IANB + BNB had better pain scores at the BMG harvest site when compared to patients who did not receive a nerve block during the first 24 hours following surgery. This enabled them to resume a normal solid diet more quicker. This effect did not last after the first POD. We can conclude that by applying this easily reproducible strategy, patients undergoing urethral reconstruction can benefit the world over.


Background: Non-image guided injection treatments (“nerve blocks”) are commonly provided in community pain clinics in Ontario for chronic non-cancer pain (CNCP) but remain controversial.Aim: We explored patients’ perspectives of nerve blocks for CNCP.Methods: We administered a 33-item cross-sectional survey to patients living with CNCP pain attending four community-based pain clinics in Ontario, Canada. The survey captured demographic information and asked about patient experiences with nerve blocks.Results: Among 616 patients that were approached, 562 (91%) provided a completed survey. The mean age of respondents was 53 (SD 12), 71% were female, and the majority (57%) reported living with CNCP for more than a decade. Fifty-eight percent had been receiving nerve blocks for their pain for >3 years, 51% on a weekly frequency. Since receiving nerve blocks, patients self-reported a median improvement in pain intensity of 2.5 points (95% CI -2.5 to -3.0) on an 11-point numeric rating scale and 66% reported stopping or reducing prescription medications, including opioids. The majority who were not retired (62%) were receiving disability benefits and were unable to work in any capacity. When asked what impact cessation of nerve blocks would have, most employed patients (52%) reported they would be unable to work, and the majority indicated their ability to function across multiple domains would decrease.Conclusion: Our respondents who received nerve blocks for CNCP attribute important pain relief and functional improvement to this intervention. Randomized trials and clinical practice guidelines are urgently needed to optimize the evidence-based use of nerve blocks for CNCP. Chronic non-cancer pain (CNCP) has a high burden of illness, affecting approximately 20% of the population globally -3. ChronMedical management of chronic pain in Canada has generally focused on pharmacotherapy . There aWith the assistance of content experts, we developed a 33-item, English-language questionnaire to capture the experiences and impressions of patients with CNCP who receive nerve blocks (Appendix 1). Numeric rating scales for outcomes and questions from the Pain Disability Index were embedded in this survey. In January 2017, we conducted a pilot survey with 31 patients to evaluate if the questionnaire adequately measured views towards, and experiences with, non-image-guided nerve blocks for CNCP. The pre-test participants were also asked to comment on the clarity and comprehensiveness of the questionnaire and the time required for completion. Feedback resulted in minor wording changes in the survey to improve comprehension and the addition of questions regarding medication side effects, and the duration of pain relief after nerve blocks. The final questionnaire provided response options as checkboxes, as a previous report has shown that closed-ended questions result in fewer incomplete questionnaires compared to open-ended questions . We alsoQuestionnaire administrationPatients were recruited from four Canadian, privately owned, community-based chronic pain clinics in Ontario, NeuPath Centres for Pain and Spine. Approximately 80% of active patients attending these clinics receive therapeutic nerve blocks which pragmatically refers to a combination of specific peripheral nerve blocks, paravertebral blocks, trigger point, scar and joint injections, using local anesthetics, such as lidocaine, bupivacaine, ropivacaine, and mepivacaine, occasionally combined with steroids. About 20% of patients attending this group of clinics discontinued blocks within the first month due to lack of efficacy and 56% continued to receive blocks for at least one year.From February 2019 to March 2020, all eligible patients attending each of the four clinics were notified, by mail or in-person, by the research team, and offered the opportunity to participate in our survey. Patients attending the clinic frequently (every two weeks or less) were approached in-person by administrative staff, and those attending less frequently were sent a letter by mail. The survey was administered at one clinic at a time for 4-6 weeks. Patients eligible to participate were (1) 18 years of age or older, (2) living with CNCP for >12 months, (3) currently receiving interventional nerve blocks, with a minimum of six treatments in the past six months, (4) fluent in English, and (5) provided written informed consent.https://www.advarra.com; project CR00142112).Patients were not excluded because of physical or mental comorbidities. Patients who agreed to participate were given a study subject number and advised that their answers to the survey would be confidential and their pain care would not be affected by their answers to the survey. Only the lead researchers (RJ and JB) and members of the research team had access to survey data and patients’ treating physicians were unaware of who participated in the study. We originally planned to survey 1000 patients but discontinued recruitment prematurely due to COVID-19 restrictions. Our study methodology and survey were approved by the Advarra Institutional Review Board (Data management and storagehttps://www.cognisantmd.com). After providing instruction on the use of the tablet, research staff entered an anonymous participant code for each individual patient, who then completed the survey independently. Patients had an opportunity to review and edit responses prior to submitting their data. All survey data was automatically entered into a validated, password-protected, secure database that was only accessible to members of the study team.After eligible patients provided informed consent to participate, they were asked to complete the questionnaire during a regular treatment visit. Data was collected on an electronic tablet, using the Ocean software platform  if normally distributed and as medians and interquartile ranges (IQRs) if not. We assessed the normality of continuous data with the Kolmogorov-Smirnov (K-S) test. As pain scores and quality of life scores were not normally distributed , we used a Wilcoxon matched-pair