BackgroundDuring the last several decades, the opioid epidemic throughout the United States has been recognized as an increasing problem. The aim of this study was to identify and implement processes throughout a single private orthopedic practice and managed ambulatory surgery centers to reduce opioid prescription pill quantity and strength, while also reducing consumption.MethodologyA baseline assessment along with the development of four separate phases was implemented. Data collection included type, dosage, and quantity of opioids prescribed after elective outpatient procedures as well as patient interviews/surveys within two weeks after surgery. Quality improvement implementation included: (a) presentations on opioid prescribing at an individual physician level, (b) internal prescription guidelines, (c) required Prescription Monitoring Program registration, and (d) patient narcotic education pamphlets after surgery. The average opioids prescribed and consumed were compared between different time points.ResultsAnalysis revealed a highly statistically significant decrease in both pills and morphine equivalent units (MEUs) prescribed  between the baseline assessment and four subsequent phases, as well as consumed  between phases one through four. Even though patients were consuming less pills and MEUs than they were prescribed on average across all phases, overall pain levels increased between phases one through four (p < 0.001), and overall satisfaction of pain control decreased between phases two through four (p < 0.001).ConclusionsOver a 24-month time frame, a single private orthopedic practice set a goal of reducing prescribing habits and with successful implementation of various measures, a significant reduction in opioids prescribed and consumed was accomplished. Interestingly, pain level and satisfaction of pain control worsened even though patients were continuing to be prescribed more opioids on average than they were consuming. Therefore, it may be normal to see these results when attempting to set the expectation for some level of pain and reduced consumption of opioid medications post-operatively. Overall, these results can be useful to healthcare administrators and surgeons looking for ways to combat the opioid epidemic. The United States (US) is in the grip of a tragic opioid epidemic. Between the years of 1999 and 2017, there have been around 400,000 deaths from opioid overdoses .Among the opioid prescriptions dispensed throughout all US retail pharmacies in 2009, orthopedic surgeons accounted for an estimated 7.7% or 6.1 million opioid prescriptions . They weAccordingly, at Twin Cities Orthopedics (TCO), one of the largest (115 physicians) private orthopedic practices in the US , the surAt the start of the project, no interventions were imposed. The aim of this project was to identify and implement processes throughout a single private orthopedic practice and managed ambulatory surgery centers (ASC) that encouraged and reduced opioid prescription pill quantity, strength, and dose, as well as opioid consumption.A quality improvement project (retrospective chart review as well as prospective patient interviews/surveys) was approved through an institutional review board. The project included four separate phases after baseline assessment and initially began in the summer of 2017 and concluded in the summer of 2019. The project was initially hypothesized by a small group of physicians questioning how pain was managed for their patients with a desire to understand the quantity and specific type of opioid being prescribed. Following development, a unanimous approval was given by ASC boards and the TCO board to evaluate current internal processes throughout the entire organization. Quality improvement interventions were implemented between phases, and the timing of phases and interventions were prospectively selected. Patient collection was focused exclusively on ASC patients who underwent an elective outpatient orthopedic surgical procedure performed by a TCO surgeon within a Revo Health-managed ASC. Excluded ASC cases were procedures involving Tenex, epidural steroid injections, and outpatient total joint replacements .PhasesBaseline assessment of prescribing included a retrospective chart review of surgical cases done across three ASCs between January 2016 and June 2016. Patients were randomly selected using Microsoft Excel randomization calculation. Data collection involved the type, dosage, and quantity of opioids prescribed after the surgical cases. Upon evaluation of these data points, the data were compared to the Centers for Disease Control (CDC) 2016 guidelines , and orgPhase one, initiated after the baseline, involved all consecutive surgeries throughout three Revo Health-managed ASCs during a two-week period starting at the end of July 2017. Prescription data of all surgical cases during this time period were reviewed. Patient consumption data were obtained by calling patients; initially 14 days ± three days post-operatively. Patients verbally consented and were asked about the utilization of their prescribed opioids. Phone calls were conducted for two business weeks and patients were called back up to three times if they did not answer. Information collected included the opioid type, dispensed dosage, and quantity of opioids prescribed after each surgical case, along with questions asked to the patient regarding their current pain level  after the procedure , how manPhase two involved all patients having surgeries at the same three ASCs during a two-week period in December 2017. Information collected was the same as it was in phase one with the addition of asking patients their satisfaction of pain control after surgery  . FollowiPhase three included all surgeries at one of the five ASCs (including the three ASCs previously viewed in phases one and two) in May, June, and July 2018. Data collection otherwise matched the parameters of phase two criteria.Phase four included all patients who responded to an electronic post-operative medication survey following their elective outpatient orthopedic surgeries at the same five ASCs. Responses were collected for a one-year time period . Responses collected matched those of phases two and three even though responses were collected via survey instead of patient interviews. Data analysis continued to monitor if there was a statistically significant decrease in average prescribing and consumption quantities for all procedures, surgeons, and facilities.InterventionsQuality improvement initiatives included numerous interventions to help combat overprescribing and overconsumption of opioids post-surgically. First, all surgeons within the practice were presented the collected data at the procedure level after baseline and each phase of data collection. The presented data included individual surgeons’ average prescriptions  benchmarked alongside the average for the practice for every procedure. Prescription guidelines for the individual procedures were also benchmarked alongside the other averages following development after phase two. Presentations occurred at all physician meetings and data were presented by the Chief Medical Officer and senior leadership. This transparent ranking report was key and well accepted by all physicians. Second, internal prescription guidelines Table  were estStatistical analysisOne-way analysis of variance and Tukey post-hoc tests, where applicable, were used to determine significant differences in prescribing habits between baseline and all four phases. Statistical analyses were performed with SPSS version 24 , and significance was set at p < 0.05.Throughout baseline and phases one through four, the average ages of patients were clinically similar , and females represented 50% or more of the population. Baseline assessment of 876 patients demonstrated 50% (438) females with an average age of 48.8 years. Of the 630 patients reviewed in phase one, there were 357 (56.7%) females with an average age of 49.0 years. Phase two revealed 549 surgical patients with 282 (51.4%) females and an average age of 46.7 years. Phase three included 1,473 total charts being reviewed and 56.3% were females (829) with an average age of 49.7 years. Phase four noted females as 59.2% (2236) and an average age of 51.3 years.Overall, there was a statistically significant decrease in both pills prescribed (p < 0.001) and MEUs prescribed (p < 0.001). There was a statistically significant decrease in pills prescribed between baseline and each of phases one through four (p < 0.001) Table . AdditioThere was also an overall decrease in both pills consumed (p < 0.001) and MEUs consumed (p < 0.001). There was a statistically significant decrease in pills consumed between phases two and four (p = 0.022) but not between phases two and three (p = 0.092) Table . There wReported pain levels for phases one through four were 1.73, 1.15, 1.52, and 2.49, respectively. There was a significant improvement in pain levels between phases one and two (p = 0.008); however, this worsened from phase two to phase four. Between phases two and three, the trend worsened (p = 0.054). Between phases three and four and overall between phases one and four, pain levels worsened . Satisfaction for phases two through four was 9.34, 8.88, and 8.09, respectively. Overall, satisfaction scores significantly worsened. There was a trend towards worsening between phases two and three (p = 0.054), between phases three and four (p < 0.001), and between phases two and four (p < 0.001).Between each phase, providers moved towards lower strength opioids and reduced the quantity of pills being prescribed. Between baseline and phase one, there was a 19% reduction in both the average number of pills and MEUs being prescribed. The four-month time frame between phases one and two resulted in a reduction in prescribing pill quantities by 10% and reduced average MEUs being prescribed by 15%. There was a reduction between phases two and three and between phases three and four in both pills  and MEUs prescribed . The overall change from baseline to phase four resulted in a 40% reduction in pills prescribed and a 43% reduction in MEUs prescribed.There has been much reporting on opioid prescribing, use, and abuse throughout the decades ,12-14. TA 2018 study by Wyles et al. showed that institutional prescribing guidelines developed by inter-departmental healthcare professionals for common orthopedic procedures decreased opioid prescribing . These rAdditionally, this current study utilized presentations to physicians. The average pills and MEUs prescribed were significantly decreased when comparing baseline to all four phases Table . TherefoNo study to our knowledge has shown the effect of patient education pamphlets on post-operative orthopedic surgery opioid consumption across a practice (compared to consumption pre-implementation). While Dwyer et al. implemented patient education regarding safe and effective opioid use, they did not compare consumption to a baseline assessment so no conclusions could be drawn . This cuIt is interesting to note that while prescribing practices and consumption patterns of opioid pain medications decreased across this project, satisfaction of pain control also decreased and pain level increased. There was an improvement in pain levels between phases one and two, but this then trended towards worsening (between phases two and three) and then worsened (between phases three and four). There was also a trend towards worsening satisfaction of pain control between phases two and three and worsened thereafter. These trends in pain levels and satisfaction of pain control could be attributed to the expectation set forth that post-operative pain is normal and the fact that patients were consuming less opioid pain medications. Additionally, external factors such as the media’s focus on addressing the opioid epidemic may have played some role in patients consuming less opioids and having more pain . On averLimitations in our project included provider-level communication, design of the project, and the media’s role. At the provider level, physician assistants (PAs) were sometimes prescribing post-operative medications. Communicating guidelines to PAs following phase two proved to be challenging at times. Although the surgeons had been informed about these measures, PAs had not. In regards to the design, consistency was important to have throughout. Patient interviews, though a script was followed, may have yielded variations; considerations were given on the organization’s staff to not lead the patient to answer the questions in a certain way. Also, phases one through three utilized patient phone interviews while phase four utilized an online questionnaire allowing patients to complete their responses from home without staff support or oversight. Lastly, the project occurred during the time when media coverage of the opioid epidemic increased drastically . These iIn conclusion, overprescribing habits of opioids will remain a problem until physicians and organizations implement alterations within their systems. During a 24-month time frame, a single private orthopedic practice set a goal to reduce prescribing and consumption of opioids and had success with implementation of internal objectives: (a) presentations on opioid prescribing at an individual physician level, (b) internal prescription guidelines, (c) required PMP registration, and (d) patient narcotic education pamphlets after surgery. The successes seen in this single private orthopedic practice can provide insight into implementation that can be useful to other organizations looking to combat the opioid epidemic.


