This study aims to study the effect of mindfulness-based program on the psychological, biomechanical and inflammatory domains of patients with chronic low back pain.A multicentre randomized and controlled clinical trial of parallel groups in patients with chronic low back pain between March 2019 to March 2020. Participants with no experience in mindfulness based intervention, were randomized to receive (36 patients) or not (34 patients) mindfulness-based stress reduction program for chronic back pain (MBSR-CBP). The program was performed in 9 sessions. Patients with chronic low back pain due to symptomatic discopathy (degenerative disc disease or herniated disc) were included. The principal outcome was changes in the blood level of cortisol and cytokines (tumor necrosis factor- α (TNF- α), interleukin-1β (IL-1β), interleukin-6 (IL-6) and interleukin-17 (IL-17)). Secondary outcomes  were measured by validated questionnaires.Of the 96 randomized patients, 70 who completed the study were included in the analysis . MBSR-CBP stopped the increase in cortisol, and reduced pro-inflammatory cytokine IL-1β (p = 0.05). It reduced depression (p = 0.046) and stress (p = 0.0438), perceived pain (p < 0.0001), and limitations related to health (p < 0.0001). It also increased the physical function (p = 0.002) and sleep quality (p = 0.05). Furthermore, it significantly increased life satisfaction (0.006), well-being (p = 0.001) and vitality (p < 0.0001). It also increased self-compassion (p < 0.0001) and significantly reduced the overidentification (p<0.0001) and catastrophization (p = 0.002).MBSR-CBP could be part of a multidisciplinary approach in the management of patients suffering from chronic low back pain. Chronic low back pain, as indicated by the Global Burden of Disease Study 2019, represents the fourth overall cause of burden in the age range of 25 to 49 years, the seventh in the age range of 10–24 years, and the sixth in the age range of 50–74 years . The oveIdentified risk factors of pain chronicity are age, genetic predisposition, sex, previous experience and attitude toward pain , 8. NonsChronic pain states are often accompanied by affective, emotional and cognitive disorders  . The staTo address this problem The US National Pain Strategy proposed the concept of high-impact chronic pain (HICP). The aim of the definition is to better identify people with significant levels of interference with life  . HICP inIn the United States neck and low back pain are the second-leading condition that increased its spending between 1996 and 2013, with $64.4 billion over 18 years . It is iInterestingly, the implementation of cognitive behavior-based program has produced a reduction of the Oswestry Disability Index (ODI) in nonsurgical and surgical patients . FurtherMBSR programs could be a good alliance in the clinical managements of patients with painful disk degeneration. In 1982, Kabat-Zinn employed an outpatient program based on the practice of mindfulness meditation for chronic pain patients that achieved a significant reduction in pain –22. The Furthermore, there are indications that reductions in stress are mediated by lowering the levels of pro-inflammatory cytokines  and influencing factors of cell transcription and gene expression –32.To study the efficacy of the MBSR program on the inflammatory, psychological and biomechanical domains of patients with low back pain and symptomatic discopathy or disk herniation, randomized controlled clinical trials have been designed and implemented. The null hypothesis has been that MBSR had no significant influence on the inflammatory biomarkers and symptoms in patients with chronic low back pain. This could be related to the absence of effect on patients’ approach toward pain, disability, well-being and overall subjective health.A multicenter randomized and controlled clinical study with parallel arms was designed and implemented. The clinical trial was conducted from March 2019 to March 2020. Three independent centers Eduardo Anitua Foundation , Complutense de Madrid University  and Nirakara Lab ) participated in the clinical trial. The trial protocol was approved by the ethics committee for research with medicaments of the Basque Country, Spain (FIBEA-01-EC/18/MIND)) On the 9th of January, 2019. The clinical trial was registered on clinicaltrials.gov . Written informed consent was obtained.Invitations to participate in the free of cost study was sent via an email to the patients database of the participating Centers, describing the study objectives, the selection criteria and the commitment required from the patient. Those interested in participating (n = 233) filled out an online questionnaire, using the Qualtrics SAAS software featuring questions related to the exclusion criteria. The inclusion criteria were: having a diagnosis of symptomatic discopathy due to degenerative disc disease or herniated disc at any part of the spine, , have been diagnosed with chronic pain no more than two years before the recruitment phase, normal or moderate mobility, normal cognitive state, have previously read and signed the informed consent form and ability and willingness to comply with the procedures included in the study. The exclusion criteria were serious psycho pathologies, suicidal thoughts, severe depression, psychosis, drug addiction, very limited functional capacity, and impaired cognitive functions , and initiate clinical, psychological or pharmacological treatments other than those used to treat pain or being experiencing drastic changes in lifestyle. Ninety six patients were initially recruited .Fourteen patients could not make the program because of the restrictions installed in Spain by State of Alarm declaration. Another 10 patients did not attend the study claiming agenda problems. Two more patients did not attend the appointment for second evaluation. Seventy patients finally participated in the study with a total of 33 patients in Vitoria and 37 in Madrid. In the experimental group, 5 patients did not attend the visit for blood extraction and 2 patients did not deliver the questionnaires. For the control group, 2 patients did not attend the visit for blood extraction and 1 patient did not deliver the questionnaires. The sample had a mean age of 53 ± 10 years (range: 33 to 73 years) and 46 patients (66%) were women. The participants assigned to the control group continued with their ongoing pain treatment without any alteration.Patients randomization to the study group was performed by a specific computer program  and was performed independently for each of the centres . PermuteAll participants (n = 70) continued with their own ongoing pain treatments. Data on the ongoing pain treatment was not collected. The experimental intervention was Mindfulness-based stress reduction program , but adaDemographic, psychological and biological variables were included in the study. Demographic and psychological variables were collected by means of an online questionnaire using Qualtrics software. Blood samples were taken at baseline and after 8 weeks. The samples were stored in a laboratory with offices in the two sites of the study and were analyzed on the same day to avoid bias. Furthermore, the samples were collected between 9:00–10:30 am. Cortisol was measured by chemiluminescent immunoassay (CLIA). The cytokines TNF-α, IL-1β, IL-6 y IL-17 were measured by multiplex immunoassay based on highly sensitive Luminex technique. All the biomechanical analysis was performed in an independent and accredited laboratory for clinical analysis.Demographic variables included sex, education level and age. The Primary variables were stress reduction (measured by the variation of cortisol in the blood) and the variation of TNF-α, IL-1β, IL-6 y IL-17 levels in blood. The sleep and breathing analysis were also included and assessed; however, data are not included in this manuscript. Secondary outcomes were mindfulness, self-compassion, pain acceptance, disability, depression, anxiety, stress, well-being, health-related quality of life and life satisfaction. These variables were assessed by the following validated questionnaires:Five Facets of Mindfulness Questionnaire—short form (FFMQ). This is a widely used measure of mindfulness that includes five factors: describing, acting with awareness, observing, not judging inner experience, and not reacting to inner experience. In addition, the total score is also used. The scale consists of 20 items rated on a 5-point Likert scale ranging from 1 to 5 .Self‐Compassion Scale-Short Form (SCS). This is a measure of compassion for oneself. It measures the extent to which there is awareness of psychological distress and the degree of kindness towards oneself. It originally includes three components: mindfulness, self-compassion and common humanity . The scaPain Catastrophizing Scale (PCS). Instrument designed to assess the coping strategies used by chronic pain patients . The invChronic Pain Acceptance Questionnaire-Revised (CPAQ-R). It measures the acceptance of chronic pain in its psychosocial dimension . AcceptaDepression, Anxiety and Stress Scale—21 Items (DASS-21). A 21-item scale widely used to measure symptoms of depression, anxiety and stress . The queSatisfaction with Life questionnaire (SWLS). Life satisfaction is the personal perception of well-being or happiness; in other words, it is the valuation of one’s own life in relation to one’s own goals, expectations or interests directly mediated by the cultural context in which one lives . The scaWHO‐5 Well Being Index. The World Health Organization’s WHO-5 index is a 5-item, 6-point Likert scale questionnaire that measures subjective well-being .Short Form-36 Health Survey (SF-36). It is a generic scale that provides a profile of health status and is applicable to both patients and the general population . The 36 Pain and Sleep Questionnaire (PSQI). The 19 items of this test look at different determinants of sleep quality . Items aAs a deviation from the original protocol, there were questionnaires (Pain Self-Efficacy Questionnaire (PSEQ), Survey of Pain Attitudes—Brief (SOPA.B), Pain Coping Inventory (PC), the Chronic Pain Grade Scale  and Brief Pain Inventory (BPI)) were not passed to the patients to reduce the overloaded on them. Furthermore, the main coping strategy for chronic pain in MBSR-CBP is acceptance and detached attention to catastrophic thoughts (assessed with the PCS and CPAQ-R questionnaires). Having the vitality subscale provided by SF-36, the Brief Fatigue Inventory (BFI) was not passed. To measure stress, DASS was used and the Perceived Stressed Scale (PSS) was omitted.Sample size was calculated a priori using G power 