Introduction and Background: Gastrointestinal (GI) recovery after major abdominal surgery can be delayed from an ongoing need for narcotic analgesia thereby prolonging hospitalization. Enhanced recovery after surgery (ERAS) is a multimodal perioperative care pathway designed to facilitate early recovery after major surgery by maintaining preoperative body composition and physiological organ function and modifying the stress response induced by surgical exposure. Enhanced recovery programs (ERPs) in colorectal surgery have decreased the duration of postoperative ileus and the hospital stay while showing equivalent morbidity, mortality, and readmission rates in comparison to the traditional standard of care. This study is a pilot trial to evaluate the benefits of ERAS protocols in living kidney donors undergoing laparoscopic nephrectomy.Methods: This is a single-center, non-randomized, retrospective analysis comparing the outcomes of the first 40 live kidney donors subjected to laparoscopic nephrectomy under the ERAS protocol to 40 donors operated prior to ERAS with traditional standard of care. Our ERAS protocol includes reduced duration of fasting with preoperative carbohydrate loading, intraoperative fluid restriction to 3 ml/kg/hr, target urine output of 0.5 ml/kg/hr, use of subfascial Exparel injection (bupivacaine liposome suspension), and postoperative narcotic-free pain regimen with acetaminophen, ketorolac, or tramadol. Short-term patient outcomes were compared using Pearsons’s Chi-Squared test for categorical variables and the Kruskal-Wallis test for continuous variables. Additionally, a multivariate analysis was conducted to evaluate factors influencing patient length of stay and likelihood of readmission.Results: ERAS protocol reduced the postoperative median length of stay decreased from 2.0 to 1.0 days (p=0.001). Overall pain scores were significantly lower in the ERAS group  despite the absence of postoperative narcotics. The average duration of surgery was shorter in the ERAS group . The average amount of intraoperative fluid used was significantly lower in the ERAS group  without affecting the donor renal function. The incidence of delayed graft function was similar in the two groups (p=0.541). A trend toward lower readmission was noted with the ERAS protocol . GI dysfunction was the most common reason for readmission.Conclusion: Application of an ERAS protocol in a laparoscopic living donor nephrectomy was associated with reduced length of hospitalization and improved pain scores related likely to intraoperative use of subfascial Exparel and a shorter duration of ileus. Restricted use of intraoperative fluids prevents excessive third spacing and bowel edema, enhancing gut recovery without adversely impacting recipient graft function. This study suggests that ERAS has the potential to enhance the advantages of laparoscopic surgery for live kidney donation through optimizing donor outcomes and perioperative patient satisfaction. Gastrointestinal (GI) recovery after major abdominal surgery can be delayed from an ongoing need for narcotic analgesia thereby prolonging hospitalization. Enhanced recovery after surgery (ERAS) is a multimodal perioperative care pathway designed to facilitate early recovery after major surgery by maintaining preoperative body composition and physiological organ function and modifying the stress response induced by surgical exposure . EnhanceLaparoscopic living donor nephrectomy (LDN) has significantly transformed the outlook for individuals considering live kidney donation since first described by Ratner et al., in 1995 . DespiteThis pilot trial is a single-center, nonrandomized, retrospective, quality-improvement project to evaluate the effectiveness of a full ERAS pathway in a laparoscopic, living-donor nephrectomy when compared with a historical cohort of patients undergoing laparoscopic donor nephrectomy with traditional standard of care. The ERAS pathway for LDN was implemented at our institute in September 2015 as part of a quality-improvement project, and from that time until present, all live kidney donors were subjected to the ERAS protocol during a laparoscopic nephrectomy. Subsequently, data was collected from 40 consecutive subjects undergoing LDN within the ERAS pathway from September 2015-October 2016 and compared with a prior cohort of 40 consecutive patients undergoing LDN with traditional standard of care from August 2014-August 2015.In this pathway, patients were kept nil per orally (NPO) for eight hours prior to surgery; no bowel preparation was used. Intraoperatively, sequential compressive devices (SCDs) were used for venous thromboembolic prophylaxis. Antibiotic prophylaxis was similar to the ERAS pathway. There were no set directions or protocols followed by anesthesia for intraoperative fluid management. Plans were individualized on a case-by-case basis. Intraoperative diuretics were used following fluid boluses with crystalloids or colloids if urine output was <0.5 ml/kg/hr. Perioperative pain management included intraoperative fentanyl boluses, postoperative IV ketorolac and IV fentanyl or Dilaudid, oral oxycodone, or Dilaudid as needed. Postoperative nausea vomiting (PONV) prophylaxis was the same as for the ERAS pathway.Patients were educated about the pathway in the surgical clinic during a preoperative visit. Preoperatively, a bowel preparation was not routinely used. Patients were allowed clear fluids until two hours prior to the start of surgery and were given a carbohydrate drink, Clearfast®, two hours before surgery after which the NPO period of two hours begins. Table Intraoperatively, low-flow anesthesia was used with the gas flow at ≤1 L/min, and a 'goal-directed fluid therapy' with crystalloid infusion was infused at 3 ml/kg/hr. Fluid therapy was further guided by recording the stroke volume (SV) and stroke volume variation (SVV) using a non-invasive cardiac output monitor. Boluses of colloid were administered to optimize SV/SVV, with 250 ml of colloid bolus given over <15 min if SV increased by >10% and not required if SV increased by < 10%. The surgeon was alerted only when the urine output was < 0.5 ml/Kg/hour. No diuretics were used. A Foley catheter was removed at end of the case. For both pathways, every patient was scheduled for a one-week clinic follow-up visit at discharge.Laparoscopic nephrectomy surgery was performed by the same three surgeons in the two cohorts. The surgical technique used was hand-assisted laparoscopy and was similar between the three surgeons. All three surgeons have been performing this surgery for over eight years, and there was no learning curve for this procedure in either cohort.The study involves retrospective data collection from the electronic medical records for both groups including:1. Patient demographics for both donor and recipient: age, gender, race, weight, body mass index (BMI), glomerular filtration rate (GFR) at donation, pre-operative baseline creatinine, and intraoperative narcotics. Donors were all healthy individuals without any pre-existing comorbidities.2. Operative events: intraoperative fluids administered to the donor and intraoperative urine output measured for the donor and postoperative day (POD) 1 urine output measured for the recipient.3. Total operative time calculated from time to incision to time to end of surgery.4. Pain assessment: pain was assessed using a 0-10 verbal response scale (VRS), where “0” represents no pain, and “10” represents worst possible pain during every shift as part of the standard of care nursing protocol. The highest and the lowest pain score reported each day were recorded from the day of surgery until discharge. The set of maximum and lowest pain scores were averaged for each patient to give each patient an average maximum and average lowest pain score. Pain scores including the morning-after-surgery pain score (taken between 8 and 9 a.m.) and the peak and lowest pain score during the duration of hospitalization were collected.5. Donor and recipient kidney function: based on donor baseline creatinine, postoperative day 1 and day 7 creatinine, recipient baseline creatinine and creatinine at discharge.6. Incidence of delayed allograft function in the recipient.7. Time to hospital discharge, i.e., length of stay (LOS).8. Readmission rates including causes: all readmissions and emergency room (ER) visits for complications related to the LDN within 30 days of hospital discharge were recorded.9. Any intraoperative events or complications.Outcome MeasuresThe primary outcome for this study was the length of stay (LOS) for the donor. LOS is defined as the postoperative number of nights in the hospital. Secondary outcomes included operative times, operative fluid volume, postoperative pain scores, percent change in donor creatinine, donor readmission rates, recipient POD 1 urine output, incidence of delayed allograft function.Statistical AnalysisData was collected from the EPIC Maestro care and Innovian® databases for all patients undergoing LDN with traditional