Juvenile idiopathic arthritis (JIA) is a cluster of autoimmune rheumatic diseases occurring in children 16 years of age or less. While it is well-known that pain may be experienced during inflammatory and non-inflammatory states, much remains ambiguous regarding the molecular mechanisms that may drive JIA pain. Thus, in this pilot study, we explored the variability of the serum proteomes in relation to pain severity in a cohort of JIA patients.Serum samples from 15 JIA patients  were assessed using liquid chromatography/mass spectrometry (LC/MS). Correlation analyses were performed to determine the relationships among protein levels and self-reported clinical pain severity. Additionally, how the expression of pain-associated proteins related to markers of inflammation (Erythrocyte Sedimentation Rate (ESR)) or morphological properties of the central nervous system  implicated in JIA were also evaluated.p < 0.05) associated with clinical pain severity. Functional properties of the identified pain-associated proteins included but were not limited to humoral immunity (IGLV3.9), inflammatory response (PRG4) and angiogenesis (ANG). Associations among pain-associated proteins and ESR , as well as caudate nucleus volume  and insular cortex thickness  were also observed.306 proteins were identified in the JIA cohort of which 14 were significantly (The current proteomic findings suggest both inflammatory- and non-inflammatory mediated mechanisms as potential factors associated with JIA pain. Validation of these preliminary observations using larger patient cohorts and a longitudinal study design may further point to novel serologic markers of pain in JIA.The online version contains supplementary material available at 10.1186/s12969-022-00662-1. In the current preliminary study, serum proteins associated with pain severity were identified in JIA patients. Pain-associated proteins had functional roles predominantly in immune or inflammatory processes.Correlations of pain-associated proteins with ESR and altered CNS morphology were also observed with ESR and altered CNS morphology were also observed.Larger-scale as well as longitudinal studies are needed to determine if evaluation of the proteome may provide a platform for identifying novel analgesic targets in JIA.The online version contains supplementary material available at 10.1186/s12969-022-00662-1. Juvenile idiopathic arthritis (JIA) is a common childhood rheumatic illness categorized into seven subtypes and characterized by musculoskeletal joint pathology present for greater than 6 weeks , 2. One The aim of this preliminary study was to identify pain-associated proteins in JIA to gain further insight into the biological underpinnings of pain in this rheumatic condition, which in turn may set the foundation for identifying novel therapeutic targets for pain treatment. In the current report, an LC/MS-based proteomics analysis of blood serum samples was performed to identify proteins that associate with clinical pain severity in a cohort of JIA patients. Subsequently, the association was examined between pain-associated proteins and other aspects of JIA, such as erythrocyte sedimentation rate (ESR), clinical juvenile arthritis disease activity score (cJADAS) , and CNSN = 15, 12.5 ± 2.8 years) were evaluated in this study . In this scale, 0 corresponds to no pain and 10 is the worst pain imaginable. The cJADAS, specifically the cJADAS-10, a composite disease activity score for JIA, which does not include an acute phase reactant, was determined for each patient at the time of enrollment [Male and female JIA patients (rollment . Blood srollment .A volume of 1ul serum was first diluted in 60 μl of urea buffer (8 M in 50 mM ammonium bicarbonate buffer) and then 15 μl of dithiothreitol  was added and the samples were incubated 30 min at 800 rpm in room temperature. A volume of 10 μl of iodoacetamide was added and an incubation was performed for 30 min at 800 rpm in room temperature in dark. A volume of 10ul of 0.05 M DTT was added to quench the alkylation and the sample was incubated 15 min at room temperature. The samples were then transferred to SP3 beads mixture (1:10 protein to beads) , previouA discovery-based proteomic workflow was performed with no depletion nor fractionation of the serum samples using the SP3 protocol followed by LC/MS analysis in data-dependent acquisition mode. An amount of 200 ng was injected on the Evosep LC system equipped with a Pepsep column  connected to a timsTOF pro mass spectrometer instrument  using the 60 samples per day. The data were searched using MSFragger software v3.1.1 using the following parameters: a maximum of three missed cleavages, oxidation of methionine residues set as variable modification and carbamidomethylation of cysteine residues set as fixed modification (other parameters were set as default).https://www.rstudio.com). In the current report, our statistical analyses were focused on determining how levels of various proteins were associated with clinical pain severity, ESR, and clinical severity (as determined by cJADAS), and also, whether and how identified pain-associated proteins were integrated with other elements of the JIA  Spearman correlation coefficients were calculated to determine correlations between protein density and clinical pain severity, while Pearson’s correlation coefficients were calculated to determine significant associations among continuous variables . Furthermore, as clinical pain severity is a subjective measure and clear cut off points are ill-defined, we aimed to investigate the serum proteome changes related to self-reports of pain using a more unbiased statistical approach by taking the extremes . Subsequently, a statistical comparison was performed using a student t-test comparing the mean difference between the High and Low pain cohorts. The results were shown by a Volcano plot with the log2 mean difference on the x-axis and the -log10 p-value on the y-axis.The data were then searched to obtain the protein identification and quantification in all samples. RStudio software packages were utilized for all statistical analyses . Furthermore, ESR values ranged from 1 to 26 (mean ESR: 10.92 ± 8.54) and cJADAS scores were between 0 and 16 (mean score: 5.17 ± 5.78).A). Functional roles of the 14 proteins ranged from humoral immunity, angiogenesis, autoimmunity and enzymatic reactions (Table p < 0.05).High throughput serum proteomics of the samples collected from 15 JIA patients identified 306 proteins. Only proteins detected in 9 or more patients were used for further analyses. Spearman’s correlation analyses between protein expression and clinical pain severity scores resulted in 14 protein that showed positive (r > 0.5) or negative (r < − 0.5) correlations with pain levels . Table P = 0.014), IGHV2–70 , IGHD , and IGLC3  , which were primarily related to humoral immunity [Amongst all 306 proteins identified in the serum of JIA patients, various proteins were associated with ESR  associations were revealed between right insular thickness values and two of the Pain-associated proteins (BTD and LGALS3BP).The left hemisphere caudate nucleus volume was not significantly correlated with any of the Pain-associated proteins Table . The rigThere is a clear need for a deeper understanding of the complex mechanisms that underlie pain in JIA and other rheumatic conditions impacting pediatric populations. The current study revealed a number of Pain-associated proteins by characterizing the serum proteome derived from JIA patients. The identified proteins ranged in their biological functions from humoral immunity, angiogenesis, autoimmunity and enzymatic reactions. Furthermore, these preliminary results further suggest the close interactions between immune and nervous systems, and the critical role immune cells and their mediators play in regulating acute and chronic pain states .Many of the identified Pain-associated proteins are involved in immune processes. LGALS3BP is a heavily glycosylated secreted molecule with an immunoinhibitory function  often foThe current sample consisted of patients who were in remission, reported pain without joint inflammation or reported pain with joint inflammation, where inflammatory status and other joint-related pathology was determined via musculoskeletal MRI. Moreover, our study confirms that pain in JIA is not always commensurate with the amount of inflammation, and also, subsets of proteins were solely associated with inflammation, but not pain. While confirmation in larger studies is necessary, we hypothesize that expression of some proteins is driven by pain and likely associated with peripheral or central sensitization, and other proteins will track more with the inflammatory status of JIA patient or JIA sub-type.A finer assessment of Pain-associated proteins in JIA is arguably obtained by differentiating patients based on additional diagnostic criteria, which include, JIA subtype , rheumatoid factor (RF) status, or antinuclear antibody (ANA) status as each can be associated with distinct JIA disease trajectories or severity . A more Previous work aimed to gain more insight into the proteomic underpinnings of pain by performing a meta-analysis of 535 pain related genes in the human cerebrospinal fluid (CSF) . These gIn prior work, JIA patients were shown to harbor altered CNS properties. Specifically, caudate nucleus volume was negatively correlated to clinical pain intensity and decreased cortical thickness of the insula was not only observed to be lower in JIA patients relative to controls, but