3.1 . Given aFor the duration of the program, participants were asked not to change their clinical habits or initiate new pharmacological or clinical treatments. If they did, the participant continued to take part in the program, but he/she was not included in the analysis, to avoid interference with the variables being tested. Python 3.8.5 was used for preprocessing the questionnaire data and merging all the databases generated in the measurement procedure . R versiχ2 = 0.34, p = 0.56), age (t(64) = 16, p = .11), education level (t(66) = 0 .07, p = 0.94) and the RMQ disability score (t(61) = .49, p = .62)  . Supplemp = .62)  describeRegarding the blood levels of cortisol, there were no significant differences between the study groups  = 2.81, p = 0.09). However, cortisol levels increased significantly in the control group only  = 5.577, p = 0.05) . Robust Furthermore, the DASS-21 questionnaire was used to assess the negative mood in three subscales: stress, anxiety, and depression . The basOverall, patients in the control group did not experience changes in relation to the variables of mindfulness and self-compassion. However, patients in the experimental group showed statistically significant changes in relation to these two variables .Specifically, the level of mindfulness in the experimental group was lower  than in the control group. The score of the "observation" subscale was significantly higher in the control group. ANOVA analysis showed a statistical significance interaction between the time and group factors in the subscales of nonreactivity  = 6.31, p = 0.015), nonjudgment  = 6.70, p = 0.012), observation  = 11.23, p = 0.001) and the global FFMQ score  = 24.60, p < 0.0001). Post-hoc analysis indicated that the MBSR-CBP program significantly improved mindfulness. Regarding the between-group comparison, differences were statistically significant after MBSR-CBP in the subscales of non-judgment and the global mindfulness score . RegardiThere is no significant interaction between groups and intervention in Pain Catastrophizing Scale (PCS) probably because both groups had significant changes before and after the program, as indicated by post-hoc analyses. Although the experimental group has significant changes in PCS, they cannot be attributed to the program . The basPain assessment was carried out using the SF-36-pain scale, a 6-level Likert scale with 2 questions, the first assessing pain intensity and the second assessing the extent to which pain has interfered with daily activities. The results show significant differences in the combined time/group effect  = 7.70, p = 0.007), with a statistically significant decrease in pain in the experimental group  = 21.31, p = 0.0001) .Although the intergroup comparison indicated no significant differences in the RMQ score, the within group analysis showed a significant reduction in the experimental group only . SubscalThe results show statistically significant changes in the combined time/group effect in WHO-5  = 11.84, p = 0.001) and SWLS  = 6.95, p = 0.011). Furthermore, only in the experimental group did both WHO-5  = 15.79, p = 0.0008), and SWLS  = 10.64, p = 0.006) improved over time .In addition to the SF-36 subscales described in previous sections, SF-36 showed significant changes in the combined time/group effect on other subscales of interest to the study sample . These sThe effect of the MBSR program has not been statistically significant on the blood cortisol level. This could be attributed to the fact that all the patients in this study had the blood cortisol within the normal reference values (6–23 μg/dl) . NeverthDirect measures related to mindfulness have significantly improved in patients in the experimental group thus suggesting that mindfulness training has had the expected effect. Patients reported an increase in mindfulness (FFMQ) and self-compassion (SF-SCS).According to the review by Haldeman et al. (2012), there is no clear understanding of the origin of chronic back pain in 98% of patients . MoreoveTaking RCTs from the report on noninvasive treatments for chronic pain by Skelly et al. , there aThe study did not include post-treatment measures, which is a limitation of the present study. Although patients and clinician were not blinded to the assigned group. The statistical analysis was performed blindly. Although the measurement of the allostatic load has not been included, the study has assessed the negative affective states in patients with low back pain and degenerative disk disease. Data on the usual therapy has not been collected and differences between patients/centre could not be excluded. However, all participants have been asked not to change their clinical habits or initiate new pharmacological or clinical treatments. Since there has been no active control group, benefits cannot be attributed specifically to mindfulness practice. Benefits may be compounded by factors like group support, teacher support, expectations and attention received. In addition, a mindfulness-based program is composed of many elements, apart from the practice itself, like pain pedagogy, lifestyle pedagogy and its impact on health, and body and stretching practices. Specific designs are needed to dismantle the contributing factors. The sample size is not large enough to generalize the results, yet the statistics are sufficiently robust to show an appreciable trend of improvement in the experimental group. Experimental designs with a larger sample size are needed to generalize the results.MBSR-CBP could remediate the negative impact of chronic low back pain on the inflammatory, psychological and functional domains. Patients who performed the program showed decrease in depression, stress, perceived pain, disability, and limitations related to health. It also increased the physical function, sleep quality, life satisfaction, well-being and vitality. In the coping with pain domain, the MBSR-CBR increased pain acceptance, self-compassion and significantly reduced the overidentification, kinesiophobia and catastrophization. It also decreased the blood level of IL-1β.S1 File(PDF)Click here for additional data file.S2 File(XLSX)Click here for additional data file.S3 File(PDF)Click here for additional data file.S4 File(PDF)Click here for additional data file.S5 File(PDF)Click here for additional data file.S1 Checklist(PDF)Click here for additional data file.


As the superiority of stereotactic body radiotherapy (SBRT) over conventional external beam radiotherapy (cEBRT) for painful non-spine bone metastases remains controversial, we conducted propensity score-matched analysis. Our results showed that the 3-month pain response rate after SBRT was significantly higher than that after cEBRT. Therefore, these findings suggest that large-scale randomized controlled trials are warranted to compare SBRT with cEBRT for painful bone metastases not involving the spine.n = 129; cEBRT, n = 105) were identified in our institutional database. To reduce the confounding effects, 162 patients were selected using a propensity score-matched analysis (n = 81 for each treatment). The OR rate at 3 months after SBRT was significantly higher than that after cEBRT . A noteworthy finding of our study is that the same trend was observed even after 6 months . The 1-year local failure rates after SBRT and cEBRT were 10.2% and 33.3% (p < 0.001), respectively. (4) Conclusions: Our findings suggest that SBRT is superior to cEBRT for pain palliation in patients with non-spine bone metastases.(1) Background: The superiority of stereotactic body radiotherapy (SBRT) over conventional external beam radiotherapy (cEBRT) in terms of pain palliation for bone metastases remains controversial. (2) Methods: This propensity score-matched study compared the overall pain response (OR) 3 months after radiotherapy among patients with painful  non-spine bone metastases. Patients with lesions that were treated with SBRT or cEBRT and whose pain scores were evaluated 3 months after radiotherapy were included in this study. Pain response was evaluated according to the International Consensus Criteria. (3) Results: A total of 234 lesions (SBRT,  Bone is a common site of metastasis in advanced cancer ,2,3, andHowever, cEBRT also has several limitations. First, cEBRT may not always be effective. Previous studies have shown that the overall pain response (OR) rate and complete pain response (CR) rate were approximately 60% and 25%, respectively . As advaStereotactic body radiotherapy (SBRT) is a high-precision radiotherapy technique that delivers a high ablative biological dose in one to five high-dose fractions, while sparing adjacent organs. SBRT has emerged as an attractive alternative to cEBRT for spinal metastases  and has The database of Tokyo Metropolitan Komagome Hospital was retrospectively reviewed to identify patients treated with radiotherapy for pain palliation in non-spine bone metastases. Patients were included in this study if they met the following criteria: (i) presence of painful bone metastases not involving the spine ; (ii) painful osseous lesions treated with SBRT from February 2013 to January 2022 or with cEBRT from February 2013 to May 2018; and (iii) evaluation of the index pain 3 months after radiotherapy. “Non-spine bone” was defined as all bones excluding the cervical spine, thoracic spine, lumbar spine, sacral spine, and coccyx. Because we performed SBRT for all patients with painful bone metastases not involving the spine who were in a good general condition since June 2018 based on the excellent outcomes of our clinical trial , the irrThis retrospective study protocol was approved by Komagome Hospital’s Institutional Ethics Review Board . Informed consent was obtained in the form of an opt-out option on the website.The SBRT technique, discussed in detail in a previous publication , is brie95% ≤ 100 % PD), and the maximum dose should be ≤170% of the PD (PTV Dmax ≤ 170% PD). The treatment was delivered by TrueBeam  and Vero4DRT  using intensity-modulated radiotherapy techniques (The prescribed dose (PD) was 30 or 35 Gy in five fractions; however, some lesions that were irradiated with 24 Gy in two fractions along with spinal metastases were included in the study. The planning goals were as follows: 95% of the PTV should receive 100%  of the PD  rate; overall survival (OS); and AEs.Pain status at the treated index lesion was measured on an NRS of 0–10, noting the worst score in the previous 3 days. Pain response was judged according to the criteria defined by the International Consensus Pain Response Endpoints and evaluated according to the NRS and the amount of analgesic consumed . ExtrapoThe propensity scores were