rank test to explore differences in median values within respondents and estimated the 95% confidence interval (95% CI) associated with the median change with the Hodges-Lehmann test. We performed all analyses using IBM SPSS 26.0 statistical software . All comparisons were two-tailed and we used a p-value <0.05 for statistical significance. Two of us  reviewed written comments independently and in duplicate to establish common themes and representative quotes. Any discrepancies were resolved by discussion.Among 616 subjects that were eligible for inclusion, 54 declined for a participation rate of 91% (562 of 616). The mean age of respondents was 53 (SD= 12), 71% were female, and approximately half were married. The majority (57%) had lived with CNCP for more than a decade and had been attending their current pain clinic for more than three years. Further, 31% of respondents had attended their current clinic for more than five years. The majority who were not retired (62%) were receiving disability benefits and were unable to work in any capacity  and advanced imaging . Almost all (95%) had seen a family physician, and many had previously attended medical specialists and surgeons regarding their pain. Most had received physiotherapy, massage, and chiropractic care. Almost all (99%) had been prescribed pharmacological treatments, and 28% had prior experience with nerve blocks. Self-reported side effects of the medication were common, with the majority endorsing dry mouth (69%), constipation (59%), impaired sleep (51%), and nausea (50%). Perceived helpfulness of prior referrals and treatments was highly variable, with the greatest endorsement for nerve blocks . Sixty-six percent of patients self-reported stopping or reducing non-prescription and prescription medications since starting nerve blocks, including a reduction in opioid use Tables -6.Table Table An improvement of 2-point is the minimally important difference for the 11-point NRS for pain . Using tWhen asked about the impact if the provincial government defunded nerve blocks for CNCP, most employed patients (52%) reported they would be unable to work in any capacity, the large majority indicated their ability to function across multiple domains would decrease, and most anticipated increased visits to their family physician and emergency department and greater use of prescription medication Table .Written commentsWritten comments regarding nerve blocks were provided by 378 respondents and these were grouped into six themes: (1) increased functioning, (2) improved mental health, (3) role in pain management, (4) improved quality of life, (5) decreased reliance on other pain relief methods, and (6) concerns regarding proposed defunding for nerve blocks for chronic pain , providing assurances that our findings are likely representative of patients with CNCP attending the four community pain clinics in Ontario that we sampled, and the piloting of our survey prior to administration.There are several limitations of this study. First, selection bias; our respondents, by inclusion criteria, were already responders to interventional treatments. Second, recall bias; our cross-sectional survey asked patients to remember their pain and functional status, and medication use, prior to starting nerve blocks and compared to their current status. As an example, respondents’ replies to medications they had reduced or stopped due to nerve blocks were inconsistent with the difference between previously and currently prescribed Table . Third, Relevant literatureOur respondents indicated a large net benefit with nerve blocks for CNCP: important reduction in pain and improved function and quality of life with few adverse events. Another cross-sectional survey of Ontario community-based pain clinics found similar results to ours . HoweverAll outpatient interventional pain clinics in Ontario are obligated to report serious adverse events that occur within 10 days of receiving treatment to the College of Physicians and Surgeons of Ontario Out of Hospital Premises Inspection Program (OHPIP). These include any patients being transferred to the ER after receiving a nerve block and all deaths from any cause within 10 days of treatment. Among the four clinics that administered our survey to their patients, there have never been more than 10 reportable events per year - the majority being vasovagal events with spontaneous recovery after a short period of observation. There were no deaths attributed to treatment.Our respondents self-reported reduced use of prescription medication, including opioids, after starting nerve block therapy. In contrast, a retrospective analysis of 47,723 patients in Ontario, Canada, who received nerve blocks for CNCP between 2013 and 2018 found no change in mean opioid dose between the year before and the year after starting nerve block therapy. This study did not rely on self-report but accessed the Narcotics Monitoring System which tracks all opioids dispensed in the province of Ontario. There were, however, within patient differences; specifically, 43% increased their use of opioids, 17% had no change, and 40% reduced their prescribed opioids one year after starting nerve block therapy [In 2020, the National Institute for Health and Care Excellence (NICE) recommended against spinal injections for managing chronic low back pain due to the lack of supporting evidence . Also inConsider a 2013 survey of 260 patients with CNCP attending a tertiary multidisciplinary pain clinic in Ontario. The majority (88%) were receiving long-term opioid therapy and no patients were receiving nerve blocks or other interventional procedures; 74% reported >40% pain relief and 68% reported >40% functional improvement. Consistent with our findings, most of these patients (68%) were disabled from working and receiving wage replacement benefits . A systeOur survey found that people living with CNCP that pursue and choose to continue with, nerve blocks reported important and meaningful benefits in pain and function as well as reduced medication use (including opioids) with few adverse effects. While observational studies provide insights into the experiences of patients, they cannot establish causality. Rigorously conducted controlled trials of nerve blocks for CNCP are required to inform effectiveness and evidence-based guidelines for interventional procedures and chronic pain, informed by both current best evidence and patients’ values and preferences, are urgently needed.