also showed a negative correlation with ESR values . BesidesWith the novelty of this investigation into proteomic alterations concerning pain in JIA, limitations of this exploratory study are noted. Mainly, the small sample size was a limiting factor in this investigation yet provides a basis for extending this work into a larger patient sample. Also, all patients were on active treatment during study evaluation, and treatment plans varied from single immune-modulatory agents  to combination therapies . Moreover, some patients also noted intermittent use of non-steroidal anti-inflammatory drugs . The type of therapy could have impacted the serum proteomic composition, particularly in specific immune-related proteins in the collected serum. In order to determine the influence of various therapies on the JIA proteome, future studies should characterize protein expression before and after treatment or before and after the onset of a new therapeutic regimen. Characterization of the proteome at multiple points post-treatment induction may also provide new biological insights towards treatment response vs. non-response.In summary, LC/MS-based serum proteomic analysis identified 14 Pain-associated proteins in the serum of JIA patients. A number of the identified proteins had functional roles in immune or inflammatory processes. This investigation provides novel insights into deviations in the proteome in relation to clinical pain in JIA patients, and could contribute to the ongoing search for prognostic markers and treatment targets for JIA pain.Additional file 1.


Thoracolumbar interfascial plane (TLIP) block has been discussed widely in spine surgery. The aim of our study is to evaluate analgesic efficacy and safety of TLIP block in spine surgery.We performed a quantitative systematic review. Randomized controlled trials that compared TLIP block to non-block care or wound infiltration for patients undergoing spine surgery and took the pain or morphine consumption as a primary or secondary outcome were included. The primary outcome was cumulative opioid consumption during 0-24-hour. Secondary outcomes included postoperative pain intensity, rescue analgesia requirement, and adverse events.2 = 71.6%) for the first 24 hours after the surgery. TLIP block significantly reduced postoperative pain intensity at rest or movement at various time points compared with non-block care, and reduced rescue analgesia requirement  and postoperative nausea and vomiting . Besides, TLIP block is superior to wound infiltration in terms of opioid consumption , and the postoperative pain intensity at rest was comparable between TLIP block and wound infiltration.9 randomized controlled trials with 539 patients were included for analysis. Compared with non-block care, TLIP block was effective to decrease the opioid consumption (WMD -16.00; 95%CI -19.19, -12.81; p<0.001; ITLIP block improved analgesic efficacy in spine surgery compared with non-block care. Furthermore, current literature supported the TLIP block was superior to wound infiltration in terms of opioid consumption. Patients undergoing spinal surgery could suffer diffuse and severe postoperative pain. inefficient pain control after the surgery weakens the rehabilitation, prolongs the hospital stay, worsens patient satisfaction, and promote the development of persistent postsurgical pain –3. AlthoRecently, several studies have compared the novel techniques that target dorsal rami of the thoracolumbar nerves to either non-block care or other regional blocks in spine surgery –12. HoweTherefore, we decided to perform a systematic review and meta-analysis to compare the analgesic efficacy of TLIP block and/or modified TLIP block to non-block care or wound infiltration respectively in patients undergoing spine surgery. we also aimed to summarize complications associated with these regional anesthesia techniques.We searched PubMed, Medline, Embase database, and Google scholar (between January 1985 and September 2020) using the following terms: “lumbar spine surgery”, “decompression”, “lumbar spinal stenosis”, “spondylolisthesis”, “thoracolumbar interfascial plane block” and “TLIP block”. We also searched the gray literature by supplementary hand searching for the TLIP block being a new regional anesthesia technique firstly introduced in 2015. Language restrictions were not used. There was no limitation on sample size.Inclusion criteria were as follows: 1) patients undergoing spine surgery; 2) comparing TLIP block and/or modified TLIP block with no block care or wound infiltration 3) pain or morphine consumption as a primary or secondary outcome; 4) randomized controlled trials. We excluded studies if they 1) had other additional treatment in experimental or control group; 2) were not able to extract data; 3) were not available for full text.Each article was reviewed by 2 independent researchers who use the double-extraction method for meeting our inclusion criteria, then it was confirmed by a third reviewer, all the disagreement was resolved before the final analysis. 2 researchers were in charge of the data extraction work. The following information was recorded: the first author, the publication time, study design, study name, participant characteristics, outcome measures, surgical procedure, time of follow-up, pain score , local anesthetic administration characteristics, postoperative analgesic administration, use of ultrasound guidance and endpoints of each study. Numerical rating scale of pain or visual analog scale was adapted to an 11-point numeric rating scale . Postoperative opioids were transformed to an equianalgesic dose of intravenous morphine assuming no cross-tolerance. The quality of the RCTs was assessed with the use of the Cochrane Collaboration’s recommended tool by 2 reviewers . 7 potenThe primary outcome was cumulative morphine consumption during the 0-24-hour postoperative period. The secondary endpoints were defined as patients’ self-reported level of pain intensity with rest or movement on 0–10 pain scales such as visual analog scales (VAS), numerical rating scales (NRS), and other validated pain scales in the postoperative period , rescue analgesia requirement, the adverse events associated with the use of TLIP block such as postoperative nausea and vomiting (PONV), block failure, and block-related complications such as neuraxial injury.2 statistics, random effect model was applied when there was high heterogeneity (I2>30%) across the studies, whereas significant heterogeneity was not observed across the studies(I2≤30%), fixed effect model was applied. Publication bias was examined by the Egger test. All statistical was executed by stata15.1. Statistical significance was represented by p<0.05.Continuous data were analyzed using weight mean differences (WMDs) or standard mean differences (SMDs) and their 95%CIs for combining various scales. Data provided as mean and standard deviation were extracted. Data provided as standard error were transformed to standard deviation (SD) through the formula: SD = SE*√n (n = sample size). Data provided as median and interquartile range (IQR) was transformed to standard deviation through the formula: SD = IQR/1.349. Data provided as the confidence interval was transformed to standard deviation through the formula: 95%CI = x±1.96*SE where SD = SE*√(n). Data provided as median and the range was transformed to standard deviation based on the sample size through the formula described by Hozo et al . When thNo patients or members of public were involved in the present study. No patients were asked to advise on the interpretation or writing up of results. The results of the present research will be communicated to the relevant patient community.We identified 75 studies in the initial literature research. Based on the inclusion criteria, 64 studies were excluded, with a selection of 11 studies for a more detailed review. 2 studies were subsequently excluded, leaving 9 randomized controlled trials . Finally2 = 71.6%) , 1711, 12 = 0.0%). 1 study reported that patients receiving TLIP block had less incidence of rescue analgesia requirement than patients receiving wound infiltration, but it was not statistically significant .5 studies reported the incidence of rescue analgesia requirement  10–12, , 20. The2 = 25.1%). 