generated using multivariable logistic regression models predictive of the radiation technique (SBRT/cEBRT), based on patient characteristics (age and Eastern Cooperative Oncology Group performance status [ECOG PS]), and tumor characteristics  or the Mann–Whitney U test (continuous variables). Fisher’s exact test was used to compare the pain response (OR and CR) rates between the two groups. As patient death without tumor recurrence was regarded as a competing risk factor, LF was estimated using the cumulative incidence function adjusted for the competing risk of death and compared using Gray’s test for equality. OS was estimated using the Kaplan–Meier method, and the log-rank test was used to compare OS between groups. A ion 1.54 .The study profile is shown in n = 267) or cEBRT (n = 654). Eighty-six and seventy-two lesions were excluded at the baseline in the SBRT and cEBRT groups, respectively, and 52 and 477 lesions were excluded at 3 months after radiotherapy in the SBRT and cEBRT groups, respectively. A total of 234 lesions  met the inclusion criteria.During the study period, 921 non-spine bone lesions underwent SBRT (Patient characteristics of the whole cohort are summarized in p < 0.001). The OR rate at 1 and 6 months after SBRT was significantly higher than that after cEBRT .The pain responses in each group are summarized in p = 0.39; others, p ≥ 0.83).The PSM analysis for reduction of confounding effects identified 81 matched pairs of lesions in each group. The matched groups of patients had similar baseline characteristics , includip = 0.052; The median follow-up duration after radiotherapy was 12 months . The matched SBRT and cEBRT groups had similar OS rates at 6 months (82.0% vs. 76.7%) and 1 year after radiotherapy . Regarding the CR rate, the difference was not confirmed at 1 month after radiotherapy . However, the CR rate of SBRT increased thereafter to more than 50%, and this analysis showed a significant difference, favoring SBRT to cEBRT at 3 months  and 6 months  after radiotherapy.Significant difference was observed in the OR rate at 3 months after radiotherapy between the SBRT and cEBRT groups , respectively  pain control, were observed, which could be due to the excellent local control of SBRT.Although the present study demonstrated the superiority of SBRT for pain palliation, randomized controlled trials comparing the pain-relieving effects between SBRT and cEBRT for bone metastases reported paradoxical results: superiority of SBRT over cEBRT ,22 and np = 0.03) [In SBRT for bone metastases, the irradiation method differs depending on the presence or absence of the spinal cord within the irradiation fields; hence, treatment methodologies for spinal and non-spine bone metastases were developed separately . Althoug = 0.03) . Another = 0.03) . The preAssuming that SBRT is superior to cEBRT, we considered the contributing factors in terms of the dose and target size. Regarding radiation dose, some meta-analyses showed a positive correlation between the prescribed dose and local control rate in spinal SBRT ,30. In cWith regards to spinal metastases, while the field of cEBRT includes spinal lesions plus one segment above and below, SBRT includes only the involved spine as the target. Although the merits and demerits of different field sizes are unknown for pain relief, there are some reports showing that a large field size may induce pain relief ,32. In aIn the present study, the CTV margin of SBRT was larger than that of cEBRT. The large CTV margin (20–30 mm) in SBRT was determined based on a previous analysis regarding patterns of intraosseous recurrence . Out-of-Ablative irradiation with SBRT has high antitumor effects, resulting in a high tumor control rate ,33. If tWe performed bone SBRT for patients in a good general condition. Contrastingly, cEBRT was provided to patients with all statuses of general condition. Hence, we selected only those patients with a good general condition among the cEBRT cohort and matched them to the SBRT group. Therefore, the finding of no significant difference in OS among the two groups may be attributed to PSM. However, OS in the SBRT group was comparatively longer than that in the cEBRT group. The high OR rate and low local failure rate of SBRT may have contributed to the maintenance of the general condition and activities and subsequent prolongation of survival .p = 0.044) according to a matched pair analysis [Fractures are relatively common AEs of bone SBRT. High-dose radiation damages the bone matrix and degrades the vascular supply to the bone, leading to bone fractures . The incanalysis . The preanalysis . AccordiThe current study has some limitations. First, this was a retrospective cohort study and not a randomized controlled trial, although PSM analysis was used to minimize selection bias. Second, the sample size was insufficient to obtain any conclusive results. Third, patients with osseous oligometastases were included in the SBRT group only. A total of 33 lesions (41%) in the SBRT group were oligometastases (24 oligometastases and 9 oligo-progressive diseases), and the SBRT was performed for curative intent. Contrarily, all cEBRTs were conducted for palliative intent. It cannot be denied that the difference might have affected the pain response because of the presence of other painful lesions.The present PMS analysis showed that SBRT for non-spine bone metastases was superior to cEBRT in terms of the 3-month pain response rate and demonstrated some advantages, such as a high CR rate and long-term pain control. The findings of this study warrant a large-scale randomized controlled trial comparing SBRT with cEBRT in a clinical setting.


Patients with chronic pain are frequently excluded from trials because of comorbidities. More inclusive studies will have better generalizability considering differences between excluded and included patients. The ability of clinical trials to inform the care of chronic pain may be limited if only an unrepresentative subset of patients are allowed to enroll. We summarize and report new insights on published studies that report on how trial exclusions affect the generalizability of their results. We conducted a PubMed search on the following terms:  OR  OR “exclusion criteria”[ti] OR “eligibility criteria”[ti]) AND pain. We only considered studies relevant if they analyzed data on (1) the prevalence and nature of exclusion criteria or (2) the impact of exclusion criteria on sample representativeness or study results. The 4 articles that were identified reported differences in patients who were included and excluded in different clinical trials: excluded patients were older, less likely to have a paid job, had more functional limitations at baseline, and used strong opioids more often. The clinical significance of these differences remains unclear. The pain medicine literature has very few published studies on the prevalence and impact of exclusion criteria, and the outcomes of excluded patients are rarely tracked. The frequent use of psychosocial exclusions is especially compromising to generalizability because chronic pain commonly co-occurs with psychiatric comorbidities. Inclusion of more representative patients in research samples can reduce recruitment barriers and broaden the generalizability of findings in patients with chronic pain. We also call for more studies that examine the use of exclusion criteria in chronic pain trials to better understand their implications. This exclusionary approach, while often necessary for efficacy or mechanistic studies, comes at the cost of having study samples that poorly represent the real-world population with the studied disease. The nature of the research question usually determines if the eligibility criteria need to be more exclusive vs more inclusive. Explanatory trials determine efficacy of an intervention under ideal circumstances and thus requires a more homogeneous population. However, these trials have to be followed by more pragmatic trials to determine the effectiveness of the same intervention under general conditions that it is intended to be applied.24Roughly 20% of adults in the United States suffer from chronic pain, with 8% experiencing high-impact chronic pain29 rheumatology,27 and infectious disease.21 Whether this same problem occurs in pain medicine has not been studied. We therefore reviewed available studies that evaluate differences in baseline characteristics or outcomes between included and excluded participants in chronic pain trials, and we summarize the impact of these exclusions on study results when applicable.The degree to which the results from a study can be applied to a larger or more heterogeneous population is referred to as generalizability, or external validity. In recent years, the generalizability of RCTs has come under scrutiny in several disciplines, including psychiatry,10 We applied the same search strategy and terms used by the CREAM project, but with a different condition of interest (pain). We did not preregister our protocol because our methods more closely resemble a literature review, rather than a systematic review.We closely emulated the methods of the Cross-disease Review of Exclusion Across Medicine (CREAM) project previously presented by Humphreys and colleagues. Their project assessed the impact of exclusion criteria in research conducted across a range of medical specialties. A detailed description of the literature review procedure can be found in the article on schizophrenia trials by Humphreys.17 Both authors chose similar studies that met our relevance criteria.Literature was primarily identified by conducting English-language searches in PubMed  on the following terms: “Eligibility criteria and generalizability” (anywhere in article), “exclusion criteria and generalizability” (anywhere in article), “exclusion criteria” (in the title of article) and “eligibility criteria” (in the title of article)  OR  OR “exclusion criteria”[ti] OR “eligibility criteria”[ti]) AND pain). This generated 822 articles. Like other CREAM projects, we then focused on patients with chronic pain by adding the search term “pain (anywhere in the article)” to the other search terms; this resulted in 24 articles. We considered studies relevant if they analyzed data on (1) the prevalence and nature of exclusion criteria and/or (2) the impact of exclusion criteria on sample representativeness or study results. We excluded studies that only reported their exclusion criteria and rate. The first authors (V.S. and T.L.) independently reviewed all these articles and their references to other studies of exclusion criteria ,13 knee osteoarthritis (1 article),11 and postoperative