care and ERP pathway. Any missing data was obtained by chart review. Patient characteristics, including demographic, operative, and postoperative data elements were summarized with descriptive statistics and compared between the pre- and post-ERAS implementation groups. Demographics were compared between the two groups using Student's t-test. Analyses were performed using RStudio. (RStudio Team (2015), RStudio: integrated development for R RStudio, Inc., Boston, MA). Normally distributed continuous variables were compared with Student's t-test. For non-normal continuous variables, p-values were calculated by the Kruskal-Wallis test. Categorical variables were calculated using the Pearson chi-square test. For all statistical tests, p-values were two-tailed, and the alpha was set at 0.05.The primary clinical outcome was LOS. The difference in LOS was assessed using the log-rank test. Secondary outcomes included readmission rates which were assessed with the Student's t-test. Multivariate regression analysis was performed for LOS and readmission rates. For comparisons of the other secondary efficacy endpoints such as operative times, operative fluids, percent change in donor creatinine, recipient day 1 urine output, incidence of delayed graft function, t-test, Chi-square test, and Fisher’s Exact test (for binary variables) as indicated were used. We also looked at the readmission rates of the outliers in each group for LOS.Pain was assessed using a 0-10 verbal response scale (VRS), where “0” represented no pain and “10” represents worst possible pain and recorded during every shift as part of the standard of care nursing protocol. The morning-after-surgery pain score was recorded between 8 and 9 a.m. The highest and the lowest pain reported each day was recorded from the day of surgery until discharge. The set of maximum and minimum pain scores were averaged for each patient to give each patient an average maximum and average lowest pain score. Pain scores were compared between therapy groups using a rank-sum test.A total of 79 live donor nephrectomies were performed during the study period (Aug 2014-Oct 2016), with 40 cases performed with the standard care protocol group (SCP) i.e., Group 1, and 39 cases in the ERAS group, i.e., Group 2. Both the groups were balanced since the baseline donor demographics were not significantly different between the two cohorts  after LDN. Group 1 (SCP) had a variable length of stay from 1-7 days, with an average stay of 2 days. For Group 2 (ERAS), the postoperative median length of stay reduced from 2.0 to 1.0 days (p<0.001). Table A univariate subset analysis was performed investigating if there was an association between the increased rate of readmission for donors with the increased LOS Table . Donors Median donor operative time was significantly shorter in Group 2 (ERAS) by 56 minutes compared to the standard protocol (248 (ERAS) v.s 304 (SCP) min, p<0.001) (Table A lower readmission rate was noted with the ERAS protocol (12.8% vs. 27.5%); although this was not statistically significant, p=0.105. In both groups, gastrointestinal complications  were the most common reason for readmission. The incidence of delayed graft function was similar in the two groups (p=0.541). Table .Finally, a logistic regression model was run to analyze donor readmissions Table , but didLive kidney donation is one of the best solutions to satisfy the growing demand for kidneys for transplantation. However, fear of postoperative pain, prolonged hospitalization, and time off work are major disincentives for live kidney donation. Following the advent of laparoscopic donor nephrectomy (LDN), there was a 25% increase in individuals willing to donate kidneys to their loved ones . Over thOf the various strategies adopted by ERAS to reduce the surgical length of stay and facilitate recovery, preoperative consumption of carbohydrate-containing clear liquids  has provided significant benefits. Overnight fasting does not necessarily reduce gastric contents or raise the pH of gastric fluid, and, hence, the American Society of Anesthesiologists’ guidelines recommend intake of clear fluids until two hours prior to the induction of anesthesia . ReducinIntraoperative fluid balance potentially plays a crucial role in early postoperative mobilization and gastrointestinal recovery. The first goal of intraoperative fluid management should be ‘zero balance fluid therapy’ targeted at maintaining central euvolemia and avoiding excessive fluid administration which can result in ‘third spacing’ and tissue edema contributing to perioperative weight gain, bowel wall edema, and prolonged ileus . TypicalThe unique aspect of the Duke ERAS protocol is the inclusion of intraoperative GDFT using crystalloid infusion supplemented by colloid boluses to maximize donor SV/SVV. With this technique, there was a significant reduction in the amount of intraoperative fluids infused in the ERP group without any influence on the donor renal function in the form of intraoperative donor urine output, percent rise in donor creatinine on the 1st postoperative day, or any adverse impact on the allograft outcome. We also postulate that reduced intraoperative fluids may have indirectly helped in reducing operative times secondary to maintained tissue planes from reduced third-space fluid losses. All three of the surgeons performing the LDN have been doing this surgery for over eight years, and with the surgical technique remaining similar in the two cohorts, the possibility of the learning curve contributing toward the reduced operative times is negligible. Less tissue edema also could have potentially contributed to the early recovery of the postoperative bowel function, facilitating early discharge and reducing LOS.The ERAS pathway is also built on multimodal pain-control strategies of which local anesthetics are a cornerstone. However, local anesthetics are relatively limited due to their shorter duration of action ≤ 7 hrs) . Using D hrs . UsThere are several limitations to this study. Due to the small number of patients included in this study, this study was not powered to identify significant differences in the rate of readmissions between the two groups. Since this was a quality-improvement project in which we implemented a perioperative protocol that has been proven to reduce the length of stay and optimize postoperative recovery in other abdominal surgeries, we did not consider conducting a randomized control trial to test our hypothesis. However, we did consider comparing outcomes between two centers performing LDN with different care pathways, i.e., SCP vs. ERP, but did not pursue this considering several confounders including different standards of perioperative care, surgeon expertise, surgical techniques, and etc. could have impacted the results. Further, we do admit that knowledge of the donor being cared in the ERP could have possibly influenced early discharge in the ERP cohort. Pain scores as such could not be validated due to the variability in the patient interpretation of pain and inconsistent timing for recording of the scores. Implementing reliable pain scales and consistent times for recording the scores could possibly resolve any bias associated with the differences in pain scores between the two cohorts. Lastly, there is a lack of data in the literature to support or refute the use of liposomal bupivacaine administered as a peripheral nerve block for the management of postoperative pain. It would be interesting to further study outcomes of this study using a similar ERP without Exparel but with the use of routine local anesthetic agents injected subcutaneously to identify if the benefit of ERP is a result of GDFT or Exparel or a combination of both. We will be addressing most of these issues along with an additional survey of patients in the follow-up period to record patient reported outcomes and satisfaction in a subsequent larger prospective randomized control trial versus a multicenter trial.Application of a special ERAS protocol in laparoscopic living donor nephrectomy was associated with a reduced length of hospitalization. Improved pain scores resulted from a combination of the intraoperative use of subfascial Exparel and a reduced incidence of postoperative ileus with a complete avoidance of narcotic pain regimens. Restricted intraoperative fluids reduced the operative times by promoting clarity of surgical planes with prevention of excessive third spacing without adversely affecting allograft outcomes. GDFT helped reduce bowel edema, thereby enhancing postoperative gut recovery. Although readmission rates were not statistically significant, a larger study may further clarify this result. This study suggests that use of ERAS may enhance advantages of laparoscopic surgery for live kidney donation through optimizing donor outcomes and improved perioperative patient satisfaction. Regular application of ERPs in the future could incentivize donors by decreasing overall postoperative complications and facilitate earlier return to work.


