Males that perceive their work as physical were more impacted by disability than pain intensity. Lower education level, lack of adaptive coping strategies and higher pain intensity were significantly associated with HRQoL being more impacted by pain perception. The identification of such classes allows for a better understanding of HRQoL dimensions and opens the gate towards optimized health-related quality of life evaluation and personalized pain management.Persistent Spinal Pain Syndrome Type 2 (PSPS-T2), (Failed Back Surgery Syndrome), dramatically impacts on patient quality of life, as evidenced by Health-Related Quality of Life (HRQoL) assessment tools. However, the importance of functioning, pain perception and psychological status in HRQoL can substantially vary between subjects. Our goal was to extract patient profiles based on HRQoL dimensions in a sample of PSPS-T2 patients and to identify factors associated with these profiles. Two classes were clearly identified using a mixture of mixed effect models from a clinical data set of 200 patients enrolled in “PREDIBACK”, a multicenter observational prospective study including PSPS-T2 patients with one-year follow-up. We observed that HRQoL was more impacted by functional disability for first class patients ( Persistent Spinal Pain Syndrome Type 2 (PSPS-T2) , also knPrevious research, investigating the relationship between quality of life and clinical outcomes in various pathologies, showed that pain intensity, psychological distress and functional disability were all correlated with HRQoL ,7,8,9. MThe identification of clusters can be performed using finite mixture models ,13,14. TThe main goal of this real-life prospective multicenter study was to identify, after 12-months of follow-up, different population subgroups based on the specific impact of pain intensity, functional disability and psychological distress on HRQoL in 200 PSPS-T2 refractory patients. Our secondary objective was to characterize these subgroups using clinical, psychological and social factors to refine the model of personalized medical management.https://clinicaltrials.gov/ct2/show/NCT02964130 (accessed on 15 March 2021).The data used for the purpose of this research consisted of PSPS-T2 patients included in the prospective, multicenter, observational PREDIBACK study. The primary objective of the PREDIBACK study was to characterize PSPS-T2 patients based on clinical, psychological and sociodemographic factors. Two hundred patients were consecutively recruited in the pain management department of 5 French centers  and monitored at baseline, 3-month, 6-month, 9-month and 12-month follow-ups. Patient recruitment started in January 2017 and was completed in March 2018. The study was approved by the ANSM (2016-A01144-47) and the Ethics Committee (CPP Ouest III) and declared at PSPS-T2 patients were identified at each site through standard clinical practice. To be eligible for this study, patients had to have had at least one spinal surgery, post-operative leg and/or low back pain for at least six months, and an average global pain score greater than or equal to 4 as measured by the Numeric Pain Rating Scale (NPRS). Patients at baseline were asked to report their average pain over a week on an NPRS scale . All the patients gave their informed consent before enrolment.Patients with one or several of the following criteria were excluded from the study: patient is or has been treated with spinal cord, subcutaneous or peripheral nerve stimulation or an intrathecal drug delivery system; has life expectancy of less than 12 months beyond study enrollment; patient is unable to undergo study assessments or to complete questionnaires independently; is a member of a vulnerable population; and investigator suspects substance abuse which might confound the study results.Patient professional activity was encoded as follows: patients were considered as (i) active when they were involved in professional activity at baseline assessment, (ii) inactive when they were retired, without any professional activity, or on sick leave, disability and long-term sick leave. There were no patients that were still students. Two patients were housewives and were considered as active. Furthermore, to identify active patients with arduous working conditions, they were asked to characterize their work as “physically demanding” or not.HRQoL was assessed by the EuroQol 5 Dimensions 5-Level questionnaire (EQ-5D-5L) . The quePain intensity was assessed using the NPRS  which isThe Oswestry Disability Index (ODI) questionnaire was used to assess functional disability . The ODIThe Hospital Anxiety and Depression Scale (HADS)  was usedThe French adaptation of the Coping Strategies Questionnaire (CSQ)  was usedStatistical analyses were conducted using the R software .Variables were described by their means (standard deviation) or by their number (percentage) depending on whether the variable was qualitative or quantitative.p-values < 0.05 were considered statistically significant.Missing values were not imputed, and data were analyzed according to an available-case principle. All tests were two-tailed and In order to assess the internal consistency of HADS, EQ-5D, and ODI questionnaires for PSPS-T2 population, Cronbach’s alpha and its confidence interval were calculated for each measurement questionnaire. Internal consistency measures whether several items from the same questionnaire measure the same general construct based on the amount of shared information. Internal validity of these questionnaires has never been studied for the PSPS-T2 population. Confidence intervals were estimated using the Bootstrap technique . A CronbIn order to estimate the correlations between our measurement variables, Pearson’s simple correlation was calculated between the different variable assessments at baseline and 12-month follow-up. Baseline and 12-month follow-up correlations were compared using a z-test after conducting Fisher transformation on the coefficients.Mixture of mixed effect models  were useAfter the classes and their respected effects were estimated, they were used as a binary dependent variable  to determine the impact of sociodemographic, psychological and cognitive-behavioral variables on class membership. Normality of distributions was verified using the Shapiro–Wilk test. Relationship between qualitative variables and class membership was verified using the Fisher exact test for non-ordinal qualitative variables and the Cochran–Armitage test for ordinal variables. The Wilcoxon rank-sum test was used to test the relationship between class membership and quantitative variables. NPRS, ODI percentage, HAD depression and anxiety scales, gender, level of education, CSQ catastrophizing, ignorance (ignoring pain sensation), reinterpretation (reinterpreting pain sensations), diversion (diverting attention from pain) and self-encouragement subscales, perceived arduous working conditions, and the interaction between gender and perceived arduous working conditions at baseline were included simultaneously in a logistic regression model in order to assess the adjusted effects of these variables on class membership . Model coefficients and their 95% confidence intervals were reported.We also studied the relationship between level of education, perceived arduous working conditions and coping strategy scores (Pearson correlation coefficients), in order to help us to interpret our bivariate and multiple regression results.Out of the 200 patients enrolled, 168 (84%) completed data at 3-month, 166 (83%) at 6-month, 145 (72.5%) at 9-month, and 146 (73%) at 12-month follow-up. Two patients completed only the sociodemographic and clinical data, but did not complete any of the evaluation questionnaires; therefore, they were used only for descriptive analysis and were removed from the other analyses. The relatively high percentage of dropout was due to the fact that the study was observational and the treatment the patients receive does not change whether they participated or not in the study.The assessment tools used in this study have shown acceptable to good internal consistency in our dataset with a Cronbach alpha of 0.693  for EQ-5D, 0.801  for the ODI, and 0.775  for the HADS scores.Correlations between different scores are presented in baseline = −0.35 and r12-month = −0.55, p < 0.0001), ODI score  and HADS depression score . ODI was moderately correlated with HADS depression score  and NPRS score . NPRS score was moderately correlated with HADS depression score . The correlation coefficients between EQ-5D index and NPRS score (p = 0.011), and ODI score (p = 0.019) significantly increased from baseline to the 12-month follow-up (p < 0.0001), the absolute difference in NPRS , and the absolute difference in depression HADS score .The EQ-5D index was significantly correlated at baseline and 12-month follow-up with NPRS (rollow-up . The absp < 0.0001). The ODI score had a greater impact on EQ-5D index  compared to the NPRS score  and the HADS depression score . The fixed effects of the NPRS and HADS scores and the ODI percentage explained 54% of the total EQ-5D index variance, while the entire model including both fixed and random effects explained 77% of the total EQ-5D index variance.p < 0.0001) and depression HADS score , whereas the effect was not significant for NPRS . Based on these results, the class 1 will be referred to as “disability class”.For class 1 patients, who comprised 68.7% (136/198) of the sample patients, the effects on EQ-5D index were statistically significant for the ODI score  and depression HADS score  had a significant effect on EQ-5D index, whereas the ODI score did not . Based on these results, the class 2 will be referred to as “pain intensity class”.For class 2 patients, who comprised 31.3% (62/198) of the study sample, the NPRS score . Furthermore, the NPRS score at baseline was lower in the “disability class” than in the “pain intensity class” . Baseline HADS anxiety score was also significantly associated with class membership showing that patients in the “disability class” presented higher anxiety levels at baseline than patients in the “pain intensity class” . The mean CSQ diversion score was significantly higher in the “disability class” than in the “pain intensity class” . Similarly, higher CSQ pain reinterpretation scores were observed in the “disability class” compared to the “pain intensity class” . Gender, age, pain duration, perceived arduous working conditions, ODI percentage, depression HADS score and CSQ catastrophizing, ignorance and self-encouragement scores had no significant impact on class membership in the univariate analysis (p > 0.22).Bivariate and multiple regression analyses results are presented in p = 0.029). On the other hand, ODI score and pain duration had no significant impact on class membership (p = 0.45 for ODI and p = 0.37 for pain duration).The multiple logistic regression analysis showed that patients with higher NPRS scores were more likely to belong to the “pain intensity class” compared to patients with lower NPRS . Neither age (p = 0.31), nor gender (p = 0.32), nor perceived arduous working conditions (p > 0.7) had a significant effect on class membership. However, the interaction between gender and perceived arduous working conditions had a statistically significant effect on class membership, showing that men who perceive their job as physical were more likely to belong to the “disability class” than to the “pain intensity class” .Regarding sociodemographic factors, patients in the “disability class” had higher mean educational level compared to the “pain intensity class” , and patients with higher HADS anxiety scores were more likely to belong to the “disability class” . We also found that the HRQoL of patients with higher self-encouragement coping scores were more likely to be in the “pain intensity class” than in the “disability” class . The remaining coping strategies were not significantly associated with class membership in multiple regression analysis .Regarding psychological factors and coping strategies, patients