Duloxetine effectively treats aromatase inhibitor-associated musculoskeletal symptoms (AIMSS) in women with breast cancer but causes low-grade toxicities. This secondary analysis examines the relationship between adverse events (AE) and patient-perceived benefit, based on patient self-report that the treatment received was beneficial despite side effects. We hypothesized that duloxetine had a favorable effect on patient-perceived benefit, even among duloxetine-treated patients who experienced AEs and who, had they been treated with placebo, would have experienced none.Principal stratification was used to estimate the effect of duloxetine vs placebo on patient-perceived benefit and Functional Assessment of Cancer Therapy-Endocrine Scale functional quality of life in the randomized, double-blind trial SWOG S1202 (n = 289). Subgroups of patients were defined by observed and counterfactual (what would have occurred had they been randomly assigned to the opposite study arm) experiences of AEs and the original primary outcome, reduction of average pain after 12 weeks of at least 2 points on the Brief Pain Inventory-Short Form.Duloxetine caused an estimated 23.4%  of patients to experience an AE even though they would have experienced none on placebo. Those patients remained more likely to report that their received treatment was beneficial than comparable patients assigned placebo , although there was no statistically significant effect of duloxetine on functional quality of life .Duloxetine resulted in higher patient-perceived benefit, even among those who would have an AE on duloxetine but none on placebo. Treatment of AIMSS with duloxetine should be considered for appropriate patients. Aromatase inhibitors (AIs) are an effective treatment for hormone receptor–positive early-stage breast cancer . HoweverDuloxetine is a serotonin-norepinephrine reuptake inhibitor used for the treatment of depression and anxiety, as well as several chronic pain conditions, including chronic musculoskeletal pain, but is not Food and Drug Administration–approved for AIMSS . The SWODespite efficacy of duloxetine in treating AIMSS, widespread use may be limited by the association of duloxetine with an increased rate of adverse events (AEs). In S1202, patients randomly assigned to duloxetine had higher rates of AEs of any grade compared with placebo (78% vs 50%) . HoweverIf it is assumed that duloxetine causes but does not prevent AEs, many patients would have had AEs regardless of treatment assignment , potentially because of the specific population studied or the context of the trial, or would have had no AEs regardless of treatment assignment . Only the difference in AE rates between treatment arms would be attributed to duloxetine (28%). It is meaningful to know whether the difference in rates of patient-perceived benefit was solely because of pain reduction when treatment assignment did not influence whether they experienced AEs, or if—even among patients for whom assignment to duloxetine caused them to have an AE when they otherwise would not have—the reductions in pain outweighed the AEs to the extent that they resulted in a higher rate of patient-perceived benefit from treatment.Previous reports from the S1202 trial do not fully describe the relationship between AEs and patient-reported outcomes such as reductions in pain, patient perception of benefit, and functional quality of life (FQOL). It is not known whether those who experienced AEs were more likely to report positive outcome or whether duloxetine caused positive outcomes in those patients who would experience an AE on duloxetine but not on placebo. We hypothesized that AEs would be positively correlated with pain reduction within each treatment group and that duloxetine would have positive effects on patient perception of benefit and FQOL even among patients who would experience an AE on duloxetine but not on placebo.After obtaining a letter of exemption from the Ohio State University institutional review board, data were obtained from the National Clinical Trials Network [NCTN]–National Cancer Institute Community Oncology Research Program (NCORP) Data Archive of the National Cancer Institute’s (NCI’s) NCTN. Data were originally collected from the SWOG S1202 clinical trial NCT01598298. A description of the trial, including complete eligibility criteria and study design, has been published previously .The S1202 trial was approved by the institutional review boards of the participating institutions. Postmenopausal women who had been receiving AI therapy for at least 3 weeks and no more than 24 months, and with average joint pain of at least 4 out of 10 on the Brief Pain Inventory (BPI)  that eitPatients were randomly assigned 1:1 to receive duloxetine or placebo. Patients assigned to duloxetine received 30 mg daily for 1 week followed by 60 mg daily for 11 weeks. Patients assigned to placebo received matching sugar capsules. Patients and physicians were blinded to treatment allocation. Patients completed questionnaires at baseline and at 2, 6, 12, and 24 weeks.Patients were classified as having an AE if they reported an AE of any grade as defined by the S1202 protocol  other thAt week 12, patients were asked to classify the received blinded treatment as beneficial with limited or no side effects, beneficial despite side effects, not worth the side effects, or not yielding improvement in symptoms. We define patient perception of benefit as “beneficial” if the patient stated that the treatment was beneficial with limited or no side effects or beneficial despite side effects. Participants who declared “none of the above” or “prefer not to answer” were classified as not reporting a perceived benefit. Patients were also asked whether they believed they had been receiving duloxetine or placebo.FQOL was assessed via the Functional Assessment of Cancer Therapy-Endocrine Scale (FACT-ES) . Change Of the 299 participants randomly assigned in S1202, 289 were eligible for the trial, and of those, 141 in the duloxetine group and 144 in the placebo group had complete baseline data see . BaselinAll analyses were performed using R (version 4.0.2). The primary analysis was restricted to patients with all included baseline variables measured (n = 285). Missing values of AE occurrence  and pain reduction  were imputed using Bayesian multiple imputation with a multinomial logistic regression model with vague priors (Gaussian with mean [SD] = 0 [10]) to allow the use of available baseline and other outcome data under the missing-at-random assumption. Credible intervals (CI) were constructed at the 95% level.The primary prespecified aim was to determine the effect of duloxetine on patient perception of benefit within strata defined by observed and counterfactual outcomes in adverse events and reductions in pain. Because the counterfactual outcomes are not observed, patients cannot be classified into strata based on observed data alone; thus, traditional methods for stratified data, such as the Cochran-Mantel-Haenszel test, cannot be used. We define basic principal strata  as subgrt statistics comparing covariate means between treatment arms within each stratum were used to confirm successful balancing of covariates by the principal score model.We adopt a commonly used assumption of monotonicity: if a patient would experience an AE on placebo, then they would also experience an AE on duloxetine, and similarly for reductions in pain. This assumption allows us to estimate the likelihood that each patient belongs to principal strata using the principal scores technique : we trait tests and χ2 tests for marginal comparisons and linear and logistic regression for baseline-adjusted comparisons, as appropriate for the type of outcome. All frequentist tests were 2-sided, and a P value of less than .05 was considered statistically significant. All credible intervals were 2-sided, and differences for which the 95% credible intervals did not contain the point of no difference  were considered statistically significant.The secondary prespecified aim was to determine the associations of AEs and positive patient-reported outcomes within each treatment group. We stratify by treatment group and compare positive patient-reported outcomes between those who reported AEs and those who did not using Of the 279 eligible patients evaluable for AEs, 108 (78.3%) in the duloxetine arm and 68 (48.2%) in the placebo arm experienced at least 1 AE other than arthralgia. When group assignment affects neither AE status nor pain reduction status , there is little evidence of a treatment effect on patient perception of benefit, except among patients who would never have an AE but always a reduction in pain (stratum NA), for whom there was a 25.9 pp difference (95% CI = 1.7 to 47.3 pp) in perceived benefit. When assignment to duloxetine causes a reduction in pain, it has a positive effect on patient perception of benefit regardless of whether the patient would have no adverse events on