Background: Regulatory barriers limit clinical trials of medical cannabis in the United States. Longitudinal cohort studies may be one feasible alternative that could yield clinically relevant information. Willingness to participate in such studies is not known.Materials and Methods: In October 2016, we surveyed a convenience sample of patients with chronic pain from two New York registered organizations . After a vignette describing a longitudinal cohort study involving weekly patient-reported outcomes and quarterly assessments of physical functioning and urine and blood tests, we asked about respondents' willingness to participate. We examined willingness to participate, duration of participation, and frequency of data collections overall and by subgroups, using multivariable logistic regression models.Results: Of 405 respondents (estimated response rate: 30%), 54% were women and 81% were white non-Hispanic. Neuropathy was the most common pain condition (67%) followed by inflammatory bowel disease (19%). Of respondents, 94% (95% CI 92–97%) thought that the study should be done, 85% (95% CI 81–88%) would definitely or probably enroll if asked, 76% (95% CI 72–81%) would participate for ≥1 year, and 59% (95% CI 54–64%) would respond to questions at least daily. Older age was the only factor associated with lower willingness to participate, lower willingness to participate for ≥1 year, and lower willingness to respond to questions at least daily.Conclusions: Nearly all respondents were supportive of the proposed study and most reported that they would enroll if asked. Enhanced engagement with older individuals may be needed to promote equal enrollment. Recruitment for longitudinal cohort studies with frequent data collection appears feasible in this patient population. One important and rapidly expanding strategy to manage chronic pain is the use of medical cannabis. As of January 2018, medical use of cannabis is legal in 29 states and the District of Columbia.Chronic pain is common in the United States, and its management is challenging. Over the past two decades, opioid analgesics have become a leading pain management strategy and dispensing has tripled.3 But beyond evidence of efficacy, there are numerous gaps in research, including patient selection, long-term treatment outcomes, and dosing of major cannabinoids such as Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). While randomized controlled trials (RCTs) are the “gold standard” of evidence, RCTs of medical cannabis (a Schedule I substance) currently face numerous hurdles in the United States both due to product availability and due to restrictive dispensing and security procedures required. Although the Drug Enforcement Administration announced a policy change to expand the number of cannabis manufacturers, currently only one entity is authorized to produce and supply cannabis to U.S. researchers.4 The cannabis products available for research are limited in scope and not necessarily comparable to cannabis products available in state dispensaries.3 Even when products are obtained for research, they typically must be dispensed in a directly observed setting. Because of these restrictions, over the last 41 years, only six clinical trials in the United States have administered cannabis to examine its effect on pain. These randomized trials all occurred in tightly controlled settings (human laboratories), for short durations (4 h to 12 days), with small sample sizes (10–55 participants).5–10In January 2017, the National Academies of Science, Engineering, and Medicine released a landmark report finding substantial evidence for cannabis' efficacy in treating chronic pain.Randomized trials might also face several other challenges. Unlike a novel pharmaceutical, many people with chronic pain have used cannabis and may bring those experiences to a study, potentially influencing results. However, in contrast, enrolling participants who are cannabis-naive may not necessarily be representative of the broader patient population because of such widespread use. In addition, strong political views and a desire to advocate for medical cannabis access may lead to enrollment of participants who are invested in a certain outcome. Finally, people with chronic pain may not be motivated to enroll in a clinical trial because of cannabis' widespread availability outside of the trial.12 While longitudinal cohort studies that simply compare those who use medical cannabis to those who do not would be inescapably confounded, more complex designs and analyses could potentially come closer to estimating causation.13 From a clinical perspective, studying medical cannabis in a naturalistic setting may also be more aligned with how the system currently operates. Physicians do not prescribe medical cannabis such as other medications, but they certify patients to purchase it. Patients then choose the dose, amount, and route of administration.Given current limitations of interventional research, observational studies are an appealing alternative. Longitudinal cohort studies of patient-reported pain outcomes are feasible, and even intensive assessments of pain  have not been found to affect participants' responses.15 The purpose of the current study is to examine willingness to participate in research among patients with chronic pain who take medical cannabis. Overall and by demographic  and clinically important subgroups , we describe willingness to participate in a longitudinal study, duration for which potential participants would join in the study, and frequency with which potential participants would provide data.Despite the urgent need for research on medical cannabis and chronic pain, willingness of the target population to participate in such research is not known. Frustration with previous treatment failures and a desire for new options may motivate patients to participate in this line of research. In contrast, experiences of stigma and marginalization from the healthcare system may dissuade patients from participating.The setting for the current study is New York State. New York State's medical cannabis program  has several features that make it a promising venue for longitudinal research on medical cannabis and chronic pain. To be certified for medical cannabis, individuals must have at least one qualifying condition  and one associated complication . After a program expansion in March 2017, after this study was conducted, patients with severe or chronic pain from any condition qualify (not just the conditions listed above). Patients can only purchase medical cannabis products from state-licensed dispensaries, which offer products with a variety of THC:CBD ratios with several different routes of administration —whole plant material is not available in New York dispensaries. As all products are third-party tested for content and allow for dosing in milligrams, cannabis use can be measured with relative precision.16 for a total estimate of 1350 eligible patients.We surveyed customers of two New York State registered organizations . In October 2016, we recruited a convenience sample of patients with chronic pain by posting fliers in dispensaries, approaching patients in waiting rooms, and sending out an electronic link via patient newsletters. Recruitment materials specified that the survey was for patients with chronic pain, but did not specify that the topic would be willingness to participate in clinical research. Respondents were offered a $15 gift card for completion of the survey. Inclusion criteria were as follows: (1) age ≥18 years, (2) registration as a patient with the New York State medical cannabis program, (3) chronic or severe pain as a qualifying complication (by self-report), and (4) able to comprehend English. We excluded respondents who completed the survey in less than 90 sec. While we could not determine the exact number of eligible patients, we estimated that the two registered organizations served 30% of an estimated 6000 medical cannabis patients in New York at the time of the survey, 75% of which have chronic or severe pain,18We created a 28-question survey to examine willingness to participate in longitudinal cohort studies among patients with chronic pain who take medical cannabis. Based on potential research participants' information needs as described in previous work, we created a vignette describing a hypothetical longitudinal cohort study involving patient-reported outcomes as well as assessments of physical functioning and urine and blood tests .17,1819After reading the description, we first asked respondents, “Do you think this study should be done?” . We then asked respondents' willingness to participate through a series of three questions: (1) “Would you participate in the study if you were asked?” , (2) “If you joined the study, would you be willing to participate for”: , and (3) “If you were texted or prompted on your cell phone to answer questions from the study, how often would you be willing to respond?” . We drew the wordings and based our answer choices for these questions from a recent study.19–38For respondents' indicating a willingness to participate in the proposed study (for any length of time), we presented a list of potential reasons why and asked participants to check all that