Some patients prescribed opioid analgesic (OA) medications for pain experience serious side effects, including dependence, sedation, and overdose. As most patients are at low risk for OA-related harms, risk reduction interventions requiring multiple counseling sessions are impractical on a large scale.This study evaluates whether an intervention based on reinforcement learning (RL), a field of artificial intelligence, learned through experience to personalize interactions with patients with pain discharged from the emergency department (ED) and decreased self-reported OA misuse behaviors while conserving counselors’ time.We used data representing 2439 weekly interactions between a digital health intervention (“Prescription Opioid Wellness and Engagement Research in the ED” [PowerED]) and 228 patients with pain discharged from 2 EDs who reported recent opioid misuse. During each patient’s 12 weeks of intervention, PowerED used RL to select from 3 treatment options: a brief motivational message delivered via an interactive voice response (IVR) call, a longer motivational IVR call, or a live call from a counselor. The algorithm selected session types for each patient each week, with the goal of minimizing OA risk, defined in terms of a dynamic score reflecting patient reports during IVR monitoring calls. When a live counseling call was predicted to have a similar impact on future risk as an IVR message, the algorithm favored IVR to conserve counselor time. We used logit models to estimate changes in the relative frequency of each session type as PowerED gained experience. Poisson regression was used to examine the changes in self-reported OA risk scores over calendar time, controlling for the ordinal session number (1st to 12th).P=.006) and extended IVR sessions (P<.001). Live counseling sessions were selected 33.5% of the time in the first 5 weeks of interactions (95% CI 27.4%-39.7%) but only for 16.4% of sessions (95% CI 12.7%-20%) after 125 weeks. Controlling for each patient’s changes during the course of treatment, this adaptation of treatment-type allocation led to progressively greater improvements in self-reported OA risk scores (P<.001) over calendar time, as measured by the number of weeks since enrollment began. Improvement in risk behaviors over time was especially pronounced among patients with the highest risk at baseline (P=.02).Participants on average were 40 (SD 12.7) years of age; 66.7% (152/228) were women and 51.3% (117/228) were unemployed. Most participants  reported chronic pain, and 46.2% (104/225) had moderate to severe depressive symptoms. As PowerED gained experience through interactions over a period of 142 weeks, it delivered fewer live counseling sessions than brief IVR sessions (The RL-supported program learned which treatment modalities worked best to improve self-reported OA risk behaviors while conserving counselors’ time. RL-supported interventions represent a scalable solution for patients with pain receiving OA prescriptions.Clinicaltrials.gov NCT02990377; https://classic.clinicaltrials.gov/ct2/show/NCT02990377 The related public health crises of chronic pain and opioid analgesic (OA) misuse continue to challenge the United States ,2. AlthoMany patients with chronic pain and risks of OA misuse can at least theoretically be identified during emergency department (ED) encounters. However, although risk reduction interventions based on motivational interviewing and cognitive behavioral therapies can be helpful -10, the Digital communication with patients via cell phone apps, text messaging, or interactive voice response (IVR) calls can facilitate OA risk monitoring and behavior change support for patients discharged from EDs -14. IdenP=.01) and pain intensity (P=.03).In a previous randomized trial of 278 patients with musculoskeletal pain, we evaluated the effectiveness of reinforcement learning (RL), a type of artificial intelligence (AI), as a strategy for increasing the efficiency of cognitive behavioral therapy for chronic pain by automatically adjusting the type and duration of counseling sessions based on patient feedback regarding their status . Compareguesses among a limited set of potential treatment options or action choices and evaluate the impact of those decisions based on some dynamic measure of feedback (the reward in RL). Over time, RL systems systematically incorporate experience with previous action choices as well as information about the user to make progressively more educated guesses that optimize the reward function. Unlike more deterministic digital interventions that use tree-structured protocols to decide what actions to take , RL systems use these repeated cycles of action choices and feedback in a dynamic, probabilistic manner to determine which actions optimize the reward score. In our previous trial of RL support for pain-related cognitive behavioral therapy  scores ,21).The methods and findings of this study are presented here in accordance with the CONSORT -AI Extension Guidelines . All parThe study was approved by the University of Michigan Human Subjects Committee (#HUM00105229) before any patient contact. The protocol is registered in ClinicalTrials.gov (#NCT02990377).Diagnostic and Statistical Manual for Mental Disorders Version 5 (DSM-V) moderate or severe opioid use disorder, were experiencing opioid withdrawal symptoms at the time of screening, were unable to communicate in English, were at acute risk for self-harm, were incarcerated, were classified as level 1 trauma , were pregnant, were under treatment for sexual assault, or had a family member or significant other enrolled in the study. Patients were approached for recruitment in person in the ED or were recruited via telephone following discharge because of COVID-19 restrictions. Participants were not compensated for completing IVR calls or telephone counseling sessions. Participants received US $20 to US $40 for completing surveys at baseline and follow-up time points and received US $5 for providing saliva samples at various time points .Potential participants were identified between November 8, 2018, and May 8, 2021, based on medical record evidence of visits to EDs affiliated with 2 large health systems. Both EDs are level I trauma centers located in the same county in Southeast Michigan, which has a median annual household income of US $75,730. Demographically, 70% of county residents are White non-Hispanic, 12% are Black or African American, 5% are Hispanic, and 13% are Asian or multiracial. In total, 11% of the county residents use Medicaid as their primary form of health insurance. Eligible patients were adults aged 18 to 70 years, presenting at the ED primarily for a pain-related complaint, and who reported any OA misuse in the previous 3 months. Misuse was defined as any score >0 on the modified COMM questionnaire . PatientAfter completing the baseline assessments, the patients were randomized with equal probability to the PowerED intervention or enhanced usual care. These analyses focused exclusively on patients randomized to the PowerED group.PowerED patients participated in 12 weeks of behavioral intervention addressing OA risk and pain management. Counseling and psychoeducation were based on motivational enhancement and cognitive behavioral principles and focused on improving patients’ OA safety profile, non–OA-related strategies for coping with pain , improving overall health , and effective communication with clinicians. Before initiating the randomized trial, the PowerED intervention content was pilot-tested and found to have positive effects on opioid misuse behaviors after discharge from the ED . In addiPowerED patients received brief (<5 minute) IVR calls up to 5 times per week, in which they responded to queries recorded in a human, female voice using their touchtone keypad. During the calls, the patients reported their use of OA prescription medications, levels of pain, and related risks. During IVR assessments, patients’ pain severity over the previous 24 hours was assessed using the pain Numerical Rating Scale . PatientEach week for each patient, PowerED selected from three options:A brief (<5-minute) IVR call including motivational messages focused on safe OA use and healthy strategies for pain management: During these calls, patients heard messages selected from 6 categories determined based on their most recent reports about pain severity  and OA use (yes vs no).An extended (5- to 10-minute) IVR call focused on OA-related risks and behavior change strategies: In these calls, patients received rotating questions focused on strategies for improving their pain and overall health, their beliefs regarding opioid use, and the importance of pain management. Using the motivational enhancement principle of supporting patients’ decisional autonomy .,21.20,21The patients’ baseline characteristics were described for the overall sample and separately within each of the 3 subgroups defined by baseline COMM scores. We calculated the total number and percentage of attempted IVR assessments that were completed within the baseline COMM score subgroups.We hypothesized that the relative frequency of decisions resulting in the selection of each of the 3 session types would evolve as PowerED gained experience with the population and learned which options were most successful in optimizing patients’ weekly OA risk scores while conserving counselor time. To test this hypothesis, we fitted a multinomial logit model predicting the 3-level outcome of selected session type , controlling for the potential correlation of weekly decisions within patients. Predictors of interest included the ordinal week of enrollment  and the session number for that patient . We used Stata’s  postestimation commands to calculate the probability distribution across session types over enrollment weeks and present those findings graphically.calendar time should be independent of within-patient temporal changes and represent a reasonable estimate of improvements over time in the intervention’s ability to target session types. As noted earlier, scores representing the patient’s OA risk behaviors in a given week had a possible range of 1 to 7, and 80.89% (1316/1627) of completed call-weeks had the best possible score of 1. Poisson regression was used to accommodate this skewed outcome distribution with a limited possible range. Regression models treated patients as random effects and other predictors as fixed effects. As we were particularly interested in PowerED’s performance within patient subgroups defined by baseline levels of OA risk, we first fitted a base model including only patients’ enrollment week and session number as predictors. We then fitted a second model including these predictors as well as dummy variables representing the main effects for baseline COMM scores of 2 to 5 and ≥6 (vs a score of 1) and interaction terms between those indicators and enrollment week. Using Stata’s postestimation command, we plotted the changes in predicted reward scores over enrollment weeks separately for the 3 levels of baseline COMM scores.We hypothesized that IVR-reported OA risk scores would improve as PowerED interacted with the population and made increasingly effective decisions. To test this hypothesis, we fitted 2 nested multilevel regression models with the week’s OA risk score as the outcome and independent variables representing enrollment week, session number, and baseline OA risk severity (3-level COMM score). The session number was included to control for within-patient changes in risk scores resulting from regression to the mean or intervention effectiveness. By controlling for session number, coefficients associated with enrollment week or P values for both the COMM by race and COMM by education differences were <.03). Participants with higher baseline COMM scores were also more likely to have moderate or severe symptoms of depression (P=.002).A total