either duloxetine or placebo (stratum ND) , an AE on duloxetine but not placebo (stratum DD) , or an AE on either (stratum AD) . Among patients for whom duloxetine but not placebo causes an AE, assignment to duloxetine has a positive but smaller effect on patient perception of benefit even when patients would have had a reduction in pain in either arm (stratum DA)  or in neither arm (stratum DN) . Credible intervals adjusted for multiple comparisons excluded 0 for all statistically significant results described above except for those in strata NA and DN. There are no statistically significant effects on FQOL in strata defined by the combination of AE and pain reduction statuses alone  or in stWithin duloxetine and placebo groups separately, the occurrence of an AE was not associated with any patient perception of benefit, belief of randomization to duloxetine, reduction in pain, or FQOL, with or without adjustment for baseline variables. A large proportion of patients assigned to placebo reported that their received treatment was beneficial. The AEs experienced in either arm were generally low grade, and a placebo effect may have resulted in a reduction in mean pain over time and therefore perceived benefit in both arms. Thus, a comparison of rates of patient-perceived benefit between arms is critical. Furthermore, many patients would have had an AE regardless of treatment assignment or would have had no AEs regardless of treatment assignment. Thus, a complete evaluation of the benefit-risk trade-off requires comparisons of rates of patient-perceived benefit among those who would have AEs on duloxetine but none on placebo.The proportion of patients reporting that the reductions in pain experienced outweighed side effects (if any) was higher in the duloxetine arm than in the placebo arm. This difference was not driven solely by patients for whom duloxetine caused a reduction in pain but no AEs, as a favorable treatment effect was present even among patients who would have had AEs on duloxetine but none on placebo. Notably, a larger proportion of patients in the duloxetine arm than in the placebo arm reported that their received treatment was beneficial, even among patients for whom duloxetine would cause an AE but not a clinically significant reduction in pain. This result may be because of a type of placebo effect: patients who experience no AE and no pain reduction on control do not perceive a benefit, whereas those who experience an AE under duloxetine believe they are receiving the active treatment and expect and eventually report a benefit. This hypothesis is supported by the close relationship between treatment effects on perception of benefit and belief of randomization to duloxetine, although the direction of causation is not identifiable from these data.These new analyses of the SWOG S1202 trial data provide evidence of a more universal benefit of duloxetine for the treatment of AIMSS with respect to patient-perceived benefit. Even among patients who would experience AEs on duloxetine but not on placebo, the benefit–-risk trade-off appears favorable to duloxetine. However, additional barriers to this use of duloxetine remain, including potential interactions with other drugs  and stigThe results of the analyses presented here are subject to a few important limitations. First, only 75% of the patients eligible for the trial and randomly assigned to a study arm had complete data for the present analyses, although there do not appear to be any systematic differences between the patterns of missing data between arms. The multiple imputation approach to analyses with missing data partially mitigate this limitation. Second, a previously conducted exploratory analysis suggested that body mass index is associated with response to duloxetine or placebo, but these data were not available from the NCORP Data Archive. Finally, the principal scores approach to stratification used for the primary analysis relies on assumptions of monotonicity and general principal ignorability, the plausibility of which must be evaluated within each specific scientific context in which they are used. We have described the monotonicity assumption in an earlier section. The general principal ignorability assumption requires that, given the available baseline variables and observed adverse event and pain reduction statuses under treatment, the outcomes under treatment are independent of the counterfactual AE and pain reduction statuses under control, and vice versa. This assumption is comparable to assumptions of no unobserved confounders in analyses of observational data using propensity scores. The assumptions necessary for these analyses of data from a parallel arm study may be obviated by a crossover study in which intermediate and final outcomes may be observed under both treatment and control. However, such a study design would introduce other complications, particularly carryover effects.Patrick M Schnell was partially supported by the National Institutes of Health/National Center for Advancing Translational Sciences grant UL1TR002733.Role of the funder: The funding source did not participate in the design of the study; the collection, analysis, and interpretation of the data; the writing of the manuscript; or the decision to submit the manuscript for publication.Disclosures: Dr Schnell has been a consultant to Merck & Co. Dr Lustberg has been a consultant to Disarm Therapeutics and Pledpharma. Dr Henry has received research support, paid to her institution, from Abbvie, Innocrin Pharmaceuticals, and Pfizer. Per NCTN/NCORP Data Archive policy, the submitted manuscript has been reviewed by the NCI and the sponsor of the original study, Eli Lilly & Company.Author contributions: All authors of this research paper have directly participated in the planning, execution, and/or analysis of this study. Patrick M Schnell: conceptualization, formal analysis, methodology, software, visualization, and writing—original draft and review & editing. Maryam B Lustberg: conceptualization and writing—review & editing. N Lynn Henry: conceptualization and writing—review & editing.Acknowledgements: This manuscript was prepared using data from Datasets NCT01598298-D1, NCT01598298-D2, and NCT01598298-D3 from the NCTN/NCORP Data Archive of the National Cancer Institute’s National Clinical Trials Network (NCTN). Data were originally collected from clinical trial NCT number NCT01598298, “A Randomized Placebo-Controlled Phase III Study of Duloxetine for Treatment of Aromatase Inhibitor-Associated Musculoskeletal Symptoms in Women With Early Stage Breast Cancer: SWOG S1202.”Patrick M Schnell was partially supported by the National Institutes of Health/National Center for Advancing Translational Sciences grant UL1TR002733.Disclaimer: All analyses and conclusions in this manuscript are the sole responsibility of the authors and do not necessarily reflect the opinions or views of the clinical trial investigators, the NCTN, the NCI, or the authors’ institutions.This manuscript was prepared using data from Datasets NCT01598298-D1, NCT01598298-D2, and NCT01598298-D3 from the NCTN/NCORP Data Archive of the National Cancer Institute’s (NCI’s) National Clinical Trials Network (NCTN). Data were originally collected from clinical trial NCT number NCT01598298, “A Randomized Placebo-Controlled Phase III Study of Duloxetine for Treatment of Aromatase Inhibitor-Associated Musculoskeletal Symptoms in Women With Early Stage Breast Cancer: SWOG S1202.” All analyses and conclusions in this manuscript are the sole responsibility of the authors and do not necessarily reflect the opinions or views of the clinical trial investigators, the NCTN, or the NCI.pkab018_Supplementary_DataClick here for additional data file.