pain after hip and knee arthroplasty (1 article).18One clinical trial and 3 review articles  met our relevance criteria.13Maas et al. analyzed the outcomes of 1148 participants in a pragmatic multicenter trial to treat low back pain. They compared the outcomes of a randomized group (n = 241) to 2 observational groups who received the studied treatment without randomization. Observational group 1 (n = 455) consisted of participants who fulfilled all eligibility criteria but were not randomized. Observational group 2 (n = 452) consisted of participants who did not meet eligibility criteria. Both observational groups 1 and 2 received the study treatment. Their sample was drawn from 16 Dutch clinics and 102 physiotherapy practices. The authors explain that the eligibility criteria of the randomized group were “standardized” and they were similar to the ones used by pain physicians in clinical practice in the Netherlands.13The most frequently applied exclusion was “psychological problems” which prevented 60.8% of participants in observational group 2 from enrolling in the RCT, including those with other exclusions (17.5%). Age and body mass index were the second (31.2%) and third (16.2%) most frequently applied exclusions, respectively. Participants with multiple overlapping criteria made up 19.2% of excluded participants. The combined effect of all criteria was to exclude 452 of 1148 (39.4%) participants who had otherwise been deemed eligible during initial screenings but were instead diverted to observational group 2. Compared to participants in the randomized group and observational group 1, those in observational group 2 were older, less likely to have a paid job, had more functional limitations at baseline, and used strong opioids more often.13Regarding outcomes from the study by Maas et al., patients who had pain from facet joints had slightly less pain relief if they were in observational group 2 compared with randomized patients . No differences in pain scores were found in observational group 2 patients who had pain from sacroiliac (SI) joints. Patients in observational group 2 also had slightly less improvement in functional status , and a lesser likelihood of perceiving treatment success . The authors report that these statistically significant differences were too small to be clinically relevant.11 did not tabulate the number of included or excluded participants, nor did they compare baseline characteristics or outcomes of excluded participants to included participants.Koog et al. reviewed 355 RCTs for knee osteoarthritis which were published up to December 2011. They divided exclusion criteria into “non–osteoarthritis-related” and “osteoarthritis-related” reasons. Ten exclusion criteria were identified in the non–osteoarthritis-related category. Inability to give informed consent was the most commonly applied non–osteoarthritis-related exclusion , followed by recent exposure to other potential treatments (61.4%) and medical conditions that make it difficult to participate in a trial (57.2%) or might pose a risk to receiving treatment (56.0%). Other psychological or psychiatric exclusions were not identified in the review; however, it is unclear whether these were included under “medical conditions.” In the osteoarthritis-related category, 9 overlapping exclusion criteria were identified. Lower boundaries of age were the most common osteoarthritis-related exclusion (58.9%), followed by exclusion of nonpainful osteoarthritis (58.3%) and limits on osteoarthritis severity (47.3%). Koog et al.1Amundsen et al. reviewed 168 RCTs for chronic low back pain published between 2006 and 2012. Exclusion criteria were noted to be highly diverse, so the authors categorized exclusion criteria into 19 themes. The most ubiquitous exclusion themes were causes of back pain from other conditions, including malignancy  or trauma (37.5%). Pregnancy was a common exclusion criterion (48.2%) as was having previous or scheduled surgery (50%). Noteworthy exclusion criteria frequently encountered in real-world patients include psychosocial conditions  (34.5%) and medicolegal issues (23.2%). Amundsen et al. did not tabulate the number of included or excluded participants, nor did they compare baseline characteristics or outcomes of excluded participants to included participants.18Finally, Pedersen et al. analyzed the exclusion criteria used in 550 RCTs investigating postoperative pain treatment for hip and knee total arthroplasty. The authors also compared baseline characteristics from 48,962 research participants enrolled in RCTs with an unrandomized clinical cohort from the Danish Hip and Knee Arthroplasty Registries from 2005 to 2019. The authors found that the most commonly used exclusion criteria were having a high American Society of Anesthesiologists (ASA) Physical Status Classification score , older age (45%), chronic opioid use (41%), neurological disorders (41%), and renal disease (40%). Psychiatric or cognitive exclusions were used in 29% of trials.18Research participants were on average younger than their clinical counterparts; however, body mass index (BMI) American Society of Anesthesiologists (ASA) physical status scores, and sex distribution were comparable. When examining trends over time, the enrolled research participants' average age has increased, and in the subgroup of patients undergoing total knee arthroplasty, BMI and ASA scores have also increased. Meanwhile, age, BMI, and ASA scores in the research cohort have not changed, although fewer women are being included in total hip arthroplasty trials over time. The prevalence of other exclusion criteria  was not reported in either cohort. The total number of included or excluded participants from the research cohort was not reported either.18 This leaves out large swaths of other common chronic pain conditions such as migraine, lumbar radiculopathy, and peripheral neuropathy. One study compared the outcomes of randomized patients with excluded patients who had received the studied treatment outside of the RCT.13 Three review articles reported on the nature and prevalence of exclusion criteria used in clinical trials18; only one of them analyzed differences in baseline characteristics by comparing trial patients with a national database of nontrial patients.18 None of the review articles estimated exclusion rates, probably because the number of patients excluded before randomization is inconsistently reported by RCTs.18The current review found very few published studies on the prevalence and impact of exclusion criteria in clinical trials for chronic pain. Disease entities were limited to knee osteoarthritis, pain after hip and knee arthroplasty, and chronic low back pain.13 Exclusions are usually designed assuming that they result in more heterogeneous outcomes. The interpretation of the authors shows that this assumption is wrong and more strict exclusion criteria were unnecessary. However, we believe that the difference in perceived treatment success is clinically impactful because patients who believe that their treatment was unsuccessful are more likely to seek additional medical care and less likely to return to work, with resultant costs to the healthcare system and society.The authors of the study that followed excluded patients with chronic low back pain argued that the differences in outcomes between randomized and excluded patients were too small to be clinically relevant, despite reaching statistical significance. We agree that the mean differences seen with numeric pain scores and Oswestry Disability Index scores are relatively inconsequential.E − I0), where IE is the incidence of harm in those with exclusionary comorbidities and I0 is the incidence of harm in those without exclusionary comorbidities. Based on data reported by Maas et al., the NNH for having exclusionary comorbidities was 8 for patients with pain from facet joints and 12 for patients with pain from SI joints. This means that for every 8 patients with exclusionary comorbidities receiving treatment for facet joint pain, 1 patient will report a lack of treatment success 3 months after treatment. Likewise, for every 12 patients with exclusionary comorbidities receiving treatment for SI joint pain, 1 patient will report a lack of treatment success 3 months after treatment. As a point of reference, the NNH for gabapentin causing somnolence7 is reported to be 11.Another way to interpret the difference in perceived treatment success is by calculating the number needed to harm (NNH) for having exclusionary comorbidities. Number needed to harm measures how many people need to be exposed to a risk factor for 1 person to experience an adverse effect or harm. A lower NNH indicates a greater risk of harm. In this case, if we define “harm” as a lack of perceived treatment success 3 months after receiving treatment, we can use the formula NNH = 1/ can influence the choice of eligibility criteria, overly restrictive exclusion criteria and exclusion of highly prevalent comorbidities may also threaten the external validity of randomized controlled trials. In the field of pain management, there are very few published studies on the prevalence and impact of exclusion criteria, and the outcomes of patients excluded from randomization are rarely tracked. The frequent use of psychiatric and psychosocial exclusions in chronic pain trials is especially concerning because chronic pain commonly co-occurs with—and in some cases, perpetuates these issues. We call for more studies that examine the use of exclusion criteria in chronic pain trials. Understanding the implications of exclusions in these trials is particularly pertinent given the complexities of patients with chronic pain. Ultimately, such studies are important to determine whether the inclusion of more representative patients in research samples can reduce recruitment barriers and broaden the generalizability of study findings across chronic pain populations.19We also recommend more transparent reporting of exclusion criteria in chronic pain trials because this will promote interpretability of results and facilitate future research on the effects of exclusion criteria. Finally, we call for more inclusive studies with less stringent exclusion criteria because this will promote generalizability of results to real-world patient populations. Although increased heterogeneity in the study population will necessitate larger sample sizes to discern an effect of an intervention, pragmatic trial designs embedded into existing practice settings can be used to recruit large numbers of participants at lower cost than conventional trials.The authors have no conflict of interest to declare.