of 228 patients were randomized to receive the PowerED intervention  over 130Participants collectively received 11,544 days of IVR assessment calls and responded approximately half of the time . Response rates were similar across the groups, as defined by the baseline COMM scores . The RL P=.006) and extended IVR sessions (P<.001).PowerED’s decisions evolved as it gained experience through interactions with patients . AnalyseP=.02) and extended IVR sessions . For example, after 120 weeks of interactions with the sample, PowerED chose live counseling 21.2% of the time for patients’ first session (95% CI 16.8%-25.6%) but only 13.8% of the time if the patient was in their final, week-12 session (95% CI 9.5%-18.1%).The coefficients presented in P≤.004). Modeling also indicated that significant improvements in weekly reward scores over calendar time were experienced specifically among patients with baseline COMM scores of ≥6 indicating the highest baseline OA risk (model 2 in P=.02). Using coefficients from model 2 in Multilevel models predicting reward scores reflecting patients’ OA risk behaviors indicated that scores improved as PowerED gained more experience through patient interactions. The model predicting scores based on both enrollment week and ordinal session number indicated that both of these 2 factors were predictive of improvements in OA risk . Moreover, improvements in patients’ risk scores over time occurred during some of the most challenging months of the COVID-19 pandemic—the time when opioid deaths were increasing and access to care for many patients was restricted . ServiceThese findings are important because despite studies demonstrating the effectiveness of brief behavioral interventions for improving pain and decreasing OA risk ,10,33, tAs our goal was to reach the broadest possible population, this study included patients with relatively low baseline COMM scores. Having a lower threshold for inclusion in OA risk reduction could have substantial public health benefits, but monitoring and behavior change support for such a population using only live counseling sessions is not a scalable option, given the millions of eligible patients. Therefore, programs such as PowerED that seek to improve patients’ risk profile while minimizing human resource use are especially vital. It is particularly encouraging that analyses demonstrated that PowerED was able to improve patients’ self-reported risk behaviors as it gained experience interacting with patients who had COMM scores of ≥6. As shown in In a previous study, an RL-supported program of pain cognitive behavioral therapy achieved outcomes that were noninferior to a standard therapist-delivered program . DespiteThe PowerED intervention used patients’ IVR feedback to make decisions regarding the most effective mode of treatment while conserving counselor time. However, a limitation of this study is that response rates to IVR assessment calls were relatively low compared with the 88% response rate in a study using a similar feedback loop to adapt treatment among US Department of Veterans Affairs patients with chronic back pain . Even whThis study and our previous study, in which we used a similar AI approach to deliver cognitive behavioral therapy to veterans with chronic musculoskeletal pain , suggestDespite these opportunities, the development and adoption of AI-supported behavioral interventions must proceed with caution and a deep understanding of the ways in which such algorithms can perpetuate or even exacerbate disparities in care. Limited diversity in AI training samples may lead to biased decisions in more heterogeneous populations ,39. PoteIn conclusion, this study demonstrates that an OA risk reduction intervention supported by RL can learn to target clinician resources through interactions with patients, with the goal of maximizing population benefits. Such programs may be particularly scalable and effective for the large population of patients with pain at risk of OA-related harms who lack access to standard behavioral health services. Given that RL systems such as this one improve through experience with patients, large-scale studies in diverse patient populations are recommended to maximize intervention effectiveness and make OA risk reduction programs available for the millions of Americans at risk for OA-related harms.


Conclusion: Statistically significant and clinically meaningful within-group improvements in thumb pain and function were observed at 12 weeks following six sessions of periosteal DN treatment. DN may be a useful intervention in the management of patients with CMC OA of the thumb.Background: Carpometacarpal (CMC) osteoarthritis (OA) of the thumb is a painful condition that affects over 15% of individuals above the age of 30 and up to 30% of post-menopausal women. Dry needling (DN) has been found to reduce pain and disability in a variety of neuromusculoskeletal conditions; however, DN in the management of CMC OA has not been well studied. Methods: Consecutive patients with clinical and radiographic evidence of CMC OA were treated with DN. The primary outcome measure was pain using the Numerical Pain Rating Scale (NPRS) at 12 weeks. Secondary outcome measures were the Upper Extremity Functional Index (UEFI-20) and the Global Rating of Change (GROC) scale. Outcome measures were collected at baseline, 4 weeks, 8 weeks, and 12 weeks. Results: Nine patients were treated for six sessions of periosteal DN over 3 weeks. Compared to baseline, statistically significant and clinically meaningful improvements were observed in thumb pain (NPRS mean difference: 2.6;  Carpometacarpal (CMC) osteoarthritis (OA) of the thumb is a debilitating hand-wrist joint condition that affects 15% of individuals over the age of 30 and up to 30% of post-menopausal women . CMC OA A primary cause of CMC OA is thought to be associated with radial subluxation from the deterioration of the anterior oblique and dorsoradial ligaments of the thumb, leading to joint incongruence, radial subluxation, erosion of the articular cartilage, inflammation, pain, and joint stiffness . CompensThe diagnosis of CMC OA is based on radiographic findings and a clinical examination ,2,5. TheSeveral studies seem to associate the etiology of musculoskeletal pain with poor circulation ,7. DN usClinically meaningful improvements in pain and disability have been reported in a number of trials where periosteal needling—i.e., moving the needle close to the bone, joint line, or cartilage, or tapping the needle repeatedly onto the bone—was utilized in patients with hip or knee OA ,21,22,23In addition, interleukin-6 mRNA expression in bone marrow has been found to diminish following acupuncture , thereby limiting inflammation and inhibiting the myelogenic osteoclast activity driving osteoarthritic degeneration . MoreoveA 2018 multi-center randomized clinical trial of 242 patients with knee osteoarthritis found the inclusion of periosteal electrical dry needling to be more effective for their pain and disability reduction than manual therapy and exercise alone . HoweverConsecutive patients who presented to the outpatient physical therapy clinic at Redington-Fairview General Hospital, Skowhegan, Maine, between August and December 2022 with a doctor’s prescription to treat thumb pain were screened for inclusion. Their ages ranged between 49 to 73 years, with a mean (SD) of 60.9 (7.7) years. The duration of symptoms ranged from 12 months to 60 months, with a mean (SD) of 29.3 (20.9) months. Baseline characteristics of the nine patients in this case series can be found in The inclusion criteria were as follows: (1) primary complaint of thumb pain lasting longer than 3 months, (2) pain with movement of the thumb, (3) limited hand function due to thumb pain, and (4) clinical evidence of CMC osteoarthritis . A positive grind test has been found as a valid and reliable test for the clinical diagnosis of symptomatic CMC OA , with a The exclusion criteria were as follows: (1) had received a steroid injection to the thumb within the past 3 months, (2) had prior surgery to the thumb, (3) had received physical or occupational therapy treatment for thumb pain within the previous 3 months, (4) had evidence of cervical radiculopathy or referred pain from the cervical spine, (5) had one or more contraindications to dry needling, including red flags , (6) a history of mastectomy or lymph node removal involving the ipsilateral side, (7) were currently pregnant, (8) had surgery involving the ipsilateral upper extremity within the past year, and (9) had pending legal action or a worker’s compensation claim regarding their thumb pain. All patients who met the criteria and agreed to participate underwent a formal informed-consent process by signing a consent form approved by the Institutional Review Board at Redington-Fairview General Hospital, Skowhegan, Maine, prior to the physical therapy evaluation. The physical therapist who examined and treated all patients had 20 years of clinical experience and was a fellow in training within the American Academy of Manipulative Therapy Fellowship in Orthopaedic Manual Physical Therapy program. The clinician had 4 years of experience in dry needling, including a 30 h APTA-accredited course in dry needling and a 54 h dry needling certification training course that included content specific to the thumb. For each patient, a thorough physical examination was conducted to verify the clinical signs of CMC osteoarthritis. This examination included a visual inspection for nodules, joint enlargement and swelling, palpation for tenderness at the joint and surrounding soft tissues, and compression/distraction special tests for joint pain and crepitus. Screening measures were performed, as indicated, to identify any co-existing injuries of the upper extremity or cervical spine. Measures of strength and the active range of motion were also recorded.Patients completed the Numeric Pain Rating Scale (NPRS) and the Upper Extremity Functional Index-20 (UEFI-20) at the initial evaluation and 4, 8, and 12-week intervals following the baseline examination. The primary outcome measure was the NPRS at 12 weeks. The NPRS was used to measure the thumb pain intensity. Patients reported the average intensity of thumb pain over the past week using an 11-point scale ranging from 0 (no pain) to 10 (worst pain imaginable) at baseline, 4 weeks, 8 weeks, and 12 weeks following the initial treatment session . The NPRThe secondary outcome measures included the Upper Extremity Functional Index (UEFI-20) and Global Rating of Change scale (GROC). The UEFI-20 was recorded at baseline, 4 weeks, 8 weeks, and 12 weeks. The UEFI-20 has been found to possess strong construct validity and high inter-examiner reliability ,44. ScorAll participants received DN 2 x per week for 3 weeks for a total of 6 treatments.Previous needling studies have used one needle inserted into the dorsal mid thenar eminence into the belly of the adductor pollicis brevis, several acupoints around the CMC joint line, and into the extensor carpi radialis longus and along the radial nerve pathway but the needles were not placed into the key muscles in the thenar eminence .For this study, a standardized dry needling protocol was used to ensure consistency , Table 2deqi response  [The standardized dry needling protocol included eight points that targeted muscle, periarticular, and perineural tissue of the affected thumb. Needles were inserted to approximate the anatomical target, then rotated to achieve myofascial tenting and elicit a  warmth) . Unidire warmth) . The neeThe patients were asked to report any adverse events they experienced during the study. An adverse event was defined as sequelae of a 1-week duration, perceived as distressing and unacceptable to the patient that required further attention . Particup > 0.05). A one-way analysis of variance (ANOVA) for repeated measures, with