Serum levels of significant lipid metabolites were replicated by ELISA in 24 JAKi-treated and 12 tocilizumab-treated patients. Pain was evaluated with patients’ assessment on a 0–100 mm VAS, and disease activity assessed using DAS28. JAKi or tocilizumab therapy significantly reduced disease activity. Acceptable pain (VAS pain ≤20) at week 24 was observed in 66.7% of JAKi-treated patients, and pain decrement was greater than tocilizumab-treated patients . Levels of omega-3 fatty acids and docosahexaenoic acid (DHA) were increased in JAKi-treated patients , which were not observed in tocilizumab-treated patients. ELISA results showed increased DHA levels in JAKi-treated patients with acceptable pain . A significant association of pain decrement with DHA change, not with DAS28 change, was seen in JAKi-treated patients. The pain reduction effect of JAKi probably links to increased levels of omega-3 fatty acids and DHA.Although Janus kinase inhibitors (JAKi) could reduce patient-reported pain in rheumatoid arthritis (RA), their mechanism remains unclear. Therefore, we examined lipid metabolites change in JAKi-treated patients and evaluate their association with pain reduction. We used  Rheumatoid arthritis (RA) is characterized by inflammation and hyperplasia of synovia, cartilage degradation, and bone erosions ,2. Pain,Janus kinase inhibitors (JAKi) exert their therapeutic effects by blocking JAK/STAT-mediated signaling implicated in RA pathogenesis. The JAKi tofacitinib (a JAK1/JAK3 inhibitor) and baricitinib (a JAK1/JAK2 inhibitor) are effective in RA treatment ,15,16. G1H nuclear magnetic resonance (NMR)-based lipidomics has been used for diagnosis or therapeutic response follow-up [1H NMR-based lipidomics [Lipid metabolomics, relatively recent research, could be employed to characterize lipid metabolites and investigate their biological roles in lipid metabolism . 1H nuclollow-up . Souto-Cpidomics . Among tpidomics , and docpidomics . These lpidomics . Many stpidomics ,30. Ther1H NMR-based lipid/metabolomics to investigate the changes in serum levels of omega-3 PUFAs and DHA in RA patients treated with JAKi or TCZ and utilized ELISA to perform a replication study on the significant lipid metabolites. Since a meta-analysis revealed similar lipid profile changes in patients treated with JAKi or TCZ [In this prospective pilot study, we used i or TCZ , we enron = 24) or IL-6R inhibitor  therapy according to the guidelines [In this prospective study, we randomly enrolled 36 active RA patients who fulfilled the 2010 classification criteria of the American College of Rheumatology/European League Against Rheumatism collaborative initiative  and wereidelines . PatientThe major outcome for pain is the proportion of patients reporting pain scores equal to or less than 20 (VAS pain ≤ 20 mm) at week 24, so-called “acceptable pain” . Pain scOvernight-fasted venous blood samples were obtained in the morning and stored at −80 °C until use. Plasma levels of total cholesterol, triglyceride, high-density lipoprotein cholesterol (HDL-c), and low-density lipoprotein cholesterol (LDL-c) were measured using enzymatic methods with a chemistry analyzer AU5800  according to the manufacturer’s instructions.1H-NMR lipid/metabolomics  [2HPO4·7H2O, 5 mL NaN3 (4%) adjusted to pH 7.4 with 1 M HCl) mixed in an Eppendorf tube. The complete sample was transferred to a 3 mm NMR tube (Bruker Match system) and measured at 310 K in Bruker Avance III NMR spectrometers operating at 600.13 MHz equipped with a maximum gradient strength of 53 G/cm. Each sample was equilibrated at 310 K for 5 min before data acquisition. Each data set was automatically processed using a line broadening of 1Hz, with the NOESY data aligned to the alanine signal at 1.49 ppm. The whole lipid/metabolites was list in A serum sample was analyzed using the Finland) ,24, withAmong the changes in lipid metabolites analyzed by lipid/metabolomics, serum levels of omega-3 fatty acids and DHA were significantly increased in JAKi-treated patients. We quantified serum DHA levels with the available commercial ELISA kit  following the manufacturer’s instruction. The coefficient of variation (CV%) for the internal standards was less than 10%.p-value < 0.05 was considered statistically significant.The results were presented as the mean ± standard deviation (SD) or the median . The nonparametric Mann–Whitney U test was used for between-group comparisons of numerical variables. Wilcoxon signed-rank test was employed to compare serum levels of lipid metabolites during follow-up in patients after a six-month therapy. The correlation coefficient was calculated using the nonparametric Spearman’s rank correlation test. A two-sided p = 0.0595, As illustrated in 1H-NMR technology, we analyzed the changes of serum levels of lipid metabolites in JAKi-treated and TCZ-treated patients at baseline and at week 24. As illustrated in Supplemental p = 0.0005; and 4.13%, IQR 3.75–5.03% vs. 4.92%, IQR 4.28–6.09%, p = 0.0056; respectively). JAKi-treated patients also had significantly increased levels of DHA and ratio of DHA to total fatty acids compared with baseline levels  (Using ctively) E,F. Howectively) .p = 0.0034; median 0.28 mmol/L, IQR 0.27–0.30 mmol/L vs. 0.35 mmol/L, IQR 0.30–0.38 mmol/L, p = 0.0061), but a nonsignificant change was observed in those reporting “unacceptable pain” after treatment  in RA patients. As shown in p = 0.028) were observed in JAKi–treated patients who reported “acceptable pain” after the treatment, while decreased DHA levels in those with “unacceptable pain” despite a low disease activity . In TCZ-treated patients, the change of DHA levels in “acceptable pain” patients was nonsignificant, in contrast to decreased DHA levels in “unacceptable pain” patients (p = 0.0313).Based on the p <0.001, p = 0.0036, p <0.0001, p = 0.848 or r = −0.367, p = 0.336, respectively), or between the decrement of CRP and the change of omega-3 FA levels in JAKi-treated or TCZ-treated patients . There was also no significant correlation between the decrement of ESR and the change of DHA levels in JAKi-treated or TCZ-treated patients , or between the decrement of CRP and the change of DHA levels in JAKi-treated or TCZ-treated patients .There was an inverse correlation between serum DHA levels and patients’ reporting pain scores after six months’ treatment with JAKi , while decreased DHA levels in those reporting unacceptable pain. Besides, we revealed a significant correlation between the change of DHA levels and pain decrement in JAKi-treated patients. Regarding TCZ-treated patients, there was no significant change in DHA levels in those reporting acceptable pain, and the serum omega-3 PUFAs or DHA levels did not show significant changes even in patients with low disease activity or remission. Given that omega-3 PUFAs and DHA attenuate nociceptive pain through central and peripheral action [JAKi are known to have an additional pain reduction effect in RA patients, but the mechanism has not been fully elucidated. Similar to the results from a matching-adjusted indirect comparison study , the pail action ,27,28, tAlthough both JAKi and TCZ induced rapid normalization of inflammatory markers in our RA patients, the use of JAKi caused greater pain reduction than TCZ treatment, indicating that JAKi therapy enhanced pain relief beyond inflammation control. Many other studies, including matching-adjusted indirect comparison, also showed that JAKi could additionally provide pain relief, which was not seen in other biologics such as TCZ ,21,22. L1H NMR-based lipid/metabolomics results showed significantly increased omega-3 PUFAs and DHA levels in patients treated with JAKi, which was not found in TCZ-treated patients. Similarly, the omega-3 PUFAs and DHA levels were significantly increased in patients with acceptable pain after 24-week JAKi treatment, which was also not observed in TCZ-treated patients. Furthermore, we replicated NMR-based lipidomics results of DHA by using ELISA, and similarly revealed increased DHA levels in JAKi-treated patients who reported acceptable pain, in contrast to decreased DHA levels in those with unacceptable pain. Our results support the finding of previous studies that the dietary supplements of omega-3 PUFAs or DHA may reduce pain and inflammation in RA [Regarding the anti-inflammatory and analgesic properties of omega-3 PUFAs and DHA ,27,28, son in RA ,30,41,42In the present study, we revealed an inverse correlation between serum DHA levels and patients’ reporting pain scores after six months’ JAKi treatment with inflammation control. Furthermore, an inverse correlation between the pain decrement and DHA levels increment was observed in JAKi-treated patients. Using a multivariate regression analysis, only the change of DHA levels could predict the pain reduction in patients after six months’ JAKi treatment. It suggests that JAKi-related pain relief may be at least partly linked to the increased DHA levels. Interestingly, there was no significant correlation between the pain decrement and the change of disease activity DAS28 scores) in our JAKi-treated patients, showing a discrepancy between the degree of RA inflammation and the severity of perceived pain. Given that omega-3 PUFAs and DHA can attenuate nociceptive pain through central and peripheral actions ,27,28, t scores iDespite the novel findings in the present study, there were still some limitations. First, this study is a pilot study enrolling a small number of biologic-naïve patients, which may reduce the statistical power. Out of ethical concerns, the enrolled RA patients were allowed to use corticosteroids or methotrexate, which may affect lipid metabolism. Nevertheless, we revealed that JAKi therapy might promote pain relief through increasing omega-3 PUFAs and DHA levels, although a large prospective study should be conducted to confirm our findings.We used NMR-based lipidomics and ELISA assays to provide biochemical evidence for the possible mechanism underlying the pain reduction effect of JAKi in RA patients: the increased omega-3 fatty acids and DHA levels. Dietary supplements of omega-3 PUFAs and DHA may have beneficial effect on pain reduction despite inflammation control in RA.