apply. Similarly, for respondents not willing to participate, we displayed a list of potential reasons why not and asked respondents' to check all that apply. We drew these potential reasons from studies examining willingness to participate in diverse types of research.39 We classified pain and interference scores from the PEG (mean of the three items) into mild, moderate, and severe using established cutoffs.40 For pain medication use, we asked about use of common medication types in the past 30 days, and for respondents reporting opioid analgesic use, we asked about the number of days used in the past 30 days. For medical cannabis information, we collected the number of months the respondent has used medical cannabis, number of days in the past 30 days used, dosage forms , and routes of administration .In addition to collecting information on respondents' willingness to participate, we collected information about respondents' sociodemographic characteristics, pain condition and medication use, and information about medical cannabis qualifying conditions and product use. For sociodemographic characteristics, we collected age, sex, race/ethnicity , education level, income, employment, and health insurance. For pain condition, we collected information on the duration of the pain condition and the frequency of pain, as well as a three-item measure of pain intensity and interference with functioning .n=338/405) provided complete data. To account for missing data, we conducted a multiple imputation procedure with chained equations.41 We performed this in stages. First, we imputed sociodemographic variables, followed by pain condition and medication use variables, then use of New York State medical cannabis products, and finally, willingness to participate in research. We assumed data were missing at random and created 20 imputed datasets. All data presented include 95% confidence intervals (95% CI) to account for the uncertainty around the imputed data.Of all respondents, 83%  using predictive margins. We also estimated contrasts . Analyses were conducted using SAS 9.4 and Stata 13. This research was approved by the Albert Einstein College of Medicine and Montefiore Medical Center Institutional Review Board (protocol 2016-6728).First, we calculated descriptive statistics  along with 95% CIs for all survey questions. Next, to describe willingness to participate in research among specific subgroups, we used multivariable logistic regression models. Our main outcomes were the three questions on willingness to participate, and we dichotomized responses for these questions. For the question, “Would you participate in the study if you were asked?,” we dichotomized responses as “definitely yes” and “probably yes” compared to “probably no” and “definitely no.” For the question, “If you joined the study, would you be willing to participate for?,” we dichotomized responses as “≥1 year” and “<1 year or would not participate.” For the question, “If you were texted or prompted on your cell phone to answer questions from the study how often would you be willing to respond?,” we dichotomized responses as “once or more daily” and “less than daily.” We selected independent variables for our models based on factors previously found to be associated with willingness to participate  and variables that delineate clinically important subgroups .n=405/1350).Of 599 respondents, 191 (32%) were excluded due to ineligibility , and 3 (0.5%) were excluded for taking <90 sec to complete the survey. Based on our estimates of the number of eligible patients, this represents an estimated response rate of 30%  followed by inflammatory bowel disease  and balanced THC:CBD forms  were used roughly equally, and sublingual tincture was the most common route of administration , and the vast majority reported that they would enroll if asked  wanted to participate because they felt that the research might help other people, and 79% (95% CI 74–83%) felt that doctors need better scientific information about medical cannabis . Of respWhile patient groups, clinicians, and policymakers have called for more research on medical cannabis, to our knowledge, this is the first study that has examined willingness of people with chronic pain to participate in such research. Not only did virtually all respondents support the proposed study but also a vast majority reported that they would enroll if asked. However, with an estimated survey response rate of 30%, willingness to participate in the study described may be as low as 26% (85%×30%) of the broader population. Our findings suggest that long-term studies involving repeated, frequent data collection are of interest to the target population and recruitment would be feasible.47–49 want research studies to include decreasing opioid dose as an end-point,50 and may seek medical cannabis as an alternative or adjunctive therapy.51 As suggested by surveys and anecdotal evidence, patients may also seek medical cannabis for the purposes of tapering or discontinuing opioid analgesics.52–59 State-level ecological studies have found associations between medical cannabis laws and lower rates of opioid prescribing and overdoses involving opioids.60–62 In the era of the opioid epidemic, rigorous patient-level studies of the impact of medical cannabis use on opioid analgesic use are urgently needed.Our findings also suggest that future studies can successfully recruit patients who take opioid analgesics, a subgroup of particular clinical importance. Such patients can have ambivalence about long-term use of opioid analgesics,63 The difference by age that we found may be due, at least in part, to the mode of data collection (phone-based), but previous surveys about technology-based studies have found mixed associations between age and willingness to participate.46 Older respondents may also have differing attitudes about research  or face other potential barriers.23 To ensure equal representation, future studies of chronic pain and medical cannabis should specifically seek to engage older adults.While patient populations and study designs are distinct, our finding of lower willingness to participate with increasing age is consistent with some, but not all, recent surveys about observational  and interventional  research.18 there are several factors which could improve willingness to participate even further. About one third of respondents who were not willing to participate reported wanting to know more information on the study. This may include more information about access to clinicians during the study, more details about the time burden of the study, more information about management of increased pain or adverse events, or even details such as the names and credentials of the investigators.17 Willingness to participate may also increase with the offer of personalized feedback at the end of the study , a feature that other potential research participants have reported valuing.19While we designed our study description based on previously described information needs of potential study participants with chronic pain,This study has several limitations. First, as we recruited a convenience sample, respondents' views may not be representative of the broader population with chronic pain who take medical cannabis. We could not assess demographic differences between survey respondents and the broader New York medical cannabis patient population because New York has not released these data. Furthermore, as New York's medical cannabis program only distributes extracts that are much more expensive than plant material, eligible patients in New York may have different sociodemographic characteristics than potentially eligible patients in other states. Second, we did not have exact numbers of eligible patients, and our estimated number (and response rate) may not be accurate. Third, we asked about willingness to participate in a hypothetical study, responses to invitations to enroll in an actual study may be different. Finally, we relied on self-report for cannabis and opioid analgesic use and did not confirm with medical records.In conclusion, we found high levels of support for a longitudinal cohort study with frequent data collection among patients with chronic pain who take medical cannabis. To the extent that future studies can reach a broad selection of patients, our findings also suggest that recruitment of representative samples is possible. While access to medical cannabis has expanded greatly, interventional research on the efficacy of cannabis for pain is still limited due to funding and regulations. Strong observational studies have the potential to fill in evidence gaps, and the current study demonstrates that patients are willing to participate.