a Greenhouse–Geisser epsilon correction, was used to compare the within-group scores over time for each continuous variable (1 for the NPRS data and 1 for the UEFI-20 data). Post hoc pairwise comparisons were performed to examine the difference between the baseline and each of the follow-up periods using the Bonferroni correction at an α level of 0.05. The statistical analysis was conducted at a 95% confidence level. All nine participants completed the outcomes through the 12-week follow-up. To quantify the magnitude of the treatment effect, the within-group effect sizes were calculated using Cohen’s d coefficient. An effect size of greater than 0.8 was considered large, an approximating 0.5 was considered moderate, and less than 0.2 was considered small.Data analysis was performed using SPSS 28.0 . Descriptive statistics, including frequency counts for the categorical variables and measures of central tendency and dispersion for continuous variables, were calculated to summarize the findings. A normal distribution for the NPRS and UEFI-20 was assessed using the Kolmogorov–Smirnov test; both outcomes were normally distributed  were treated for six visits over a 3-week period (2 times per week). All patients completed all six treatment sessions. p = 0.024) decrease in thumb pain (NPRS) after six dry needling treatment sessions ; however, no significant differences in thumb pain intensity (NPRS) were found between 4 and 8 weeks (p = 0.729), and 8 and 12 weeks (p = 0.594). Compared with the baseline, large  within-group effect sizes were observed for thumb pain intensity (NPRS) at 4 weeks (Cohen’s d = 0.875), 8 weeks (Cohen’s d = 0.939), and 12 weeks (Cohen’s d = 0.888). A significant improvement in thumb pain intensity  was observed between the baseline and 12 weeks (p = 0.010) decrease in disability (UEFI-20 score) after six sessions of DN ; however, no significant differences in disability (UEFI-20) were found between 4 and 8 weeks (p = 0.511), and 8 and 12 weeks (p = 0.678). Compared with the baseline, large  within-group effect sizes were observed for disability (UEFI-20) at 4 weeks (Cohen’s d = 1.11), 8 weeks (Cohen’s d = 1.05), and 12 weeks (Cohen’s d = 1.08). A significant improvement in disability (UEFI-20 mean difference: 21.33) was observed between the baseline and 12 weeks  GROC scores were +4.0 (2.1) at 4 weeks, +2.4 (3.0) at 8 weeks, and +2.2 (2.9) at 12 weeks follow-up, indicating “moderately better” and “slightly better” outcomes in the short and medium term, respectively. p = 0.029) and function  at 12 weeks. Notably, most improvement was observed at 4 weeks; however, this improvement appeared to persist following the completion of the treatment regimen at 3 weeks and through the final follow-up at 12 weeks. Four out of the nine subjects exceeded the MCID of a 2 or more points (NPRS 0–10) reduction in pain at 4, 8, and 12 weeks. For the disability, eight out of nine subjects exceeded the MCID of 10% improvement for the UEFI-20 at 4 weeks, and six out of nine subjects met the MCID of 10% improvement at 8 weeks and 12 weeks. In addition, six of the nine patients scored themselves at 4 or better at the 4-week interval, indicating that more than 60% of the patients reported a “moderate” improvement in their condition by the completion of the six sessions of periosteal dry needling to the CMC joint. Nine patients with CMC OA were treated for six sessions of periosteal DN over 3 weeks. Statistically significant and clinically meaningful within-group improvements were observed in thumb pain (NPRS mean difference: 2.6; Barnard et al. found no difference between real and sham acupuncture for basal thumb pain ; in addiThe underlying mechanisms as to why the patients receiving DN around the CMC joint experienced a reduction in pain and an improvement in function remain to be elucidated. However, a number of studies have found periosteal needling—i.e., moving the needle close to the bone, cartilage, or joint line—leads to clinically meaningful improvements in pain and disability in patients with hip and/or knee OA ,23,49. MAlthough a cause-and-effect relationship cannot be inferred from the results of a case series, clinically meaningful within-group changes in pain and function were observed; nevertheless, these changes may be due to natural history, changes in activity levels, the Hawthorn effect , and/or This case series suggests that periosteal DN may be a useful intervention for pain and disability reduction in patients with basal thumb pain associated with OA of the CMC joint. Randomized clinical trials are needed to determine the effectiveness and between-group effect sizes when compared to an active comparison or control group.


Anal fissure is one of the most common anal disease characterized by intense anal pain, and deterioration of patients quality of life. Treatment is mainly based on the topical administration of calcium antagonist or nitric oxide ointments, and in cases refractory to medical treatment patients can undergo surgery. This study aims to assess the efficacy and safety of Levorag emulgel in the treatment of acute and chronic fissures using of a validated scoring system.A prospective observational study was carried out on patients with anal fissures between February and May 2022. The efficacy of the treatment was evaluated using the REALISE score, a new validated scoring system that rates VAS for pain, NSAID use, pain duration, bleeding, and quality of life (QoL), recorded after 10, 20 and 30 days from the beginning of treatment.p = 0.05) after 20 days. At the 30-day proctological examination, 22 patients (61%) were pain free . Pain duration after defecation measured according to the REALISE score, showed a significant decrease after 10 days, from a median value of 2 (IQR 1–4) to 1 (IQR 1–1.2) (p < 0.005). The median value of the REALISE score decreased significantly, from 15 (IQR 11–19.25) at first proctological evaluation to 4  after 30 days of treatment. At day 30, complete fissure healing was achieved in 30 patients (80%). The healing rate was 82% and 78% in patients with acute and chronic anal fissures, respectively.Forty patients  with acute  or chronic  anal fissures entered the study. The median anal pain score according to the VAS scale decreased significantly from 7 (IQR 4.7–8) at baseline to 1 (IQR 0–3.2, The use of Levorag® Emulgel may represent a safe and effective non-invasive first line treatment in patients affected by acute or chronic anal fissure. Anal fissure (AF) is one of the most common anal disease characterized by intense and prolonged anal pain after defecation, bleeding, and considerable deterioration of patient's quality of life . AF is oWhen conservative treatments fail, surgical options including internal anal sphincterotomy, anal advancement flap, and anal stretch/dilation may be considered , 10.None of these medical treatments are completely free from side effects such as headaches, migraines, and pruritus ani, while surgical approach can cause bleeding, abscesses, fistulas, and considerable risk of fecal incontinence –13.This study aims to evaluate the safety and effectiveness of Levorag® Emulgel, a topical ointment which favors pain relief, microperfusion of the anoderm and the reepithelization process, 14, in A prospective observational study was carried out in a tertiary proctology unit on patients with anal fissures between February and May 2022. After receiving approval from the local ethics committee, patients of both sexes aged 18 to 85 years with acute or chronic anal fissures were enrolled. Exclusion criteria included previous medical or surgical treatment, perianal Crohn's disease, previous anorectal operations, prolapsed hemorrhoids, rectal prolapse, functional disorders of the defecation and continence, and pregnancy. Acute fissures were defined as recent (within 6 weeks) ulcerations of the anoderm, while chronic anal fissures persisted for more than 6 weeks, with sentinel tags and/or induration of the lateral margins of the fissure and/or exposure of the internal anal sphincter. Demographic data and detailed clinical histories were recorded, including information about anal pain intensity and duration, bowel habits, and stool consistency   before tp value < 0.05 was considered statistically significant. Statistical analysis was carried out using RStudio (R version 4.0.3 (2020-10-10) Copyright (C) 2020 The R Foundation for Statistical Computing).Continuous parameters were reported as median and interquartile ranges. Categorical variables were recorded as numbers and percentages. Comparisons of categorical variables were performed by the Chi-square and Fisher's Exact test, where appropriate. Comparisons between groups were made by the Mann-Whitney U test. A Forty patients  with acute  or chronic  anal fissures entered the study after giving an oral informed consent.p < 0.005) 10 days later and to 1  after 20 days. At the 30-day proctological examination, 22 patients (61%) were pain free . Pain duration after defecation measured according to the REALISE score, showed a significant decrease after 10 days, from a median value of 2 (IQR 1–4) to 1 (IQR 1–1.2) (p < 0.005). This score did not change after 20 and 30 days . With regard to bowel habits at the first evaluation, 8 patients (22%) had stool type 2 according to the Bristol stool scale, while 24 (67%) and 4 (11%) patients had type 3 and 6, respectively. The median value of the REALISE score at the first clinical evaluation was 15 (IQR 11–19.25) with a significant reduction at 10 days to 8 . At 20 days, a median value of 6  was recorded. Between 20 and 30 days after the onset of treatment, the score decreased to 4   completed both telephone interviews and a proctological evaluation at day 30. Four out of forty patients (10%) who did not complete the follow-up, underwent internal anal sphincterotomy (1 patient) and calcium antagonist-based ointments 10 days after the first consultation (3 patients). Previous pregnancies were reported by 14 women (58%) . Four pa= 0.139) . At day Non-operative management is the first-line approach for treating anal fissures, as it can provide relief the associated anal spasm with pain decreases and healing of the fissure in about 60 to 80% of the cases .A recent survey among gastrointestinal surgeons in the Netherlands reported that initial treatment consists of conservative measures including administration of fibers/laxatives and topical ointments .In the past few decades, several topical ointments have been proposed as non-invasive treatments for anal fissures. Currently, the Association of Coloproctologists of Great Britain and Ireland recommends diltiazem as first-line treatment for chronic anal fissures  with a hBotulinum toxin can also be used as conservative treatment being more effective than nitrates and calcium channel blockers even if but the local injection is painful and its effect is temporary .In this study, the administration of Levorag® Emulgel, a topical ointment with natural anti-inflammatory agents, botox-like effect, and immune-stimulating properties, resulted in complete healing in 80% of patients with acute or chronic anal fissures. These results are in agreement with data published by Digennaro et al.  who repoNordholm-Cartensen et al.  reportedA preliminary study by Giordano et al.  on the uIn our analysis, the healing rate was higher than other medical treatments using topical ointments, however the small sample size and the inclusion of acute anal fissures may limit the reliability of the study. Other limitations of this study are the lack of a control group and the use of only the Bristol scale to evaluate bowel habit.In conclusion the use of Levorag® Emulgel may represent a safe and effective non-invasive first line treatment in patients affected by acute or chronic anal fissure. Multicenter prospective randomized studies with long-term follow-up are expected to confirm our results.