1 study reported that patients receiving TLIP block had less incidence of PONV than patients receiving wound infiltration .6 studies assessed the impact of TLIP block on the incidence of PONV in patients undergoing spine surgery  10–12, , 18, 20.One study reported 2 patients experienced unsuccessful TLIP block, this would translate to an incidence (95%CI) of 0.8%  when considering the aggregate number of patients . There hThe current evidence showed that TLIP block is clinically superior to non-block care with regard to the cumulative opioid consumption, acute pain intensity, rescue analgesia requirement, and PONV in the postoperative period for patients undergoing spine surgery. Besides, TLIP block also reduced the cumulative opioid consumption compared to wound infiltration, but the postoperative pain intensity at rest was comparable during the first 24h after surgery between TLIP block and wound infiltration, only limited evidence showed that TLIP block attenuated pain intensity at movement during the first 8h after surgery and reduced the incidence of PONV and rescue analgesia requirement, more quantitative studies comparing these regional anesthesia techniques are needed to confirm the findings.Our results are of clinical importance, because spine surgery is extremely painful and the postoperative pain is usually hard to control, besides, and massive use of opioids is associated with adverse clinical events , 22. TheOur meta-analysis found statistically significant difference in PONV and rescue analgesia requirement between the TLIP block and non-block groups. Additionally, according to our systematic review, we found no major adverse events and complication related to the TLIP block. Current evidence showed that TLIP block is a promising regional anesthesia technique for spine surgery.TLIP block is a type of interfascial plane block that targets the dorsal rami of the thoracolumbar nerves, in classic TLIP block, the local anesthetic was injected between the multifidus and longissimus muscles by advancing the needle from lateral to medial side . Due to Wound infiltration has been reported to barely reduce the opioid consumption several times, because its analgesia effect depends on the absorption of the local anesthetic , 26, 27.There were also alternative regional anesthesia techniques that target the ventral rami such as retrolaminar block and erector spine block being reported to have analgesia effect after spine surgery , 28–31. Our study was also inevitable in shortage. First, significant heterogeneity was observed in some of our results, although sensitivity analyses were done, we did not identify the source of heterogeneity. Second, we did not examine a dose-response effect of the TLIP block as the dosage used in the included studies did not provide enough variability. Third, there was significant inter-study difference in the way of reporting opioid dosages and pain scores, the diversity in the pain intensity assessment tools  and follow-up time might lead to heterogeneity and deviation in the analysis. Fourth, the sample size of included studies was relatively small, with the largest study only including 80 patients, Fifth, few studies reported the length of hospital stay, the time to first analgesia request, length of PACU stay, future studies should perform the analysis of TLIP block by using the above data.S1 Checklist(DOC)Click here for additional data file.S1 Data(XLSX)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.


Different distraction techniques have been used in dentistry and have shown great results in managing anxious pediatric patients specially during local anesthesia administration. One of the recently invented techniques is virtual reality. The purpose of the study was to evaluate the effect of virtual reality distraction on anxiety and pain during buccal infiltration anesthesia in pediatric patients.Healthy, cooperative 6- to 12-year-old children requiring buccal infiltration anesthesia were randomly assigned to a test or control group. In the test group, local anesthesia was administered while the subjects were watching a cartoon video using virtual reality goggles. Subjects in the control group watched a cartoon video on a screen during the administration of local anesthesia. To assess anxiety in both groups, heart rate was recorded using a pulse oximeter at five time points: (1) once the subject sets on the dental chair as a baseline; (2) when video is on; (3) at topical anesthesia application; (4) during needle insertion; (5) after the administration of local anesthesia. The face, legs, activity, cry, consolability (FLACC) behavioral pain assessment scale and the Wong–Baker FACES pain rating scale were used to assess pain.P = 0.034 and P = 0.004, respectively) regardless of the distraction technique used. Younger subjects and subjects with higher baseline heart rate reported higher mean Wong–Baker FACES pain rating scale score , controlling for all other variables.A total of 50 subjects were included with a mean age of 8.4 ± 1.46 years. Twenty-nine (58.0%) of the subjects were females. The mean heart rate at all time points except baseline was significantly higher among the test group compared to the control group. Multiple regression analysis showed that younger subjects and females had higher mean FLACC behavioral pain assessment scale scores (Female subjects and the younger age group were more likely to report higher pain scores during local anesthesia administration regardless of the type of distraction used.The study was retrospectively registered in ClinicalTrials.gov with the identifier: NCT04483336 on 23/07/2020. Proper pain control and discomfort reduction during dental treatment, especially among children, can maximize a child’s cooperation, overall satisfaction, build a good dentist–patient relationship, and enhance patient compliance . It has Distraction as a behavior guidance technique is defined by the American Academy of Pediatric Dentistry (AAPD) as “the technique of diverting the patient’s attention from what may be perceived as an unpleasant procedure” . AudioviA published study testing the effect of VR distraction during inferior alveolar nerve block and pulpal therapy showed significantly more reduction in pain among subjects who received VR distraction when compared with subjects who were treated without the use of VR distraction . AlthougThis parallel randomized controlled trial was conducted in the Pediatric Dentistry department of King Abdulaziz University, Faculty of Dentistry (KAUFD) between March and July 2019. The study protocol was approved by the Research Ethics Committee of the Faculty of dentistry (REC-FD) at King Abdulaziz University (136-11-18). The study was registered in ClinicalTrials.gov with the identifier: NCT04483336. Reporting of the study follows the protocol established by the Consolidated Standards of Reporting Trials Statement (CONSORT) checklist . HealthyA randomization sequence with an allocation ratio of 1:1 was generated using computer software and was kept with a dental assistant who was not involved in the data collection to ensure allocation concealment. Each time a new subject was enrolled in the study, the dental assistant was asked to provide the allocation assignment of the subject. Due to the nature of the study, neither the subject nor the investigators were blinded to the group allocation. However, the group allocation was coded by the primary investigator to blind the statistician of the group labels.At the beginning of the dental visit, subjects were asked to choose a video from a list of popular cartoon shows. In the test group, the subjects wore VR goggles  connected to a mobile phone and the chosen video was played Fig. . In the Subjects’ heart rates (HR) were recorded using a pulse oximeter  at five time points: (1) once the subject is on the dental chair as a baseline; (2) when video is on (about 3 min later); (3) at topical anesthesia application (about 2 min later); (4) at needle insertion (about 2 min later); (5) immediately after the administration of local anesthesia (about 1 min later).During local anesthesia administration, the face, legs, activity, cry, consolability (FLACC) behavioral pain assessment scale  was recon = 25) was set as the required sample size. GPower 3.1.9.2 software was used for sample size calculation. The Mann–Whitney U and Chi-square tests were used to compare the baseline characteristics, HR, FLACC behavioral pain assessment scale, and the Wong–Baker FACES pain rating scale score between the test and the control groups at 0.05 significance level. Since HR was measured repeatedly, a two-way mixed ANCOVA test was used to check for interaction effects among age, gender, group, and time points with HR as the dependent variable. Multiple linear regression analysis was used to predict the effects of VR on HR and FLACC behavioral pain assessment scale controlling for possible confounding by age, gender, and the baseline HR. Similarly, ordinal logistic regression was used to model the effects of VR on Wong–Baker FACES pain rating scale scores, to check for interactions, and to control for possible confounding by age, gender, and the baseline HR.Sample size was calculated using the data of HR from Nuvvula et al.  It was fP = 0.254), gender (P = 0.774), provider (postgrad vs. intern) (P = 0.258), location of local anesthesia (maxilla versus mandible) (P = 0.544), owning a VR device (P = 1.00), previous dental experience (P = 1.00), or Frankl’s behavior classification for those who had previous dental experience (P = 1.00).An illustration of the subjects’ recruitment, randomization, allocation, completion of local anesthesia administration, and analysis are represented in the CONSORT flow diagram Fig. . A totalP = 0.153). Although there was a statistically significant difference between the test and control groups in the mean HR at video on (P = 0.012), at topical anesthesia application (P = 0.047), at needle insertion (P = 0.017), and after buccal infiltration anesthesia (P = 0.001), the mean change in HR from the baseline to these time points was not statistically different between the test and control groups . The mean score of the FLACC behavioral pain assessment scale measured after the local anesthesia procedure was slightly higher among the test group (2.58 ± 1.99) compared with the control group (2.18 ± 2.29); however, the difference was not statistically significant (P = 0.497). The mean Wong–Baker FACES pain rating scale score was lower among the test group (2.40 ± 2.82) compared with the control group (2.72 ± 2.99); however, the difference was not statistically significant (P = 0.707).Table P = 0.347), time*gender (P = 0.223), or time*age (P = 0.592). The effect of using VR on changes in the HR from the baseline to each time point was further