Endorectal balloons (ERBs) are routinely used in prostate proton radiation therapy to immobilize the prostate and spare the rectal wall. Rectal gas can distend the rectum and displace the prostate even in the presence of ERBs. The purpose of this work was to quantify the effects an ERB with a passive gas release conduit had on the incidence of rectal gas. Fifteen patients who were treated with a standard ERB and 15 with a gas‐release ERB were selected for this retrospective study. Location and cross‐sectional area of gas pockets and the fraction of time they occurred on 1133 lateral kilovoltage (kV) images were analyzed. Gas locations were classified as trapped between the ERB and anterior rectal wall, between the ERB and posterior rectal wall, or superior to the ERB. For patients using the standard ERB, gas was found in at least one region in 45.8% of fractions. Gas was trapped in the anterior region in 37.1% of fractions, in the posterior region in 5.0% of fractions, and in the sigmoid region in 9.6% of fractions. For patients using the ERB with the gas‐release conduit, gas was found in at least one region in 19.7% of fractions. Gas was trapped in the anterior region in 5.6% of fractions, in the posterior region in 8.3% of fractions, and in the sigmoid region in 7.4% of fractions. Both the number of fractions with gas in the anterior region and the number of fractions with gas in at least one region were significantly higher in the former group than in the latter. The cross‐sectional area of trapped gas did not differ between the two groups. Thus gas‐release balloon can effectively release gas, and may be able to improve clinical workflow by reducing the need for catheterization.PACS number: 87.56.Da As radiation therapy technology has matured, the delivery of increasingly conformal radiation fields with commensurately smaller margins at higher doses has become commonplace. This approach to treating prostate cancer has been shown to achieve better tumor controlIn the treatment of prostate cancer, numerous methods have been developed to combat these uncertainties. These methods include daily imaging of implanted fiducials to reduce setup uncertainty,Rectal gas is a consistent problem in prostate cancer radiation therapy. Gas distends the rectum and thereby displaces the prostate Fig. . FurtherERBs are commonly used as a means of reducing prostate movement. Prior to simulation and treatment, a balloon is inserted into the patient's rectum and then inflated. Typically water filled balloons are utilized in patients receiving proton radiation therapy, while air filled balloons are utilized in patients receiving photon or X‐ray therapy. The introduction of the balloon helps prevent posterior prostate motion by immobilizing the prostate against the pubic symphysis in the anterior direction and against the full bladder in the superior direction. In addition to confining the location of the prostate, the rectal balloon also displaces the rectum's contents, thus decreasing variability in prostate position due to gas or stool.Recent attempts to reduce the effects of rectal gas have included using ERBs designed to passively alleviate rectal gas. However, the effectiveness of these gas‐release ERBs has yet to be assessed. The purpose of this study was to quantitatively evaluate the effect of the new gas‐release balloon on the amounts and locations of rectal gas during proton treatment for prostate cancer.Thirty prostate cancer patients treated with proton therapy in 2011 at our institution were included in this institutional review board‐approved retrospective study. The average age of the patients at the time of treatment was 62 years old (range: 46–72). All patients were treated for T1c, T2c, or T2a prostate cancer. Parallel opposed passively scattered proton beams were used to treat each patient to 76 Gy (RBE) in 38 fractions (2 Gy/fx).The new ERB design  incorporates an open conduit through the balloon stem Fig. . The purFifteen of the selected patients had been treated using a standard ERB  and the other 15 using the gas‐release ERB . The gas‐release ERB incorporates a passive gas‐release conduit through the balloon stem, a fiducial bead at the balloon tip, and a stopper at the balloon base to facilitate reproducible depth of insertion. The ERBs were inserted immediately before simulation computed tomography (CT) and all treatment fractions. All balloons were inflated with 100 mL of water so that their density would be homogeneous with that of the surrounding tissue.0.3920 mm2 area on the plane containing the isocenter. A total of 1133 images (36–38 per patient) were available for analysis. Patient information was removed from each image. Information identifying the model of the ERB used was also removed to avoid biasing the study. This involved obscuring regions of images in which the presence or absence of landmarks  would identify the model of ERB used.We analyzed the data from the lateral kV images that were taken at the time of daily treatment for patient alignment and assessment of gas in the rectum. The distance from the X‐ray source to the imager (SID) was 323 cm. The distance from the X‐ray source to the gantry isocenter (SAD) was 273 cm. In the resulting images, a pixel corresponded to a 0.3920 by After preparing the images, we inspected each image for the presence of gas. Pockets of gas were identified according to several characteristics. First, pockets of rectal gas typically have well‐delineated borders. Second, gas pockets cause distinct changes between daily images of the same patient; by examining multiple images in succession, gas pockets can be distinguished from anatomical features that resemble gas pockets. Finally, before an image feature is identified as gas, the possibility that it is an air bubble in the ERB has to be ruled out. Because patients are imaged while supine, bubbles typically float anteriorly; thus, bubbles in the ERB can be identified by their location in the anterior region of the rectum, their curved anterior border matching the contour of the balloon, and their level posterior border. Figure After identifying the gas pockets in all images, we recorded the location and cross‐sectional area of each pocket. The location of each gas pocket was classified as occurring in one of three regions: between the ERB and the anterior rectal wall, between the ERB and the posterior rectal wall, and superior to the ERB in the sigmoid colon (limited to 7 cm superior from the top of the ERB and 4 cm anterior or posterior to it). The cross‐sectional areas of the gas pockets were also recorded. The cross‐sectional area of the gas pockets was determined by measuring the dimensions of each pocket in terms of pixels and converting to physical distance using a conversion of 0.3920 mm per pixel. This method assumes that gas pockets lie in the plane containing the isocenter. This assumption is valid as the rectum is directly posterior to the prostate where the isocenter is placed. The number, size, and location of gas pockets were recorded for each fraction for each patient.The percentage of fractions with rectal gas in at least one region was calculated for each patient, as were the percentages of fractions with gas in the anterior, posterior, and sigmoid regions. The mean cross‐sectional area of rectal gas pockets was also calculated for each region for each patient. These calculated values were then averaged over the standard ERB and gas‐release ERB patient groups. Finally, a two‐tailed t‐test for independent samples was used to determine whether the differences between the two groups' results were statistically significant. Statistical analysis was performed in Microsoft Excel 2007 and p‐values less than 0.05 were considered to indicate a statistically significant difference.±2.8% of fractions . A comparison between the two patient groups indicates that the difference between the numbers of fractions with gas in one or more regions was statistically significant (p<0.00001), as was the difference in the number of fractions with gas in the anterior region (p<0.0000001). The differences between the number of fractions with gas in the posterior and sigmoid region were not statistically significant.For the patients using the standard ERB , gas was present in one or more of the three regions in 45.8% 1.3 cm2±0.3 cm2, 1.0 cm2±0.4 cm2, and 1.5 cm2±1.0 cm2, respectively , we chose to use only lateral images. These images provided critical information on rectal gas in the anterior rectal region that was in the treatment field, whereas anterior–posterior kV images, which lack depth information, would not have allowed us to distinguish between gas trapped anteriorly and posteriorly.Lateral kV images from daily radiation treatments of 30 prostate cancer patients treated at our institution were examined for the presence of rectal gas. A standard ERB was used for 15 patients, and a modified ERB designed to passively allow gas release was used for the remaining 15 patients. The modified ERB significantly decreased the overall frequency of fractions with gas present in any region by decreasing the frequency of fractions with gas present between the rectal balloon and the anterior rectal wall, the most common location of rectal gas. We conclude, therefore, that the gas‐release ERB effectively removes rectal gas and should be used in patients receiving proton radiation therapy.