Regional anesthesia is an important aspect of the overall anesthetic plan for patients. It has the potential to offer superior benefits compared to opioid-based treatment and is an important component of Enhanced Recovery after Surgery (ERAS) protocols. The use of the pectoral type I (PECS I) and pectoral type II blocks (PECS II) has been shown to reduce postoperative pain and opioid consumption in patients undergoing complete mastectomy and breast surgery. We describe the use of dexamethasone and dexmedetomidine to prolong the analgesic effects of these regional blocks in a patient undergoing total mastectomy with lymph node dissection. Regional anesthesia is an important aspect of the overall anesthetic plan for patients. It has the potential to offer superior benefits compared to opioid-based treatment, reduce postoperative pain, and decrease the use of total opioid consumption in patients postoperatively . RegionaOur patient was a 68-year-old Caucasian female with a past medical history of breast cancer, atrial fibrillation, osteoporosis, and major depressive disorder. The patient was diagnosed with cT2NOMO breast carcinoma with breast tumor characteristics demonstrating estrogen receptor (ER) and progesterone receptor (PR) positive and human epidermal growth factor receptor 2 (HER2) negative. After diagnosis, the patient completed neoadjuvant therapy with doxorubicin hydrochloride and cyclophosphamide, followed by treatment with paclitaxel before undergoing total mastectomy with lymph node dissection. Prior to the surgery, the patient underwent PECS I and PECS II blocks with 0.2% ropivacaine combined with 5 mg of preservative-free dexamethasone and 25 μg of dexmedetomidine. We administered 6 mL of the solution between the pectoralis muscles for the PECS I block, while another 10 mL was deposited between the serratus anterior and pectoralis minor muscles for the PECS II block. The surgery proceeded under general anesthesia maintained with volatile anesthetics with no additional opioids after 100 µg of fentanyl on induction.The patient reported minimal postoperative pain after the surgery. She did not require any opioid pain medication for pain control while recovering in the PACU. Additionally, the patient reported that her pain was well controlled throughout her hospital stay. The patient reported pain scores ranging from 0 to 2/10 for five days after the procedure. She had minimal use of pain medications, which included acetaminophen, NSIADs, and low dose gabapentin on the first night after the surgery, but no opioid medication usage during the remainder of the postoperative course.The use of the PECS I block for providing postoperative analgesia in patients undergoing breast surgery was first described in 2011 by Blanco et al. as an alternative approach to both paravertebral and epidural blockade . With thThe utilization of regional anesthesia has clear benefits in reducing postoperative pain and opioid consumption in patients undergoing surgeries such as mastectomy with lymph node dissection. Given the postoperative pain relief seen with PECS I and PECS II blocks, the technique may be an important aspect of the pain regimen for patients undergoing similar surgical procedures. Additionally, this report demonstrates the utility of combining dexamethasone and dexmedetomidine to the PECS I and PECS II nerve blocks and adds to the growing literature suggesting increased benefit with adjuvants during regional anesthesia. To date, there are mostly case reports and case series suggesting the benefits of utilizing both dexamethasone and dexmedetomidine for prolonged analgesia in fascial plane blocks. To our knowledge, this is among the first reports to describe combined dexamethasone and dexmedetomidine in PECS I and PECS II blocks. Further studies should be conducted to explore the safety and efficacy of the combination of dexmedetomidine and dexamethasone as adjuvants to local anesthetic in regional anesthesia.


Chronic pain is associated with anhedonia and decreased motivation. These behavioral alterations have been linked to alterations in the limbic brain and could explain the increased risk for obesity in pain patients. The mechanism of these behavioral changes and how they set in in relation to the development of chronic pain remain however poorly understood. Here we asked how eating behavior was affected in low-back pain patients before and after they transitioned to chronic pain, compared to patients whose pain subsided. Additionally, we assessed how the hedonic perception of fat-rich food, which is altered in chronic pain patients, related to the properties of the nucleus accumbens in this patients’ population. We hypothesized that the accumbens would be directly implicated in the hedonic processing of fat-rich food in pain patients because of its well-established role in hedonic feeding and fat ingestion, and its emerging role in chronic pain. Accordingly, we used behavioral assays and structural brain imaging to test sub-acute back pain patients (SBP) and healthy control subjects at baseline and at approximately one-year follow-up. We also studied a sample of chronic low-back pain patients (CLBP) at one time point only. We found that SBP patients who recovered at follow-up (SBPr) and CLBP patients showed disrupted eating behaviors. In contrast, SBP patients who persisted in having pain at follow-up (SBPp) showed intact eating behavior. From a neurological standpoint, only SBPp and CLBP patients showed a strong and direct relationship between hedonic perception of fat-rich food and nucleus accumbens volume. This suggests that accumbens alterations observed in SBPp patients in previous works might protect them from hedonic eating disruptions during the early course of the illness. We conclude that disrupted eating behavior specifically sets in after pain chronification and is accompanied by structural changes in the nucleus accumbens. How chronic pain affects eating behavior and body weight is still poorly understood. The premise that appetitive drives such as eating and chronic pain are mechanistically linked is grounded in the fact that both pain and eating interact with motivational states and affect decision making –5. This According to the "fear-avoidance model," pain patients may become obese due to lack of sufficient physical activity. Specifically, chronic pain leads to aversion to movement in pain patients as a way to avoid exacerbating their pain, and later to "deconditioning", and gradually patients become intolerant of physical activity ; HoweverAn alternative explanation is that chronic pain and obesity interact at the level of the central nervous system. The brain plays a key role in the regulation of energy intake and expenditure , with read-libitum in healthy controls but not in CLBP patients, indicating the presence of disrupted satiety signals in the latter group Reviewers' comments:Reviewer's Responses to Questions  Comments to the Author1. Is the manuscript technically sound, and do the data support the conclusions?  The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: YesReviewer #2: Yes**********  2. Has the statistical analysis been performed appropriately and rigorously?   Reviewer #1: YesReviewer #2: Yes**********  3. Have the authors made all data underlying the findings in their manuscript fully available?PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.  The Reviewer #1: YesReviewer #2: Yes**********  4. Is the manuscript presented in an intelligible fashion and written in standard English?  PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.Reviewer #1: YesReviewer #2: Yes**********  5. Review Comments to the Author  Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. Reviewer #1: This is a well done study addressing a complex relationship between the hedonic qualities of food and chronic pain along with evaluation of the NAc. The findings are in many ways counter-intuitive and somewhat difficult to appreciate but have important implictions. The main suggestion is that the abstract should be re-written to provide the interpretation of the findings regarding the role of the NAc in disruption of hedonic quality in SBPr patients while a dysfunctional accumbens in the SBPp group protects them against disruption. It would also be helpful to provide better definition in many places in the manuscript of the term "disruption" - what exactly was being disrupted in the context of the sentence? It will also be interesting to see the outcomes of the proposed opioid studies.Reviewer #2: Yezhe Lin and collaborators have investigated whether Chronic pain precedes disrupted eating behavior in low-back pain patientsThis research is original and suggest that chronic pain precedes disrupted eating behavior in low-back pain patients and that such disruption is directly related to structural changes in nucleus accumbens. In spite of that, some aspects need to be clarified.Globaly , The manuscript is difficult to follow and deserves to be simplified or reorganized by example :- In Methods section, I suggest to include a schematic diagram describing the groups and procedures- Section results should be simplified and the figures numbers must follow as far as possible their order of quotation in the manuscript- In all the figures , bar graph shall be a contrasting colour- Legend of figure 2 (A-C) is omitted- Insert the groups in fig 2 and Fig 5- A few tapping errors must be corrected**********  6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.If you choose “no”, your identity will remain anonymous but your review may still be made public.Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.  Reviewer #1: NoReviewer #2: Nohttps://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.