analyzed using multiple linear regression to control for possible confounding by age, gender, and baseline HR and is presented in Table Since HR was measured at five different time points in each group, two-way mixed ANCOVA was used to test if interactions existed among the variables of time, age, gender, and group. The results showed no statistically significant interactions between time*group P = 0.47, time*P = 0.017 and P = 0.001, respectively). In the adjusted model, younger subjects had a statistically significant higher mean score on the FLACC behavioral pain assessment scale by 1.20 (0.09–2.30) compared with older subjects controlling for gender, the baseline HR, and group. Also, females had a significantly higher mean score on the FLACC behavioral pain assessment scale by 1.68 (0.58–2.78) compared with males controlling for all other variables. Being in the test group did not have a statistically significant effect on the mean FLACC behavioral pain assessment scale when other predictors were controlled for . The baseline HR was also associated with higher scores of the pain rating scale even when controlling for age, gender, and group (P = 0.010). In addition, younger subjects were significantly more likely to report higher pain scores of the Wong–Baker FACES pain rating scale  compared with older subjects controlling for other variables in the model. The use of VR did not have significant effect on pain scores (P = 0.188) adjusting for age, gender, and the baseline HR , which may have increased variability between subjects. However, there was no significant difference in provider-type distribution between the test and control groups. Another limitation of the study is that assessment of VR distraction was performed during local anesthesia only. Therefore, further long-term randomized controlled clinical trials on a larger sample size should be conducted to assess VR distraction during other dental restorative, pulpal, and surgical procedures.Future studies may consider using VR systems with integrated eye tracking and compare its effect in reducing pain and discomfort with the traditional VR systems in children during dental procedures. Advances in VR technology may have serious ramifications on the effectiveness of VR analgesia during dental procedures. Virtual reality gadgets with higher resolutions and wider field of views were found to be effective in significantly reducing thermal pain on the skin and the time spent thinking about the pain compared to low resolution and narrower field VR systems . AdditioThe utilization of virtual reality goggles has a similar effect to screen distraction on heart-rate levels and pain during buccal infiltration anesthesia among pediatric patients. Female subjects, younger subjects, and subjects with higher baseline heart rates were more likely to report higher pain scores during local anesthesia administration regardless of the type of distraction used. Further research is needed to assess the effect of virtual reality distraction during various dental procedures other than anesthesia.


Head and neck cancer (HNC) and its treatment can leave devastating side effects with a relevant impact on physical and emotional quality of life (QoL) of HNC patients. The objectives were to examine the amount of dysphagia, voice problems, and pain in HNC patients, the impact of sociodemographic, behavioral, and clinical factors on these symptoms, the psychometric properties of the EAT-10, and the relationship between these symptoms and QoL variables.HNC patients attending for regular follow-up from 07/2013 to 09/2019 completed questionnaires (Eating Assessment Tool-10 (EAT-10); questions from the EORTC QLQ-C30 and EORTC H&N35) on dysphagia, voice problems, pain, fatigue, and QoL collected with the software OncoFunction. Associations between prognostic factors and symptoms were tested with analyses of variance (ANOVAs). Associations between the symptom scales and QoL variables were expressed with Pearson correlations.r = 0.51). QoL was strongly correlated with dysphagia and pain , while the association with voice problems was weaker (r = − 0.28).Of 689 patients, 54.9% suffered from dysphagia, the EAT-10 proved to be a reliable measure. The mean voice score was 37.6 (± 33.9) [range 0–100], the mean pain score 1.98 (± 2.24) [range 0–10]. Trimodality treatment was associated with the highest dysphagia scores. Dysphagia, voice problems, and pain significantly correlated with each other, the highest association was found for dysphagia and pain (Dysphagia is an important symptom in HNC patients greatly affecting patients’ QoL and significantly correlating with voice problems and pain. In the last decades, improvements in diagnostic technologies and advancements in surgery, radiation, chemo- and immunotherapy led to improved local tumor control and lower mortality rates in head and neck cancer (HNC) patients . The numThe objectives of this study were (a) to explore the amount of dysphagia, voice problems, and pain in a large cohort of HNC patients, (b) to examine the impact of sociodemographic, behavioral, and clinical factors on these symptoms, (c) to test the psychometric properties of the EAT-10, and (d) to examine the relationship between these symptoms and QoL variables.The sample comprised HNC patients who attended the outpatient clinic for head and neck cancer of a University hospital for regular follow-up appointments from July 2013 to September 2019. Inclusion criteria were diagnosis of HNC and age older than 18; patients with severe cognitive impairment, patients who refused participation, and those who were unable to read or complete the questionnaires on the tablet computer were excluded.The data were collected with the software OncoFunction basing on the International Classification of Function . The useThe Eating Assessment Tool-10 (EAT-10) is a validated, symptom-specific self-assessment instrument designed to rate the patient´s perception of their swallowing impairment –18 and hFor measuring voice problems, we used two questions of the questionnaire EORTC QLQ-H&N35 . The resPain was assessed with a single item, ranging from 0  to 10 (maximum possible pain).The EORTC QLQ-C30 is one of the most frequently used instruments to analyze health-related QoL . It inclFor the EAT-10, we calculated part-whole-corrected item-test-correlations and Cronbach’s alpha for measuring internal consistency. A confirmatory factor analysis (CFA) was calculated to test the model fit of the one-dimensional model of the EAT-10. We used the coefficients CFI, TLI, RMSEA, and SRMR.The associations between  prognostic factors and the symptoms were statistically tested with analyses of variance (ANOVAs) including age and sex as covariates.Associations between the symptom scales and quality of life variables were expressed with Pearson correlations. The CFA was calculated with MPlus, all other analyses were performed with SPSS, version 20.Among the 1026 patients who were eligible for the study, 710 completed the EAT-10, 860 completed the Voice scale, and 871 the Pain scale. We restricted the analyses to those patients who completed all of these three questionnaires, which resulted in a sample of 689 patients. Table rit coefficients were greater than 0.60. The internal reliability  was very good.Table 2 (DF) = 578.124 (35), CFI = 0.890, TLI = 0.858, RMSEA = 0.153, and SRMR = 0.055.The CFA results of the one-dimensional EAT-10 model resulted in the following coefficients: ChiUsing the EAT-10 cutoff ≥ 3 for abnormal dysphagia, 378 of the patients (54.9%) suffered from dysphagia. 217 patients (31.5%) had a score of 0 , and 223 patients (32.4%) showed scores ≥ 10. 125 patients (18.1%) needed a tracheotomy and 107 (15.5%) required a feeding tube to ensure nutrition.M (Mean) = 37.6, SD = 33.9, and Cronbach’s alpha = 0.93. A proportion of 35.1% (n = 242) of the patients had no voice problems at all (score = 0), and 8.6% of the patients (n = 59) reached the maximum score of 100 on the voice scale.The voice scale yielded the coefficients M = 1.98 and SD = 2.24. Of the 689 patients, 277 patients (40.2%) were completely free from pain with a score of 0, and 162 patients (23.5%) reported a pain score of 4 or above.The mean score and the SD of the pain scale (range 0–10) were M = 2.3) than males (M = 1.9), while there were no significant gender effects in dysphagia and voice problems. The oldest age group (≥ 70 years) was characterized by the lowest burden in the three symptoms, the differences in dysphagia and pain were statistically significant.Table With respect to behavioural factors, like alcohol drinking and smoking, there were no significant differences regarding pain, voice problems and dysphagia. Occupied patients reported significantly less pain, dysphagia and voice problems than those who were not occupied.Tumor localization had a significant impact on all three symptoms while tumor stage and presence of metastases had a significant effect on the EAT-10 scores but not on the pain and voice scale. Patients with small HNC had significantly less dysphagia than those with advanced ones. Oropharynx cancer led to the highest dysphagia scores while larynx and hypopharynx tumors resulted in significantly more voice problems. Patients with oral and oropharynx cancer reported significantly more pain than patients with HNC of other localizations.Trimodality treatment was associated with the highest dysphagia scores, chemoradiation resulted in slightly lower scores, the lowest scores had patients who were only treated by surgery. There were no significant