BackgroundAlthough the mechanisms of the formation of anti-dense fine-speckled 70 (anti-DFS70) antibodies are not fully known, there is evidence in the literature that allergic reactions may play a role in their formation. Immunoglobulin E (IgE)-mediated immunopathological mechanisms are increasingly being elucidated in diseases such as atopic dermatitis and urticaria-related diseases. We aimed to reveal its relationship with anti-DFS70 in allergen-sensitive patients with positive specific IgE (sIgE) levels.MethodologyThe study included samples of 758 patients who underwent antinuclear antibody (ANA) screening and allergen-sIgE testing between January 2019 and January 2022. Patients’ clinical diagnoses were retrospectively obtained from the hospital information management system. ANA was tested according to the instructions of the manufacturer by the indirect immunofluorescent antibody method using HEp-2 cell substrates . Allergen-sIgE was determined by chemiluminescence on the Immulite 2000 XPI system  according to the instructions of the manufacturer.ResultsANA pattern was detected in 74 samples included in the study. ANA-positive patients were divided into DFS70 (+) and DFS70 (-) groups. A statistically significant increase in the DFS70 pattern was observed in patients with a positive allergen-sIgE test (p < 0.0001). Both allergen-sIgE and DFS70 positivity were statistically significant in younger age groups (p < 0.05). The most common diagnosis was urticaria-related conditions in 23 (31%) patients with a positive allergy test.ConclusionsOur study shows that the positivity of the DFS70 pattern is increased in allergen-sensitive patients. Therefore, the allergen-sIgE-mediated allergic disease should be considered in patients with isolated anti-DSF70. Studies with related disease groups are needed to determine whether there is a relationship between anti-DFS70 and allergy-related disease in these patients. If an immunopathological mechanism is not found, these false-positive results can be considered clinically insignificant, and unnecessary consultations can be avoided. Autoantibodies detected in systemic autoimmune rheumatic diseases are usually directed against nuclear antigens and are called antinuclear antibodies (ANAs). Diseases in which ANAs are positive belong to a broad spectrum of diseases and are referred to as ANA-related rheumatic diseases (AARDs) . The indDFS70 antibodies are commonly found in the serum of healthy individuals -7. IsolaOn the other hand, immunoglobulin (Ig) E plays a well-documented role in the classical allergy pathway to exogenous allergens. The importance and cellular and molecular implications of IgE autoantibodies in various diseases are still being researched, but the link between IgE antibodies and autoimmunity is increasing . WatanaEnvironmental stressors, including allergens, can trigger oxidative events and inflammation in certain tissues, resulting in a response characterized by an increase in the DFS70 antigen. There is evidence that overexpression of intracellular autoantigens in a pro-inflammatory environment can lead to the formation of autoantibodies . TherefoStudy populationAmong 28,506 serum samples submitted from different clinics for ANA screening, 7,382 specific allergy tests were examined in the Department of Medical Microbiology Laboratory of Health Science University İzmir Tepecik Training and Research Hospital between January 2019 and January 2022. Our study group comprised 758 patients being tested for both ANA and allergen-sIgE. Patients’ clinical diagnoses were obtained retrospectively from medical records.ANA screeningANA was tested according to manufacturer instructions by the IIF method using HEp-2 cell substrates . IIF method was screening dilution 1:100. After slide preparation, the two experts identified the DFS patterns as the anticellular 2 patterns according to the International Consensus on ANA models .The DFS staining pattern is defined as dense fine-speckled staining of the nucleoplasm of HEp-2 cells and the chromosomal plate of metaphase cells with heterogeneity in size, brightness, and density of speckles. All IIF-ANA-positive sera were classified into either a DFS70 (+) group or a DFS70 (-) group according to the IIF-ANA pattern.Allergen-sIgE detectionCladosporium herbarum, cultivated ryegrass, Dermatophagoides pteronyssinus, mugwort); dust panel 1 ; mite panel 1 ; animal panel 2 ; and grass panel 1  to