with higher HADS depression scores were more likely to belong to the “pain intensity class”  with an average of 10.91 ± 3.10 years of education in non-working patients (including retired patients), 10.42 years ± 4.67 in working patients who did not perceive their job as physical, and 10.92 ± 3.75 years in working patients who perceived their job as physical. Furthermore, statistical analysis did not show significant correlations between educational level and the different CSQ scores for catastrophizing , pain ignorance , pain reinterpretation , diversion  and self-encouragement  scores. We also observed moderate correlations between HADS anxiety score and CSQ catastrophizing score  and between HADS anxiety score and CSQ ignorance score . No significant correlation was observed between HADS anxiety score and diversion , reinterpretation  and self-encouragement  CSQ scores.The relationships between the different factors used in the multiple regression analysis showed that level of education was not significantly associated with perceived arduous working conditions . Sociological studies clearly indicated, based on the traditional model of masculinity, particularly present in individuals with lower education levels and a lower social gradient of health , that they traditionally have a more physically demanding work [The literature has shown that cultural and sociodemographic characteristics are related to how patients perceive their pain and to how much it impacts on their quality of life ,48,49. Iing work ,50. It cing work . Patienting work , the autAside from the relatively large sample size and the prospective design, the strengths of this study also included the novel application of model-based statistical clustering. This allows overcoming the use of subjective goal identification tools. When patients are asked about what impacts them the most, the majority of patients tend to aim for pain intensity relief, as they believe that functional improvement is a necessary following of pain relief . In our Despite the study strengths, some limitations must be considered. First, our study sample was exclusively drawn from a PSPS-T2 population, which did not allow us to extend our findings to the general pain population, including acute and chronic general or widespread pain and non-operated patients. Another limitation is that we focused solely on pain intensity, functional disability and depression when describing HRQoL. Although it is clear that these three components represent major dimensions of quality of life, having significant consequences on patient HRQoL, there are other chronic pain components, which we deliberately did not include in our study, such as expectations, social insecurity or lack of sleep, which might also contribute to building on a holistic HRQoL model. A new cohort study including patients with widespread acute and chronic pain, aiming to focus with more clarity on all dimensions of quality of life could yield more specific biopsychosocial clustering and optimized characterization of pain-related quality of life. Furthermore, we assume that the extension of this pilot work should be based on a larger cohort, as a prospective registry, to bridge this gap and address two specific goals—external validation and expansion of the results of this study—since there is an obvious lack in literature regarding how chronic pain patients belonging to distinct latent subpopulations are affected individually by different components of pain.From a clinical perspective, the identification of patient clusters, determined from their social and cognitive-behavioral characteristics, could help physicians to tailor personalized care, to propose “à la carte” programs and ultimately reinforce therapeutic alliance, thereby improving patient outcomes. Patients highly impacted by their functional disability could be preferentially oriented towards therapies and programs that have demonstrated a specific impact on disability, such as cognitive-behavioral-based physical therapies ,54, to cApplying a mixture of mixed effects models to data of chronic pain patients might lead to the development of new pain evaluation strategies and to better understanding of HRQoL dimensions. The results of this study can be considered as a starting point to refine a multidimensional, personalized, cluster-based, composite evaluation of HRQoL in chronic pain patients, which could impact on the optimization of pain management.


Rotation to BuNa in patients with CNCP and OUD was accompanied by reductions in (i) opioid misuse, (ii) opioid craving, (iii) the severity of co-occurring psychiatric symptoms, and (iv) self-reported pain. BuNa as opioid agonist treatment may therefore be a beneficial strategy in CNCP patients with OUD. The limited sample size and the observational nature of this study underline the need for the replication of the current findings in large-scale, controlled studies.Patients with chronic non-cancer pain (CNCP) often use opioids for long periods of time. This may lead to opioid use disorder (OUD) and psychiatric symptoms: mainly depression and anxiety. The current study investigated the effect of buprenorphine/naloxone (BuNa) rotation on opioid misuse, craving, psychiatric symptoms and pain in patients with CNCP and OUD. Forty-three participants with CNCP and OUD were converted from a full mu-receptor agonist opioid  to BuNa, in an inpatient setting. Opioid misuse, craving, co-occurring psychiatric symptoms, and pain perception were determined at baseline and after a two-month follow-up, using the following self-report questionnaires: Current Opioid Misuse Measurement (COMM), Visual Analog Scale (VAS-craving and VAS-pain) and Depression, Anxiety and Stress Scale (DASS), respectively. VAS-craving and VAS-pain were also determined immediately after conversion. A total of 37 participants completed the protocol. The mean COMM decreased from 17.1 to 6.7 (F = 36.5;  Worldwide there has been a marked increase in opioid prescriptions for chronic non-cancer pain (CNCP) since the mid-1990s . ParticuDespite the effectiveness of opioids as analgesics in severe acute pain, there is limited evidence for the long-term analgesic effects of opioids ,5. In adThe combination of prescription OUD and CNCP poses a clinical challenge since, on the one hand OUD requires the tapering of opioids, while on the other hand this might temporarily increase pain and craving, hindering the successful detoxification of opioids ,19,20,21n = 19) and did not distinguish between the conversion to methadone or BuNa. Finally, buprenorphine is a full kappa-opioid receptor antagonist, which has been associated with antidepressant and anxiolytic effects [Buprenorphine OAT, optionally provided as a combination therapy with naloxone, might be of specific interest for the treatment of patients with prescription OUD and co-occurring CNCP, given its pharmacological profile ,25. Bupr effects ,41,42,43 effects ,45,46. T effects ,49,50,51 effects .Since the effects of BuNa OAT on opioid misuse, craving and psychiatric outcomes have hardly been studied in CNCP patients with co-occurring OUD, the aim of the current study was to explore the effectiveness of BuNa in patients with CNCP and OUD. The primary objective was to study the effectiveness of BuNa in reducing opioid misuse and craving. Secondary objectives included exploring the effects of BuNa on the severity of co-occurring psychiatric symptoms and self-reported pain. Specifically, we tested the hypotheses that opioid rotation to BuNa: (i) reduced current opioid misuse, (ii) reduced opioid craving, (iii) improved psychiatric symptoms, and (iv) reduced self-reported pain.In this prospective, open-label, observational study, patients with CNCP and OUD were rotated in an inpatient setting from their full mu-opioid receptor agonist to BuNa. The regional medical ethical board approved this study (2015–1551) and all participants gave written informed consent.n = 43) with CNCP, who fulfilled criteria of chronic pain syndrome (longer than 6 months) and had a co-occurring prescription OUD according to Diagnostic and Statistical Manual of Mental Disorders 5 (DSM-5) [Participants ( (DSM-5) ,53, wereThe rotation from full agonist opioids to BuNa took place in an inpatient Medical Psychiatric Unit. In the first week of admission, long-acting morphine mimetics , if used, were switched to dose-equivalent, short-acting oxycodone. On the first morning of the consecutive week all short-acting oxycodone was stopped. After complaints of withdrawal arose, guided by the objective withdrawal scale (OOS) and subjective withdrawal scale (SOS) , the firSocio-demographic data  were collected on admission, as well as some baseline clinical data . Screening for current psychiatric disorders was performed using the Mini International Neuropsychiatric Interview (MINI-Plus) ,57 by trOpioid misuse was assessed using the Current Opioid Misuse Measure (COMM) ,60,61. TFurthermore, opioid craving was assessed as an index of opioid misuse severity, using a visual analog scale (VAS-craving). The VAS-craving was a quantitative measurement where the participant quantifies their current state of craving by marking a point on a scale form 0–100, with 0 as no craving at all and 100 as the most severe craving imaginable . VAS-craPsychiatric symptom severity was assessed using the Depression, Anxiety and Stress Scale (DASS) . The DASSelf-reported pain was measured using a visual analog scale (VAS-pain). Similar to the VAS-craving, the VAS-pain was assessed on a horizontal line, of which the left end of the scale represented “no pain” and the right end “the most severe pain imaginable”. Participants quantified their current pain intensity by marking a point (from 0 to 100) on the line . The VASAfter written informed consent, participants were planned for admission for opioid rotation to BuNa. Baseline measurements (T0) of COMM, VAS-craving, DASS, VAS-pain, OOS/SOS, and MINI-Plus were taken on the second day of admission, prior to any change in opioid use. During the rotation procedure, the measurements  were taken up to six times a day to facilitate dose titration of BuNa. Only the last measurement of the VAS-craving and VAS-pain before discharge (T1) was analyzed, in order to avoid state-dependent effects of the rotation on outcome measures. Two months post discharge follow-up measurements were performed (T2), including COMM, VAS-craving, DASS, and VAS-pain.In order to test our hypothesis, a per protocol analysis was used, given the small sample size and naturalistic explorative study design. Participants who still used BuNa at follow-up were considered completers. Descriptive data for continuous variables were presented as means and standard deviation (SD). Descriptive data for categorical variables were summarized by frequency and percentage. To answer our primary question, a univariate mixed model was performed with COMM scores as dependent variable, and time as a fixed factor (two levels). Subsequently, additional univariate mixed-model analyses were used to explore the effect of rotation to BuNa on craving (VAS-craving) and pain severity (VAS-pain), with time as a fixed factor with three levels. Finally, a multivariate mixed-model analysis was used to test the effects of BuNa rotation on the severity of psychological symptoms , with subscale (three levels) and time (two levels) as fixed factors. For all the mixed models, compound symmetry was used as covariance type. All statistical tests were carried out at the 0.05 level of significance using SPSS v.25 .p = 0.015). No other significant differences were found between dropouts and completers . Furthermore, the number of participants with current opioid misuse (COMM> 9) also decreased . After rotation to BuNa, craving levels reduced over time from 39.3 (SE = 4.23) at baseline, to 21.6 (SE = 4.34) after rotation and 5.3 (SE = 4.34) at follow-up . Post hoc analyses showed a decrease in craving levels from baseline to the final day of admission (T0-T1: p < 0.000), and from baseline to follow-up (T0–T2: p < 0.000).Secondary outcomes:After