 While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool,  6 Dec 2021We would like to thank both reviewers for their interest in our work and their constructive feedback which helped improve the manuscript. Please find below point by point response to the reviewers comments.Reviewer #1: This is a well done study addressing a complex relationship between the hedonic qualities of food and chronic pain along with evaluation of the NAc. The findings are in many ways counter-intuitive and somewhat difficult to appreciate but have important implications. Thank you!The main suggestion is that the abstract should be re-written to provide the interpretation of the findings regarding the role of the NAc in disruption of hedonic quality in SBPr patients while a dysfunctional accumbens in the SBPp group protects them against disruption. As per the reviewer’s suggestion we re-wrote the abstract to provide the interpretation of the role of the NAc in the disruption of hedonic processing. We now write: Chronic pain is associated with anhedonia and decreased motivation. These behavioral alterations have been linked to alterations in the limbic brain and could explain the increased risk for obesity in pain patients. The mechanism of these behavioral changes and how they set in in relation to the development of chronic pain remain however poorly understood. Here we asked how eating behavior is affected in low-back pain patients before and after they transition to chronic pain, compared to patients whose pain subsides. Additionally, we assessed how the hedonic perception of fat-rich food, which is altered in chronic pain patients, relates to the properties of the nucleus accumbens in this patients’ population. We hypothesized that the accumbens will be directly implicated in the hedonic processing of fat-rich food in pain patients because of its well-established role in hedonic feeding and fat ingestion, and its emerging role in chronic pain. Accordingly, we used behavioral assays and structural brain imaging to test sub-acute back pain patients (SBP) and healthy control subjects at baseline and at approximately one-year follow-up. We also studied a sample of chronic low-back pain patients (CLBP) at one time point only. We found that SBP patients who recovered at follow-up (SBPr) and CLBP patients showed disrupted eating behaviors. In contrast, SBP patients who persisted in having pain at follow-up (SBPp) showed intact eating behavior. From a neurological standpoint, only SBPp and CLBP patients showed a strong and direct relationship between hedonic perception of fat-rich food and nucleus accumbens volume suggesting that accumbens alterations observed in SBPp patients in previous works might protect them from hedonic eating disruptions during the early course of the illness. We conclude that disrupted eating behavior specifically sets in after pain chronification and is accompanied by structural changes in the nucleus accumbens. It would also be helpful to provide better definition in many places in the manuscript of the term "disruption" - what exactly was being disrupted in the context of the sentence? We thank the reviewer for this suggestion. We tried to rephrase or explain the word disruption to be more specific all through the manuscript in the revised version. It will also be interesting to see the outcomes of the proposed opioid studies.We strongly agree with the reviewer on this future step. We are in the process of applying for funding to do these experiments. Reviewer #2: Yezhe Lin and collaborators have investigated whether Chronic pain precedes disrupted eating behavior in low-back pain patientsThis research is original and suggest that chronic pain precedes disrupted eating behavior in low-back pain patients and that such disruption is directly related to structural changes in nucleus accumbens. In spite of that, some aspects need to be clarified.Globaly , The manuscript is difficult to follow and deserves to be simplified or reorganized by example:- In Methods section, I suggest to include a schematic diagram describing the groups and proceduresWe thank the reviewer for this excellent suggestion. We now added a new figure  which depicts a schematic diagram describing the groups and the procedures.- Section results should be simplified and the figures numbers must follow as far as possible their order of quotation in the manuscriptPer the reviewer’s suggestion we have now simplified the presentation of the results. We added a table (Table 4) to report the caloric intake separately from tables 1-3. We as much as possible now quote the figures in the order of their numbers. In addition we grouped supplementary tables 7-9 into one supplementary table 7 hence reducing the number of tables in the supporting information from 12 to 10. - In all the figures , bar graph shall be a contrasting colour.Per the reviewer’s suggestion we changed all the colors of all our figures to ensure an adequate contrast. - Legend of figure 2 (A-C) is omittedThe legend of Figure 2  were inserted. - Insert the groups in fig 2 and Fig 5We inserted the groups in Figures 2-5 which are now numbered Figure 3-6 because we added a new Figure 1. - A few tapping errors must be correctedTyping errors were corrected.AttachmentResponse2Rev.docxSubmitted filename: Click here for additional data file. 10 Jan 2022
 PONE-D-21-22332R1

 Chronic pain precedes disrupted eating behavior in low-back pain patients

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 While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool,  15 Jan 2022We thank the reviewers and the editor for their critiques. We have now thoroughly corrected the linguistic errors in the manuscript. 21 Jan 2022Chronic pain precedes disrupted eating behavior in low-back pain patientsPONE-D-21-22332R2Dear Dr. Geha,We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at onepress@plos.org.If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact Kind regards,Naim Akhtar Khan, PhD, DScAcademic EditorPLOS ONEAdditional Editor Comments :The revised MS is acceptable for the publication.Reviewers' comments: 2 Feb 2022PONE-D-21-22332R2 Chronic pain precedes disrupted eating behavior in low-back pain patients Dear Dr. Geha:I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. onepress@plos.org.If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact plosone@plos.org. If we can help with anything else, please email us at Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staffon behalf ofProfessor Naim Akhtar Khan Academic EditorPLOS ONE


A minimally invasive approach to radical prostatectomy offers improved ambulation and discharge times. Postoperative pain control is one of the key factors that facilitates rapid recovery. With the aim to assure adequate analgesia and minimize the use of opioids, application of truncal nerve blocks has been proposed in a number of endoscopic procedures. The aim of this double-blind, placebo-controlled study was to evaluate the efficacy of bilateral posterior quadratus lumborum block (pQLB) in alleviating pain and reducing postoperative opioid demand in patients following endoscopic extraperitoneal and laparoscopic prostatectomy. We enrolled 50 patients who were diagnosed with prostate cancer and scheduled for prostatectomy. They were randomized to receive preoperative, ultrasound-guided pQLB with the use of either 30 ml of 0.375 % ropivacaine (ropivacaine group) or 30 ml of 0.9 % NaCl (placebo group). Our primary endpoint was opioid consumption in the first 24 hours after surgery. Secondary endpoints were pain intensity at predefined timepoints and the incidence of nausea and vomiting and pruritus. No differences were detected between the ropivacaine and placebo groups in intravenous oxycodone consumption during the first 24 hours after surgery. Similarly, there were no differences in pain intensity at any of the timepoints assessed. The rate of nausea and vomiting was equal in both groups and pruritus was not observed. Application of bilateral pQLB does not reduce opioid consumption after minimally invasive prostatectomy.  In recent years, minimally invasive techniques have gained popularity in the surgical treatment of prostate cancer. Laparoscopic radical prostatectomy (LRP) and robotic-assisted laparoscopic radical prostatectomy (RALP) improve postoperative recovery and ambulation with preserved oncological outcomes Basiri, 2018). Despit018. DespAlthough effective in alleviating abdominal wall pain, these techniques cannot block the visceral component of pain. The quadratus lumborum block (QLB) technique, first described in 2007 by Blanco as the most posterior modification of TAP block, is said to be more potent in blocking somatic pain, with the option to reduce visceral pain, due to the spread of local anesthetic towards the paravertebral space and a numbing effect on the sympathetic trunk  on postoperative opioid consumption and pain control after laparoscopic or extraperitoneal endoscopic radical prostatectomy .The study protocol was approved by the institutional Ethics Committee on 4 July 2018 (83/PB/2018) and performed at the Department of Anesthesiology and the Department of Urology, Orlowski Hospital, Center of Postgraduate Medical Education, Warsaw, Poland. It is reported in accordance with the Consolidated Standards of Reporting Trials (CONSORT) guidelines on reporting parallel group randomized trials and was registered at ClinicalTrials.com (NCT03600129). The CONSORT flow diagram is shown in Figure 1https://www.graphpad.com/quickcalcs/randMenu/) for 50 subjects. Before the surgery, the sequentially numbered, sealed, opaque envelope containing the group allocation and a description of the solution to be used for the block placement was handed to an anesthetist not involved in the perioperative care of the patient enrolled in the study. A total of 60 ml of study solution was prepared for each patient: 2 × 30 ml of 0.375 % ropivacaine in the ropivacaine group or 2 × 30 ml of 0.9 % sodium chloride  in the placebo group. All syringes were labelled in the same way and handed to anesthetist responsible for conducting the anesthesia and block placement, who was blinded to the group allocation. The primary endpoint of the study was oxycodone consumption in the first 24 hours after surgery.Fifty patients agreed to participate in the study and were enrolled between July 2018 and October 2019 after signing the informed consent form. Online randomization with a 1:1 allocation ratio was performed by using GraphPad QuickCalcs randomizer . Once intravenous access was secured with an 18G cannula, slow infusion of balanced crystalloid was initiated