Chronic nonmalignant pain (CNMP), defined as persistent pain that is not attributable to a potentially life-limiting condition and has a duration of at least 3 months, is widespread in the United States. Moderate-to-severe CNMP often is treated with opioid analgesics, and there is ongoing debate regarding appropriate allocation of opioids to treat CNMP because long-term treatment can result in problematic side effects, drug misuse, or abuse leading to detrimental medical, social, and economic consequences. Furthermore, therapeutic strategies arising from concerns about the misuse of opioids may impede the treatment of patients who require strong analgesics for adequate pain relief. While current CNMP management includes nonpharmacologic and pharmacologic approaches, including acetaminophen, nonsteroidal anti-inflammatory drugs, and opioids, there is debate regarding the risk-benefit profile of opioids for chronic pain treatment.Mitigation of opioid misuse and abuse and proper administration of opioid analgesics must be balanced against providing appropriate analgesia. To accomplish this, managed care policies could implement guidelines that focus on evaluating risk characteristics for opioid misuse and abuse, use opioid dose-sparing strategies, and encourage the use of alternative analgesics or nonpharmacologic therapy when appropriate. The purpose of this review is to examine challenges and costs associated with CNMP management using opioids and to summarize alternative therapeutic approaches. For example, the U.S. Food and Drug Administration (FDA) has stated that there is no evidence to suggest that CNMP should be treated with different pharmacotherapies than cancer-related pain, but they have restricted the use of some analgesics to patients with persistent cancer pain.5As the world population ages, the health care systems must increasingly consider long-term management of conditions affecting an older population, including chronic pain, which is defined as pain that persists longer than would be expected for resolution of the underlying etiology (often defined as pain lasting more than 6 or 12 weeks).7 Opioids are some of the most commonly prescribed drugs to treat moderate-to-severe chronic pain, and their use in CNMP has steadily increased despite uncertainty regarding their long-term efficacy and related safety and economic concerns.12 The Consortium to Study Opioid Risks and Trends (CONSORT) study, which examined opioid use in the United States using pooled insurance data comprising greater than 1% of the U.S. population, found the prevalence of long-term opioid use—defined as more than 120 days of dispensed medication for CNMP—to be between 3.9% and 4.7%.13 While drug diversion  and abuse  have occurred concurrently with the increases in opioid prescriptions, some patients still receive inadequate pain control, and there are other concerns surrounding opioid use for CNMP.18 Other potential problems with long-term opioid use for chronic pain include questions of cost-effectiveness, which compares the costs and outcomes based on the likelihood of positive and negative consequences; side effects associated with long-term use; whether these patients are receiving adequate analgesia; and quality-of-life improvements.21Chronic pain affected approximately 100 million people in the United States in 2011 and was associated with economic consequences ranging from $560 billion to $635 billion annually in medical care and decreased productivity, underscoring the need for more effective pain management strategies.23 Thus, a detailed examination of current practice patterns in chronic pain management, patient responses to therapy, and nonopioid analgesic use may identify areas that could be targeted for improvement. The purpose of this commentary is to discuss challenges and costs associated with CNMP management using opioids and alternative approaches to treatment.A goal of managed care is to provide employers with a package of health care benefits that are affordable and meet the health care needs of employees.Diagnostic and Statistical Manual of Mental Disorders, 5th edition, that include tolerance, dependence, and continued use despite adverse consequences,24 can be associated with misuse  and diversion, which is becoming increasingly common.26 At the same time, many patients who would benefit from opioid pharmacotherapy are denied these drugs due to prescribers’ fear of regulatory sanctions if patients intentionally or unintentionally harm themselves.6 Some studies suggest that few chronic pain patients develop opioid use disorder, but estimates of the number of patients who develop opioid use disorder have been inconsistent.20 Often, such trials do not evaluate opioid dependence or addiction, and the topic of addiction specifically in chronic pain patients has received little attention, even as the number of opioid prescriptions has increased.28 Roland et al. (2013) have reported that the overall prevalence of opioid abuse in the United States managed care population doubled from 2005 to 2010, with an overall prevalence during the study period of 0.195%.29 This marked increase in the number of opioid prescriptions since the early 2000s underscores the importance of investigating the safety and efficacy of current therapeutic strategies.23 Results from the 2013 National Survey on Drug Use and Health indicate that approximately 4.8% of people aged 12 years or older reported nonmedical use of analgesics during the previous year.30 Consistent with these findings, nonmedical use of analgesics is the second most common form of illicit drug abuse in the United States (17.3%) after marijuana (61.8%).31In the United States, opioid use disorder, which is defined by a series of behaviors in the 32 Longer-term use also carries risk of conditions such as opioid-induced hyperalgesia (increased sensitivity to pain), which was thought to be a symptom of withdrawal but now has been recognized during continuous opioid use.33 A small observational study found that opioid-using CNMP patients exhibited significantly greater pain scores when administered a cold-pressor test.34 Another study of chronic pain patients found that opioid use was associated with significantly higher pain and unpleasantness scores when patients received an injection, and the increase in pain scores correlated with opioid dose and duration of use.35 Thus, care providers can face additional challenges in providing adequate analgesia for opioid-using patients who are also experiencing acute pain or who require treatment for painful clinical procedures.36 Opioid use for treatment of chronic pain has also been identified as a risk factor for central sleep apnea and hypoxemia in small studies, affecting up to 30% of opioid users.39 Opioid-induced sleep apnea has also been identified as a potential cause of opioid-related mortality.40 Psychosocial disorders may also affect CNMP patients using opioids; a survey using the Prescribed Opioids Difficulties Scale (PODS), which asks patients to rate concerns and difficulties on a scale from “strongly agree” to “strongly disagree,” found that, while high PODS scores were not correlated with patients’ pain intensity, they correlated strongly with depression symptoms, concerns over dependence on opioids, and opioid-related problems with concentration or arousal.41The potential for abuse is not the only risk associated with opioid use for chronic pain. Opioid use is associated with a number of side effects , and a 242 Another review of studies that investigated the prevalence of “problem use” in CNMP patients, which included an array of behaviors from addiction to misuse, found that the prevalence of “problem use” varied widely, from 0%-50% of CNMP patients.26 A 2011 study of more than 2,300 chronic pain patients found that the lifetime prevalence of opioid use disorder was 34.9%, with risk factors including age less than 65 years, history of substance abuse, antisocial personality disorder, and a prescription for psychotropic drugs.43 These studies suggest that, while opioid use disorder among CNMP patients may be difficult to estimate, risk factors such as a history of substance abuse have a large impact on whether a patient will exhibit characteristics of opioid use disorder. Accidental overdose of opioid medications is also a concern when prescribing opioids for CNMP. CONSORT data used to investigate opioid overdose among CNMP patients showed that patients receiving an opioid dose of 100 milligrams (mg) or more had a 1.8% annual overdose rate—8.9 times that of patients receiving 20 mg or less per day.44 A large study of overdose deaths among West Virginia residents—93.2% of which were related to opioid analgesics—found that 36.9% of decedents had documented prescriptions for the medications resulting in fatal overdose.45 These results suggest that a substantial proportion of opioid overdoses are not due to diversion. A panel of experts examining opioid-related deaths that occurred over a decade identified a variety of potential factors involved in overdose cases, including undiagnosed comorbidities, physician error, patient nonadherence, and use of other drugs such as benzodiazepines. A disproportionately high number of deaths were attributed to methadone compared with the number of prescriptions, possibly due to the different pharmacokinetics of methadone compared with morphine.40 Overdose rates reflect unintentional misuse of prescribed opioids as well as use of diverted opioids, which are commonly used for pain relief.26 Since the rates of diversion and nonmedical use of prescription analgesics are increasing in the United States with detrimental consequences, including overdose, the costs to public health of opioid use disorder and overdose must be weighed against the importance of adequate treatment of chronic pain.46Opioid use disorder and unintentional overdose resulting from prescribed opioids are serious potential consequences of opioid treatment for CNMP. The extent of opioid use disorder, particularly in patients with legitimate prescriptions for chronic pain, can be difficult to estimate. A 2008 meta-analysis that investigated studies of addiction and aberrant drug-related behaviors in CNMP patients found that, while the overall percentage of patients considered to be addicted was 3.27%, it was 0.19% in studies that included only patients with no history of alcohol or illicit drug abuse or addiction, suggesting