Electroencephalogram (EEG)-derived pain threshold index (PTI) has been developed as a novel pain recognition indicator and has been proved to be useful in the prediction of acute postoperative pain in adults. Evidence of its usability in children is limited. The aim of this study was to investigate the prediction value of this novel pain indicator PTI for acute postoperative pain in children.A total of 80 patients undergoing laparoscopic surgery under general anesthesia were enrolled. Blood pressure, heart rate (HR), surgical pleth index (SPI), PTI, and EEG-derived sedative index-wavelet index (WLI) data were recorded at the end of the surgery. The postoperative pain scores Face, Legs, Activity, Cry, Consolability (FLACC) were obtained in the emergence room 5 min after the children wake up. Receiver-operating characteristic curve was performed to analyze the predictive value of PTI, SPI, HR, and mean arterial pressure (MAP). The consistency between SPI and PTI was also evaluated.Results showed that the areas under curves (95%CI) of PTI and SPI were 0.796 (95% CI: 0.694–0.895) and 0.753 (95% CI: 0.632–0.874), respectively, with the best cut-off value of 58 and 45 to discriminate between mild and moderate to severe pain.This study suggested that PTI obtained at the end of the surgery could predict acute postoperative pain in children with an acceptable accuracy. It will help with early recognition and treatment of postoperative pain, thus reducing the pain in children. In addition, PTI had a good consistency with SPI in predicting acute postoperative pain in children. Emergence agitation (EA) is the most common adverse event during early recovering from general anesthesia, especially for preschool-aged children, presenting as excitation, restlessness, nonpurposeful movement, inconsolability, and disorientation, which significantly increases the risk of self-injury and prolonged hospital stay and requires additional nursing staff and medical care costs , 2. HoweTimely identification and management of postoperative pain would be helpful to reduce or prevent EA incidence. However, it is very challenging to reach an appreciable analgesic level without respiratory depression due to the lack of reliable pain assessment tools, especially for those pediatric patients during early recovery from general anesthesia. Many objective pain assessment methods, such as pupil diameter, skin conductance (SC), heart rate variability (HRV), analgesia/nociception index (ANI), and surgical pleth index (SPI), have been used to evaluate the intensity of noxious stimulation and guide intraoperative analgesia under general anesthesia in adult patients –6. HowevRecently, a novel pain recognition index, pain threshold index (PTI) based on integrated electroencephalogram (EEG) wavelet analysis was developed to reflect the antinociceptive state under general anesthesia by Beijing Easymonitor Technology Co., Ltd, Beijing, China. The theoretical base of the PTI algorithm was based on dissecting the scalp EEG signals into both cortical and subcortical signals by EEG wavelet analysis. Our previous study showed that PTI can be used to predict the hemodynamic reactivity induced by endotracheal intubation and skin incision in pediatric patients . AdditioThis prospective observational clinical study was approved by the Ethics Committee of the Shanghai Children's Medical Center (SCMCIRB-K2021003-1) and registered on the Chinese Clinical Trials Registry (ChiCTR2100054032). The study was performed between December 10, 2021, and August 30, 2022. After obtaining written informed consents from parents, the patients undergoing elective surgery of laparoscopic hernia repair were enrolled in this prospective observational study. The flow diagram of this trial is shown in β receptor blockers, or any other drugs suspected of interacting with sympathetic nerve balance.The pediatric patients of American Society of Anaesthesiologists (ASA) I–II aged 2–7 years who were scheduled for nonemergency laparoscopic hernia surgery under general anesthesia were included. Exclusion criteria included preoperative chronic pain history, neuropsychiatric disease, craniotomy history, severe cardiovascular disease, drug dependence, arrhythmia and pacemaker implantation history, use of vasoactive drugs during data collection and intraoperative use of ketamine, For pediatric patients younger than 4 years old, 0.5 mg/kg midazolam was administered orally as premedication 20–30 min before entering the operating room. Other patients without premedication received 0.1 mg/kg midazolam IV during induction. The standard anesthetic management was adopted during perioperative period. In brief, all the patients were induced with propofol (2–4 mg/kg), fentanyl (2 µg/kg), and rocuronium (0.6 mg/kg). After successful intubation, ultrasound-guided bilateral abdominal transverse fascia block was conducted before surgery. General anesthesia was maintained with propofol (5 mg/kg h) and remifentanil (0.2–0.3 µg/kg min), with or without sevoflurane according to the hemodynamic changes during the surgery. In addition to standard monitoring, data on blood pressure (BP), heart rate (HR), SPI, EEG-derived sedative index-wavelet index (WLI), and PTI were recorded at the end of the surgery (during skin closure). During the data collection period, the WLI was not permitted to increase to >60. To avoid interference from the medications, vasoactive drugs and naloxone were not used. Patients will be excluded from this study if these drugs are necessary. The patients were sent to the post-anesthesia care unit (PACU) after extubation for recovery. The Face, Legs, Activity, Cry, Consolability (FLACC) evaluation was performed 5 min after the patients woke up. The children were considered awake when they were able to open their eyes when called and can respond purposefully. If the pain score was greater than 4 points, then pain treatment was guided by our standard protocol in PACU and not influenced by this study.SPI measurement was performed from a finger on the side opposite to the Non-Invasive Blood Pressure (NIBP) measurement through a saturation sensor . The plethysmographic waveform was continuously recorded and reanalyzed to produce the normalized pulse plethysmographic amplitude (PPGAnorm), and the normalized heartbeat interval (HBInorm). The published equation for the value (0–100) is SPI = 100 − (0.7 × PPGAnorm + 0.3 × HBInorm) .EEG-derived WLI and PTI were monitored with a multifunction monitor . After the skin of the forehead and mastoid was cleaned with alcohol cotton pads, the EEG collection electrodes were placed on the patients’ forehead and mastoid. The placement of the electrodes was followed by the instruction from a previous study . Real-tivia the continuous wavelet transforms, binary discrete wavelet transforms, and the frequency domain reconstruction algorithm. Furthermore, it was analyzed by the waveform recognition algorithm, the spectral analysis algorithm, and the wavelet analysis algorithm. Finally, the values of WLI (0–100) and PTI (0–100) are displayed on the monitor screen in real time as dimensionless scores, and the values are updated every 2 s.The principle of the EEG-derived PTI calculation is based on the wavelet algorithm, which was described in detail in a previous study . BrieflyP < 0.05 was considered as statistically significant. According to the results of previous research, area under the curve (AUC) of PTI was 0.772. We assume an AUC of 0.75 with α = 0.05, β = 0.10, and a 15%–20% loss of patients because of protocol violations; the sample size calculated was 66. We finally recruited 80 patients and 72 were included for final analysis. Continuous data were expressed as mean ± standard deviations (SD) while categorical variables were presented as category counts. Bland–Altman analysis was used to characterize the consistency between SPI and PTI. Receiver-operating characteristic (ROC) curves and the associated AUC were analyzed to characterize the predictive value of SPI, PTI, HR, and mean arterial pressure (MAP) for postoperative pain defined as FLACC ≥4. For the description of the best-fit cut-off values, Youden's point (highest combined sensitivity and specificity) was used.Statistical analyses were performed using the IBM SPSS Statistical 21.0  and GraphPad Prism 8.0.1 , and We initially recruited 80 patients who met the inclusion criteria during the study period. Eight patients were excluded due to protocol violation and technique problem. Finally, data from 72 patients were included for final analysis. The flow chart of the study is present in P < 0.05) had a good predictive accuracy for postoperative acute pain compared with SPI , HR  and MAP . According to ROCs, the best-fit (highest combined sensitivity and specificity) cut-off values were defined to distinguish mild pain from moderate-to-severe pain after surgery. The cut-off value of PTI were 58 with the sensitivity of 0.80 and specificity of 0.71. In contrast, the cut-off values of SPI and HR were 45 with sensitivity of 0.60 and specificity of 0.88 and 87 with sensitivity of 0.73 and specificity of 0.64, respectively. The ROC curves of these indexes to predict postoperative acute pain are displayed in To analyze the ability of the SPI, PTI, HR and MAP to predict postoperative acute pain, ROC curves were plotted and the associated AUCs were calculated. The results showed that PTI  of PTI and SPI and found that the PTI < 58 had an 80.6% (95% CI: 67.7%–93.5%) NPV to exclude moderate to severe pain. The NPV for SPI < 45 for the absence of moderate to severe pain was 73.5% (95% CI: 61.1%–85.9%).The values of SPI and PTI were measured simultaneously at the end of the surgery. To study whether PTI had good agreement with SPI, the Bland–Altman plot was used. The Bland–Altman plot of the difference between PTI and SPI against the mean of PTI and SPI in the 72 patients showed that the mean difference (bias) of the measurements between PTI and SPI is 17.97. The SD of the difference is 15.62. The 95% limit contains 95% (69/72) of the difference values, which revealed that there is a good consistency between PTI and SPI, suggesting that PTI can be used to measure pediatric pain nociception under general anesthesia like SPI. The result was shown as In this study, we found that PTI obtained at the end of the surgery could predict the occurrence of acute postoperative pain with an acceptable accuracy in children. Furthermore, there was a good consistency between PTI and SPI at the end of pediatric surgery, which is in line with adult patients. In addition, HR instead of MAP can also be used as an indicator for acute postoperative pain.PTI as a novel EEG-derived pain recognition index has been used to predict hemodynamic reactivity induced by trachea intubation and skin incision in pediatric patients and predict acute postoperative pain in adult patients between mild and moderate-to-severe pain . In thisIt is well-known that SPI derived from the analysis of the plethysmographic pulse wave amplitude and interval could reflect the different levels of autonomous nerve system activation, which is often caused by pain stimulation. Mounting studies have shown that SPI has the potential to reflect intraoperative noxious stimulation and guide the administration of opioids in adult patients , 11, andAlthough our study also demonstrated that the PTI has a good consistency with SPI in predicting the incidence of acute postoperative acute pain in pediatric patients, SPI is affected by heart rates or rhythm changes induced by drugs affecting sympathetic tone or changing HR, cardiac diseases, and changes in blood volume. Therefore, these factors should be ruled out when SPI is used to reflect the noxious stimulation, which is quite different from PTI since it is based on EEG wavelet analysis.The changes of hemodynamic parameters including HR and blood pressure are usually used to monitor the response to noxious stimulations and reflect whether the analgesic level is sufficient during general anesthesia. In our study, we found that HR instead of MAP can also be used as an indicator for acute postoperative pain. However, the heart rate changes rapidly and is easily affected by external factors. Also, in children, heart rate is highly variable with age, so we cannot yet conclude that heart rate can predict postoperative pain, and further research is needed.There are also some limitations in our study. First, only children aged 2–7 years old were included into our study, and our result cannot be extended to patients younger than 2 years or older than 7 years. Second, when PTI was measured at the end of surgery, the WLI value reflecting the sedative depth was restricted to less than 60, whether WLI value over 60 can affect the predictive accuracy of PTI is unknown. Third, no vasoactive drugs and opioid antagonists were used in our study. Whether these medicines can affect the predictive accuracy of PTI is also unknown. In addition, due to the confidential consideration, we cannot provide more detailed explanation about the algorithm used by this equipment. The possible mechanism we can speculate is that PTI reflects the cortical pain threshold state before noxious stimulations through separating the integrated scalp EEG signals into cortical and subcortical neuronal activities using EEG wavelet analysis. More studies are needed to confirm this approach.In conclusion, PTI obtained at the end of the surgery could be used to predict the incidence of acute postoperative pain in children aged 2–7 years with an acceptable accuracy and it has a good consistency with SPI. The index can help with early recognition and treatment of postoperative pain, thus improving perioperative comfort and satisfaction of children.