correlations between voice problems and pain with treatment modality. Worse Eastern Cooperative Oncology Group performance status (ECOG) scores (2–4) were correlated to the highest burden in the three symptoms.Patients with BMI < 20 showed significantly higher values in EAT-10 and pain while obese patients reported lower values. Duration of post-therapeutic follow up did not reach any significance.Using the criterion for dysphagia given by the authors of the EAT (score ≥ 3), 54.9% of the sample suffered from dysphagia. The frequency of dysphagia in relation to the tumor type and treatment is presented in Figs. p < 0.001. The highest association was found for the relationship between dysphagia and pain (r = 0.51). QoL was strongly correlated with dysphagia and pain , while the association with voice problems was somewhat weaker (r = − 0.28).The correlations between the three symptom scales and the two additional scales fatigue and QoL of the EORTC QLQ-C30 are given in Table The first aim of the study was to assess the burden of specific symptoms experienced by the HNC patients. About half of the patients (54.9%) suffered from dysphagia. The tracheostomy and feeding tube rates show that aspiration and the associated protection of the respiratory tract and securing of nutrition are relevant problems after therapy of HNC. When examining swallowing function, both fiber optic endoscopic evaluation of swallowing (FEES) and videofluoroscopy are considered to be the gold standard in dysphagia assessment . We did M = 1.98  seems to be a hint that pain is not the predominant phenomenon in our patient cohort although HNC is characterized by a significantly greater pain perception compared to other tumors [The mean pain score of r tumors . Becauser tumors , which ir tumors . In a str tumors .The EAT-10 proved to be a reliable measure. The internal consistency was very good . Other studies also found such excellent reliability coefficients , 27. NevConcerning gender, there were no significant differences in two of the three symptom scales (dysphagia and voice problems) between males and females. Females reported slightly more pain than males. However, concerning age, there were more pronounced differences between the groups: older patients (70 years and above) reported the lowest burden. Since there are no normative scores for the symptom scales, based on samples of the general population, we cannot estimate to what degree these age differences are due to normal age affects, and to what degree they are HNC-specific. The quality of life questionnaire EORTC QLQ-C30 includes eight symptom scales. For these scales, there are normative scores , 28, andAlcohol consumption and smoking were not significantly associated with the symptoms. Here it is impossible to conclude a causal relationship. Alcohol drinking and smoking may result in health problems, but it is also possible that patients with severe health problems decided to give up smoking and drinking. Longitudinal studies are necessary to explore the causality in this patient group.All measured patient-reported outcomes were associated with employment status. It is important to improve these symptoms since many HNC patients are not of retirement age and could work for many more years. In the process of return to work and resuming everyday life, dysphagia, pain, and voice problems represent great barriers which were also demonstrated by previous studies , 30.Analyzing tumor site, we found significant differences between hypopharynx/larynx cancer against oral cavity/oropharynx location with significantly better results in terms of voice problems for the latter but less pain in larynx/hypopharynx cancer. Considering tumor stage, as anticipated and demonstrated in previous studies, there was significantly more dysphagia in advanced tumor stages, on the other hand, no significant differences regarding voice problems and pain were noted. This is surprising at first sight, but there was a tendency towards better voice and less pain with smaller tumor stage. Patients affected by carcinomas of the hypopharynx/larynx and oral cavity showed a better swallowing function in comparison to those affected by oropharynx cancers who also had the highest frequency of dysphagia. Similar results could be shown in a previous study by Carmignani et al. , while oWhen treatment strategy was considered, dysphagia has the highest incidence (71.1%) and was significantly worse in patients undergoing trimodality treatment (surgery + RT + CT), the group undergoing exclusive surgery had the lowest frequency of dysphagia (33.7%) and the lowest scores in the EAT-10. Voice problems and pain were not significantly correlated with treatment modality but there was a tendency for higher scores in the trimodality and surgery + radiation group. Existing literature on the correlation between treatment modality and symptoms has been inconclusive , 24. As 2 had the highest scores in the EAT-10 which seems logical since swallowing difficulties without sufficient supplementation lead to weight loss. The patients are in a vicious circle because malnutrition, in turn, leads to decreased activity, inducing more weight loss and lethargy [Concerning body weight, patients with body mass index ≤ 20 kg/mlethargy , 33.r = − 0.39) was nearly as high as that of pain (r = − 0.40), while the association between voice problems and QoL was somewhat weaker (r = − 0.28). This underlines the importance of dysphagia for the total assessment of QoL in HNC patients. Cramer et al. [Previous studies suggest that swallowing disturbances, voice impairments, and pain have a major impact on QoL. This is confirmed by our data. Dysphagia, voice problems, and pain were associated with QoL. The impact of dysphagia (r et al.  analyzedr et al. .Regardless of QoL, the assessed symptoms are important for patient’s prognosis. Previous studies in HNC patients showed that the presence of pain and dysphagia at the time of diagnosis is associated with impaired survival –40. In aOur study is limited by its cross-sectional design. Patients were surveyed at different times in their treatment course; however, there were no significant disparities with regard to the time since diagnosis. In patient-completed surveys, there is the risk that not all patients provide all answers; therefore, only patients who fully completed all three questionnaires were included. Due to cross-sectional design of this study, baseline pre-treatment assessments of dysphagia, voice problems, and pain were not performed. Longitudinal research with inclusion of pre-treatment baseline values will enrich the knowledge of amount of dysphagia, voice problems, and pain in HNC patients and its course over time. Therefore, longitudinal studies are planned to be conducted in the future.The prevalence of HNC survivors is rising, and this trend is ongoing. For this reason, attention should be turned to QoL issues for HNC survivors. Previous reviews have shown that PRO surveys in cancer clinical practice can improve patient satisfaction with care and consultation outcomes . Therefo


Patients with Parkinson’s disease (PD) often experience pain, which fluctuates in “on” and “off” states, but the underlying mechanism is unclear. The nucleus accumbens (NAc) is a central component of the mesolimbic dopaminergic pathway involved in pain processing. We conducted resting-state functional magnetic resonance imaging (rsfMRI) analysis to explore the relationship between the neuronal synchronization of NAc with pain-related brain regions and pain intensity in “on” and “off” states. We assessed 23 patients with sporadic PD based on rsfMRI and pain intensity using the revised Short-Form McGill Pain Questionnaire. Patients with PD displayed higher pain intensity scores in the “off” state than in the “on” state. The pain intensity in the “off” state was substantially correlated with the functional connectivity (FC) between the NAc and primary motor/sensory cortices and contralateral NAc. Changes in pain intensity from the “on” to “off” state displayed correlations with those between the right (rNA) and left NAc (lNAc) and the right precentral gyrus (rPreCG) /right insular cortex (rIC) from the “off” to “on” state. Aberrant bilateral NAc and rNAc–rPreCG/rIC FC in the “off” state were closely related to pain symptoms developed from the “on” to “off” states. These results suggest that the NAc in the mesolimbic pathway is related to pain in PD and may help understand the mechanism of pain development in patients with PD. In recent years, researchers have gained interest in non-motor symptoms of Parkinson’s disease (PD). Several non-motor symptoms, including pain, affect patients with PD . Pain isSeveral pathways involved in sensory processing modulate pain . These pAbnormal neuronal synchronization in brain networks is related to the development of pain in PD ,10. We hWe enrolled consecutive patients with sporadic PD who visited Nara Medical University Hospital  between June 2020 and May 2021. A total of 23 patients fulfilled the inclusion and exclusion criteria. The major inclusion criteria were: (1) presenting confirmed PD and meeting the UK PD Society Brain Bank criteria ; (2) beiPatients with PD were observed for one week prior to MRI examinations and were assessed in the “on” and “off” states, which correspond to states when dopamine replacement therapy is effective and symptoms are controlled and when the treatment effect wears off and symptoms re-emerge. The MRI examinations were performed on each patient during both the “on” and “off” states