that the risk of addiction is low in most patients.49 The Centers for Disease Control and Prevention have noted that deaths from overdoses of opioid analgesics were responsible for nearly 40% of deaths from poisoning in 2006, making it the second leading cause of injury death among 34-54 year olds.50 White et al. (2005) used an administrative database of pharmacy claims to determine mean annual health care costs of opioid abusers from the perspective of a private payer.51 White et al. reported that the mean annual direct health care costs for opioid abusers were more than 8 times higher than those for nonabusers from a private payer perspective .51 In that study, drug costs were found to be more than 5 times higher in opioid abusers compared with nonabusers .51 In addition, the performed multivariate regression analysis that controlled for comorbidities showed that average health care costs for opioid abuse are approximately 1.8 times higher than those for depression, a common comorbidity in chronic pain patients.51 In 2007, prescription opioid abuse cost $55.7 billion, which included $25 billion in health care costs, $25.6 billion in workplace costs, and $5.1 billion in criminal justice costs.48 The majority of the associated health care costs resulted from medical and prescription expenses ($23.7 billion).48The economic consequences of opioid misuse, whether resulting from opioid diversion, opioid use disorder, or poor treatment adherence, are substantial.52 Stratification of the analyzed population by factors typically associated with the misuse of medication, including a history of depression and aberrant behavior  revealed that 80% of patients had at least 1 factor typically associated with medication misuse, and 24% had at least 3 factors. The majority of claims (82%) consisted of patients who were uncooperative with respect to care (69%) or clinicians who managed medications inappropriately (59%). Among the medication malpractice claims evaluated, death was the most common outcome (57% vs. 9% in other chronic pain claims). Long-acting opioid and additional psychoactive medication use and the presence of at least 3 risks for medication misuse were associated with increased mortality rates in opioid users. Twenty-four percent of these patients reported addiction to prescribed opioids; however, the term addiction was not defined in the study.52 McAdam-Marx et al. (2010) reported that, in a Medicaid population with an opioid abuse prevalence of 8.7 cases per 1,000, patient costs were significantly higher in opioid abusers than in age-, gender-, and state of residence-matched controls.53 Furthermore, as with any type of substance abuse, people who abuse opioids are more likely to incur severe injuries as a result of their abuse that require multiple treatments, which are likely to escalate costs.54 Unintentional overdose also increases patient costs, whether it is due to opioid use disorder or to unintentional misuse. A 2009 report of the total cost of prescription opioid poisoning in the United States estimated the direct costs at $1.76 billion annually, with indirect costs estimated to be $13.9 billion annually.55An analysis of 8,954 malpractice claims collected from 2005 to 2008 by Fitzgibbon et al. (2010) showed that the vast majority (94%) of medication management claims were related to patients being prescribed opioids for management of chronic pain.16 Furthermore, these statistics should be assessed cautiously. Patients receiving opioid therapy frequently suffer from severe pain and have an increased morbidity.46 Although opioid use increases health care costs,55 it is unclear whether reductions in opioid prescription rates would decrease costs because of the significant nonopioid-related financial burden associated with disease processes for which opioids are prescribed.The extensive health care and societal costs reported for opioid abuse and misuse underscore the need for efforts to alleviate this burden. However, it is important that these efforts do not hinder patient access, especially in an era where pain is often poorly managed.23 In addition, the type of insurance coverage often dictates which opioids are prescribed based on the costs to the payer.18 Long-term opioid therapy may cause adverse outcomes , which are not associated with the development of drug dependence, although opioids are indicated if pain is sufficiently severe.57 Acetaminophen is effective in the management of a variety of pain conditions and is a first-line therapy for knee and hip osteoarthritis when clear inflammation is not present.61 However, acetaminophen is not innocuous; acute overdose of the drug may cause fatty liver damage.62 NSAIDs have gained widespread use in the management of chronic pain in the past half century; however, NSAIDs are associated with dose-related gastrointestinal, cardiovascular, and renal adverse events (AEs) that can occur at any point following treatment, and these AEs can increase health care costs.65 All NSAIDs, including nonprescription and cyclooxygenase (COX)-2 selective agents, have been associated with an approximately 1.5-fold increase in the risk of vascular events.66 Evans et al. (1995) reported that the risk of hospital admission for acute renal failure was approximately double for NSAID users compared with NSAID-naïve patients.67 The gastrointestinal, cardiovascular, and renal AE risks associated with NSAIDs are reduced with lower doses and less frequent use.66 As a consequence, various investigative and new technologies and modes of drug delivery have been developed with a focus on lessening the risk of AEs by avoiding absorption via the gastrointestinal tract  and/or permitting the delivery of drugs with low systemic exposure but with equivalent efficacy compared with standard formulations (submicron particle formulations).69 In addition, use of opioids and NSAIDs concurrently is mutually dose sparing, thus reducing the potential for AEs and associated costs with both drug classes.74 This dose-sparing effect allows patients who require opioid therapy to use lower doses of NSAIDs and opioids, providing good pain relief and lowering the risk of complications associated with either drug.In order to provide alternatives and attempt to reduce the risk of misuse in CNMP patients, there is an increasing emphasis on the use of nonopioid analgesics and multimodal therapeutic regimens.85 Several anticonvulsant agents are useful in neuropathic pain and fibromyalgia and may be cost-effective alternatives to opioids  reported that carbamazepine is more cost-effective than tramadol and gabapentin for the treatment of neuropathic pain in patients lacking renal or cardiovascular disease .80 Tricyclic antidepressants are drugs of choice in neuropathic pain, according to the International Association for the Study of Pain.81 The selective serotonin reuptake inhibitors may lessen pain perception by improving depressed mood but are not analgesics, per se. The serotonin-norepinephrine reuptake inhibitor duloxetine was approved by the FDA for the management of neuropathic and some types of nociceptive pain.85 In a subset of patients with painful diabetic neuropathy who completed a 52-week clinical trial, Wu et al. (2006) determined that, from employer and societal perspectives, duloxetine was more cost-effective than gabapentin (56%), venlafaxine (36%), and amitriptyline (15%).85 From the payer perspective, there was a trend toward increased cost-effectiveness of duloxetine compared with the standard therapy.85 In a cost-utility analysis that estimated the cost per amount of utility gained for several neuropathic pain therapies, the tricyclic antidepressant amitriptyline was shown to be more cost-effective than tramadol and gabapentin for neuropathic pain in patients without renal or cardiovascular disease.80 Although amitriptyline and other tertiary end-chain tricyclic antidepressants are associated with serious AEs related to their anticholinergic activity, the secondary end-chain agents, most notably desipramine, are associated with far less anticholinergic and sedative side effects—one-quarter for desipramine and one-half for nortriptyline compared with amitriptyline.86Adjunctive analgesic therapy may be effective in CNMP. Analgesic adjuncts used to treat CNMP include anticonvulsants, antidepressants, and short courses of muscle relaxants, among others. opioids .75-77 Ga87 Short courses of muscle relaxants may be a useful adjunct therapy to analgesics when administered intermittently for durations not exceeding 1 week; however, this combination is associated with an elevation of central nervous system AEs and should be used with caution.87 Overall, the integration of multi-modal therapy is an important aspect of individualized patient care, and effective individualized therapy may reduce health care costs by improving patient quality of life and minimizing AEs.Muscle relaxants have demonstrated efficacy in musculoskeletal pain management when used for short durations (4-7 days).8 These interventions have been found to alleviate pain in some chronic pain patients, including those with low back pain or osteoarthritis, the 2 most common conditions that result in CNMP in the United States.8 Acupuncture has shown modest benefits for pain from osteoarthritis.88 A meta-analysis of a few studies found that use of braces and therapeutic insoles may provide small benefits for knee osteoarthritis.89 For low back pain, transcutaneous electroconvulsive therapy has shown efficacy in some patients, and meta-analyses have shown that massage, behavioral modification, and exercise show modest benefits.93 However, many of the studies are small, and the costs of these therapies compared with conventional treatments has not been thoroughly assessed.Nonpharmacologic interventions, such as exercise, physical therapy, and psychotherapy that are aimed at self-management can be effective adjuncts to pharmacotherapy, and such multi-modal approaches can reduce overall costs of care and reduce the amount of opioid-containing medications used.19 A study investigating outcomes in CPP patients found that patients enrolled in a CPP showed significantly better outcomes in a number of categories, including pain severity, interference in daily activities, distress, and ability to rest.94 Careful monitoring of dose may also limit the potential for development of opioid use disorder, since a nonescalating dose may be key in