Expansion of clinical guidance tools is crucial to identify patients at risk of requiring an opioid refill after outpatient surgery.The objective of this study was to develop machine learning algorithms incorporating pain and opioid features to predict the need for outpatient opioid refills following ambulatory surgery.Neural networks, regression, random forest, and a support vector machine were used to evaluate the data set. For each model, oversampling and undersampling techniques were implemented to balance the data set. Hyperparameter tuning based on k-fold cross-validation was performed, and feature importance was ranked based on a Shapley Additive Explanations (SHAP) explainer model. To assess performance, we calculated the average area under the receiver operating characteristics curve (AUC), F1-score, sensitivity, and specificity for each model.There were 1333 patients, of whom 144 (10.8%) refilled their opioid prescription within 2 weeks after outpatient surgery. The average AUC calculated from k-fold cross-validation was 0.71 for the neural network model. When the model was validated on the test set, the AUC was 0.75. The features with the highest impact on model output were performance of a regional nerve block, postanesthesia care unit maximum pain score, postanesthesia care unit median pain score, active smoking history, and total perioperative opioid consumption.Applying machine learning algorithms allows providers to better predict outcomes that require specialized health care resources such as transitional pain clinics. This model can aid as a clinical decision support for early identification of at-risk patients who may benefit from transitional pain clinic care perioperatively in ambulatory surgery. Opioids play an essential role in acute perioperative pain management. Increased attention to pain management as a quality metric has brought to light an overuse of prescription opioids contributing to an epidemic across the United States. The United States has had increased opioid prescriptions filled in the immediate postoperative period; a study reported that the mean dose of opioids prescribed for most surgical procedures in the United States was higher than that prescribed in other countries . Opioid-Persistent opioid prescribing is often postsurgical , in whicThe objective of this study was to develop machine learning–based predictive models that may aid in the identification of patients likely to require opioid refills after their initial discharge prescription. Specifically, pain score patterns were incorporated  into the models. We focused on patients who underwent ambulatory surgery, which included orthopedic surgery , nonmastectomy breast surgery, urology , minimally invasive surgery , colorectal surgery , and gynecology . We hypothesized that the use of neural networks that incorporate various features, including recovery room pain phenotypes, may identify patients at higher risk. The pain phenotypes included patterns in patient-reported pain scores in the recovery room, including trajectory of pain and median and maximum pain scores.Data were retrospectively collected from the electronic medical records of patients who underwent outpatient surgery from January to July 2020 at a single ambulatory surgery center. The outpatient surgeries included in the analysis included orthopedic surgery , nonmastectomy breast surgery, urology , minimally invasive surgery , colorectal surgery , and gynecology .Our institutional review board (Human Research Protections Program) waived the consent requirement and approved this retrospective study (protocol 210099).The primary outcome of interest was a binary variable , in which 0 was defined as “no opioid refill” and 1 was defined as the patient “needed to refill their outpatient opioid prescriptions” within 2 weeks after surgery (no opioid refill vs opioid refill). This was captured retrospectively from the electronic medical record by review of the following: (1) any telephone note describing patient calling in for opioid renewal; (2) any progress/office visit note from primary care provider, pain medicine specialist, or surgical provider describing the need for opioid refill; or (3) any renewal order in the medication list for opioids within this time frame. On postanesthesia care unit (PACU) discharge, all patients were prescribed up to 5 days of opioids. For perioperative multimodal analgesia, all patients received preoperative acetaminophen unless contraindicated. For a subset of surgical procedures, regional nerve blocks were routinely offered preoperatively . Intraoperatively, patients may have received fentanyl, hydromorphone, ketamine, ketorolac, and dexmedetomidine at the discretion of the anesthesiologist. In the PACU, patients were given oxycodone, fentanyl, and hydromorphone, as needed.2), English-speaking, comorbidities, regional nerve block performance, general anesthesia, intraoperative ketamine, intraoperative total intravenous anesthesia, opioid consumption, and pain scores . These features were included, as they were determined to be relevant to postoperative opioid use based on clinical judgement and previous research [Features that were integrated into the model were collected retrospectively from the electronic medical record system. The data included age (years), sex , body mass index  for the receiver operating characteristic curve. The final version of each model was then validated on the test set and the AUC was reported. Feature importance from the neural network was ranked based on Shapley Additive Explanations (SHAP).Python (v3.10.1) was used for all statistical analyses. Patient and surgical characteristics were compared with chi-squared test  and Wilcoxon rank sum test (continuous). A generalized linear mixed model fit by maximum likelihood was implemented to model the features to the primary outcome of opioid refill. The random effect in this model was the surgical procedure. All features were included in the model, and their association with the outcome was reported by their respective odds ratios (ORs), 95% CI, and Synthetic Minority Oversampling Technique (SMOTE) for Nominal and Continuous algorithm and random undersampling were both implemented using the imblearn library . These tRandom undersampling of the majority outcome is frequently used to reduce the impact of imbalanced data sets; however, SMOTE oversamples were used to create synthetic minority class examples to balance the minority class with the majority class. SMOTE uses samples from the minority class and a set number of nearest neighbors—in this case, 5—to generate synthetic cases from the sample class. Combining the 2 techniques as outlined yielded positive outcomes. Both techniques were only applied on the training set. Different combinations for proportions of minority to majority class were analyzed, ranging from 0.25 to 1.00. After performing k-fold cross-validation, the parameter “sampling_strategy” for the SMOTE class from imblearn was optimal when set to 0.24 and the parameter “sampling_strategy” for the RandomUnderSampler class from imblearn was optimal when set to 0.94. Optimal results were based on which hyperparameters produced the highest performance metrics for the model .Four different machine learning classification models were evaluated: neural network, logistic regression, random forest classifier, and support vector classifier. For each model, the following sampling methods were compared: oversampling the training set via SMOTE, undersampling the majority class in the training set, a combination of SMOTE and undersampling of the majority classes, and no oversampling or undersampling technique. The results from the sampling method that provided the optimal results were reported. For each model, all features were included as inputs. One-hot encoding was used for categorical features. Using the Keras interface for the TensorFlow library, a shallow feedforward neural network was constructed. The rectified linear unit function was used as the activation function. The final output layer used the sigmoid activation function, and the overall model used the Adam optimizer. Repeated k-fold cross-validation was used to tune the hyperparameters to find the optimal parameter values for the number of hidden layers (1), number of neurons per hidden layer (100), maximum number of iterations (300), batch size (16), and learning rate (0.0001).C , which was 0.3.The logistic regression classifier predicts the probabilities of the different outcome possibilities based on the input. A newton-cg solver regression model was implemented without