and 1 g of paracetamol and 4 mg of dexamethasone was given intravenously. Then, general anesthesia was induced with 100 µg of fentanyl and 2-2.5 mg/kg of propofol. Rocuronium 0.6 mg/kg was used for muscle paralysis. Anesthesia was maintained with sevoflurane in the oxygen/air mixture, with the use of repeated boluses of 100 µg of fentanyl as required for hemodynamic stability, at the discretion of the anesthetist who was responsible for the whole procedure.After induction of general anesthesia and before surgical draping, bilateral pQLB under ultrasound guidance was performed. All blocks were placed with patient in the supine position, with a contralateral tilt to facilitate sufficient ultrasound visualization of the desired posterolateral area of the abdominal wall. After thorough disinfection of the area and maintaining sterile conditions throughout the procedure, the linear ultrasound probe  was placed in the transverse plane above the anterior superior iliac spine and moved cranially until typical layers of the external oblique (EO), internal oblique (IO) and transversus abdominis (TA) muscles were visualized. Then, the probe was moved laterally and posteriorly to visualize and trace the muscular layers of the abdominal wall. Once the posterolateral border of TA was identified, the probe position was adjusted to visualize the hyperechoic middle layer of the thoracolumbar fascia on the posterior surface of quadratus lumborum (QL) muscle, which extends from the posterior aponeurosis of the TA and IO. Using the in-plane technique, a 22G spinal needle was introduced in the lateroposterior direction and advanced until it reached the posterior surface of the QL, at which point a distinct 'pop' is usually felt, indicating that the needle tip has entered the fascia. The position of the needle tip was confirmed with hydrodissection. In the ropivacaine group, 30 ml of 0.375 % ropivacaine was injected after negative aspiration for blood, whereas in the placebo group, 30 ml of 0.9 % sodium chloride was injected in the same manner. The deposition of the injectate in the desired space was observed and confirmed with ultrasound. The procedure was repeated on the other side. pQLB was either placed by an anesthetist with > 5 years of experience in peripheral nerve blocks and regional anesthesia (BH or KB) or an anesthesia trainee with at least 2 years of experience, in which case the whole procedure was supervised hands-on and the infusion of the injectate started only after the target needle position was approved by the aforementioned anesthetists. During the surgery, the patient was placed in the supine and steep Trendelenburg position with shoulder support and marked pelvis protrusion. In each case, five-port surgical access was established through minor skin incisions and the specific setup of the ports did not differ between the two types of surgery. Throughout both intraperitoneal and extraperitoneal procedures, the insufflation pressure did not exceed 12 mm/Hg except for an occasional increase to 20 mm/Hg to aid Santorini plexus hemostasis, as required. In contrast to EERP, LRP involved extended removal of pelvic lymph nodes as described previously . BesideOnce the surgery reached the stage of vesicourethral anastomosis, 2 g of metamizole and 8 mg of ondansetron were given. After trocars were removed and the operating table was returned to its neutral position, the neuromuscular blockade was reversed with neostigmine to facilitate the extubation of the trachea. The intraoperative data recorded for the purpose of the study were duration of surgery and anesthesia, estimated blood loss and the total intraoperative dose of fentanyl.After surgery, the patient was moved to the post-anesthesia care unit (PACU). Oxycodone in an intravenous patient-controlled analgesia (IV-PCA) pump  was prepared and connected to the patient's intravenous line. Routine postoperative analgesia was administered intravenously and consisted of 1 g of paracetamol and metamizole every 6 hours and 50 mg of dexketoprofen every 8 hours. The PCA pump was set to deliver 2 mg boluses with a 5 minute lock-out time and a maximum dose of 10 mg of oxycodone in 1 hour, with no background infusion. The method of using PCA was explained to patients prior to enrolment. The dose of oxycodone delivered in the assessed time intervals was derived from the PCA pump's internal memory, while the record of any additional pain intervention was extracted from PACU nursing records. Pain intensity was assessed by using the Numeric Rating Scale (NRS) at the predefined time intervals and every time the patient complained of pain. Episodes of nausea, vomiting and pruritus were noted and recorded. http://cran.r-pro-ject.org).The routine mode of postoperative oxycodone administration at our institution is 5 mg by subcutaneous injection given in 3-hour intervals, with intravenous boluses of 2 mg for breakthrough pain. Sample size calculation was based on the results of the retrospective analysis of PACU charts of minimally invasive prostatectomy cases, which revealed that the average of two doses (10 mg) was usually required in the first 24 hours after surgery. As we assumed at least a 25 % reduction in opioid requirement to be of clinical significance in this case, the number of required cases was 16 in each group for the test to achieve 80 % power at the level of significance of 0.05. Randomization was performed for 50 cases to allow for a number of dropouts. The data were assessed for normality by using the Shapiro-Wilk test. An unpaired Student's t-test was used to compare normally distributed data and the Mann-Whitney U-test was used to compare continuous data with a non-normal distribution. Continuous data are presented as mean ± standard deviation (SD) or median [interquartile range (IQR)]. For comparison of dichotomous variables, Fisher's exact test was employed, and the data are presented as number (%). The analyses were performed with R version 3.5.1 . Patient demographics and surgery-related data are presented in Table 1The total oxycodone consumption in 24 hours was not different between the patients in the ropivacaine and placebo groups. Postoperative data are given in Table 2The NRS was similar in the ropivacaine and placebo groups. No differences were found in pain levels at rest at 1, 6, 12 and 24 hours after surgery, as well as during a cough 24 hours after the surgery. The maximum NRS 1 hour following surgery was 7 in the placebo group and 8 in the ropivacaine group (data not shown). The incidence of nausea and vomiting was low and similar in both groups; pruritus was not noted.See also the Supplementary data.This study found no differences in postoperative opioid consumption and pain intensity in patients undergoing minimally invasive prostatectomy and given pQLB compared with patients given the sham block. Using a double-blind, placebo-controlled study design, we were not able to detect the expected differences in the primary and secondary endpoints. Ultrasound-guided pQLB is described as a safe and straightforward technique, as the point of local anesthetic deposition is relatively superficial and separated from the abdominal cavity by the QL muscle, minimizing the risk of intraperitoneal injection and bowel injury. In most cases, the procedure can be performed easily in the supine position, which reduces the time needed to place the block and makes it convenient to be performed after induction of general anesthesia. It results in the anesthesia of the nerve fibres innervating the anterior and lateral abdominal wall . MoreovEndoscopic techniques in urology have developed to the point where most of the major procedures are performed using a minimally invasive approach . Similar findings have been reported after the use of QLB in other urologic procedures. In their placebo-controlled study, Dam et al. showed a significant reduction in the opioid requirement during the first 12 hours after surgery and shorter hospital stay after percutaneous nephrolithotomy when unilateral transmuscular quadratus lumborum block (TQLB) was employed . In a sSurprisingly, our results failed to reproduce the above findings with the use of pQLB for LRP and EERP. Despite the different approach, both of these procedures involve multiple skin incisions for port insertion and extensive extraperitoneal manipulation in the lower abdomen and pelvis, which concludes with vesicourethral anastomosis. Therefore, the resulting somatic pain is primarily conducted through the fibres of the low thoracic and high lumbar segments, while visceral pain is mediated by the sympathetic trunk and parasympathetic pathways.In our opinion, the most likely explanation for the lack of differences in pain intensity after the block performed with local anesthetic and placebo in our patients is a specific distribution of anesthesia after pQLB. Despite the spread of local anesthetic to the paravertebral space and numbing of the thoracic sympathetic trunk, the level of anesthesia appears not to be sufficient for the extent of extraperitoneal pelvic surgery. The visceral component of pain derived from the surgical trauma to the pelvic floor, the bladder and the proximal urethra is likely to play a significant role. It is conveyed via the parasympathetic (S2-S4) and sympathetic (T10-L2) fibres that form the pelvic plexus. Moreover, animal studies have shown that the parasympathetic component is likely to be dominant . Hence,Similarly, a different characteristic of pain distribution may be the reason for which our results did not reproduce the outcomes of studies where TAP was used for RALP : they fThere are a few limitations of our study. First, to maintain the double-blind assessment, the analgesic effect of the block was not assessed at any point of the study. Second, it can be argued that pain related to extraperitoneal and laparoscopic procedures may differ and thus these cases should not be analyzed together. Third, the sample size calculation was based on retrospective data regarding intermittent, 'when required' dosing of subcutaneous opioids. A different mode and route of opioid administration (PCA) used in the study could have resulted in a different effective dose. Fourth, the fact that all cases were performed by a surgeon (DJ) with extensive experience in LRP and EERP  could affect the postoperative pain levels. Therefore, our results may not be representative for all minimally invasive prostatectomy procedures.Our results suggest that ultrasound-guided pQLB does not reduce the postoperative opioid requirement after LRP and EERP.The authors declare that they have no conflict of interest.