determine their allergy status.Allergen-sIgE was determined by chemiluminescence on the Immulite 2000 XPI system  according to the manufacturer’s instructions. Values below 0.35 IU/mL were considered negative. Values of 0.35 IU/mL and above were divided into six classes (I to VI), and the results were reported according to the manufacturer’s instructions. Class I was between 0.35 and 0.69 IU/mL; class II was between 0.7 and 3.4 IU/mL; class III was between 3.5 and 17.4 IU/mL; class IV was between 17.5 and 49.9 IU/mL; class V was between 50 and 100 IU/mL; and class VI was above 100 IU/mL. Patients were tested for the following different panels: food panel 1 ; food panel 5 ; tree panel 7 ; inhalant panel 8  and performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki.Statistical analysisThe chi-square test was used to compare the categorical variables of allergy test positivity, ANA test positivity, ANA test dilution, and sex. Comparisons between the levels of the categorical variables in relation to the age of the patients were performed using the Mann-Whitney U test and the Kruskal-Wallis test. Statistical analyses were performed using SPSS statistics version 21 . A p-value <0.05 was considered statistically significant. Data are presented as mean ± standard deviation (SD), number (n), and percentage (%).The selected cohort included 758 sera  from children and adults analyzed for routine testing for ANA and allergen-sIgE Figure . The selThere was a statistically significant dependence between study groups and age . The Dunn test was applied for further pairwise analysis. A significant difference was observed only between the ages of DFS (+)-allergen sIgE (+) and DFS (-)-allergen sIgE (-) (p < 0.05)  and DFS70 (-) groups were statistically significantly different . The DFS70 (+) group was significantly younger compared to the individuals in the DFS70 (-) group. There was no significant difference between the sex of the DFS70 (+) and the DFS70 (-) group p = 0.144). A total of 23 allergen-sIgE-positive and 51 allergen-sIgE-negative samples were identified in the selected cohort. See Table 44. A totThe mean age was 28.8 ± 18.77 years (range = 1-65 years) in 74 patients, and there was no normal distribution with respect to age. The sex distribution of the subjects included in our study was 73% (54/74) women and 27% men (20/74). The median age of women and men was statistically significant . The mean age of women was 32.44 ± 19.29 years (range = 1-65 years). The mean age of men was 18.95 ± 13.26 years (range = 2-43 years).When specific IgE-positive patients were examined according to their clinics, urticaria-related conditions were the most common. There was no significant difference between the DFS70 (+) group with urticaria-related conditions (p = 0.417). See Table Environmental factors that increase oxidative stress and inflammation include infectious agents, unhealthy diet, irradiation, pro-oxidants, and allergens. DFS70 is thought to support cellular protection against environmental stressors . There iIgE autoreactivity was first discovered and described in AD, where IgE autoantibodies are very common ,19. IgE In our study, allergen-sIgE levels were higher at younger ages (p = 0.015). The study by Amici et al.  includedThe study by Albesa et al. , which aOur study had several limitations. First, our sample size was small. It is necessary to investigate a larger population of allergic or allergen-sensitized patients with different disease groups. Second, because this study was retrospective, we were unable to determine whether the anti-DFS70 antibodies produced in patients with IgE to an allergen were of the IgG-only type. Prospective studies can be designed by forming a larger study group than the disease groups that may be associated with this condition.Our data show an increased positivity of the DFS70 pattern in patients with positive allergen-sIgE which could be associated with the disease pathogenesis. Therefore, if ANA is requested and only the DSF70 pattern is detected, physicians may also consider allergen-specific sensitization or allergy, especially in younger patients. Further studies are needed to determine whether there is a relationship between anti-DFS70 and allergy-related diseases in these patients. If an immunopathological mechanism is not found, these false-positive results can be considered clinically insignificant, and unnecessary consultations can be avoided.