Acute coronary syndrome accounts for more than 15% of the chest pains. Recently, Hess et al. developed North American Chest Pain Rule (NACPR) to identify very low-risk patients who can be safely discharged from emergency department (ED). The present study aimed to validate this rule in EDs of two academic hospitals.A prospective diagnostic accuracy study was conducted on consecutive patients 24 years of age and older presenting to the ED with the chief complaint of acute chest pain, during March 2013 to June 2013. Chest pain characteristics, cardiac history, electrocardiogram findings, and cardiac biomarker measurement of patients were collected and screening performance characteristics of NACPR with 95% confidence interval were calculated using SPSS 21.From 400 eligible patients with completed follow up, 69 (17.25 %) developed myocardial infarction, 121 (30.25%) underwent coronary revascularization, and 4 (2%) died because of cardiac or unidentifiable causes. By using NACPR, 34 (8.50%) of all the patients could be considered very low- risk and discharged after a brief ED assessment. Among these patients, none developed above-mentioned adverse outcomes within 30 days. Sensitivity, specificity, positive prediction value, and negative prediction value of the rule were 100% (95% CI: 87.35 - 100.00), 45.35 (95% CI: 40.19 - 50.61), 14.52 (95% CI: 10.40 – 19.85), and 100 (95% CI: 97.18 - 100.00), respectively.The present multicenter study showed that NACPR is a good screening tool for early discharge of patients with very low-risk chest pain from ED. Acute c from ED -8. This Study design and settingA consecutive prospective diagnostic accuracy study was conducted on adult patients who presented to the EDs of Imam Khomeini and Shariati Hospitals, Tehran, Iran, with chest pain as their primary complaint during March 2013 to June 2013. Informed consent was obtained from every patient and the data were kept confidential. The Institutional Review Board of the hospitals and ethic committee of Tehran University of Medical Sciences approved the study protocol. ParticipantsAll adults older than 24 years with chief complaint of anterior chest pain presenting to ED were enrolled. As in Hess et al. study, patients were excluded if there was ST segment elevation at least in two contiguous leads on the initial ECG, hemodynamic instability (persistent heart rate greater than 100 beats/min or less than 50 beats/min or systolic blood pressure persistently below 90 mmHg), an unreliable clinical history, a chest pain caused by trauma, a documented history of cocaine abuse , a non-cardiac terminal illness, pregnancy, previous enrollment within the past 30 days, or inability to receive follow-up by telephone . Studied hospitals were tertiary-care university-affiliated centers with more than 600 beds each. They have an annual ED visit rate of approximately 40,000 patients. All diagnostic tests and therapeutic procedures were performed at the discretion of the attending physician, according to routine ED practice. Patients presenting to the ED with definite signs and symptoms of developing ACS (e.g. ST-elevation or elevated cardiac biomarkers) were consulted with a cardiologist and admitted directly to the coronary care unit afterwards. Other patiens were admitted and observed in the ED. Serial ECGs and cardiac markers were obtained and further decisions were made according to the results. A team of well-trained research assistants worked in a scheduled set of shifts and enrolled eligible patients. Data gatheringet al. study, past history of CAD was defined as at least 50% coronary stenosis on angiography; demonstrated ECG changes, perfusion defects, or wall motion abnormalities on exercise, pharmacologic, or rest imaging studies; or previous documentation of acute myocardial infarction  were recorded on specific data collection forms by research assistants. As in Hess farction . Accordifarction . In ordeAssigning patients to one of NACPR groups was done retrospectively and no intervention was performed to implement the rule during admission. All the ECGs were reviewed by two investigators blinded to final outcome , and a third investigator (MJ) resolved disagreement. The definition in Hess et al. study was used to define ECG abnormality . By consOutcomesMyocardial infarction (ST-elevation and non ST-elevation), coronary revascularization, cardiac death, and no other definite cause found in investigation were considered as 30 days outcomes. Outcomes were defined same as original derivation study of NACPR . The menNACPRAccording to NACPR, two groups of patients are eligible for early discharge. The first group includes patients younger than 40 years of age with a normal primary ECG, reporting very low-risk chest pain characteristics, and without history of ischemic chest pain. The second group of patients consist of patients 41-50 years of age with normal troponin level 6 hours after the pain onset, in addition to the criteria mentioned for the first group .Statistical analysisMinimum sample size required for the present study was calculated to be 400 cases, considering 100% sensitivity of NACPR (95% CI: 97.1 -100), 20.9% specificity (95% CI: 16.9 – 24.9), 0.06 p value, and 0.048 desired precision . Therefore, a total of 409 patients were finally enrolled. 400 of which had follow-up completed . ReviewiBaseline characteristic of patientsThe mean age of the 400 enrolled patients was 56.77 ± 12.52 (25 - 87) and 213 (53.3%) cases were male. The baseline characteristics of patients are summarized in Screening characteristics of ruleBased on the results of screening with NACPR, 34 (8.5%) cases were in very low-risk group for developing 30 day adverse outcomes and were eligible to be discharged from ED. Based on the results of the present study, NACPR has 100% sensitivity and negative predictive value in predicting very low-risk patient for developing 30 day adverse outcomes of MI, revascularization, and death among those presenting to ED with chest pain. Having used NACPR, 34 patients (8.50%) would have been eligible to be included in the very low-risk group and could be discharged from the ED. None of the 166 patients who developed aforementioned outcomes within 30 days would have been included in the very-low-risk group by implementation of this rule. In our study, sensitivity and negative likelihood ratio were similar to those found by Hess et al. and Mahler et al. (100% and 0%). The specificity in our study (14.53%) was lower than the original study 20.90%) but higher than Mehler et al. study (5.6%) , 9. This0% but hiClinical decision rules are developed in order to facilitate the decision making process in common and important clinical conditions. Acute chest pain has a high prevalence, which calls attention to develop rules. These rules use easily obtainable elements in history, clinical examination, and simple tests, to safely rule out hazardous conditions . Data in the United States showed that approximately 2% of patients with ACS are misdiagnosed and inappropriately discharged from the EDs . FurtherIn 1990s, some rules for cardiac care unit admission were developed based on observation with 3% misrate , 12. LatIn a prospective study, Hess et al. derived a clinical decision rule for identification of patients with very low-risk chest pain who could be safely discharged from ED without further objective cardiac testing such as stress tests . By adheRecently Vancouver Chest Pain Rule was developed according to methodological standards by utilizing biomarkers . ChristeJalili et al. found sensitivity of 95.1% and specificity of 56.3% for Vancouver Chest Pain Rule. The PPV and NPV were fairly similar . In addition to having lower yields in comparison to NACPR, there are some debates over this rule. For example, Hess et al. study showed that some elements in Vancouver Chest Pain Rule have insufficient inter-observer reliability . RecentlLimitationsOur study faces some limitations. Although this rule assesses chest pain, like Hess et al. study, we did not study unstable angina independently. In addition, non-chest pain presentation of cardiac origin was not included in the rule, which precludes its application in these patients. During the study period, inter-observer agreement was not assessed in our study in regard to gathering patient information by research assistants and ECG assessment by HM and SV, which in turn may increases the risk of performance bias. As shown in the Hess et al. study, several other factors such as presence or absence of observation units can also affect the costs. However, due to lack of accurate and detailed financial records, we were not able to determine the use of financial resources and find out if costs had been minimized by early discharge of very-low-risk patients. Another limitation in our result interpretation is 10% failed enrollment or follow up. In addition, even the most accurate rules are unlikely to be applied in practice if they are not considered reasonable by the end-user, therefore, these rules should consist of simple and sensible elements . End-useIn summary, our study proved that the prediction rule proposed by Hess et al. is a sensitive decision tool for diagnosing very-low-risk chest pain patients who can be discharged early from the ED.