specifying individual class weights. This model provided a baseline score and helped make the case for improvement over the evaluation metrics. Repeated k-fold cross-validation was used to tune the hyperparameters to find the optimal parameter value for The random forest is an ensemble approach, which has been proven effective for a variety of classification problems. To tune the hyperparameters, we performed repeated k-fold cross-validation to find the optimal parameter values for maximum depth (75), minimal samples required to be at the leaf node (4), minimal samples required to split an internal node (4), and number of estimators (100) .C, which was 130. A support vector classifier maps the data onto an n-dimensional space (n being the number of features) and then identifies the hyperplane decision boundary that best separates the data into 2 classes by maximizing the distance between the hyperplane and the nearest data point in either class. K-fold cross-validation was used to tune the hyperparameters to identify the optimal parameter value for The primary performance metric of interest was the AUC for the receiver operating characteristic curve. In addition, we reported F1-scores, sensitivity, and specificity.To effectively tune the hyperparameters of the models, stratified k-fold cross-validation was implemented on the training set to observe the sensitivity, specificity, F1-score, and AUC scores, for 10 splits. For each iteration, the data set was split into 10 groups (folds). One fold served as the test set with the other 9 serving as the training set. When assessing the effectiveness of SMOTE and random undersampling, only the training folds were changed. This process was repeated until each fold served as the test set once. Every model exhibited improved performance metrics when SMOTE and random undersampling were applied.P=.005) and had a regional nerve block performed . Those who required opioid refills had higher total perioperative opioid consumption , preoperative pain scores (P<.001), maximum PACU pain scores (P<.001), and median PACU pain scores (P<.001). There were 1333 patients and 28 unique surgical procedures included in the final analysis, and 144 (10.8%) patients refilled their opioid prescription within 2 weeks after outpatient surgery. Univariate analysis revealed that patients who required opioid refills were more likely to be smokers , substance abuse history , regional block performed , total opioid consumption (MEQ mg) intraoperatively and in PACU , and median PACU pain score (NRS) . A feature that was significantly associated with decreased odds of opioid refill was English-speaking patients .The need for opioid refill within 2 weeks after ambulatory surgery was modeled utilizing a mixed effects logistic regression analysis fit by maximum likelihood, in which the random effect was the surgical procedure . FeatureP values were performance of a regional nerve block, maximum pain score in the PACU, median pain score in the PACU, active smoking history, and total opioid consumption (intraoperative and PACU) . The final model was then validated on the test set, which yielded an AUC of 0.75 . The feand PACU) .Next, various other machine learning–based models were implemented to predict the need for opioid refills after ambulatory surgery. Based on k-fold cross-validation, the average AUCs from models with optimized hyperparameters were identified for support vector machine , random forest , and logistic regression  . The finWe demonstrated that a shallow feedforward neural network and other machine learning approaches that integrated pain score patterns had adequate performance to predict the need for opioid refills within 2 weeks following ambulatory surgery. The features with the highest impact on model output were active smoking history, intraoperative opioid consumption, PACU opioid consumption, regional nerve block utilization, as well as maximum and median pain scores in the PACU. The importance of pain score patterns  in predicting opioid refills is interesting and highlights the association of PACU analgesia and opioid consumption with the requirement for more opioids following the initial prescription. This neural network may be useful in identifying patients at risk who require a longer duration of opioid use so that the limited hospital resources can be better utilized in a precise manner.Previous studies have reported the utilization of machine learning for predicting postoperative opioid use in ambulatory surgery ,17. NairOpioids remain the cornerstone for acute postoperative pain management, and the perioperative period is often the patients’ first introduction to prescription opioids. Our study’s patient cohort was primarily opioid-naïve; only 4.6% 55/1189) of the patients in the non–refill group and 5.6% (8/144) of the patients in the refill group reported preoperative opioid use. Studies have shown surgical procedure as an independent risk factor for prolonged opioid use ,20. Othe189 of thAn estimated 67%-92% of the prescribed opioids for postoperative pain remain unused ,32, leavThe use of regional anesthesia was associated with opioid refilling. It is important to note that there is no causality that may be drawn from these results but rather an association. It may be that the use of regional anesthesia was associated with surgeries that were more painful in nature, and despite pain scores being likely lower in the PACU, this group would more likely require additional opioids as outpatients when compared to other surgical procedures that are less likely to receive regional anesthesia for pain management. Other potential limitations include the variability in surgery type, which may range in pain level, both during surgery and during recovery, as well as the subjective nature of pain scores. Despite these limitations, the features that have been identified are actionable and trackable in future studies.There are several limitations in this study—mainly due to the inherent limitations of a retrospective analysis. First, the primary outcome (opioid refills) may potentially be underestimated, as we captured this data based on clinical notes and orders in the electronic medical record system. It is possible that the need for opioid refills was missed in some patients who sought care outside of our health care system (and thus not recorded in our records). However, we extracted the data via a manual clinician review to optimize accuracy as much as possible. A prospective study would be needed to assess the incidence of postsurgical opioid refills more accurately. Second, an issue of generalizability is also of concern, as this is single-institution data. Model performance  could decrease in a surgical population outside of this institution. To avoid the issue of overfitting and, thus, limited generalizability, we calculated the metrics from k-fold cross-validation and furthermore used a holdout data set for validation. What is needed is a high-quality prospective study that can more accurately capture the features and outcomes from each patient and, subsequently, be validated at external institutions.Early identification of at-risk patients prior to their elective surgical procedure is the key. These patients can then be referred to establish care with a dedicated and comprehensive transitional pain program. Built on solid evidence-based medicine, this multidisciplinary transitional pain service includes anesthesiology, pharmacy, psychiatry, and physical therapy. Patients are often evaluated preoperatively to help manage expectations regarding anticipated postoperative pain and offer preoperative weaning when appropriate. This anesthesiologist-led team makes recommendations about intraoperative and immediate postoperative pain management , includiApplying machine learning algorithms to electronic health data allows providers to develop models to predict more accurately and therefore appropriately allocate the limited health care resources . In this study, we showed that the need for regional anesthesia, high intraoperative opioid consumption, increased PACU pain scores, and opioid consumption were important features in models predicting outpatient opioid refills. Although providers are aware of the potential risk factors of opioid misuse, it remains challenging to accurately predict patients that will benefit from services as an outpatient. This prediction model serves as an example of a model that could be formalized into clinical decision support tools to help us better understand which patients will benefit from transitional pain clinics following ambulatory surgery.