rotation from opioids to BuNa, opioid misuse, as indexed by the mean COMM score, decreased from 17.1 (SE = 1.40) at baseline, to 6.7 (SE = 1.45) at follow-up . Post hoc analyses showed a decrease in all the subscales of the DASS . Lastly, self-reported pain on the VAS-pain reduced from 51.3 at baseline to 37.2 at follow-up . Post hoc analysis showed that this was mainly driven by an improvement in self-reported pain from baseline to follow-up (T0–T2: p = 0.013).The severity of psychological symptoms on the DASS declined from baseline to follow-up  current opioid misuse, (ii) opioid craving, (iii) psychiatric symptoms, and (iv) self-reported pain. Thirty-seven of the 43 participants finished the trial. Patients dropping out was mainly due to the inadequate pain control of BuNa (four out of six participants). As hypothesized, the opioid rotation to BuNa reduced current opioid misuse and opioid craving, and improved psychiatric symptoms and self-reported pain. This suggests that opioid rotation to BuNa could have beneficial effects in patients with CNCP and OUD.n = 19), (ii) with participants showing higher baseline craving and (iii) could not distinguish between methadone and BuNa rotation. Furthermore, it should be noted that about one fourth of participants still exceeded the cut-off value for opioid misuse on the COMM at follow-up. This may indicate that after BuNa OAT some patients may still misuse opioids. Future studies should address how to support these patients in gaining control over their opioid use. In addition, future research might consider a broader assessment of opioid misuse. For instance, using biomarkers for the use of opioids (urine testing), or DSM-5 criteria for OUD.Our findings are in compliance with previous research, suggesting that buprenorphine  reduces opioid misuse and craving in people with OUD ,39,67,68A possible explanation for the observed reduced misuse and craving of opioids after rotation to BuNa might be due to the slower dissociation rate of buprenorphine, compared to most full mu-opioid receptor agonists . FurtherThe beneficial effects of rotation to BuNa on depression, anxiety and stress, as observed in the current study, are also in line with previous research, showing antidepressant properties of buprenorphine in patients with depression ,51, in pIt should be mentioned that, since four patients dropped out due to inadequate analgesia, the analgesic effects of BuNa rotation may be overestimated in the current study. In addition, participants who dropped out of the study showed higher baseline OME levels in comparison with the analyzed participants. This may indicate that participants with a higher OME at baseline are more likely to fail the conversion to BuNa. As can be seen in n = 37) and observational design, generalization of the study results is limited and prevents drawing firm conclusions regarding the effectivity of BuNa as OAT for patients with CNCP and OUD. Furthermore, with a follow-up period of two months, our study did not investigate the long-term potential of BuNa. Future randomized studies, with a larger study population, longer follow-up period and a control group, are necessary to confirm our findings. In addition, our study population consisted of mainly males (62.2%) and patients with nociceptive pain (54.1%). Future studies should evaluate whether our findings are also apply to females and patients with non-nociceptive pain.The current findings should be interpreted in the light of several study limitations. Due to the relatively small study population (It should be noted that opioids should preferably be discontinued in patients with CNCP. Some studies suggest that opioid tapering might be beneficial in CNCP patients . In methFinally, future research should also explore the beneficial effects of non-pharmacological interventions in patients with CNCP and OUD, for instance in addition to BuNa rotation. Cognitive Behavioral Therapy and Mindfulness are effective in reducing pain ,84,85 anIn conclusion, this prospective observational study showed that the rotation from full mu-opioid receptor agonists to BuNa had beneficial effects on opioid misuse, opioid craving, the severity of co-occurring psychiatric symptoms, and the pain perception of patients with CNCP and OUD. These findings suggested that BuNa rotation might be a valuable strategy in CNCP patients with OUD. Future studies should replicate these findings, and explore which patients benefit the most from rotation to BuNa, as 14% of our participants dropped out of the trial, mainly due to inadequate analgesia.


Study 2 (n = 39) was a 3-month double-blinded randomized trial comparing placebo to duloxetine, a dual serotonin–noradrenaline reuptake inhibitor. Across two independent studies, we found that patients with chronic pain present alterations in the functional circuit related to the serotonin transporter, when compared with age-matched healthy controls. Placebo responders in Study 1 presented with higher pre-treatment functional connectivity enriched by the dopamine transporter compared to non-responders. Duloxetine responders presented with higher pre-treatment functional connectivity enriched by the serotonin and noradrenaline transporters when compared with non-responders. Neurotransmission-enriched functional connectivity mapping might hold promise as a new mechanistic-informed biomarker for functional brain alterations and prediction of response to pharmacological analgesia in chronic pain.Chronic pain is a world-wide clinical challenge. Response to analgesic treatment is limited and difficult to predict. Functional MRI has been suggested as a potential solution. However, while most analgesics target specific neurotransmission pathways, functional MRI-based biomarkers are not specific for any neurotransmitter system, limiting our understanding of how they might contribute to predict treatment response. Here, we sought to bridge this gap by applying Receptor-Enriched Analysis of Functional Connectivity by Targets to investigate whether neurotransmission-enriched functional connectivity mapping can provide insights into the brain mechanisms underlying chronic pain and inter-individual differences in analgesic response after a placebo or duloxetine. We performed secondary analyses of two openly available resting-state functional MRI data sets of 56 patients with chronic knee osteoarthritis pain who underwent pre-treatment brain scans in two clinical trials. Study 1 ( et al. report that patients with chronic knee osteoarthritis pain show altered connectivity in functional circuits related to the molecular systems underlying pain regulation. The functional mapping of these circuits might hold promise as a new neuroimaging biomarker to predict analgesic response.Martins   Therefore, developing mechanism-based biomarkers that can guide analgesic treatment selection for chronic pain patients based on the prediction of treatment response remains an unmet target and a clinical need.Pain is a world-wide leading cause of disability, constituting one of the primary reasons for people to seek healthcare.12 Currently, it is generally accepted that chronic pain is a multifactorial entity entailing physical, psychological, emotional and social aspects.1 Preclinical studies have offered insights into key central mechanisms that might contribute to chronic pain, including sensitization phenomena in an array of nervous system pathways, imbalances in the facilitatory and inhibitory descending modulation pathways from the brain that regulate the transmission of noxious information in the spinal cord, neuroinflammation and glial dysfunction, among others.13–17 These findings have fuelled substantial interest in developing neuroimaging-based biomarkers that could unravel how chronic pain affects brain functioning and what form of brain pathophysiology in these patients can be targeted by different treatments.19 While a range of preliminary diagnosis, prognosis and treatment response brain biomarkers have been suggested , to date these biomarkers have provided minimal direct clinical application in the management of chronic pain patients.Part of this problem stems from our limited understanding of the neurobiological mechanisms underlying chronic pain and, hence, of the mechanisms through which most of these pharmacological treatments might produce persistent pain relief in chronic pain patients.20 However, neuroimaging-based biomarkers of brain function [i.e. such as those based on measurements of blood oxygenation level dependent (BOLD) signal]21 are not specific for any neurotransmission system, limiting the potential mechanistic understanding of how these biomarkers might contribute to explain treatment response. The same limitation applies to the potential neuroimaging biomarkers in unravelling functional changes in neuromodulatory pathways that could guide drug development or repurposing for patients with chronic pain.12Most pharmacological analgesic treatments target specific neurotransmission pathways. For instance, duloxetine, a dual antidepressant often used to manage pain in chronic pain patients, inhibits the reuptake of both serotonin and noradrenaline, increasing their bioavailability in the synapses.This study aims at advancing our understanding on the pain-induced functional alterations in the brain, exploring their link with the neurobiological processes underlying chronic pain and inter-individual differences in analgesic response to pharmacological treatment. Our main hypotheses are that (i) patients with chronic pain present functional alterations in key neurotransmission-related circuits associated with pain control and regulation, when compared with age-matched healthy controls (HCs) and (ii) pre-treatment inter-individual differences in the functional connectivity (FC) of these neurotransmission-related circuits can predict analgesia in response to placebo and pharmacological intervention.22 using the recently developed Receptor-Enriched Analysis of Functional Connectivity by Targets (REACT) multimodal framework  imaging.24 These data sets included HCs (n = 20) and patients with chronic knee osteoarthritis (OA) pain (n = 56) who underwent pre-treatment brain scans in two clinical trials. Study 1 (n = 17) was a 2-week single-blinded placebo pill trial. Study 2 (n = 39) was a 3-month double-blinded, between-subject, randomized trial comparing placebo (n = 20) to duloxetine (n = 19).To test these hypotheses, we performed secondary analyses of two openly available resting-state functional MRI (rs-fMRI) data setsramework ,23 whichBox 1Receptor-Enriched Analysis of functional Connectivity by TargetsREACT is a multimodal framework specifically developed to enrich the analysis of fMRI data with information on the spatial distribution of selected molecular systems, using molecular templates derived from PET and SPECT imaging. This integrated analysis allows us to identify functional networks associated with specific molecular systems and explain functional alterations in terms of the underlying molecular substrates of the brain.How it works: REACT is based on a two-step multivariate regression analysis performed at the subject level. In the first general linear model (GLM), the molecular templates are used as independent variables to inform the model on the spatial configuration of the neurotransmitters under investigation and estimate the dominant BOLD fluctuations of the functional networks related to each molecular system. Regions with high density of neurotransmitters will have a stronger weight in the estimation of the dominant BOLD fluctuation of the corresponding functional network when compared with the regions with lower molecular density. For example, the SERT, which has a high density in the basal ganglia and thalamic regions, will provide a SERT-related functional circuit where those regions will be key centres of the network. On the contrary, regions with a low distribution density of SERT will have a low contribution in the estimation of the functional circuit associated with this neurotransporter.In the second