over two testing days. Patients were assessed using the Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) part III, Numerical Rating Scale , and SF-MPQ-2 at the time of the MRI examination ,13,14. S2, flip angle (FA) = 90°, field of view (FOV) = 212 × 212 mm2, slice thickness = 3.2 mm, and voxel size = 3.3 × 3.3 × 3.2 mm3, for a total of 40 slices. Two runs, each with 245 volumes, were performed for each patient. The T1-weighted structural images were acquired with the following parameters: TR = 1900 ms, TE = 2.75 ms, inversion time = 900 ms, matrix size = 256 × 256 mm2, FA = 9°, FOV = 256 × 256 mm2, slice thickness = 1 mm, and voxel size = 1.0 × 1.0 × 1.0 mm3, for a total of 192 slices. The patients were instructed to keep their eyes centered on the fixation cross and to not think about anything during the acquisition phase [Patients underwent MRI examination on the two testing days: one testing day was an “on” day and the other one was an “off” day. The MRI examinations were preceded by a clinical assessment based on the MDS-UPDRS Part III, NRS, and SF-MPQ-2. Functional and structural MRI data were acquired using a 3-Tesla MRI scanner  with a 20- or 32-channel head coil at Nara Medical University Hospital. A total of four patients received MRI scans with a 20-channel head coil because of postural instability. The functional images were acquired using a gradient-echo echo-planar pulse sequence sensitive to blood oxygen level dependent (BOLD) contrast with the following parameters: repetition time (TR) = 1190 ms, echo time (TE) = 31 ms, matrix size = 64 × 64 mmon phase .The MRI data were preprocessed using the Statistical Parametric Mapping software, version 12 (SPM12), and the CONN toolbox, version 17, in MATLAB  . The preThe resting-state FC analysis was performed using a seed-based approach using the CONN toolbox. Region of interests (ROIs) were selected from the FMRIB Software Library Harvard-Oxford cortical and subcortical structural atlases . Based ot-test. Correlations between scores on the clinical assessments and FC values were assessed using the Pearson’s correlation coefficient. The Shapiro-Wilk test was used to assess the normality of data distribution. p-values of <0.05 were considered statistically significant, and a non-significant trend was established for a p-value between 0.05–0.15. A correlation was considered strong if the coefficient (r) was >0.40.All statistics were performed using MATLAB version R2020a. The means of the obtained values were compared between the “on” and “off” states using the paired two-sample p < 0.05). There was a non-significant trend for higher NRS scores in the “off” state than in the “on” state (p = 0.068). Moreover, patients displayed higher SF-MPQ-2 total and affective subscale scores in the “off” state than in the “on” state (p < 0.05). There was a non-significant trend for higher continuous, intermittent, and neuropathic subscale scores of SF-MPQ-2 in the “off” state than in the “on” state . These results indicate that patients with PD experience pain, as well as motor disability, during the “off” state in their daily life.Twenty-three patients with PD  were enrolled in this study. The demographic characteristics and clinical features of the 23 patients with PD are summarized in r = 0.40) with FC between the right NAc (rNAc) and right precentral gyrus (rPreCG) (r = 0.44), right postcentral gyrus , and left NAc , whereas neuropathic subscale scores displayed a positive correlation with FCs of bilateral NAc with the bilateral PreCG and PostCG  . Dividind PostCG . In contd PostCG . The corr = −0.54 and −0.43, respectively) and between the rNAc and lNAc (r = −0.40). Regarding the subscales, continuous subscale scores displayed a correlation with FC of the rNAc with bilateral PreCG/PostCG and lNAc from “on” to “off” state, whereas neuropathic subscale scores displayed a correlation of FC between the bilateral NAc and bilateral PreCG/PostCG , continuous (r = −0.45), and neuropathic (r = −0.44) subscales (r = −0.48) and neuropathic (r = −0.48) subscales (r = −0.42; We conducted further analysis to explore whether the change in FC between the NAc and primary motor/sensory cortices in the ipsilateral hemisphere was related to pain intensity from “on” to “off” state. The changes in FC between the rNAc and rPreCG from “on” to “off” state displayed a negative correlation with the corresponding changes in the SF-MPQ-2 total (ubscales . The chaubscales . The chaThe results of current study revealed that aberrant FC associated with the NAc was related to pain symptoms, as both FC and pain symptoms were shown to change between the “on” and “off” states in PD.As the disease progresses, patients with PD undergo treatment adjustments and show several motor complications, such as levodopa-induced dyskinesia, wearing-off phenomenon, and on-off fluctuations . In PD, In previous studies, patients with PD showed more frequent and severe pain symptoms during the “off” state compared to the “on” state ,24. The The mesolimbic pathway, which comprises dopaminergic neurons, plays an important role in pain processing. Dopaminergic neurotransmission in the mesolimbic pathway is impaired in patients with chronic pain ,27, as wThe current study provides novel insights into a potential mechanism underlying fluctuating pain in PD; however, several limitations should be considered. First, this clinical study was a pilot study with a limited sample size. In addition, since healthy subjects present less fluctuations in pain, we could not implement a proper control group of healthy subjects . TherefoWe conducted an rsfMRI analysis in patients with PD to explore the relationship between neuronal synchronization of the NAc and pain. The NAc in the mesolimbic pathway is suggested to be involved in the perception and modulation of pain symptoms ,27. Aber


Patient-controlled analgesia (PCA) is an effective method for controlling acute pain, including postoperative pain in adults and in children from five years of age, pain resulting from labor, trauma, or other medical situations, or chronic and malignant pain. The treatment consists of a mini-computer-controlled infusion pump permitting the administration of on-demand, continuous, or combined doses of analgesic (mainly opioid) variations in response to therapy, which allows pain to be significantly controlled. Intravenous (IV)-PCA minimizes individual pharmacodynamics and pharmacokinetic differences and is widely accepted as a reference method for mild or severe postoperative pain. IV-PCA is the most studied route of PCA; other delivery methods have been extensively reported in the literature. In addition, IV-PCA usually voids the gap between pain sensation and analgesic administration, permitting better recovery and fewer side effects. The most commonly observed complications are nausea and vomiting, pruritus, respiratory depression, sedation, confusion and urinary retention. However, human factors such as pharmacy preparation and device programming can also be involved in the occurrence of these complications, while device failure is much less of an issue. Patient-controlled analgesia (PCA) has been used since the early 1970s to relieve multiple categories of pain, including acute, such as postoperative or labor pain, or chronic, such as palliative care or cancer pain . The goaAccording to the revised international association for the study of pain definition  the new Although significant improvement has been made in the anticipation and management of postoperative pain in recent decades, a non-negligible percentage of patients might still have moderate to severe postoperative pain .Patient-controlled analgesia (PCA) preceded by initial intravenous titration is an effective strategy for postoperative analgesia, as it may rapidly provide an adequate analgesic dose upon arrival at the postoperative care unit (PACU).While intravenous and epidural administration remain the most commonly used modes of PCA, several alternative modes are also available in the clinical setting. These alternative routes of administration include oral, transdermal, inhaled and intranasal, each with its own potential benefits or risks .This paper update is a narrative review of only opioid IV-PCA  for clinicians involved in the management of acute postoperative pain. The search strategy used three electronic databases: PubMed (MEDLINE/Index Medicus), the Cochrane  and Google Scholar, which were searched for pertinent studies and reviews published between January 2010 and December 2021; animal studies were excluded. Search items included postoperative pain, PCA, patient-controlled analgesia, opioids, parenteral opioids, opioid side effects and morphine. When new updated information was not available older studies were referenced in some areas.Surgery can result in moderate or severe pain, which can initiate complications in the postoperative period after the procedure. Although anticipation of postoperative pain and its management has been positive for decades, a significant proportion of patients still have high pain scores with non-optimal pain relief ,4,5.Predictors of postoperative pain and analgesic consumption have been assessed in several studies ,10,11,12PCA indications are large, since many surgeries yield high pain scores. Several risk factors for high postoperative pain scores have been established ,7. NearlIt is generally recognized that the benefits of PCA are adaptation to individual patients’ needs by giving patients control over their own pain, relatively fast onset of action, predictable