preventing addiction and other negative consequences of opioid use for chronic pain.95 These results suggest that improvements in patient management may improve outcomes and reduce costs over time, despite the initial costs of establishing interdisciplinary pain clinics.19Alternative beneficial strategies to reduce the rate of opioid use disorder and their associated costs are interdisciplinary comprehensive pain programs (CPP), in which clinicians with expertise in pain management work to provide multimodal pain treatment, whereby dose and treatment are individualized with the goal of functional restoration. A 2006 review of CPP found that enrolled patients returned to work sooner than non-CPP patients and estimated that CPP may result in a lifetime health care savings of up to $400,000 per patient.Opioid use in chronic pain patients has increased over the last decade with a concurrent increase in opioid misuse and opioid use disorder, which have significantly impacted rising health care costs and public health. Opioid misuse costs the health care system billions of dollars annually; opioid prescriptions for CNMP result in thousands of malpractice claims each year; and detrimental side effects of opioid use for CNMP can result in suboptimal patient care. However, many CNMP patients have benefitted greatly from opioid therapy for moderate-to-severe chronic pain. The 2012 FDA-mandated Risk Evaluation and Mitigation Strategy for extended-release and long-acting opioids requires pharmaceutical companies to provide patients with medication guides and to educate clinicians on patient counseling; selection; and assessment of the risk for patient misuse, dependency, and addiction. Additional strategies that could be adopted include opioid dose-sparing strategies, including use of NSAIDs and adjunctive therapies such as anticonvulsants, antidepressants, and muscle relaxants, as well as nonpharmacologic interventions. Furthermore, implementation of comprehensive pain programs may decrease costs while improving outcomes for CNMP patients.The aforementioned multimodal approaches should be recognized by the medical community with the goal of facilitating appropriate drug use and minimizing drug diversion and misuse. Moreover, the implementation of such strategies may improve patient care by providing effective pain relief to patients with CNMP who require these drugs. Taken together, cost-effective strategies designed to incorporate alternative therapies along with more appropriate management of opioid use should decrease the prevalence of opioid abuse (overuse/underuse), while also ensuring that future CNMP patients who require opioid therapy receive adequate pain relief.


Technetium-99 m 3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) and technetium-99 m sodium pyrophosphate (PYP) are the two most commonly used radiotracers for cardiac amyloidosis (CA), but no studies have directly compared them. Therefore, in this study, we directly compared the diagnostic and clinical utility of DPD and PYP scintigraphy in patients with CA.Ten patients with CA were enrolled. Eight clinical variables and 12 scintigraphic parameters were used. Clinical variables were age, sex, estimated glomerular filtration rate (eGFR), N-terminal pro brain natriuretic peptide (NT-proBNP), and the results of electromyography (EMG), a sensory test, electrocardiogram, and echocardiography (EchoCG). Four heart retention ratios  were calculated from the DPD and PYP scans and two visual scoring systems  were used. Comparative analyses were performed between radiotracers and between visual scoring systems using clinical variables and scintigraphic parameters.Twenty DPD parameters and nine PYP parameters had significant associations with age, eGFR, NT-proBNP, EchoCG, and EMG. DPD parameters had more frequent significant associations with clinical variables than PYP parameters. Compared to visual scores in the DPD scan, the proportion of patients with higher visual scores in the PYP scan was relatively greater than those with lower visual scores, and there were more patients with a visual score of 2 or higher in PYP scans than DPD scans.DPD scintigraphy may reflect the disease severity of CA better than PYP scintigraphy, whereas PYP scintigraphy may be a more sensitive imaging modality for identifying CA involvement.The online version contains supplementary material available at 10.1186/s12880-023-01054-x. Cardiac amyloidosis (CA) is one of the most common restrictive infiltrative cardiomyopathies (CMs). It has a poor prognosis, with the clinical outcome dependent on the type of amyloid fibril deposition and the extent of organ and tissue involvement . VariousAmong radiotracers for cardiac scintigraphy, DPD and PYP are two most commonly used radiotracers for ATTR CA . In a prSeveral scintigraphic parameters have been proposed for cardiac scintigraphy with bone-seeking radiotracers. In semi-quantitative analyses, Gallini et al. used six indices to identify CA patients : heart/wOur aim in this study was to directly compare DPD and PYP scintigraphy in patients with CA to evaluate their diagnostic and clinical utilities. For comparative analyses, the scintigraphic parameters of four heart retention ratios  and two visual scoring systems  were used. In addition, the clinical value of each visual scoring system was investigated.We retrospectively reviewed the medical records of patients with CA diagnosed at Samsung Medical Center between August 2017 and July 2020. All study patients underwent both DPD and PYP scintigraphy, and the period between DPD and PYP scintigraphy was less than six months. Experienced cardiologists (D.K. and J.-O.C.) diagnosed patients with CA based on histopathological, genetic, cardiac-related, and hematologic findings. Endomyocardial or extracardiac biopsies were taken to identify amyloidosis, and immunohistochemistry staining was performed using these tissue specimens. Transthyretin (TTR) gene analysis was performed to confirm TTR gene mutations using deoxyribonucleic acid extracted from peripheral blood. CMR, EchoCG, ECG, DPD and PYP scintigraphy, cardiac biomarker levels, and cardiac complications and comorbidities were evaluated to assess cardiac-related findings. Hematologic findings were evaluated based on serum free-light chain quantification and serum and urine protein electrophoresis with immunofixation. Cardiologists diagnosed patients with CA using invasive and non-invasive diagnostic criteria for CA based on the histopathological, genetic, cardiac-related, and hematologic findings described above . FinallyThe Institutional Review Board (IRB) of Samsung Medical Center approved this retrospective study (IRB number: 2022-08-111). Informed consent was waived by IRB of Samsung Medical Center due to the retrospective nature of the study. This study was conducted according to the Declaration of Helsinki 2013 and its later amendments or similar ethical standards.We used the same acquisition protocol for DPD and PYP scintigraphy. Three hours after intravenous injection of DPD or PYP (740 MBq), anterior and posterior whole-body (WB) scans were performed using a dual-headed gamma camera  equipped with a low-energy, high-resolution collimator. The matrix size of images was set to 256 × 1024. Scan speed and scan length were 20 cm/min and 195 cm, respectively.An experienced nuclear medicine physician (J.L.) interpreted and analyzed WB planar images using Xeleris Functional Imaging Workstation version 4.0 . Two visual scoring systems, Perugini and Dorbala , 15, 16,Four semi-quantitative heart retention ratios were calculated on WB planar images using ROIs based on a previous study Fig.  10]. Th. Th10]. In this study, eight clinical variables and 12 scintigraphic parameters were used. Clinical variables were age, sex, estimated glomerular filtration rate (eGFR), NT-proBNP, and the results of electromyography (EMG), a quantitative sensory test, ECG, and EchoCG. Clinical variables were assessed within 3 months of initial diagnosis of CA. Among these, the results of EMG, sensory test, ECG, and EchoCG were converted into dichotomous variables according to abnormal findings. In EMG, a sympathetic postganglionic sudomotor dysfunction was considered an abnormal finding. In ECG, atrioventricular block, atrial fibrillation, ventricular arrhythmia, and sinus bradycardia were considered abnormal findings. In the quantitative sensory test, abnormal findings were those that exceeded the cooling and vibration thresholds. EchoCG results were classified into two categories according to diastolic dysfunction; a diastolic dysfunction grade of 1 or higher was considered an abnormal finding. Twelve scintigraphic parameters comprised eight retention ratios and four visual scores in DPD and PYP scans. The eight heart retention ratios were DPD H/WBp, DPD H/P, DPD H/S, DPD H/CL, PYP H/WBp, PYP H/P, PYP H/S, and PYP H/CL. The four visual scores were DPD Perugini, DPD Dorbala, PYP Perugini, and PYP Dorbala.Comparative analyses were performed between radiotracers and between visual scoring systems using clinical variables and scintigraphic parameters. The Shapiro-Wilk test was used to assess the normality of continuous variables. Mann-Whitney U test was used to compare differences between dichotomous variables. Fisher’s exact test was used to assess nonrandom associations between two discrete dichotomous variables. Spearman’s correlation was used to measure the strength of linear relationship between two continuous variables. Statistical analyses were performed using MedCalc statistical software . All statistical tests were two-tailed, and a P value < 0.05 was considered statistically significant.2 (range of 67–115 mL/min/1.74 m2), and 1,212 pg/mL , respectively. Among the study patients, more than half of the patients had abnormal EMG (80%) and sensory test (90%) findings, and half of the patients had abnormal ECG findings (50%). Eight (80%) patients had diastolic grade 1 or higher on EchoCG.In this study, 10 patients diagnosed with CA were enrolled  between DPD and PYP scans, and a significant correlation was observed in Perugini scores between DPD and PYP scans Table . Among tMore frequent significant correlations between visual scores and heart retention ratios were observed in DPD scans than in PYP scans, and significant correlations between visual scores and heart retention ratios were observed more frequently in the Perugini system than in the Dorbala