GLM, the dominant BOLD fluctuations estimated in the previous step are used as independent variables to assess the contribution of each voxel to each dominant BOLD fluctuation associated with the molecular systems under investigation. This analysis will return a set of functional connectivity maps, one for each molecular system being examined.Of note, while in the first GLM, the areas used as reference regions in the kinetic models for the quantification of the PET/SPECT images are discarded from the analysis because target density in those regions cannot be reliably measured, in the second GLM, every area is taken into account as the BOLD signal is reliably measured in every voxel of the brain. The regions excluded from the first GLM analysis can show either positive or negative functional coupling with the overall receptor-enriched functional network, depending on their positive or negative correlation with the dominant BOLD fluctuation.What it means: When the REACT-based functional maps are compared between groups , significant increases or decreases of functional connectivity in brain areas of the functional network related to a specific molecular system can be interpreted as an altered involvement of those areas to the normal functioning of the network. Therefore, this suggests a potential relationship of the functional alterations with the underlying mechanisms involving that molecular system.Template choice: Different types of molecular templates can be used in REACT, according to the specific hypotheses of each study and templates availability. To explore the brain mechanisms underlying a certain disorder, the distribution of neurotransmitter transporters might be more suited to capture the full architecture of a certain system than the distribution of specific receptors, which might not capture the complete picture of neurotransmission related to the specific system. In the case of a drug challenge targeting specific neurotransmitters, the optimal approach would be to use the maps of those specific receptors, if drug binding is known.26 Furthermore, they have also been implicated in placebo analgesia (i.e. dopamine and opioids)27 and correspond to the main molecular targets of duloxetine (i.e. SERT and NET),20 whose treatment response was effectively studied herein.We focused our analyses on the functional circuits related to the serotonin transporter (SERT), noradrenaline transporter (NET) and dopamine transporter (DAT), and the µ-opioid receptor, as general indicators of the regional distribution of the neurotransmission related to the serotonin, noradrenaline, dopamine and opioid systems, respectively. When available, the distribution of neurotransmitter transporters is better suited to capture the full architecture of a certain system than the distribution of specific receptors, which might not capture the full picture. We informed our selection of molecular targets by the fact that these neurotransmitters play pivotal roles in pain regulation, namely in those descendent modulatory pathways controlling the spinal transmission of nociceptive information.22 of patients with chronic knee OA pain who underwent pre-treatment brain scans in two clinical trials. The full details on demographics, inclusion and exclusion criteria have been provided in the original article.22 Here, we will simply present a brief summary to help the reader to contextualize. Study 1 was a 2-week single-blinded placebo pill trial where 17 patients with OA  ingested a lactose placebo pill once a day for 2 weeks. Study 2 was a 3-month double-blinded randomized trial in which 39 patients with OA ingested either placebo pills  or duloxetine  at a dose of 30 mg for the first week and escalated to 60 mg for the rest of the treatment period, except for the last week, when the dose was decreased back to 30 mg. In addition, Study 1 also included 20 age-matched HC subjects . Of note, the authors of this study were not blinded to the treatment arms.For this work, we used two openly available rs-fMRI data setsFor Studies 1 and 2, behavioural and clinical parameters were obtained before and after treatment, while brain scans were collected only before treatment. Patients were asked to discontinue their medications 2 weeks before the beginning of the trial and were provided with acetaminophen as rescue medication. All participants gave written informed consent to procedures approved by the Northwestern University Institutional Review Board Committee (STU00039556).a priori on an individual basis as at least a 20% decrease in VAS pain from baseline to the end of treatment period; otherwise, subjects were classified as non-responders. This threshold for analgesic response was chosen following the same procedure adopted by the previous study on these data sets.22 While the choice of this threshold is arbitrary, we note that a 20% reduction in VAS ratings of pain is higher than the 15% considered to be minimal clinically important.28 As a further reference, a 30% reduction in VAS ratings of pain is typically considered a clinical important pain diminution.29Patients from both studies completed a general health questionnaire, a Visual Analogue Scale (VAS) on a 0–10 scale for their knee OA pain, the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), the Beck Depression Inventory (BDI) and the Pain Catastrophizing Scale (PCS) (note we could only access the raw VAS and WOMAC data). All questionnaires were administered on the day of brain scanning. In Study 2, to partially compensate for regression to the mean effects, VAS was measured three times over a 2-week period prior to the start of treatment and after cessation of medication use, averaged, and used as baseline. Analgesic response was defined 2*-weighted echo-planar sequence .For all participants in Studies 1 and 2, imaging data were collected with a 3 T Siemens Trio whole-body scanner. A 3D T1-weighted anatomical scan was obtained for each participant using a Magnetization Prepared Rapid Acquisition Gradient Echo acquisition . Functional MRI data were obtained during rest using a multi-slice T30 non-brain tissue removal with the Brain Extraction Tool (BET),31 an initial spatial smoothing with a 6 mm full width at half maximum (FWHM) Gaussian kernel  and de-noising with an independent component analysis (ICA)-based Automatic Removal Of Motion Artifacts (ICA-AROMA).32 Additionally, subject-specific white matter (WM) and CSF masks, obtained from the segmentation of the subjects’ structural images and erosion to minimize the contribution of grey matter partial volume effects, were used to extract and regress out the mean WM and CSF signals from each participant’s pre-processed data set. A high-pass temporal filter with a cut-off frequency of 0.005 Hz was applied, followed by an additional spatial smoothing at FWHM = 6 mm, to obtain a final smoothing of the functional MRI (fMRI) images of ∼8 mm . A study-specific template representing the average T1-weighted anatomical image across subjects was built using the Advanced Normalization Tools (ANTs).33 Each participant’s data set was co-registered to its corresponding structural scan, then normalized to the study-specific template before warping to standard Montreal Neurologic Institute (MNI)152 space. Images were finally resampled at 2 mm3 resolution.The rs-fMRI data sets from Studies 1 and 2 were pre-processed using the FMRIB Software Library (FSL). Pre-processing steps included volume re-alignment with MCFLIRT,123I-Ioflupane SPECT images from 30 HCs without evidence of nigrostriatal degeneration.34 The NET atlas is a publicly available template of the [11C]MRB PET brain parametric maps from 10 HCs .36 The SERT atlas is a publicly available template37 of [11C]DASB PET images of 210 HCs from the Cimbi database.38 The µ-opioid receptor map is a publicly available template of [11C]Carfentanil PET images of 89 HCs (https://identifiers.org/neurovault.image:115126). All molecular atlases were normalized by scaling the image values between 0 and 1, although preserving the original intensity distribution of the images, and masked using a standard grey matter mask. Of note, for each atlas, we masked out the regions that were used as references for quantification of the molecular data in the kinetic models for the radioligands, namely the occipital areas for DAT, NET and µ-opioid receptor, and the cerebellum for SERT. Finally, we resampled the SERT image to have all atlases in standard MNI space with 2 mm3 voxel size.For the analysis with REACT, we used the templates of the molecular density distribution of the DAT, NET, SERT and µ-opioid receptor. The DAT map is a publicly available template of 24 In brief, the functional circuits related to the DAT, NET, SERT and µ-opioid receptor systems were estimated using a two-step multivariate regression analysis40 implemented with the fsl_glm command of FSL. In the first step, the rs-fMRI volumes were masked using a binarized mask derived from the molecular atlases to restrict the analysis to the voxels for which the density information of the neurotransmitter was available in the templates. Then, the molecular templates were used as a set of spatial regressors to weigh the rs-fMRI images and estimate the dominant BOLD fluctuation related to each molecular system at the subject level. Those subject-specific time series were then used as temporal regressors in a second multivariate regression analysis to estimate the subject-specific spatial map associated with each molecular atlas. The output consists of four maps per subject, each one reflecting the molecular-enriched FC associated with a specific neurotransmitter. At this stage, the analysis was conducted on the whole grey matter volume. Both data and the design matrix were demeaned (–demean option); the design matrix columns were also normalized to unit standard deviation with the –des_norm option.39A detailed explanation of the REACT methodology and its applications can be found elsewhere.1) and HC by running exploratory whole-brain two-sample t-tests, for each neurotransmission system separately, after controlling for age and gender. For this and all subsequent whole-brain analyses, we applied cluster-based inference within Randomise,41 using 5000 permutations per test and contrast, considering a cluster significant if PFWE < 0.05, corrected for multiple comparisons using the null distribution of the maximum cluster size across the image. We also applied the Bonferroni correction to correct for multiple comparisons across molecular systems and contrasts investigated. To validate the findings from the exploratory analyses, we then conducted hypothesis-driven analyses comparing patients with OA from Study 2 (OA2) and HC. We extracted the mean neurotransmission-enriched FC values in OA2 and HC from the clusters where we found significant OA1 versus HC differences and compared the two groups. For this and all subsequent hypothesis-driven analyses, we performed frequentist and Bayesian two-sample t-tests in SPSS (version 27), controlling for age and gender. Beyond the case–control group differences, we also investigated whether molecular-enriched FC in these clusters would be able to predict the pain ratings (VAS) at baseline in each of the two groups of patients using both frequentist and Bayesian Pearson’s correlations (bootstrapping 1000 samples) in SPSS.We first compared the FC associated with each neurotransmitter system between patients with OA from study 1  by testing whether FC predicts baseline VAS using frequentist and Bayesian Pearson’s correlations in SPSS.As a further check, we examined whether the molecular-enriched FC differences in OA2 for those systems showing significant FC differences between placebo responders and non-responders in OA1, extracting the mean neurotransmission-enriched FC values in the placebo OA2 sub-set from the significant clusters and performing two-sample t-tests in SPSS.We then performed a hypothesis-driven analysis in the placebo OA2 data, which allowed us to examine FC differences between responders and non-responders to placebo and duloxetine. For each