Myofascial pain syndrome (MPS) is a common chronic pain syndrome that may affect quality of life, daily living activities, and psychological status. Ultrasound (US)-guided rhomboid intercostal block (RIB) is a recently defined plane block and used for chronic pain such as postmastectomy syndrome and MPS. Our aim was to evaluate the efficacy of US-guided RIB for the management of pain, quality of life, physical disability, and patient satisfaction in MPS.In this prospective study, between February and March 2021, a total of 30 patients who applied with the diagnosis of MPS, were included. The patients received US-guided RIB. Pain intensity was evaluated using a numerical rating scale (NRS) at pretreatment, and just after the intervention, at day 1, and 1, 2, 4, and 6 weeks after the intervention. At pretreatment and 6 weeks after treatment, Short Form-36 Health Survey (SF-36) for health-related quality of life, Neck Disability Index (NDI), and patient satisfaction were evaluated.There was a statistically significant decrease in average NRS immediately after treatment, at day 1 and week 1,2,4, and 6 compared to the pretreatment (p < 0.0001). The average SF-36 scores advanced at 6 weeks after treatment. There was a statistically significant reduction in mean NDI scores throughout the follow-up period (p < 0.001).Our study demonstrated that RIB had improved neck function, physical and mental quality of life, and patient satisfaction in MPS. Therefore, we think US-guided RIB could be an alternative treatment modality in patients suffering from MPS. Myofascial pain syndrome (MPS) is a common chronic pain syndrome accompanied by sensory and motor symptoms as well as autonomic phenomena. It is characterized by the presence of myofascial trigger points defined as palpable, hyperirritable bands or nodules. Contractile activity of myofascial trigger points and nociceptor stimulation responding to pathological processes in the muscle fascial layer leads to myofascial pain . The paiWith the increasing use of ultrasound technology in regional anesthesia and pain medicine, newly defined interfascial plane blocks (IFB) have become more popular. Ultrasound (US)-guided rhomboid intercostal block (RIB) is a thoracic plane block recently defined by Elsharkawy et al. in a patient presenting with multiple rib fractures . RIB invCurrently, a variety of superficial injection techniques, including trigger point injections, LA injections, dry needling, and acupuncture are commonly used in MPS . HoweverClinicalTrials.org PRS under registration no. NCT04751110. STROBE checklist was used to help design and conduct the study.Local ethics committee approval  was obtained for this prospective, observational study. Our study was designed and conducted in accordance with the ethical principles specified in the Helsinki Declaration. All participants were informed about the study, and written informed consent was obtained from all patients. This study was registered at The inclusion criteria for the study were as follows: (1) be aged between 18 and 60 years; (2) experienced pain for at least 12 weeks in the thoracic paravertebral region between T2-T9; (3) presence of at least one active myofascial trigger point (MTrPs); and (4) pain with a numerical rating scales (NRS) score ≥3 lasts for at least three months. The active MTrP diagnosis was based on the fulfillment of all the following criteria: (1) palpable taut band; (2) presence of a hypersensitive tender spot within the taut band; (3) patient recognition of familiar referred pain symptoms upon compression of the nodule; and (4) painful limitation of full stretch range of motion (12).The exclusion criteria for the study were as follows: (1) cervical radiculopathy, fibromyalgia, shoulder joint disease, chronic fatigue syndrome, rheumatic diseases, history of surgery or traumatic event, and malignancy as a cause of pain (2) use of anticoagulants; (3) history of bupivacaine or dexamethasone allergy; (4) history of injection for MPS within the last six months; (5) decline to participate; and (6) pregnancy.While the patient was positioned prone and the ipsilateral arm adducted across the chest, under aseptic conditions, a linear high-frequency ultrasound transducer was placed 2–3 cm medial of the medial border of the scapula on the sagittal plane at the T5–T6 level. Cutaneous and subcutaneous layers, the trapezius muscle, rhomboid major muscle, intercostal muscle, ribs, and pleura were visualized . We inseDescriptive data collected at baseline included age, gender, and body mass index (BMI). Patients were assessed at baseline, just after the intervention, at day 1, and 1, 2, 4, and 6 weeks after the intervention.The NRS is a widely used scale to assess the severity of pain felt by a patient. The patient rates pain on a scale of 0 to 10, with 0 representing ‘no pain’ and 10 representing ‘worst pain’ imaginable. The NRS has been shown to have a strong correlation with descriptive scales, as well as high sensitivity and reliability . TherefoThe secondary outcome measures were quality of life, neck function, and