To investigate the effect of lumbar and sacroiliac joint (SIJ) manipulation on pain and functional disability in patients with lumbar disc herniation (LDH) concomitant with SIJ hypomobility.Twenty patients aged between 20 and 50 years with MRI-confirmed LDH who also had SIJ hypomobility participated in the trial in 2010. Patients who had sequestrated disc herniation were excluded. All patients received five sessions of spinal manipulative therapy (SMT) for the SIJ and lumbar spine during a 2-week period. Back and leg pain intensity and functional disability level were measured with a numerical rating scale (NRS) and the Oswestry Disability Index (ODI) at baseline, immediately after the 5th session, and 1 month after baseline.A significantly greater mean improvement in back and leg pain was observed in the 5th sessions and 1 month after SMT. Mean changes in ODI in the 5th session and 1 month after treatment also showed significant improvement. The MCIC for NRS and ODI scores in the present study were considered 20 and 6 points, respectively. Therefore, the mentioned improvements were not clinically significant in the 5th session or at 1-month follow-up.Five sessions of lumbar and SIJ manipulation can potentially improve pain and functional disability in patients with MRI-confirmed LDH and concomitant SIJ hypomobility.IRCT2017011924149N33), registered 19 February 2017 (retrospectively registered).Irct.ir (Identifier:  Common low back problems include disc prolapse, spinal stenosis and low back pain . Disc heLumbar disc herniation commonly presents with low back pain, and this problem is usually associated with sacroiliac joint (SIJ) disorders. In fact, up to 30.7% of patients with LBP and sciatica also have SIJ dysfunction . ResearcGenerally speaking, most patients with SLDD prefer conservative treatments to surgical intervention. To date, evidence has supported several conservative treatments for SLDD including traction , McKenziThe use of spinal manipulative therapy (SMT) for patients with SLDD has also been suggested; however, its safety and indications have remained debatable, particularly in individuals with disc disruption or instability . In thisSome studies reported significant clinical improvements in patients with SLDD after manipulation in comparison to traction , heat 11 and shaSacroiliac joint hypomobility has usually been overlooked in the management of patients with LDH and low back problems. However, there is no conclusive evidence for the effectiveness of SMT in the treatment of patients with LDH, and the evidence to date is contradictory. Therefore, the present study aimed to investigate the effect of SMT applied to the lumbar spine and SIJ to treat patients with SLDD who also had SIJ hypomobility.well straight leg raise (SLR) test, indicating rather large disc herniation and poor prognosis for conservative treatments [Twenty patients  aged 20–50 years old with MRI-proven unilateral LDH were included IN 2010 if they had SLDD in the L4-L5 or L5-S1 segment concomitant with ipsilateral SIJ hypomobility .This was a pre–post test quasi-experimental study. The participants were selected among patients referred to physical therapy clinics of Shiraz, Iran. Sample size was calculated based on the NRS pain score reported in a previous related study  in the lateral recumbent position, with his or her upper foot in the popliteal fossa of the lower leg. Standing opposite to the patient, the therapist grasped the patient’s lower shoulder and arm and applied right rotation until motion was felt in the desired segment of the lumbar spine. The patient was rolled toward the therapist, with his or her arms positioned around the therapist’s right arm. The therapist’s right forearm was in contact with the patient’s right axilla and pectoral region to maintain appropriate rotation from above. In this position, the therapist applied a high-velocity low-amplitude thrust to the pelvis in an anterior direction with his or her left forearm placed behind the patient’s right hip. The therapist pressed the spinous process of the upper vertebra downward with his or her right thumb, while pulling the spinous process of the lower vertebra upward with his or her left thumb. The procedure was done in a way that avoided exacerbating the patient’s pain at the barrier point  Fig. 1)1).Fig. 1The patients lay supine on a treatment table, with their fingers interlocked behind their head. The therapist stood contralateral to the side to be manipulated and moved the patient onto his or her side, then leaned toward the dysfunction side, rotated the patient, and exerted a quick thrust to the anterior superior iliac spine in the posterior and inferior directions , 19 Fig.Fig. 2SaThe scores for back and leg pain were recorded separately on an NRS of 0 to 100, in which 0 indicated no pain and 100 indicated the worst perceived pain . The minThe patients’ functional disability level was determined with the Oswestry Disability Index (ODI), a 10-item questionnaire in which each item is scored from 0 to 5 . The maxParticipants were also assessed with the SLR and slump tests to diagnose LDH, and standing flexion, sitting flexion and Gillet tests were used to diagnose SIJ hypomobility. Although the evidence is contradictory, some studies have reported acceptable reliability for the SIJ test. –27 The rThe data were analyzed with the Statistical Package for Social Sciences (SPSS), version 21.0 . The Kolmogorov–Smirnov test of normality was conducted for all quantitative variables. Repeated measure ANOVA was used to assess the trends in changes in the NRS and ODI scores. Individual time point differences were determined by the Bonferroni post hoc test, and the results of the five clinical tests were analyzed with the McNemar test.P = 0.034) and at 1-month follow-up (P = 0.047) compared to the baseline value. In addition, statistically significant improvement in the leg NRS score was seen in the 5th session (P = 0.010) and at 1-month follow-up (P = 0.006). Because the MCIC for NRS scores in the present study was 20 points, NRS score improvements in back and leg pain were not clinically significant in the 5th session or at 1-month follow-up  and at 1-month follow-up (P = 0.001). Because the MCIC for ODI score in the present study was 6 points, the improvements were not considered clinically significant at the 5th session or at 1-month follow-up . The findings also indicated 95% improvement in the results of the SIJ hypomobility tests after SMT. We also observed a 20% improvement in the SLR test results and a 15% improvement in the slump test in the 5th session and at 1-month follow-up after SMT, although these changes were not statistically significant  improved significantly in the 5th session and after 1-month follow-up compared to baseline values, whereas no statistically significant improvement was observed in the SLR and slump tests. Spinal manipulative therapy may enhance mobility of the SIJ and lumbar vertebrae, and affect the muscles in these regions, thus accounting for the improvement in pain and functional ability. However, significant changes in the slump and SLR tests may require additional interventions such as soft tissue manipulation and nerve mobilization, which were not tested in this study.In one controlled trial, SMT and sham manipulation were compared in 102 participants with MRI-confirmed LDH; the SMT group showed significantly greater improvement in back and leg pain after 6 months . NeverthIn a prospective cohort study, Leemann et al., investigated the effect of high-velocity, low-amplitude SMT in patients with acute or chronic MRI-confirmed LDH, and reported clinically significant improvement in back and leg NRS and ODI scores in both short-term and long-term assessments . In a foBurton et al., also compared SMT with chemonucleolysis in the treatment of patients with SLDD, and reported greater improvements in back pain and disability in the first few weeks in the SMT group . Their SThe results of previous studies have shown that SMT is effective in the treatment of LDH . The stuOur study had some limitations which should be noted. The pre–post test design did not include a control group; consequently, the results cannot be considered evidence in support of the clinical efficacy of SMT for patients with LDH and SIJ hypomobility. A controlled trial is advisable in which combined manipulations are compared to lumbar or SIJ manipulation separately, to elucidate whether using both lumbar and SIJ manipulation together yields better outcomes than using a single type of manipulation. The small sample size and lack of long-term follow-up are other limitations. In addition, we are aware that measuring physiologic responses to SMT by recording electromyographic activity of the spinal muscles, the myotomes and dermatomes of the involved nerve roots, would strengthen the results of future studies. Also, more reliable tests for SIJ dysfunction are available and should be used in future studies. Despite these limitations, we addressed some shortcomings of previous studies. The strengths of the present study were matching of the physical examination findings with imaging findings, considering SIJ hypomobility in the treatment of patients with LDH, and the application of spinal thrust manipulation alone rather than a combination of therapeutic methods.Spinal manipulative therapy can potentially improve pain, functional disability and SIJ mobility in patients with LDH concomitant with SIJ hypomobility; therefore, it can be implemented in physical therapy programs for these patients. However, further studies with larger sample sizes, longer follow-up periods and real control groups should be done to provide more accurate results.