functional circuit, we performed a two-way analysis of covariance (ANCOVA) in Randomise to interrogate an interaction effect between treatment type (duloxetine and placebo) and treatment response (responders and non-responders) on FC, controlling for age and gender. For each significant interaction, we extracted the mean FC values within the significant clusters and ran post hoc tests in SPSS to evaluate the simple main effects of treatment response within each group separately, controlling for age and gender. Levene’s test was also performed to check the homogeneity of variances. We also calculated frequentist and Bayesian Pearson’s correlations between the mean FC and baseline VAS in the placebo and duloxetine groups separately.Finally, we tested whether different patterns of pre-treatment FC related to neurotransmission underlie differences in response to different analgesic treatments. We investigated this question using the OA42: BF < 1/10, strong evidence for an alternative hypothesis; 1/10 < BF < 1/3, moderate evidence for an alternative hypothesis; 1/3 < BF < 1, anecdotal evidence for an alternative hypothesis; BF > 1, anecdotal evidence for the null hypothesis; 3 < BF < 10, moderate evidence for the null hypothesis; BF > 10, strong evidence for the null hypothesis.All Bayesian analyses were implemented in JAMOVI, using the default uninformative priors from the software. An increase in Bayes factor (BF) in our analyses corresponds to an increase in evidence in favour of the null hypothesis. To interpret BF, we used the Lee and Wagenmakers’ classification schemehttps://openneuro.org/datasets/ds000208/versions/1.0.0.43All MRI data of Studies 1 and 2 are available at 44 that can be downloaded from https://github.com/ottaviadipasquale/react-fmri.The code for performing the REACT-based fMRI analyses is now available as a python package22 on sociodemographic and clinical variables that might help to interpret our novel imaging findings. For a detailed description of sociodemographic and clinical variables, we refer the reader to the original article published elsewhere.22Here, we report in detail only the results of our analyses on molecular-enriched FC and summarize below some of the main findings from the original analysesIn Study 1, eight patients met the criteria for placebo response and nine patients were classified as non-responders. Responders and non-responders did not differ in baseline pain ratings, age, disease duration, depressive symptoms, pain catastrophizing or medication use at the entry of the study. In Study 2, from those allocated to placebo, 10 patients met the criteria for responders and the other 10 were classified as non-responders. From those allocated to duloxetine, 8 met the criteria for responders and 11 were classified as non-responders. Patients allocated to placebo did not differ in baseline pain ratings when compared with those randomized to duloxetine. In both groups, responders and non-responders did not differ in baseline pain ratings, age, disease duration, depressive symptoms or medication use at the entry of the study. However, in both groups, non-responders showed higher pain catastrophizing than responders. Both placebo and duloxetine produced significant reductions in pain ratings after 3 months of treatment; however, the extent of pain relief did not differ between those treated with placebo and those treated with duloxetine. The clinical variables of knee pain at baseline and pain relief  as measured with the VAS are reported in 45We used the templates of the molecular density distribution of the DAT, NET, SERT and µ-opioid receptor in the REACT analysis to estimate the corresponding molecular-enriched FC maps of these systems for every subject of the two data sets. In 1 and HC. We found significant differences in NET- and SERT-enriched FC (PFWE < 0.05) between the two groups   =  ], and increased SERT-related FC in four clusters including the superior and middle frontal gyri and precentral gyrus ; the frontal pole and middle frontal gyrus ; the frontal pole, frontal medial cortex and anterior division of the paracingulate gyrus ; the paracingulate and superior frontal gyri . We also found decreased SERT-enriched FC in the OA1 group in one cluster including the superior and middle temporal gyri, supramarginal gyrus and angular gyrus . Of note, only the increase in the SERT-enriched FC survived the Bonferroni correction for multiple comparisons across maps and contrasts. We did not find any group differences in the DAT- and µ-opioid-enriched FC.We investigated our first main research question by comparing the FC associated with each neurotransmitter system between OAo groups . Specifi2 and HC. The two-sample t-tests showed significant differences in SERT-enriched FC , which were similar in direction and magnitude to those observed when we compared OA1 and HC. This analysis identified a similar pattern of alterations in SERT-enriched FC across the two cohorts of patients with OA , but 0.0254 and 0.0557 times more likely in the contrasts HC > OA2 and HC < OA2 in the SERT-enriched FC , respectively.The results from the Bayesian analysis of the same data showed that the null hypothesis of a group difference in the NET-enriched FC between HC and OAOf note, we did not find a consistent pattern of association between NET- and SERT-enriched FC and pain intensity .1 differ in pre-treatment FC associated with any of the neurotransmitter systems we explored. We found that placebo responders, when compared with non-responders, showed significant increases in DAT-enriched FC in the central and parietal opercular cortex, Heschl’s gyrus, anterior division of the superior temporal gyrus, planum polare and planum temporale  and SERT-enriched FC raclopride to D2/D3 dopamine receptors in the basal ganglia, possibly reflecting increases in the release of dopamine in these regions.27 The same study also reported placebo-induced decreases in [11C]carfentanil binding to the µ-opioid receptors, pointing to engagement of the endogenous opioid system during placebo-induced analgesia. However, changes in [11C]raclopride binding in the nucleus accumbens emerged as the strongest predictor of placebo-induced analgesia, accounting for 25% of the variance alone. Another study has shown that individual differences in reward response can explain placebo-induced effects and expectations.72 The differences in DAT-enriched FC between patients who responded versus those who did not respond to administration of placebo reported here are broadly compatible with this idea. Assuming that higher DAT-enriched FC might be driven by strongest dopamine-related neurotransmission within the dopaminergic circuits (which we index here through DAT density distribution in the brain), then it is plausible that those patients with strongest dopamine-related neurotransmission might benefit the most from expectancy effects, which rely on dopamine release and are at the core of the placebo effect.Our second main finding was the observation that patients experiencing analgesia in response to a course of 2 weeks of placebo administration (Study 1) present higher pre-treatment DAT-enriched FC  than patients who did not respond. DAT-enriched FC was not related to disease burden prior to the start of placebo treatment in Study 1, diminishing the possibility that the measure is related to regression to the mean rather than a true placebo response. Furthermore, this difference is also unlikely to be confounded by differences between responders and non-responders in disease duration, depressive symptoms, pain catastrophizing or medication use since the groups did not significantly differ in any of these variables .74 Hence, it is possible that while inter-individual differences in DAT-enriched FC are particularly relevant to explain differences in short-term response to placebo, other mechanisms might be involved in the long term. Until further larger studies will revisit these findings, we urge for some caution when interpreting this association between pre-treatment DAT-enriched FC and placebo response. We also note the lack of differences between placebo responders and non-responders on µ-opioid-enriched FC, despite previous evidence that the endogenous opioid system is recruited during placebo-induced analgesia.27 However, as explained above, whether that might reflect the fact that FC was measured at rest or that some carry-over effects of previous analgesic treatments biased this result is unclear.This finding was nevertheless not replicated in the hypothesis-driven analysis on data from Study 2, where placebo responders and non-responders did not differ in pre-treatment DAT-enriched FC. The lack of between-group differences was supported by the Bayesian analysis, where the null hypothesis was 2.46 times more likely than the alternative hypothesis. We should highlight though that there is at least one important methodological difference between Studies 1 and 2 that could potentially account for this discrepancy. In Study 1, placebo response was evaluated after 2 weeks of placebo administration, while in Study 2, the placebo protocol lasted for 3 months. Studies have shown that the duration of administration is a determinant of placebo response.22 Altogether, these findings suggest that pre-treatment NET- and SERT-related FC at rest might hold promise as a biomarker for duloxetine analgesia response in patients with chronic OA pain.Our third key finding was the observation that patients who responded to duloxetine showed higher pre-treatment NET- and SERT-enriched FC (but not DAT- or µ-opioid-enriched FC) than those who did not respond, while in those patients allocated to placebo, we observed the opposite trend—i.e. lower pre-treatment NET- and SERT-related FC. NET-enriched FC was not related to disease burden prior to the start of placebo or duloxetine treatment, diminishing the possibility that the measure is related to regression to the mean rather than a true response. SERT-enriched FC was also not related to baseline pain ratings in the duloxetine group. Furthermore, these differences are unlikely to be driven by differences between responders and non-responders within each group in disease duration, depressive symptoms or medication use, since the groups did not significantly differ in any of these variables .20 The main mechanisms suggested to underlie the analgesic effect observed under duloxetine include enhancement of descending inhibitory pain pathways from the brain through potentiation of serotoninergic and noradrenergic transmission, with consequent inhibition of ascendant transmission of nociceptive inputs from the spinal cord20 .75 This mechanism has received indirect support from a previous study linking response to duloxetine in painful diabetic neuropathy to the integrity of the descending pain inhibitory pathways, as assessed by conditioned pain modulation.76 Therefore, the fact that only pre-treatment differences in SERT- and NET-enriched FC exist between duloxetine responders and non-responders matches the pharmacodynamics of the drug and aligns with the basic drug mechanisms through which most likely it induces analgesia. Based on this observation, we suggest that target-enriched FC mapping might open a new avenue in neuroimaging biomarkers of pharmacological treatment response in chronic pain, bringing the advantage of allowing to establish a clearer mechanistic link between the measured neuroimaging biomarker and the neurotransmission-related mechanisms through which a pharmacological treatment targeting a specific neurochemical system might induce analgesia. For instance, since duloxetine acts by inhibiting the reuptake of serotonin and noradrenaline, it is conceivable that its ability to enhance serotoninergic or noradrenergic transmission is moderated by the availability of these neurotransmitters in the synapses, promoting lower accumulation of serotonin/noradrenaline in those where synthesis capacity and tonic release is reduced. Following this line of thought, patients with lower bioavailability of serotonin/noradrenaline, which for