N = 1334 chronic musculoskeletal pain patients, aged 18–65, who were assessed for Interdisciplinary Multimodal Pain Rehabilitation (IMMR) in Swedish specialist rehabilitation. Prescriptions were tracked across a two-year target period after assessment. In total, 9100 opioid prescriptions were prescribed to 55% of the sample . Prediction of LTOT was analyzed separately for those who did (24%) and did not (76%) receive IMMR. The odds of receiving opioids was similar for these subsamples, after controlling for differences in baseline characteristics. In both samples, there were significant associations between patient characteristics and future opioid prescriptions. Dysfunctional pain coping was a unique predictor of LTOT in those who received IMMR while pain intensity and depressive symptoms were unique predictors in those who did not receive IMMR. The results underscore that opioid treatment is common among patients in chronic pain rehabilitation and relates to pain and psychological factors. Understanding in detail why these factors relate to opioid prescription patterns is an important future study area as it is a prerequisite for better management and fundamental for preventing overuse.While against recommendations, long-term opioid therapy (LTOT) for chronic pain is common. This study aimed to describe the prevalence of opioid prescriptions and to study the association of patient characteristics  with future LTOT. The sample included  Chronic pain is one of western societies’ largest public health problems . About oInterdisciplinary Multimodal Pain Rehabilitation Programs (IMMRPs) offer a well-coordinated interdisciplinary treatment conducted by a multidisciplinary team  and showAlthough opioids are important tools for treating acute postoperative and traumatic pain, their comparative effectiveness and usefulness for chronic pain is questioned ,12. In bThe prevalence of opioid prescriptions and whether there are any differences between subsamples in opioid prescription prevalence.The associations of opioid prescriptions with patient characteristics  within each sample.The predictive value of patient characteristics for LTOT within each sample.Given that patients with chronic pain are frequently prescribed opioids while evidence and guidelines call for carefulness, it is important to increase our understanding of why patients receive long term prescriptions. This is a complex question where societal, systemic and contextual factors, attitudes and beliefs of prescribing physicians and patients, as well as how these interact in clinical encounters play a role . ThiThis is a prospective cohort study analyzing the relation between patient reported data collected during multidisciplinary assessment and individual opioid prescription data collected during a two-year period after this assessment. The study was granted ethical clearance by the Umeå University Ethics Committee (D-nr: 2013/192-31 and 2017/438-32).Subjects are consecutive patients with chronic pain, who were referred, mostly from primary care, to clinical rehabilitation departments at two university hospitals in the north and the middle of Sweden between 2008 and 2012. Subjects were patients in regular health care service, they were assessed and received treatment on an outpatient basis. Inclusion criteria for the IMMRP were disabling chronic pain, age between 18 and 65 years, no further medical investigations needed, written consent to participate and agreement not to participate in other parallel treatments. Exclusion criteria were ongoing major somatic or psychiatric disease, a history of significant substance abuse and state of acute crisis.N = 1624 patients, N = 1334  patients could be included in the analytical sample. N = 290 (17.8%) patients were excluded because of missing data on target independent variables. The patients who were excluded did not differ from the analytical sample in terms of age, pain intensity, pain coping or anxiety symptoms. There were however small but significant differences in education  = 4.61, p = 0.03), spreading of pain  = −2.22, p = 0.03), sex  = 4.73, p = 0.03), depressive symptoms  = 2.35, p = 0.02), IMMRP participation  = 7.65, p = 0.006) and prescribed opioids one year before assessment  = 4.46, p = 0.02).From a target sample of The patients filled out a paper and pencil questionnaire with instruments included in the Swedish Quality Registry for Pain rehabilitation (SQRP)  as part Assessed demographics included age, sex and education .Assessed pain characteristics included pain intensity and number of pain locations. Pain intensity was assessed with a numerical pain rating scale, asking patients to rate average pain during the past week on a scale of 0–10 with endpoints ‘no pain’ and ‘worst possible pain’. The number of pain locations was assessed using 36 predefined anatomical areas (18 on the front and 18 on the back of the body). Areas were summed to form a total score ranging from 0–36.The Hospital Anxiety and Depression Scale (HADS)  was usedPain coping was assessed using pain coping classifications of the (WHY) MPI. The (WHY) MPI is a psychometrically sound, 61-item self-report questionnaire measuring psychosocial, cognitive and behavioral correlates of chronic pain ,35. ThroN = 1334 patients received assessment by a physician and typically also a psychologist, physiotherapist, social worker and occupational therapist. N = 321 (24%) also participated in an IMMRP. Participation in an IMMRP is dependent on the multidisciplinary assessment outcome  as well as on whether the patients themselves consent to participate and agree not to engage in other parallel treatments [All eatments ,39. The Opioid prescriptions were extracted from the Swedish Prescribed Drug Register across a window of one year before (to control for prior use), and two years after (the target period) the year during which assessment took place. This target period was chosen as it extends beyond the IMMRP (duration three to four months) and its follow-up period (1 year) while at the same time retaining a proximity to time of baseline assessment and IMMRP that may reasonably affect prescription patterns. The Swedish Prescribed Drug Register includes prescription and dispensing dates and information on products and prescribers for all Swedish dispensed prescription medications . The regIn line to Swedish rules and regulations, and after ethical clearance, data from the SQRP was delivered to independent data officials at the Swedish National Board of Health and Welfare who conducted the data linkage with The Swedish Prescribed Drug Register. SQRP data were linked with prescription records on an individual basis, using Swedish person identification numbers. Data were thereafter de-identified and subsequently delivered back to the research team.Anatomical Therapeutic Chemical (ATC) codes were used to identify opioids prescribed between 1 July 2005 and 31 December 2017. In line with previous studies, we did not include opioids used for intravenous distribution, treatment of Substance Use Disorder (SUD) or other diagnoses that were not relevant for the aim of this study, e.g., cough . For speOpioid prescriptions were operationalized as follows: (1). Whether opioids were prescribed during the two-year target period: yes/no; (2). Whether opioids were classified as weak  or strong opioids. (3). Whether patients had long-term opioid therapy (LTOT). There is not one agreed upon definition of LTOT, but, as in Sweden opioids are prescribed for a maximum of 3 months’ supply , we defiAll statistics were performed in SPSS (version 24.0). As assignment to IMMRP participation was non-random, the cohort was analyzed as two subsamples: those who do and do not participate in an IMMRP after assessment. T-tests and Chi-squared tests were used to study baseline and opioid prescription differences between the two samples. Point-biserial and Phi correlations were used to study univariate associations between baseline patient characteristics and opioid prescriptions within each sample. Logistic regressions were used to model multivariate associations between predictors (baseline patient characteristics showing significant univariate associations with LTOT) and LTOT within each sample. In all predictive models, assessment location was controlled for. Analyses were performed with, and without, controlling for strong opioids prescribed during the year prior to assessment.N = 741 (55%) of the 1334 patients  during the two-year target period. The proportion of strong opioids was 31%. The most common weak opioids prescribed were tramadol (46.9%) and codeine/paracetamol (19.8%). The most common strong opioids prescribed were oxycodone (11.3%) and morphine (7.5%).The overall prevalence and distribution of different kinds of opioids for the total sample are displayed in 2 (1) = 23.29, p < 0.001), age ; no IMMRP sample, M = 41.6, (Sd = 11.6); t(1332) = 4.10, p < 0.001) and the proportion of the sample who were prescribed strong opioids during the year prior to assessment  = 9.41, p = 0.002).N = 40 (12.5%) patients who received a strong opioid prescription whereas there were N = 203 (20%) who received a strong opioid prescription among those who did not participate in the IMMRP. This is a significant difference (χ2 (1) = 9.40, p = 0.002) but the odds of receiving a strong opioid prescription among those who did not participate in the IMMRP was not significantly higher after controlling for baseline differences between samples , p = 0.09).N = 77 patients (6%) received LTOT during the two-year target period. The distribution of LTOT was different for those who did and did not participate in the IMMRP. Specifically, among those who did participate in the IMMRP, there were N = 10 (3%) patients who received LTOT while there were N = 67 (7%) who received LTOT among those who did not participate in the IMMRP. This is a significant difference (χ2 (1) = 5.43, p = 0.02) but the odds of receiving LTOT among those who