Instrumentation group patients had a significantly longer hospital stay but no ICU stay. In-hospital and 90-days mortality rates were similar in both groups. The mean follow-up was 26.6±12.4 months. No further surgeries were performed. Infection levels and neurological status were improved in both groups at discharge. At the second-stage analysis, significant improvements in the blood infection parameters and the neurological status were detected in the decompression group. Octogenarians with PVO and SEA have a high adverse events risk after surgical procedures. Surgical decompression might contribute to earlier clinical recovery in older patients. Thus, the surgical approach should be discussed with patients and their relatives and be carefully weighed.Despite increased life expectancy due to health care quality improvements globally, pyogenic vertebral osteomyelitis (PVO) treatment with a spinal epidural abscess (SEA) remains challenging in patients older than 80 years. We aimed to assess octogenarians for PVO prevalence with SEA and compare after-surgery clinical outcomes of decompression and decompression and instrumentation. A retrospective review of electronic medical records at a single institution was conducted between September 2005 and December 2020. Patient demographics, surgical characteristics, complications, hospital course, and 90-day mortality were collected. Comorbidities were assessed using the age-adjusted Charlson comorbidity index (CCI). Over 16 years, 35 patients aged ≥80 years with PVO and SEA were identified. Eighteen patients underwent surgical decompression (“decompression group”), and 17 underwent surgical decompression with instrumentation (“instrumentation group”). Both groups had a CCI >6 (mean±SD, 8.9±2.1 vs. 9.6±2.7, respectively;  Despite accelerating improvements in the quality of health care worldwide, pyogenic vertebral osteomyelitis (PVO) with concomitant spinal epidural abscess (SEA) remains a potentially devastating condition. PVO is caused by bacterial infection of the vertebral bodies that can extend into the adjacent intervertebral disc , while SIn the case of older and frail patients, the choice of therapy remains controversial, considering perioperative risks associated with patients’ poor general clinical condition. The scarcity of robust evidence concerning the optimal treatment for PVO with SEA in older adults, especially in octogenarians, hampers physicians who must quickly decide whether to perform a surgical procedure.Owing to the lack of clinical evidence on this topic, we aimed to assess and compare the clinical course and determine morbidity and mortality rates after surgical decompression only versus surgical decompression with instrumentation, exclusively in octogenarians.We retrospectively evaluated the clinical and imaging data collected from our institution’s database between September 2005 and December 2020. This study was approved by the local ethics committee of our institution (no. 880/2021) and conducted in accordance with the Declaration of Helsinki. The requirement for informed consent was waived because of the retrospective nature of the study. Patients aged ≥80 years with PVO and SEA across the thoracic and lumbar spine were consecutively enrolled. The diagnosis was based on magnetic resonance imaging (MRI)  [Patients were allocated into two groups: (1) surgical decompression only (decompression group) and (2) surgical decompression with spinal instrumentation (instrumentation group). Furthermore, as an additional tool to classify our cases, we applied the classification system of Pola et al. . Accordi.6–0.63) , 18.Considering all that points, the attending surgeon decided for decompression only or decompression with instrumentation. A CT-based point-to-point navigation system was used to perform spinal instrumentation, as previously described by our study group .In line with our institutional treatment protocols, blood samples or intraoperative cultures were collected prior to administration of IV antibiotics. Thereafter, IV antibiotics were initiated immediately. After identifying the bacterial specimens, the choice of IV antibiotics was adapted to reflect the antibiogram results.t-tests for continuous variables and chi-squared tests for categorical variables. The Wilcoxon rank test was applied to evaluate changes in C-reactive protein (CRP), leukocytes, and neurological status (as MS) of each group at discharge. Because these procedures are uncommonly applied in patients aged >80 years, and because our sample was relatively small, we could not perform a multivariate analysis to adjust for potential confounders. A p-value ≤ 0.05 was set as statistically significant.Categorical variables are presented as numbers and percentages. Continuous variables are presented as means ± standard deviations and were verified as normally distributed using the Shapiro–Wilk test. Baseline characteristics, duration of surgery, number of treated spinal levels, perioperative and postoperative complications, LOS, ICU stay, readmissions, reoperations, and mortality were compared groupwise using independent n = 24, 68.6%). Eighteen patients were allocated to the decompression group and 17 to the instrumentation group, respectively. No significant intergroup differences in comorbidities were observed. Both groups had a CCI > 6, indicating a poor prior baseline reserve . No significant differences were observed between the groups regarding the extent or location of the SEA. The lumbar spine was the most amenable region in both groups, followed by the thoracic region. Patients in both groups presented with a lumbar abscess with an extension to at least two levels. Blood infection parameters were relatively high, with CRP levels 173 ± 15.8 mg/L in the surgical decompression group and 150.3 ± 14.6 mg/L in the instrumentation group (p < 0.005). No differences were observed in motor impairment as measured by ASIA scoring . In addition, the number of operated levels was significantly greater in patients with instrumentation than in patients with mere surgical decompression . Notably, while patients of the instrumentation group had significantly longer hospital LOS, the ICU stay was similar between both groups. Concerning the in-hospital mortality, no significant differences were obtained. The 90-day mortality rate was 23.5% in patients undergoing instrumentation versus 5.6% in patients with surgical decompression only; however, this difference did not reach statistical significance (p > 0.05). Moreover, in both groups, infection levels and neurological status showed significant improvement at discharge. Overall, the mean follow-up period was 26.6 ± 12.4 months, and no additional surgery was necessary due to secondary instability. Furthermore, no screw loosening or displacement was seen on radiographs.As shown in Table p = 0.029). A detailed breakdown of all recorded complications is provided in Table Staphylococcus aureus was detected in about half of the patients in the instrumentation (70.6%) and decompression (44.4%) groups, either in blood or intraoperative samples. The next most frequent pathogen in both groups was Escherichia coli (instrumentation: 16.7% vs. decompression groups: 11.8%), followed by Enterococcus sp. (instrumentation: 11.1% vs. decompression groups: 5.9%), Pseudomonas aeruginosa (instrumentation: 5.6% vs. decompression groups: 5.6%), and multiple pathogens (instrumentation: 5.6% vs. decompression groups: 5.6%) respectively. No pathogens were identified in 16.7% of the decompression group and 5.9% of the instrumentation group.We observed a significant intergroup difference only in the occurrence of pleural effusion, with higher rates in the instrumentation group , and grade of disability as defined by the MS score. Notably, patients undergoing pedicle screw fixation and surgical decompression had substantially longer surgical time and duration of hospitalization but no longer ICU stays. Also of note, among patients who opted for a surgical decompression procedure, we observed a significant improvement in the infection parameters and motor function at discharge, while in the instrumentation group, only the reduction in CRP levels reached statistical significance.Kim et al. retrospectively studied 16 patients aged > 65 years with PVO and SEA. Almost all patients (87.5%) underwent surgical decompression only . Three pIt is well known that the C-reactive protein (CRP) is elevated in more than 90% of cases with epidural abscess and PVO and is considered as the most specific marker for treatment response . Alton eNoteworthily, patients undergoing surgery showed a trend towards improvement of the motor function, while the CRP levels decreased significantly, thus indicating the start of recovery after spinal infection. No significant differences were shown between both groups in terms of the laboratory infection parameters at discharge or the motor function, hence supporting that both techniques should be considered when deciding for surgery. However, the advantages and shortcoming of each method should be thoroughly discussed and considered. Lee et al. in their retrospective analysis of 47 patients with a mean age of 56 years did not find any differences concerning the neurologic function as well . Here, iAnother retrospective analysis of 135 patients with PVO and SEA aged 18–88 years found that surgery led to significant improvements in neurological condition compared to medication alone . About hIn a retrospective analysis of 40 patients with spinal abscess, Du et al. found that greater age (> 60 years) and the presence of comorbidities such as diabetes mellitus, respiratory, renal, or tumor diseases, and thrombocytopenia might significantly contribute to higher mortality rates evaluated 30 days postsurgery. They did not determine the surgical procedure . Their oHospital-acquired infection (HAI) is a serious complication of the modern health care system. As the elderly population increases globally, the number of geriatric patients admitted to the ICU has also increased strikingly. For instance, patients over 65 years account for 42–52% of those in the ICU . Risk faThe safety of spinal instrumentation in the setting of infection might have been viewed with some controversy in the past few decades. In case of unresponsiveness to conservative treatment, a surgery aims to eradicate the infection focus, restore the neurological function, relieve the pain, and protect or restore spinal alignment. Rayes et al. in their retrospective study on 37 patients with spinal infection performed solely instrumentation surgery. In almost 80% of the cases, a successful arthrodesis was observed, while failure of implants did not occur in any case . In anotIn the current context, whether to perform surgical decompression alone or to supplement decompression with instrumentation in cases with active spinal infection is still a subject of debate. Albeit decompression is the primary goal for the treatment of SEA, the concern of surgeons for the occurrence of secondary spinal instability led them to combine decompression with spinal stabilization . Dietz et al. described in their retrospective analysis based on claims data from 2662 patients with spinal infections including SEA and PVO that decompression with instrumentation resulted in better outcomes in terms of re-admission and re-operation. Herein, it is important to highlight that their cohort consisted mainly of younger individuals with an overall mean age of 56.6 years with a low rate of comorbidities, which might have influenced both decision-making and the natural course of the disease. Nevertheless, the authors advocated that the decision-making was mainly guided by the surgeon’s experience. Interestingly, another study comparing patients undergoing decompression alone vs. decompression and instrumentation for spinal infections stated that the choice of the surgical procedure was determined by the attending neurosurgeon treating the patient at each time due to the lack of clear consensus . In conjThe main strength of the current study is that we are the first to examine the outcomes of octogenarians undergoing surgery for SEA. However, this study has some limitations. First, we examined a relatively small cohort of patients. Nevertheless, since there is a lack of robust evidence of the clinical course of such a devastating disease in older individuals, we believe that our findings greatly clarify the clinical picture. Second, the minimum follow-up period of 12 months was relatively short; by gathering long-term data, other relevant findings not captured in the current study might have been revealed. Third, as this is a retrospective study, selection bias may have been present. Larger studies might be needed to elucidate potential candidates for non-operative management with antibiotic therapy only.Based on our observation of a fast recovery in patients undergoing surgical decompression only, one might argue that surgical decompression might be the key treatment strategy for the patients studied here. However, we believe a multidisciplinary approach primarily involving experienced spine surgeons is needed to determine an adequately individualized therapy for frail older patients with severe baseline histories. Larger studies are needed to investigate the trends observed in our patient population further.Due to a steadily increasing average life expectancy, spine surgeons frequently encounter older patients requiring surgical therapy. Our results show that surgical decompression only and decompression with instrumentation can be considered safe treatments strategies for patients with SEA older than 80 years. It seems that older patients undergoing only surgical decompression might recover neurologically and clinically more quickly than patients who had additional instrumentation. However, the surgical treatment should be clearly discussed with the patient and their relatives. We hope this study will serve as a basis for developing a consensus on the best treatment strategy for frail patients confronting such a devastating illness.