this reason might show lower SERT- and NET-related FC connectivity, might not benefit from duloxetine treatment. We should highlight though that at this point any relationship between bioavailability of specific neurotransmitters and target-enriched FC remains speculative and will require validation in further studies.Duloxetine is a non-selective inhibitor of the reuptake of serotonin and noradrenaline, which enhances their bioavailability at the synaptic level.77 This superiority is thought to be linked to the fact that antidepressants which also increase the levels of noradrenaline by inhibiting NET might block the spinal transmission of nociceptive input directly through acting on spinal α2 receptors.20This empirical observation matches the clinical evidence that non-selective inhibitors of the reuptake of serotonin and noradrenaline might be superior to selective inhibitors of the reuptake of serotonin in promoting analgesia in patients with chronic pain.Our study has some limitations worth mentioning. First, although REACT improves the specificity of FC analysis, the approach remains relatively indirect and relies on molecular templates estimated in independent cohorts of healthy individuals. Therefore, further specification from intra-regional variation across patients is not possible using the current data set as it would require PET data for each ligand and patient. In any case, it should be noted that although the use of molecular templates of healthy subjects on clinical populations could be seen as a sub-optimal strategy, there would be at least two main disadvantages in using patient-specific templates. First, if the molecular data set used to create the template is not from the same patient cohort, changes in target density for that template might not overlap with the one of the data set under investigation due to factors that might differentially affect the molecular layer . Second, the functional networks estimated from such templates might not properly weight the contribution of the core regions of the molecular systems being examined, eventually resulting in a network that does not reflect the specific features of the molecular system. For these reasons, templates of healthy populations should be adopted in this kind of analyses.79 However, from the findings we gathered in this study, we suggest that future studies expanding this approach to other chronic pain populations and drug classes are worth investing and might be fruitful.The second limitation of our study is the relatively small sample size of both cohorts. This was in part mitigated by the fact that we attempted to replicate some of our findings in Study 1 using a second cohort of patients from Study 2. However, the issue of small sample sizes was even more prominent in the comparisons between responders and non-responders to placebo and duloxetine. Therefore, while our study provides an important proof-of-concept, future larger studies attempting to replicate our findings will be pivotal. Finally, our findings are restricted to patients with OA and to the prediction of placebo and duloxetine response in this group of chronic pain patients; hence, direct extrapolation to other chronic pain conditions or other pharmacological analgesics should be avoided. Indeed, chronic pain manifests in a range of clinical phenotypes; and even within the boundaries of a specific chronic pain syndrome such as OA, it is likely that different pathophysiological mechanisms are in play in different patients.80In conclusion, while further clinical validation in larger cohorts is warranted, this study shed light on the functional brain alterations induced by chronic pain and inter-individual differences in brain function that might underlie variability in the response to pharmacological analgesia. The mechanistic insights provided by the molecular-enriched FC mapping might help characterize chronic pain mechanisms, enabling rational and individualized treatment choice. Ultimately, these informed decisions might contribute to decrease unnecessary exposures of patients to ineffective therapies and undesirable side-effects, facilitate treatment adherence and accelerate pain control without long periods of treatment trial-and-error, decreasing the chance that the pain becomes intractable.fcab302_Supplementary_DataClick here for additional data file.


Video-assisted thoracoscopic surgery (VATS) is a minimally invasive procedure, but patients may still experience intense pain, especially during the early postoperative period. Intrathecal morphine (ITM) is an effective pain control method that involves a simple maneuver and has a low risk of complications. This study aimed to study the effectiveness of ITM for pain control in patients who undergo VATS.A randomized controlled study was conducted who were in ASA classes 1–3, aged over 18 years, and scheduled for elective VATS. Patients were randomized into two groups: the ITM group (n = 19) received a single shot of 0.2 mg ITM before general anesthesia; and the control group (n = 19) received general anesthesia only. For 48 hours after surgery, other than intravenous patient-controlled analgesia (IVPCA) morphine, patients received no sedatives or opioid medications except for 500 mg acetaminophen four times daily orally. Postoperative pain scores and IVPCA morphine used, side effects, sedation at specific time-points, i.e., 1, 6, 12, 24, and 48-hours and overall treatment satisfaction scores were assessed.p = 0.006) and differed at the first (7 [p = 0.007) and sixth hours (3 [p = 0.002). The cumulative dose of post-operative morphine (median [IQR]) in ITM group was also lower (6 ) in ITM group were significantly lower than control group (repeated-measure ANOVA, first (7 , 7 vs 8 first (7 , p = 0.0hours (3 , 5 vs 5 lower (6  vs 19 [1lower (6 , 28, p =ITM could reduce pain scores and opioid consumption after VATS compared to IVPCA-opioids. However, pain scores and opioid consumption still remained high. No difference in patient satisfaction was detected. Video-assisted thoracoscopic surgery (VATS), which is considered a minimally invasive approach, is widely performed in place of procedures that formerly required open thoracotomy , 2. Its http://www.clinicaltrials.in.th (TCTR20201005002). The study was retrospectively registered because it was not a requirement for obtaining study approval and miscommunication between study team. The authors confirm that all ongoing and related trials for this drug/intervention are registered.This study was a pilot prospective randomized controlled study conducted in Thai patients scheduled for elective VATS at Ramathibodi Hospital. The study obtained approval from the Committee on Human Rights Related to Research Involving Human Subjects, Faculty of Medicine, Ramathibodi Hospital . The first subject was recruited on August 17, 2015, and the final subject was followed up on May 12, 2016. The study was registered on the Thai Clinical Trial Registry (TCTR) at Inclusion criteria were patients undergoing elective VATS, who were aged over 18 years, and had an American Society of Anesthesiologists (ASA) physical status I to III. Exclusion criteria were unwillingness and/or inability to provide written informed consent to participate in the study, pregnancy, contraindication to spinal block, history of allergy to opioids, receiving opioid therapy for chronic pain, history of severe postoperative nausea and vomiting (PONV) that required treatment, history of previous surgical intervention at spinal T12–L5 level or significant spinal deformity, learning difficulties or communication problems, and retaining the endotracheal tube after the operation.http://www.randomization.com) with a block size of two. Assignments were made based on sequentially numbered randomization numbers on the randomization envelopes. Randomization envelopes were prepared and sealed by the independent person involved in the study. The study was a single-blind study. There was an inability to blind patients, surgeons, anesthesiologists, and inpatient care nurses/staff in the ITM group from administering ITM and the lack of intrathecal placebo in the control group. Only the outcome assessor, an acute pain nurse, was blinded to the group assignment.The eligible patients were randomized using the sealed envelope technique on the day of VATS into either Group 1 (ITM group), who received 0.2 mg ITM, or Group 2 (control group), who received intravenous (IV) patient control analgesia (IVPCA) morphine, at an allocation ratio of 1:1. The randomization scheme was generated by an independent person involved in the study  using the website, Randomization.com  at over 90%. IVPCA was then started using a patient-controlled anesthesia (PCA) device, programmed to deliver morphine at a concentration of 1 mg/ml, 1 mg/dose, and no basal rate, with lockout duration of 5 minutes. The limit for 4 hours was 40 mg. Other than IVPCA morphine, patients received neither sedatives nor opioids. During the postoperative period, all patients were given 500 mg acetaminophen four times daily orally for 48 hours. Oxygenation, ventilation and level of consciousness were monitored once every hour for the first 12 hours, once every 2 hours for the next 12 hours and once every 4 hours for the next 24 hours until 48 hours. All patients were encouraged by physical therapists to ambulate, as per the thoracic surgery protocol of the hospital.Patients were then transferred to a recovery room for close monitoring for 1 hour before being moved to the ward, in accordance with hospital protocol. All patients received an oxygen mask with a nebulizer flow of 8–10 L/min and fraction of inspired oxygen of 0.4 to maintain blood oxygen saturation  from 0 = no pain at all to 10 = worst possible pain imaginable, was used to measure pain intensity at the specific time-points. IVPCA morphine consumption and incidence of common side effects (PONV and pruritus) were also recorded at the same time points.PONV and pruritus were recorded simultaneously using a three-point ordinal scale . Patient sedation was evaluated using the five-point sedation Ramsay’s score   values < 0.05 were considered significant.All statistical analyses were carried out using STATA 15.1 . Descriptive statistic, i.e., frequency, means (±SD), median with interquartile ranges (IQR), and/or minimum and maximum (min-max) were used to described the data. Continuous data were compared using the Mann-Whitney test. Comparisons of categorical data were performed using chi-square or Fisher’s exact tests, as appropriate. Interval data (pain score and morphine consumption across time) were analyzed for between-group effects using a repeated-measures analysis of variance (repeated- measure ANOVA). Probability . None of the patients dropped out of the study . The demp = 0.006 and p = 0.029, respectively). The pain scores differed significantly 1 hour after VATS (median [IQR] (min-max): 7 [p = 0.007) and 6 hours (median [IQR]: 3 : 3 , 7 (2–9) vs[IQR]:n groups .p = 0.006). No difference in the time to first postoperative morphine administration was observed between the groups. The subgroup comparison of pain scores between tumor surgery  and pleurectomy showed no significant differences.The cumulative dose of morphine used within the first 48 hours post-operation in the ITM group was significantly lower than that in the control group (median [IQR] (min-max): 6 , 20 . However, there were no significant differences in the incidence of sedative effects or PONV. The incidence of pruritus was significantly higher in the ITM group than in the control group 6 hours  and 12 hours  post-operation  for two time points only, i.e., 1- and 6-hours post-operation. However, although scores were significantly lower in the ITM group than in the control group, pain scores remained high during the first hour following the operation. In the present study, we used 0.2 mg of ITM for post-VATS pain control, based on the study of Suksompong et al., which demonstrated that 0.2 mg of ITM was effective as same as 0.3 mg of ITM for postoperative pain control for standard thoracotomy with a similar degree of side effects [p = 0.029). The ITM group required less morphine for postoperative pain than did the control group for up to 24 hours; however, after 24 hours, both groups had similar morphine demands. These results are consistent with previous studies on ITM use in patients undergoing other minimally invasive cardiac surgeries [The study reported no differences between the two groups for factors that may impact pain scores and morphine requirements  , 34–38.  