did not participate in the IMMRP was, although coming close, not significantly higher after controlling for baseline differences between samples , p = 0.06).A total of In the sample who participated in the IMMRP, receiving a prescription of at least one opioid (any) during follow-up was significantly associated with lower education, less spread pain, more dysfunctional coping, less interpersonally distressed coping and having been prescribed an opioid (any) during the year prior to assessment. Receiving at least one strong opioid prescription during follow up was significantly associated with sex , more dysfunctional coping and having been prescribed a strong opioid during the year prior to assessment. Receiving LTOT during follow up was significantly associated with more spread pain, more dysfunctional coping and having been prescribed an opioid (any or strong) one year prior to assessment.In the sample who did not participate in IMMRP, receiving a prescription of at least one opioid (any) during follow up was significantly associated with lower education, more pain, more spread pain, more dysfunctional coping, less interpersonally distressed coping, more depressive symptoms and having been prescribed an opioid (any or strong) the year prior to assessment. Receiving at least one strong opioid prescription during follow-up was significantly associated with age (being older), more pain, more dysfunctional coping, more depressive symptoms and having been prescribed an opioid (any or strong) one year prior to assessment. Finally, receiving LTOT during follow up was significantly associated with more pain, more dysfunctional coping, more depressive symptoms and having been prescribed an opioid (any or strong) one year prior to assessment.p-values shifted, the odds ratios for these predictors were unchanged.In the sample who did not participate in the IMMRP, the analysis showed that pain intensity and depressive symptoms were significant predictors of LTOT, irrespective of whether strong opioid prescription in the year prior to assessment was controlled for. Dysfunctional pain coping was not significant in these analyses.p-value was close to significance , and prevalence of strong opioid use and LTOT was relatively low, it could be that IMMRP participation itself is related to future opioid use. Future studies, making use of the whole Swedish Quality Registry for Pain rehabilitation  could focus on the effect of IMMRP participation on opioid use. Not only would larger numbers ensure sufficient power, such studies could use methods such as propensity score matching to maximize comparability between those who do and do not participate in IMMRP after assessment.In this prospective cohort study on patients with chronic pain, we found that more than half (55%) of the participants received opioids during the two years after a multidisciplinary assessment in specialist rehabilitation care. For those who received opioids, the median number of prescriptions was six, and of all opioids prescribed a third were strong opioids. The sample who, after assessment, did not participate in the Multidisciplinary Rehabilitation Program (IMMRP) had a higher likelihood of future prescription of strong opioids and long-term opioid therapy (LTOT) compared to those who did participate in the IMMRP. However, this increased likelihood was non-significant after controlling for differences in baseline characteristics. Specifically, patients who did not participate in the IMMRP were more likely to be male, were older and had higher degree of strong opioid use prior to assessment. Non-significance after controlling for these variables suggests that the association of IMMRP participation with opioid prescription may be accounted for by these patient characteristics. However, as the The apparent interrelation between patient demographic characteristics, opioid prescription history and choice of pain treatment raises the important question of whether the prescription of strong opioids may discourage patients from engaging with non-pharmacologic (or at least non-opioid-intensive), self-management-oriented treatments like the IMMRP. While this study cannot provide a definite answer to this question, within group analyses of the sample not receiving IMMRP showed that there is a consistent association between opioid prescription history, pain, depressive symptoms, dysfunctional pain coping and future opioid prescriptions. In a previous study on this same sample, we found that non-IMMRP participation was also related to higher levels of previous healthcare seeking, pain-related fear as well as with a lower level of pain acceptance .One possible explanation for these associations may be that these patients have gotten caught up in so called ‘misdirected problem solving’ . The misOne main finding of this study is that, besides pain, depressive symptoms were a unique predictor of future long-term opioid therapy (LTOT) for those not receiving the IMMRP. This is in line with previous research where mental health disorders are common in patients with LTOT ,24. WhilWhile direct comparisons should be done cautiously, it is of value to note that there were no significant associations between pain intensity and depressive symptoms and opioid outcomes in the sample participating in IMMRP while these associations were consistently significant in the non-IMMRP sample. For both groups, there were significant univariate associations between dysfunctional pain coping and different operationalizations of opioid outcomes and in the multivariate analysis predicting LTOT, dysfunctional pain coping was a unique predictor in the subsample participating in IMMRP, after controlling for prescription history. One possibility is that IMMRP participation may have influenced the associations between pain, depressive symptoms, dysfunctional pain coping and risk for LTOT. Possibly, the treatment program influenced depressive symptoms and pain (or their association). Unfortunately, this study does not contain follow up data on IMMRP outcome that can support this hypothesis, but future studies using the SRPQ registry could study this.In the IMMRP sample, there was a significant association between widespread pain and LTOT, indicating a decreased likelihood of future LTOT for those who have widespread pain. However, this association did not retain significance after controlling for opioid prescription history. This suggests that those with widespread pain were less likely to receive opioids before as well as after IMMRP. This could be related to a following of guidelines within this subgroup, as these highlight the lack of efficacy for opioid treatment for fibromyalgia where widespread pain is a cardinal symptom .There were no significant correlations between LTOT and demographic variables in either of the samples. The same was true for correlations between anxiety and any of the opioid outcomes. Nor was interpersonally distressed coping found to be of high relevance for opioid outcomes, showing no significant associations with future strong opioid prescriptions or LTOT. There was however an inverse association between interpersonally distressed coping and any opioid prescriptions, suggesting that patients expressing more interpersonally distressed coping when it comes to management of their pain condition were less likely to be prescribed an opioid. Possibly but speculatively, interpersonally distressed patients elaborate more on their psychosocial difficulties during the clinical encounter, which has been found to be inversely related to the likelihood of a doctor initiating a biomedical intervention .In this study there are limitations, first regarding those excluded (18%) due to missing data. Excluded participants differed from the included participants in some but not most variables. Specifically, those not included in the analyses had a lower level of education, had less spread pain, a slightly higher level of depressive symptoms, were more likely to be men, have a history of opioid prescription and have participated in the IMMRP. Although these differences were mostly small, suggesting that any bias may not be large, loss of participants due to missing data may have affected the internal and external validity of the results.Second, there are also some limitations related to sample selection and power. The sample in this study consists of patients from two university clinics in Sweden. Even if there are differences between pain rehabilitation clinics in Sweden, the patients in this study can be said to generally represent the study population of patients with chronic musculoskeletal pain in specialist care Sweden . The numThird, choices of how opioid use was operationalized may have influenced results. While we follow previous research , the demFourth, there are limitations regarding measurement of the pain coping profiles. The use of coping profiles using the MPI incorporates a range of biopsychosocial characteristics and provides little detail on the specific pain psychological mechanisms that may be relevant for understanding the pain problem. For example, measures of pain acceptance, pain catastrophizing or pain related fear would have added detail to the understanding of possible mechanisms that may link pain psychological aspects to opioid use.Finally, there are limitations regarding study design. This is an observation study, meaning we cannot draw any conclusions on causal processes explaining the associations.This study shows that opioid treatment is common among patients with chronic pain seeking care in specialized pain rehabilitation clinics. It also indicates associations between individual characteristics and opioid prescriptions in Swedish pain rehabilitation, specifically pain and depressive symptoms. Understanding how individual characteristics interrelate and relate to prescription patterns and long-term opioid use is a prerequisite for better management and fundamental for preventing overuse.