patient satisfaction degree after treatment. The quality of life (QoL) was assessed via SF-36, which consists of 36 items encompassed in 8 dimensions: physical function, physical role, bodily pain, general health, vitality, social function, emotional role, and mental health and 2 summary values for Physical Component Summary (PCS) and Mental Component Summary (MCS) . SubscalDisability was measured by using the Neck Disability Index (NDI). The Turkish version of this scale was found valid and reliable. The questionnaire consists of 10 items in which each section is scored on a 0–5 rating scale, and the total score ranges from 0 to 50. Higher scores indicate greater disease severity . NDI meaSample size calculations were performed using G*Power software version 3.1.9.7  according to our preliminary study data. In this study, we found the mean NRS score 2.5± 0.8 at 6 weeks. Using the results of this previous study and considering the NRS as a primary outcome, a sample size of 30 patients was determined to be necessary in order to detect a %20 difference, an α level of .05, and power of 80%.Data were analyzed using the SPSS version 23.0 statistics program . Continuous quantitative data with normal distribution were presented as numbers, mean ± standard deviation, with abnormal distribution were presented as median (interquartile range). The compatibility of the variables to normal distribution was checked with a Kolmogorov–Smirnov test. The paired sample test was applied to parametric data for the statistical evaluation of repeated measurements. For abnormally distributed variables, intragroup distribution was compared using Friedman’s test. If present, within group comparisons of the differences were evaluated using the Bonferroni adjusted Wilcoxon signed ranks for post hoc analysis. P < 0.05 was considered statistically significant.χ2 = 105.94, p < 0.001) using a Friedman test. When binary time points were compared to find source of difference in NRS scores, there was a statistically significant difference immediately after treatment, at day 1 and week 1,2,4, and 6 compared to the pretreatment NRS (p < 0.001) . In total 53.3% of patients were very satisfied with pain management, 36.6% were satisfied, and 3.3% were not satisfied (All 30 patients diagnosed with MPS completed the study. The demographic characteristics of patients are summarized in < 0.001) . There watisfied . ChangesIn this study, we evaluated the clinical effect of US-guided RIB in patients with MPS. Our results showed that the severity of pain was significantly reduced after the block procedure for a 6-week follow-up period. Also, our study demonstrates that RIB improves the quality of life, disability, and patient satisfaction in the majority of the patients.The ultrasound revolution has shown its effect on the practice of regional anesthesia and pain medicine. Nowadays, there is increasing interest and, therefore, new research studies in US-guided IFB. RIB is a recently demonstrated IFB as an alternative technique to the paravertebral and thoracic epidural block. The literature on RIB provides evidence that this technique can lead to effective and long-lasting perioperative analgesia in breast and thoracic surgeries ,18. SimiFascia opens the possible keys for understanding the etiopathogenesis of pain syndromes such as chronic low back pain, myofascial pain syndrome, and fibromyalgia ,28. SeveFascia has a dynamic structure regarding its mechanical and physiological properties. The autonomous contractile elements it has and the movement of the musculotendinous structures attached to it explain the dynamic properties of the fascia. . PerformIn MPS, sensitization of polymodal type receptors (PMR) plays an important role in the development of the MTrPs. Superficial approaches such as dry needling, trigger point injections, and acupuncture provide analgesia by activating cutaneous PMR . StimulaSome limitations of this study should be considered. First, it had a short follow-up period; the effects were evaluated in only 6 weeks. Second, although our study could be criticized for the lack of a sham group, we considered that it is unethical to apply RIB in a placebo group with saline or intentionally puncture the fascia of muscles. However, this study could provide data for a sample size calculation for future randomized controlled trials. Third, NRS, Visual Analogue Scale, McGill pain questionnaire, and Pain Rating Scale are widely used scales for assessing pain intensity, however, we only used the NRS score as a primary outcome measure.In conclusion, this observational clinical study demonstrated that the US-guided RIB could be an alternative treatment modality in patients suffering from myofascial pain. Furthermore, our study showed that RIB had improved neck function, physical and mental quality of life, and patient satisfaction among patients with MPS. We suggest that RIB may gain an essential place in the treatment algorithm of MPS. However, further clinical studies are required to compare its effectiveness and safety to conventional techniques performed in MPS.