system Table . DPD PerDPD parameters showed more frequent significant associations with clinical variables than PYP parameters Table . SignifiTo the best of our knowledge, this is the first study to directly compare DPD and PYP scans in patients with CA. Although DPD and PYP are the two most commonly used radiotracers for ATTR CA , no stud10%amyloid, and a significant negative correlation was observed between eGFR and log10%amyloid [In this study, DPD scans reflected the disease severity of CA better than PYP scans. Twenty DPD parameters and nine PYP parameters showed significant associations with age, eGFR, NT-proBNP, EchoCG, and EMG, suggesting that DPD parameters express the severity of CA better than PYP parameters. Previous studies reported that DPD and PYP parameters showed significant associations with age, eGFR, NT-proBNP, EchoCG, and EMG. Ternacle et al. demonstrated that the detection rate of CA using endomyocardial biopsy or autopsy increased noticeably as age increased . Löfback%amyloid . This pr%amyloid . In addi%amyloid , and Har%amyloid . In a pr%amyloid . As in p%amyloid . As in pCompared to DPD scintigraphy, PYP scintigraphy seems to be more sensitive at identifying CA involvement. In previous studies, both DPD and PYP scans were shown to have high sensitivity and specificity for myocardial uptake in patients with pathologically confirmed ATTR CM . In the There were more frequent significant correlations between radiotracers and between visual scores and heart retention ratios using the Perugini system than the Dorbala system, whereas the Dorbala system reflected the disease severity of CA better than the Perugini system. Between DPD and PYP scans, Perugini scores showed significant correlations, but Dorbala scores showed no significant correlations. This is because the changes in visual scores of the Dorbala system were relatively large compared to those in the Perugini system. There were good correlations between Perugini visual scores and retention ratios in both DPD and PYP scans. On the contrary, there were good correlations between Dorbala visual scores and retention ratios only in DPD scans. In other words, significant correlations between visual scores and heart retention ratios were observed more frequently in the Perugini system than in the Dorbala system. These results provide evidence that there are better correlations between Perugini visual scores and heart retention ratios than Dorbala visual scores and heart retention ratios. However, contrary to the results of this study, a previous study of patients who underwent DPD scintigraphy and SPECT/CT with suspicion of CA reported that Dorbala visual scores were more significantly associated with H/CL and H/WB ratios than Perugini visual scores . TherefoThis study has several limitations. First, it was a retrospective single-center study, and the small sample size likely resulted in insufficient statistical power. Therefore, it is necessary to verify the results of this study in a prospective, large-scale multi-center study. Second, most of the enrolled patients in this study had ATTR CA (90%), whereas only a single AL CA patient (10%) was enrolled, limiting the generalizability of our findings. Third, our study used only DPD and PYP planar scintigraphy, and there was no direct comparison between DPD and PYP SPECT/CT. Asif et al. suggested that planar image-derived visual scores, while showing outstanding accuracy for SPECT myocardial uptake, were misclassified in a small proportion of patients (2.3%) . TherefoDPD scintigraphy may reflect the disease severity of CA better than PYP scintigraphy, whereas PYP scintigraphy may be a more sensitive imaging modality for identifying CA involvement. In addition, Perugini visual scores and heart retention ratios showed stronger correlation in both DPD and PYP scans than Dorbala visual scores and heart retentions ratios, but the Dorbala system may reflect the disease severity of CA better than the Perugini system.Below is the link to the electronic supplementary material.Supplementary Material 1


Pain is the main symptom of osteoarthritis (OA) with approximately 50% of patients reporting moderate-to-severe pain. Total knee replacement (TKR) is the ultimate treatment option to alleviate pain in knee OA. Nevertheless, TKR does not provide complete relief for all as approximately 20% of patients experience chronic postoperative pain. Painful peripheral stimuli may alter the central nociceptive pathways leading to central sensitisation that can influence treatment response in patients with OA. Currently, there is no objective protocol for detecting whether a patient will respond to a given treatment. Therefore, there is a need for a better mechanistic understanding of individual factors affecting pain relief, consequently informing personalised treatment guidelines. The purpose of this research is to examine the feasibility of conducting a full-scale mechanistic clinical trial in painful knee OA investigating the analgesic response to intra-articular bupivacaine between those with or without evidence of central sensitisation.The Understanding Pain mechanisms in KNEE osteoarthritis (UP-KNEE) study is a feasibility, double-blinded, placebo-controlled randomised parallel study in participants with radiographically defined knee OA and with self-reported chronic knee pain. The study involves the following assessments: (1) a suite of psychometric questionnaires; (2) quantitative sensory testing; (3) magnetic resonance imaging (MRI) scan of the knee and brain; (4) a 6-minute walk test; and (5) an intra-articular injection of bupivacaine or placebo (sodium chloride 0.9%) into the index knee. Assessments will be repeated post intra-articular injection apart from the MRI scan of the knee. Our aim is to provide proof of concept and descriptive statistics to power a future mechanistic trial.Ethical approval was obtained from the Health Research Authority (HRA) (REC: 20/EM/0287). Results will be disseminated via peer-reviewed journals and scientific conferences. The results will also be shared with lay audiences through relevant channels, such as Pain Centre Versus Arthritis website and patient advocacy groups.NCT05561010. The study attempts to address a knowledge gap by providing mechanistic understanding of the factors contributing to the individual pain relief in knee osteoarthritis.The feasibility design will support a future main trial.Patients were involved in the development of the study protocol. They helped to identify the most relevant outcome measures, which were reordered to prioritise the patients’ preferences.Owing to the nature of the feasibility study, no formal hypothesis testing will be performed in this trial. It will provide descriptive statistics which will inform the design and sample size requirements of a future definitive mechanistic trial.Knee osteoarthritis (OA) is a leading cause of pain, functional disability and is a substantial economic burden on society and healthcare systems.Painful peripheral stimuli may alter the central nociceptive pathways leading to central sensitisation that can influence treatment response in patients with OA.10 11Validated proxies, including questionnaires, neuroimaging and quantitative sensory testing (QST), have been used to examine pain sensitisation. However, a gold standard to diagnose pain sensitisation in a clinical setting is lacking, and individualised mechanism-based treatment in knee OA remains a pressing need.Given the necessity for better understanding of the mechanisms of pain relief in knee OA, the purpose of this research is to examine the feasibility of conducting a full-scale mechanistic clinical trial investigating the analgesic response in knee OA between those with or without evidence of central sensitisation. The use of intra-articular bupivacaine, as an experimental medicine approach, has been shown to significantly reduce knee pain 1 hour after injection in previous studiesThe primary objective of the UP-KNEE study is to evaluate the feasibility of a main definitive trial by:collecting data to inform sample size calculation;testing the recruitment process;Timing of the outcome measures;Testing the robustness of randomisation;Testing the integrity of the research protocol; andqualitative assessment of the acceptability of the methods of the feasibility study.The secondary objective of the study is to explore correlations of the analgesic response with indicators of central and peripheral pain mechanisms derived from MRI of the brain and knee, questionnaires and QST.For the future main trial, the hypothesis is that the analgesic response to a peripherally targeted intervention aiming to reduce knee pain will reveal two groups. The non-responders group will be patients with predominantly centrally driven pain characteristics, who will show less analgesic response to the peripherally targeted intervention while the responders group will be patients with predominantly peripheral pain who will show a greater analgesic response to the peripherally targeted intervention. Both groups will respond similarly to placebo. However, this feasibility study is not intended to test the hypothesis of the main trial.The study will be a feasibility, double-blinded, placebo-controlled randomised parallel study in participants with radiographically defined knee OA and with self-reported chronic knee pain. The study design was guided by the recommendations of the Consolidated Standards of Reporting Trials (CONSORT) 2010 statement extension to randomised pilot and feasibility trials.1610.1136/bmjopen-2023-072138.supp1Supplementary dataThis is a single-centre study. The study activities will be carried out at the Sir Peter Mansfield Imaging Centre, University of Nottingham.This is a feasibility study aiming to provide first proof of concept and descriptive statistics to power a future diagnostic trial. We aim to recruit 50 participants (25 to each group). This would be a large enough sample to assess the feasibility and inform a main trial based on statistical methodological papers providing recommendations about sample size requirements for feasibility and pilot studies.17–19The inclusion criteria are; patients aged 45 years and older who have the capacity to give informed consent and have radiographically defined OA knee changes (Kellgren and Lawrence Grading System K/L>2/4) with knee pain, particularly self-reported knee pain at the most severely affected