effects . This ma effects , 41; how effects –44. Althurgeries , 46 and urgeries , 48. A murgeries . Boussofurgeries . In thisurgeries –52. Seveurgeries –55. Our Pruritus is the most common adverse effect of ITM, with a reported incidence of 30%–100% . In the No patients in this study had respiratory depression, and the sedation scores were comparable across groups. Furthermore, ITM did not impact hospital stay duration or reoperation. In terms of patient satisfaction, a single dose of 0.2 mg ITM followed by IVPCA morphine provided the maximum satisfaction score for postoperative analgesia, although scores did not differ between groups. We did not identify the cause of patient dissatisfaction, whether by pain, nausea, pruritus, or other reasons. Therefore, the ITM technique is safe for VATS. Our study demonstrated that the ITM technique, a simple procedure with a low technical failure rate and low risk of serious complications, is suitable for incorporation into a multimodal analgesic scheme for postoperative pain control, especially during the first 24 hours following VATS.In terms of patient satisfaction, a single dose of 0.2 mg ITM followed by IVPCA morphine provided the maximum satisfaction score for postoperative analgesia; although scores did not differ between groups. We did not identify the cause of patient dissatisfaction, whether by pain, nausea, pruritus, or other reasons.No patients in the study had respiratory depression, and sedation scores were comparable across groups. Furthermore, ITM did not impact hospital stay duration or reoperation. Therefore, the ITM technique is safe for VATS. Our study demonstrated that the ITM technique, which is a simple procedure that has a low technical failure rate and a low risk of serious complications, is suitable for incorporation into a multimodal analgesic scheme for postoperative pain control, especially during the first 24 hours following VATS.We did not use an intrathecal placebo in the control group because of ethical reasons. Therefore, the patients, surgeons, anesthesiologists, and inpatient care nurses/staff were not blinded, which may introduce biases toward outcomes. The dose of 200 micrograms of morphine may be imprecision because the actual amount of morphine is very small and challenging to measure in routine clinical practice. Furthermore, various types of operations may induce different levels of pain severity, although we did not find differences in pain scores between operation types. Additionally, the number of portal incisions may impact postoperative analgesia after VATS –60, wherIn this present study, we did not perform covariate adjustment analysis due to the small sample size. We calculated the sample size based on pain scores only. A larger sample size and covariate adjustment are suggested for future study. The pain scores and the amount of IV morphine administration in this study were still high in both groups. Adding NSAIDs for future research may reduce pain scores and the amount of morphine in the patients receiving ITM. Finally, we assessed pain by asking patients to rate their overall pain. Although pain scores were lower in the ITM group, we did not assess whether this was regarding pain at rest or during movement, which is another limitation of the study. In addition, using the single-scale satisfaction measurement to evaluate the patient satisfaction may not precise as the method of multi-scale satisfaction. The study was retrospectively registered in the TCTR Database but the study was reviewed and approved by the hospital ethical committee prior to commencing the study.This study demonstrated that ITM reduced pain scores and opioid consumption in the first 24 hours after VATS compared to solely IVPCA-opioids. However, the pain scores and opioid consumption had still remained high in the ITM group and no difference in patient satisfaction was detected. These findings suggested that ITM should not be used as a sole method of analgesia but it may have an excellent opioid-sparing effect as part of multimodal analgesia management.VATS is a minimally invasive operation for various thoracic procedures. The advantages of this technique are fewer pulmonary complications, shorter hospital stays, and faster recovery compared with open thoracotomy. However, despite these distinct benefits, postoperative pain remains a significant concern. Although we have developed numerous methods for pain control following VATS, such as thoracic epidural, paravertebral, erector spinae, serratus anterior, and intercostal nerve blocks, these techniques require a high level of skill, additional training, and an ultrasound machine to perform the procedure.ITM is a cost-effective method for pain control without the need for additional training or expensive devices, especially during the first postoperative day following VATS. Not only is it simple but it also has a low risk of technical complications or failure. Moreover, it can provide analgesia without inducing motor and sensory deficits. Therefore, ITM should be considered as a suitable option for postoperative multimodal analgesia.S1 Dataset(XLSX)Click here for additional data file.


This study retrospectively studied the incidence of chronic post-surgical pain (CPSP) following single-stage implant-based breast reconstruction (IBBR) and evaluated the possible risk factors. This was a retrospective cohort study, involving all patients undergoing single-stage IBBR between January and December 2019. The follow-up was completed between January and March 2021. The scores for satisfaction (SS) were based on the BREAST-Q, while the pain burden index (PBI) was used to assess the degree of CPSP. The questionnaires were completed by 159 patients. CPSP occurred in 48.43% of the patients, 2.52% of them being severe cases. Significant predictors for the development of CPSP in the univariate analysis included severe acute postoperative pain (PP), a history of preoperative chronic pain, psychological disorders, SS with the reconstructed breasts, and whether there were any regrets about having had the reconstruction. Multivariate analysis identified severe acute PP (odds ratio (OR) = 2.80, 95% confidence interval (CI) = 1.16–6.79, p = 0.023), a history of preoperative chronic pain , and the SS  as being independently associated with the development of CPSP. In subgroup analysis, the PBI of the patients in the SS < 12 group (p < 0.001), the bilateral group (p < 0.01), and the severe acute PP group (p < 0.005) was significantly higher than the PBI of those in the control groups. This study demonstrated a significant incidence of CPSP following single-stage IBBR, and the patients with lower SS of their reconstructed breasts developed more CPSP. Lower SS, bilateral procedures, and severe acute PP were predictors of higher PBI.Trial registration: Registered in Chictr.org.cn registry system on 24 February 2020 (ChiCTR2000030139). With the increase in survivorship, more attention is now being paid to optimizing the quality of life. In line with this, surgical procedures have become less aggressive, with the move from radical mastectomy to modified radical mastectomy, to simple mastectomy, and to breast-conserving surgery, and from axillary lymph node dissection (ALND) to sentinel lymph node biopsy (SLNB), without impairment of the therapeutic effect. Today, direct-to-implant reconstruction (single-stage) following a mastectomy offers another choice to patients who do not have the opportunity to have breast-conserving surgery or are unwilling to conserve the breast due to the necessity of undergoing radiotherapy or the slightly higher incidence of local relapse. However, although women with breast cancer now have more opportunities to maintain their appearance, for many patients, intractable chronic post-surgical pain (CPSP) negatively impacts their quality of life.Breast cancer is the most commonly diagnosed form of cancer among women in China, affecting 304,000 patients per year2. In our previous study, we found that the rate of chronic pain after mastectomy is about 40–50%3. It was reported that for patients receiving single-stage implant-based breast reconstruction (IBBR), no more incidence of CPSP was found4. However, studies on CPSP in patients with single-stage IBBR have often had a very small sample size, and there has been no separate analysis of patients who received a tissue expander and those who had an implant. Apparently, it is not precise to calculate the incidence of CPSP of these two different surgical procedures together.CPSP is reported to be one of the most serious problems for patients who have survived breast cancer. The pathogenesis of CPSP is complicated and needs elucidation, and no effective treatment methods are currently available. Post-mastectomy pain has been estimated to affect 20–50% of patientsThere is a surgical team at the Cancer Hospital of the Chinese Academy of Medical Sciences, Beijing that specializes in single-stage IBBR for women with breast cancer. Owing to the depth of their experience in single-stage IBBR and the large sample size, it was decided to retrospectively study the incidence of CPSP following single-stage IBBR and evaluate the possible risk factors, including the size of implant, postoperative complications, whether a biological matrix was used, whether patients regretted having the IBBR, and their scores for satisfaction (SS) with the reconstructed breasts, all of which have been rarely mentioned in previous studies.This was a retrospective cohort study. All patients who underwent single-stage IBBR at the Cancer Hospital of the Chinese Academy of Medical Sciences, Beijing, between January and December 2019 were included. The female patients, aged between 18 and 60, were identified for inclusion in the study and attended follow-ups between January and March 2021. This study was approved by the Ethics Committee of National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences. Electronic medical records were reviewed, and the patients’ details were collected including age, body mass index (BMI), menstrual status, history of psychological disorders, history of preoperative chronic pain, the severity of postoperative pain (PP), type of surgery, whether a biological matrix was used, the size of implant, whether they had unilateral or bilateral single-stage IBBR, axillary interventions including SLNB and ALND, and the duration of surgery and anesthesia. The incidence of adjuvant therapy, namely radiation therapy, chemotherapy, and endocrinotherapy, was also documented.All the surgical procedures were performed by the same surgical team using the same standardized techniques. All patients received IBBR right after mastectomy, and biological matrixes were used in some of them. The technique for single-stage IBBR with a biological matrix was to release the inferior origin of the pectoralis major muscle and create a subpectoral pocket. The biological matrix, which was tailored according to the individual case, was fixed to the chest wall to cover and support the lower and lateral areas of the implant and was used to completely close the pocket due to the insufficiency of the pectoralis major muscle. The implant and biological matrix were infiltrated with an antibiotic solution for at least 10 min  before the submuscular IBBR.Standard general anesthesia was induced using sufentanil 0.3–0.6 μg/kg, propofol 1–2 mg/kg and cisatracurium 0.2–0.4 mg/kg. After laryngeal mask airway insertion, the patients were mechanically ventilated to maintain the end-tidal carbon dioxide concentration at 35–45 mmHg with a fresh gas flow of 2 L/min 