drug delivery and side effects, and high scores of satisfaction, despite suboptimal postoperative pain relief in some specific surgeries ,25.Multiple studies involving morphine for postoperative analgesia display a wide range of inter- or intra-individual variability in morphine requirements but also in plasma morphine concentrations ,34,35,36The effectiveness of PCA is mostly related to the old concept of “minimal effective analgesic concentration” (MEAC), defined as the smallest plasma concentration of morphine at which the pain is relieved . To achiTo reach this target, a controlled and progressive increase in the plasma level of opioids is necessary, which is achieved by titration. Titration means that the drug is administered as a bolus of small doses . TitratiMorphine, a hydrophilic agent and hydromorphone, remains the most commonly used drug for postoperative analgesic titration compared to lipophilic opioids such as fentanyl, sufentanil, alfentanil, or remifentanil , as thesThe maximum concentration after a bolus injection is around six minutes, explaining the delay between further titration injection or the “lock out” period necessary while PCA is used ,40. DuriIV morphine titration allows the dose to be adapted to the patients’ needs and can provide reliable immediate relief of postoperative pain after a wide range of surgical interventions in both young and elderly patients . TitratiIt should be emphasized that morphine titration to alleviate acute postoperative pain might not always be effective or possible due to the early appearance of side effects or other complicating factors, such as tachyphylaxis; therefore, it is appropriate to define an alert dose for titration to use alternative methods to alleviate pain .Most side effects of opioids administered via PCA are related to opioids, such as nausea and vomiting, sedation, apnea, hypoxemia, hypoventilation, pruritus and postoperative delirium (POD).The ventilatory depressant effects of morphine are the most serious side effects. Although they can be patient-related, they are mostly related to a default in preparation, prescription, or administration, as well as a device failure.A recent comparison of the side effects of different opioids given in an equianalgesic dose revealed that no significant or clinically relevant difference should be expected in terms of nausea, vomiting and pruritus when comparing different types of opioids .Considering POD, a recent study did not find a difference in its incidence between morphine IV-PCA and fentanyl patient-controlled epidural analgesia (PCEA). After a propensity score matching patient characteristics, it was concluded that POD occurs regardless of the route and dose of opioid administration .Naloxone is reported to decrease the overall incidence of opioid side effects. A pooled analysis study examining IV naloxone (either as a continuous infusion or IV-PCA) revealed a decrease in pruritus and nausea with no increase in pain scores. Overall, the use of IV naloxone is not associated with any significant changes in opioid consumption nor with the risk of sedation or emesis ,44. In oWhile IV-PCA can be used in most types of surgery, it may not provide the best quality of analgesia, especially in dynamic conditions. For example, in open abdominal surgery, epidural analgesia has been considered the gold standard for perioperative analgesia and provides significantly better pain relief both at rest and in dynamic situations . HoweverAlthough the literature praising PCA-IV for its efficiency in controlling multiple entities of postoperative pain is abundant, according to systematic reviews, the quality of pain relief as determined by assessment of pain intensity scores was only slightly superior to specific non-PCA technique-controlled parenteral opioid  regimens; in two meta-analyses ,34, PCA As effective and safe alternatives to traditional PCA and with the added benefits of being non-invasive, easy to use and making early patient mobilization possible, newer PCA systems may complement multimodal pain management or replace certain regimens in hospitalized patients with acute postoperative pain  Table 2Table 2.Explaining the PCA pump system to patients is generally performed before surgery at the anesthetic consultation; however, re-instruction after surgery is reported to be effective for optimizing PCA to increase the quality of analgesia. In this way, patients use this technique more efficiently, especially when multiple variables, including dynamic pain, are integrated .In terms of patient’s satisfaction, PCA is again reported to have an edge over non-PCA methods, which does not necessarily mean that the quality of analgesia is superior to the alternative technique .Although several opioids have been studied for use in IV-PCA, according to systematic reviews, there is not enough significant clinical evidence to consider the relevant superiority of other opioids on postoperative analgesia compared to morphine IV ,34 Tabl.Two recent papers ,56 invesA major human issue associated with adverse effects is non-anticipated/authorized administration of IV bolus doses of an analgesic by either family, friends, or hospital staff, known as PCA by proxy . In a daMultiple and/or successive individual or collective errors can combine to result in a serious adverse event. Both equipment design and human factors play a critical role at multiple levels in generating serious adverse events . On the Morphine titration is appropriate pain management in pediatric patients because of the limitation in dosage and decreasing the incidence of adverse events. Nevertheless, interindividual variation is also present in this population.Opioid infusions in children are useful, but adequate dosing and titration require careful supervision. Nevertheless, morphine titration in pediatrics has limitations, as pain scores are not always obtainable in the PACU and the validity of self-reported pain intensity scores may be unreliable in children with developmental and neurological disabilities, thereafter affecting the analgesic protocol and necessitating close monitoring ,48. Morphine PCA is used for children above 4–6 years of age experiencing painful surgery, such as scoliosis and pectus excavatum repair ,65. In aElderly patients represent a large and rapidly increasing proportion of surgical patients. Management of postoperative pain should focus on minimizing adverse effects.In normal elderly patients, titration should not be much different; however, for patients older than 90 years and frail patients, a protocol using boluses of 1–2 mg with a greater time interval and a limitation of the total dose is recommended .A retrospective study involving over 10,575 patients comparing older and younger patients using IV fentanyl PCA concluded that, when IV-PCA was used for postoperative pain control, a higher percentage of younger patients required rescue analgesics, while elderly patients required more rescue antiemetics. The addition of ketorolac or ramosetron to the PCA of young and elderly patients can be effective in preventing rescue analgesic or antiemetic use . On the Obese patients with obstructive sleep apnea (OSA) are at an increased risk of upper airway obstruction and require close monitoring. Intermittent IV injections of morphine boluses can be used in these patients. Obesity prolongs the elimination half-life of lipophilic drugs such as fentanyl and sufentanil; however, morphine may be used cautiously in patients with sleep apnea syndrome (OSA) without non-invasive positive pressure . Indeed,PCA, without a background infusion, is a safe and effective method of analgesic delivery. However, if patients are known to have OSA, more intensive monitoring is recommended .Opioid-tolerant patients require additional adjustments when using IV-PCA as the main source of analgesia. Opioid-tolerant patients have significantly higher opioid requirements compared to opioid-naïve patients in the intra- and postoperative period ; therefoNew modalities of PCA administration are currently under investigation. Lee et al. described a variable feedback infusion rate plus demand in comparison to the constant baseline infusion model plus demand in spinal fusion surgery, whereby the variable model used significantly less analgesic and had significantly less demand than the constant base model; however, there was no difference in side effects . RecentlBesides adequate titration, non-pharmacological factors could play a part in optimum pain relief, such as preoperative teaching, adequately addressing patients’ concerns about pain assessment and information about pumps. Adequate knowledge of these factors should help in better clinical care and outcome. Limitations of this study include a bias selection, as the quality of the studies was not classified, and their interpretation, which might have been biased by the own experience of the author.Despite the lack of new evidence, IV-PCA administration of opioids, especially morphine, has only a light superiority for quality of analgesia compared to non-PCA opioid-based analgesic regimens. Nevertheless, morphine IV-PCA, as a component of multimodal analgesia for acute postoperative pain, remains a well-accepted/adopted technique by patients and health care providers, resulting in a high level of satisfaction, while the incidence of side effects is equivalent to non-PCA opioid-based techniques. This modality of analgesia will still be valid and useful for the coming years, pending careful selection of patients with appropriate indications.