side measuring between 30 and 80 mm on a 100 mm Visual Analogue Scale (VAS) for rest, use or night pain and being able to perform the 6-minute walk test (6MWT). The VAS anchors are: 0 as ‘no pain’ and 100 as ‘the worst pain imaginable’.The exclusion criteria are; patients having major medical, neurological and psychiatric comorbidities that would preclude completion of the study protocol. Patients who have a diagnosis of OA in any joint other than the knee with pain VAS≥30 mm, fibromyalgia, systemic or local knee infection, severe coagulopathy or taking anticoagulant therapy, known hypersensitivity to bupivacaine, taking neuropathic pain medications for their OA-related pain such as strong opioid analgesics and antiepileptic drugs will also be excluded. Known contraindications for MRI are also exclusion criteria.The trial flow is summarised in Informed, written consent will be obtained prior to any research activities . The par10.1136/bmjopen-2023-072138.supp2Supplementary dataSealedEnvelope.com) will be used for stratified randomisation to either intra-articular injection of bupivacaine or sodium chloride 0.9%. This facility generates codes that are concealed from the research team to either group. To mitigate against risk of allocation imbalance with respect to whether pain is predominantly centrally or peripherally driven, stratification will be based on the scores of the Central Aspects of Pain in the Knee (CAP-Knee) questionnaire, which will be sent to participants before the research visit. Participants will be randomised on a 1:1 allocation basis to either bupivacaine or placebo. To ensure blinding of the investigators to the participant’s group assignment, an authorised research nurse will prepare the allocated treatment. The randomisation schedule will be embedded by the research nurse in a secure password-protected folder to achieve allocation concealment.Eligible participants will be randomised in a 1:1 allocation ratio. An online computer service , the interventions will include an assessment to check patients’ suitability to undergo intervention with a local anaesthetic (bupivacaine) or placebo (sodium chloride 0.9%) intra-articular knee injection. During the visit, all participants will be invited to undertake the following assessments: (1) complete health questionnaires; (2) undergo QST; (3) MRI scan of the knee and brain; (4) perform a 6MWT; and (5) participants will then receive an intra-articular injection of bupivacaine or placebo into the index knee. Assessments will be repeated post intra-articular injection apart from the MRI scan of the knee.2010.1136/bmjopen-2023-072138.supp3Supplementary dataThe timings of the postinjection assessments were chosen based on the impact of the timing of bupivacaine administration on its analgesic effects. As the time to peak concentration is 43.4±23.1 min based on previous research using bupivacaine for peripheral analgesia,Questionnaires will be used to rate the pain severity and to evaluate psychosocial constructs. The questionnaires set include painDETECT,31At the end of the research visit, the participant will also be asked to fill in a custom-made questionnaire with open-ended questions intended to further investigate aspects of study feasibility and acceptability of the research methods.The self-paced 6MWT is aimed to be the functional outcome measure as it can assess the submaximal level of functional capacity. Participants will be requested to undertake a paced walk and are also allowed to stop and rest during performing the test. Participants will be asked to rate the level of knee pain ‘pain this instant’ before and immediately after the test finishes using the 0–100 VAS. The walking course of the 6MWT will be 30 m in length with a mark every 3 m.QST is a psychophysical technique evaluating sensory response to standardised mechanical or thermal stimuli. The study will use static pain parameters; pressure pain detection threshold (PPT), and dynamic parameters; temporal summation of pain (TSP) and conditioned pain modulation (CPM). Several lines of evidence suggest that QST can be used to phenotype OA pain based on mechanisms. Enrolled patients will undergo the following QST measures: PPT, TSP and CPM, which will be performed according to a standardised methodology10.1136/bmjopen-2023-072138.supp4Supplementary dataBupivacaine or sodium chloride 0.9% will be administered via the intra-articular route by a member of the research team  with appropriate competence in intra-articular injection and the recognition and management of the potential adverse effects. The injection will be carried out under aseptic conditions.For intra-articular injection, the injected volume of either bupivacaine 0.25% (5 mL) or sodium chloride 0.9% (5 mL) will be the same for each participant. Bupivacaine was selected for the intra-articular injection to achieve analgesia because this was shown in previous studies to significantly reduce knee pain in participants with knee OA 1 hour after injection.12 13The participants will also undergo a short structural MRI of the knee at 3 T in order to define synovitis, bone marrow lesions and other structural pathologies in the knee joint. MRI of the knee will be evaluated using the validated semiquantitative MRI Osteoarthritis Knee Score (MOAKS).35The participants will undergo a multimodal MRI scan of the brain at 3 T before and after the intra-articular injection. This study will use the functional MRI (fMRI) protocol from studies in pain imaging that can characterise spontaneous chronic pain.36–38The change in pain score using a 100 mm VAS during the 6MWT from baseline to 1 hour after intra-articular injection with bupivacaine or placebo.The change in pain score using the VAS at rest from baseline to 1 hour after intra-articular injection with bupivacaine or placebo.QST: the change scores of PPT, TSP and CPM from baseline to post intra-articular injection with bupivacaine or placebo.fMRI of the brain: the change in brain network activity from baseline to post intra-articular injection with bupivacaine or placebo.MOAKSFeasibility assessment: the number and percentage of eligible participants who are recruited and randomised to the study from the date of recruitment opening until the date of recruitment closing, as well as protocol completion rates and missing data rates.Feasibility assessment: evaluation of effective randomisation of participants to the study arms using a study-specific checklist and assessment of the randomisation protocol throughout the study.Feasibility assessment: a study-specific questionnaire will be administered to participants to assess the acceptability of the study at the end of the research visit.The collection, storage, processing and disclosure of personal information, data collection and management will comply with the requirements of the General Data Protection Regulation 2018. Handling of data will follow the policies and the procedures of the Sponsor (NUH NHS Trust) and the University of Nottingham. All personal data will be anonymised, and all further data analysis will be done without any reference to personal identifiable participant data.The trial conduct will be monitored by the Sponsor (NUH NHS Trust).Considering the feasibility nature of the study, no formal hypothesis tests will be performed to statistically compare the two study arms and descriptive statistics will be presented. Appropriate parametric or non-parametric statistics will be used according to the data characteristics.Summary statistics will be used to evaluate feasibility objectives such as the feasibility to recruit, timing measurements, to describe the sample and to inform the future main trial by providing power and sample size calculation. Participant acceptability feedback will be qualitatively synthesised using thematic analysis.Primary and secondary outcomes will be descriptively summarised by group as follows:Correlations between the change of pain score and QST measurements at baseline and after intra-articular injection with bupivacaine or placebo.Correlations between the change of pain score and brain network activity at baseline and after intra-articular injection with bupivacaine or placebo using predefined seeds in the pain processing regions.Correlations between the change of pain score and the level of joint damage quantified by MOAKS and measured at baseline.Estimates of between-group effect will be reported as estimates with 95% CIs without p values.In view of the exploratory nature of the study, missing data will not be imputed. The proportion of missing data for each outcome will be described.Differences in effects will be reported descriptively for primary and secondary outcomes between the following subgroups:Based on the stratification variable according to CAP-Knee Questionnaire scores with respect to whether pain is predominantly centrally or peripherally driven.The patients will be divided into responders and non-responders based on a cut-off value of ≥17 mm reduction in VAS post injection.39The study was deemed a low-risk study by the Sponsor (NUH NHS Trust). Adverse events will be recorded and reported according to the policies of the local Research Ethics Committee and NUH NHS Trust.40The study protocol and documents have been reshaped according to input received in two patient and public involvement (PPI) events via Pain Centre Versus Arthritis PPI advisory group. This advisory group was composed of people with OA who provided constructive feedback on the outcome measures and the study methods, which led to enhanced study design. The PPI will be maintained throughout the study and will help with dissemination of the study findings and outcomes to ensure a broader perspective.The study has been approved by the Nottingham Research Ethics Committee 1 (REC Reference: 20/EM/0287). The study results will be disseminated through peer-reviewed journals and communicated at scientific meetings and conferences. The results will also be presented in relevant patient websites. Authorship eligibility will be based on the recommendations from the International Committee of Medical Journal Editors (ICMJE).This feasibility randomised controlled trial will provide first proof of concept to a future main trial. The study has the scope to enhance the understanding of knee OA pain mechanisms and to pave the way for individualised treatment in knee OA.HRA approval has been obtained. Recruitment was initiated in late 2022.