60% oxygen. Anesthesia was maintained by constant inhalation of 1.5–2.5% sevoflurane and a constant infusion of remifentanil at a rate of 0.1–0.2 μg/kg/min. Sufentanil 0.1 μg/kg was added intraoperatively as required. At the end of surgery all patients received 100 mg of flurbiprofen. For patients whose visual analogue scale (VAS) was ≥ 4 within 48 h after the operation, the same dose of flurbiprofen was repeated.5. The follow-up survey collected data concerning the development of CPSP, including its onset, location, frequency, and intensity, as well as therapeutic interventions and postoperative complications. All patients attended follow-ups between January and March 2021. They completed questionnaires about breast satisfaction and determined CPSP and pain burden index (PBI) at the same time intervals.CPSP was defined as: (1) pain developing or increasing in intensity after a surgical procedure. (2) Pain duration of at least 3–6 months. (3) Pain is either a continuation of acute post-surgery pain or develops after an asymptomatic period. (4) The pain is either localized to the surgical field, projected to the innervation territory of a nerve situated in the surgical field, or referred to a dermatome. (5) Other causes of pain should be excluded, e.g., infection or continuing malignancy6, and the questionnaires were completed online or by phone. PBI was calculated using data collected in the questionnaire. It was calculated by adding the pain severity scale (0–10) from the anatomic locations of the breast, axilla, chest wall, and arm, and multiplied by the frequency of pain at each site . The VAS level of immediate PP has been recorded carefully by a nurse from the Department of Anesthesiology. VAS ≥ 7 was defined as severe PP. Psychological disorders, including emotional distress, depression, anxiety, and anger, were assessed using short-form instruments from the Patient-Reported Outcomes Measurement Information System (PROMIS). Alcohol excess was defined as drinking more than 100 g of alcohol/day longer than 3 years.The satisfaction that patients felt about their reconstructed breasts was evaluated using the BREAST-Q (BREAST-QTM-BREAST CANCER CORE SCALE VERSION 2.0.) The satisfaction scale used four questions: How do your breasts look when you are dressed? Do you feel comfortable in your bra? Can you wear tight-fitting clothes? How do your breasts look when you are naked? The highest SS was 16, while the lowest was 4, and the higher the score, the greater the level of satisfaction. Although the physical well-being section in the BREAST-Q contains items concerning pain or other uncomfortable feelings, it cannot be used to evaluate pain intensity. Therefore, in this study, the CPSP data were collected using the breast cancer pain questionnaire first developed by Gartner et al.Statistical analysis was performed using SPSS version 21.0. Data were presented as mean ± standard deviation. Risk factors for the development of CPSP were compared using logistic regression. Multivariate logistic regression was performed for the selected variables. Odds ratios (ORs) were reported with a 95% confidence interval (95% CI). As the highest SS was 16, and the patients whose SS was ≥ 12 were ordinarily more satisfied with their breasts than those with SS < 12, we divided the patients into the SS ≥ 12 vs. SS < 12 groups to compare their PBIs. Besides, the PBIs of the other subgroups, including the unilateral vs bilateral groups, the severe acute PP vs non-severe acute PP groups, and the history of chronic pain vs no history of chronic pain groups, were also compared using a Mann–Whitney U test. A significance of p < 0.05 was used.This article does not contain any studies with animals performed by any of the authors. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.Informed consent was obtained from all individual participants included in the study.The study involved 182 patients who underwent single-stage IBBR between January and December 2019. One patient, who died from metastasis, was excluded from the final analysis. The questionnaires were completed by 159 patients. The baseline characteristics of the participants are summarized in Table CPSP occurred in 48.43% of the patients in this cohort Table . The amoUnivariate analysis of all the patient characteristics was performed to identify variables associated with the development of CPSP. The factors identified as having an increased risk of CPSP included severe acute PP, a history of preoperative chronic pain, and psychological disorders Table . As wellThe significant variables from the univariate analysis were included in the multivariate analysis Table . Severe In the subgroup analysis, the patients were divided into the SS ≥ 12 vs. SS < 12 groups, unilateral vs bilateral groups, severe acute PP vs non-severe acute PP groups, and a history of chronic pain vs no history of chronic pain groups. The PBI of all the subgroups was compared, and the data is presented in Fig. This study showed that 48.43% of the patients who received single-stage IBBR following mastectomy developed CPSP and 2.52% were severe cases. Moreover, the patients who had lower SS developed more CPSP. Severe acute PP, a history of chronic preoperative pain, regretted having single-stage IBBR, and psychological disorders were also proven to be risk factors of CPSP, while lower SS, bilateral procedures, and severe acute PP were predictors of higher PBI.7. However, even in severe cases, no one in this study got treatment for pain because they considered that it was inevitable following breast cancer surgery, so they simply tolerated it.Wink et al. found that, according to the National Surgical Quality Improvement Program database, the overall incidence of complications in 1,612 one-stage alloplastic reconstructions was 9%, whereas the incidence was 8.2% in this study. As the average age of patients with breast cancer is falling in China, more patients who have no chance of breast-conserving surgery are likely to consider single-stage IBBR. However, the incidence of CPSP after surgery has not been well-researched yet. At the same time, there is not enough awareness of the potential for treating CPSP, which means that the quality of life of some patients with CPSP is being unnecessarily neglected. There were 2.52% severe cases of CPSP (VAS ≥ 7) in this study, which was similar to the 2.1% reported by Roth9. This is likely to have led to a degree of inaccuracy because reconstructing with a tissue expander or an implant involves two different kinds of procedures, whereas this study enrolled 159 patients who all received single-stage IBBR. Moreover, all the cases were recruited within 1 year, and their operations were performed by the same specialized surgical team, which means that the changes in operational methods and differences in operational skills were comparatively few.This study assessed the risk factors of CPSP following single-stage IBBR, including a history of chronic preoperative pain, acute PP, BMI, and age, as well as factors that were rarely investigated previously, namely SS, postoperative complications, the size of the implant, whether a biological matrix was used, and whether patients regretted having the IBBR. Table 13, CPSP was proven to be significantly related to a history of chronic preoperative pain, psychological disorders, and severe acute PP, while lower SS, and regret for having had the IBBR were also found to be connected with higher incidence of CPSP. This result is a reminder to surgeons and anesthesiologists that it is important to communicate adequately with patients and let them make decisions after full consideration, and that it is essential that they not only understand the risk of developing CPSP after surgery, but they are also aware that it can be treated. In addition, increasing the patient’s SS with the reconstructed breast might help control CPSP. This would be a different approach from the situation at present, where CPSP management has substantially contributed to the current opioid crisis14. In this study, none of the patients had ever sought treatment, even for severe pain, which indicates that the issue of CPSP after breast cancer surgery has greatly been ignored by patients and healthcare workers alike in China. It is the responsibility of surgeons and anesthesiologists to educate patients and inform them that CPSP is a problem that can and should be treated.Consistent with previous studies15. Or thirdly, patients with lower SS developed more psychological distress caused by an unexpected appearance, which predisposed them to develop CPSP more easily16.How to explain the phenomenon that the lower SS was associated with a higher incidence of CPSP? Firstly, low SS might be associated with a lack of sensation and physical feeling and poor sexual and poor physical well-being, which could negatively influence self-confidence and self-identity, and meanwhile increase the incidence of CPSP. Secondly, patients had different cultural and educational backgrounds, which means they had different cognitive levels. Those who had more positive cognition tended to achieve higher SS and had fewer incidences of CPSP18. Although it has been reported that regional anesthesia  did not reduce the frequency and severity of CPSP in breast cancer patients19, regional anesthesia technique is still a feasible option for CPSP treatment. Medicines, including opioids, non-steroidal anti-inflammatory drugs, anti-depressants, anti-epileptics, etc., might be effective. Physical therapies such as massage and thermal therapy might help. However, further research is warranted to study the prevention and treatment of CPSP in the future. Recently, the study by Caputo et al. reported that prepectoral implant positioning improved the level of SS with breast appearance and reduced the intensity of immediate PP, which provides patients willing to receive IBBR an alternative for CPSP prevention20. Regional nerve blocks such as intercostal nerve blocks were reported to be an effective way to control immediate PP22, as severe PP was one of the risk factors of developing CPSP, so reginal nerve blocks might have potential effects in CPSP prevention.For the treatment of CPSP, the development of transitional pain services, which identifies patients at risk and treats them early in a multidisciplinary approach, is suggestedThis study does have several limitations. First, it is a single center retrospective study with recall bias. Data collection was limited to the information present in the electronic medical records. The number of patients undergoing bilateral single-stage IBBR was too small for meaningful statistical analysis. However, seven out of nine patients who received bilateral single-stage IBBR developed CPSP, which suggested that bilateral IBBR might be one of its risk factors, which needs further elucidation in the future. Performing prophylactic single-stage IBBR following a mastectomy is not advisable, because CPSP might become a serious problem. Second, in our hospital, there is a specialized surgical team responsible for performing breast reconstruction surgery. In this study, we have enrolled only the patients from this surgical team to minimize surgical technique related bias. Therefore, we conducted a single-arm cohort study, and no control patients receiving mastectomy without immediate breast reconstruction were included.In conclusion, this study demonstrated a significant incidence of CPSP following single-stage IBBR. It was possible to identify patient-specific characteristics associated with an increased risk of CPSP. Patients who have a lower SS developed more CPSP, and it is clear that lower SS, bilateral procedures, and severe acute PP are predictors of higher PBI. Although nearly half of the patients in this study experienced CPSP, none of them had ever pursued treatment. Both anesthesiologists and surgeons should be encouraged to counsel patients on the course and risks of CPSP following single-stage IBBR, and they should be made more aware of the potential need to solicit aggressive CPSP management for symptomatic women.