COMT, rs6746030 of SCN9A, and rs1799971 of OPRM1. In total, 193 participants (46.2%) experienced pain. Compared to pain-free PD patients, PD patients with pain had an earlier age of onset, longer disease duration, and higher depression and motor severity (P < 0.01). The frequencies of COMT rs4680 “A” allele were higher in PD patients with pain than those without pain . Pain severity was significantly associated with disease duration (P = 0.02), and COMT rs6267 T allele (P < 0.01). We stratified PD by status of depression and the association between COMT rs6267 “GT” genotype and pain severity remained significant (P < 0.01). Furthermore, pain severity was significantly higher in participants having COMT rs4680 “GG” and “GA” genpotypes than those having “AA” genotype (P = 0.04). We concluded that depression and COMT rs4680 “GG” and “GA” genotypes and COMT rs6267 “GT” genotype contribute to pain in PD patients.Pain is a distressing symptom of Parkinson disease (PD). We aim to determine whether the genetic variants of chronic pain-related genes contribute to pain in PD patients. We included 418 PD patients and evaluated pain severity on King’s PD pain scale. We genotyped rs6267, rs6269, rs4633, rs4818 and rs4680 of  Sensory complaints, particularly pain, are one of the most common nonmotor symptoms; nearly 43% of patients with PD experience primary pain related to dysfunction of the nociceptive system in early PD stages, in which motor symptoms are not yet prominent3. Furthermore, patients with PD present a reduction of the pain threshold for both thermal and pain stimulation5. The pathophysiological mechanisms of PD pain arise from dysfunction of the peripheral and central compartments of the nociceptive pathways8. Treatment with levodopa could not only relieve pain but also increase the pain threshold in patients with PD9; this observation confirms that the mesolimbic dopamine pathway and nucleus accumbens have profound roles in pain modulation10. Because substantial interindividual variability can be observed in pain perception and response to medications, the single nucleotide polymorphisms (SNPs) of several genes involved in the nociceptive pathways have recently been implicated in pain sensitivity in patients with chronic pain syndromes13. Notably, among these genes, catechol-O-methyltransferase gene (COMT) encodes a key metabolizing enzyme that degrades catecholamines including dopamine, epinephrine, and norepinephrine11. It therefore contributes to maintaining the homeostasis for a variety of pivotal biological systems including pain perception, mood, and responses to both physical and emotional stressors. A functional SNP in codon 158  of COMT has been shown to modulate pain perception and contribute to differences of pain perception14. Haplotypes composed of combinations of alleles of rs6269, rs4633, rs4818, and rs4680 of the COMT gene were previously shown to affect COMT activity and grouped COMT function into three haploblocks based on pain response, which covered about 96% of the people tested15. Furthermore, COMT is also a key enzyme that metabolizes dopamine, which is a pathognomonic neurotransmitter deficiency in patients with PD. Thus, the examination of the role of COMT polymorphisms and haplotypes with pain perception and severity is of considerable importance in patients with PD.Parkinson disease (PD) is a multidimensional neurodegenerative disorder with both motor and nonmotor symptomsCOMT and the μ-opioid receptor (OPRM1) and sodium channel Nav1.7 (SCN9A), to the risk and severity of pain in PD. We genotyped rs6267, rs6269, rs4633, rs4818 and rs4680 of the COMT gene, rs6746030 of the SNCA9A gene, and rs1799971 of the OPRM1 gene. Because haplotypes formed by rs6269, rs4633, rs4818, and rs4680 of COMT gene constituted central COMT locus haploblock that is associated with pain response, COMT haplotypes were also analyzed in the multivariate regression model to examine the independent effects of various clinical and genetic risk factors contributing to pain in patients with PD.Despite the accumulating evidence regarding the complex neural circuits involved in the pathophysiology of pain in patients with PD, data on the specific genetic and molecular mechanisms potentially associated with PD pain remain limited. Our study was based on the hypothesis that PD-related pain shared part of the common mechanism with other chronic pain syndromes, and we assumed that pain-related genes identified for these syndromes also play roles in the risk of PD pain. Therefore, in this study, we explored the contribution of SNPs of nociception-related genes, including P < 0.01), longer disease duration , higher BDI scores , and higher UPDRS part III scores  and total scores . The patients’ clinical characteristics and medical comorbidities are listed in Supplementary Table We initially recruited 656 patients who received clinical diagnoses of PD; among them, 238 patients were excluded because they did not meet the inclusion criteria or were unwilling to participate in this study. In total, 418 PD patients were enrolled. Of them, 193 (46.2%) reported pain , whereas the remaining 225 did not . Compared to pain-free PD patients, those reported pain had earlier age of motor symptom onset  scores, was significantly correlated with the intensity of pain perception, defined by the King’s PD pain scale (KPPS)  was higher in PD patients with pain than pain-free PD patients , and the presence of the “A” allele increased the susceptibility of pain in patients with PD . The genotype or allele frequency of COMT rs6267, SNCA9A rs6746030, and OPRM1rs1799971 did not differ between PD patients with pain and pan-free patients. Furthermore, because haplotypes formed by rs6269, rs4633, rs4818, and rs4680 of COMT gene constituted central COMT locus haploblock that is associated with pain response15, we examined whether combinations of alleles (haplotypes) that were formed by the aforementioned four SNPs of COMT affect the susceptibility to pain in patients with PD. Three COMT haploblocks were previously determined in a prior study by linkage disequilibrium analysis15. There are two major forms of COMT enzyme: membrane bound and soluble forms. There were three COMT SNPs  located within the central coding region for both membraneous and soluble forms of COMT. Because the association with pain sensitivity was previously observed for SNPs rs6269 and rs4818, located in the central COMT locus haploblock, in patients with a chronic pain syndrome15, we therefore focused our analyses on the haplotype covering this central haplobolck, reflecting the order of occurrence from 5′ to 3′ in the COMT gene as rs6269, rs4633, rs4818 and rs4680, respectively   than in those having the wild-type “AA” (6.9 ± 10.2) and heterozygous “AG” (8.1 ± 11.0) genotypes (P = 0.02)  Fig. . The pai02) Fig. . Pain se971 Fig. .Figure 3COMT gene are also reported to associate with depression16. We next examined the distribution of genotypes and estimated odds ratio of the studied candidate SNPs of COMT, SNCA9A, and OPRM1 in relation to the risk of depression in our PD patients. Among 418 enrolled participants with PD, 328 patients (78.5%) were diagnosed with depression. The frequency of the COMT rs4680 “GA” and “AA” genotypes was modestly higher in PD patients with depression than those without depression . However, after Bonferroni correction with conservative P value for significance, all the studied genotype or allele frequency of COMT rs6267, COMT rs6269, COMT rs4633, COMT rs48418, COMT rs4680, SNCA9A rs6746030, and OPRM1rs1799971 did not significantly differ between PD patients with and without depression. In addition, while assaying the contribution of the aforementioned SNPs, COMT haplotypes and clinical variables in risk of depression in PD patients using a stepwise multivariate regression analysis, we found only the motor disability (UPDRS part III scores) and COMT rs6267 T allele contribute to the risk of depression in PD , and COMT rs6267 “T” allele  were significantly correlated with pain severity  increased the risk of PD-associated pain. The COMT rs6267 “GT” genotype was associated with increased pain intensity in patients with PD with pain, even after stratified by depression status. Furthermore, the pain severity was significantly higher in participants homozygous for COMT rs4680 “GG” and heterozygous for “GA” genpotypes than participants homozygous for “AA” genotype in the subgroup of PD patients without depression. In addition to the exonic SNPs of COMT, rs6267 and rs4680, we did not find any significant associations between central COMT haploblock and susceptibility or intensity of pain perception in our PD population. Our findings suggested that, in addition to depression, genetic variants of COMT rs6267 and rs4680 can also modulate pain sensitivity in patients with PD.Our study that enrolled a relatively large-sample number of PD patients with different pain status showed that depression was significantly associated with pain susceptibility in patients with PD. The COMT rs4680 are more susceptible to and have an increased risk of pain compared to those having “GG”. The COMT rs4680  is a functional exonic variant that substitutes the amino acid valine for methionine at codon 158 and determines the stability of COMT, a key metabolising enzyme for catecholamines, including dopamine and norepinephrine17. Its activity is mainly determined by the rs4680  variant of COMT; according its activity, COMT is categorized as a high , intermediate , and low  metabolizer. The relationship between the p.V158M polymorphism of COMT and pain sensitivity has been consistently examined in healthy individuals; the results have shown that the carriers of the “GG” (Met/Met) genotype have an increased sensitivity to painful stimuli19 and increased brain activity over the pain-related anterior and midcingulate cortex after painful laser stimuli20. In addition to increasing pain susceptibility in control individuals, the met158 allele of COMT was found to be associated with the risk of chronic pain syndromes, such as migraine21, temporomandibular joint disorder15, and fibromyalgia11. These findings combined with our results in PD patients with pain suggested that COMT “AA” (Met/Met) variant—associated with lower COMT enzymatic activity—leads to increased pain sensitivity and that this is a common downstream nociceptive pathway in PD and other chronic pain syndromes. Laboratory evidence has shown that low COMT activity leads to increased pain sensitivity because catecholamine levels are elevated and the β-adrenergic mechanism is activated. These findings are of considerable clinical importance, suggesting that pain conditions resulting from low COMT activity or elevated catecholamine levels can be treated with pharmacological agents that block both β2- and β3-adrenergic receptors22. Further investigations with larger samples are required to clarify the role of COMT rs4680 Met/Met variant in PD pain.Our results showed that patients with PD having homozygous “AA” (Met/Met) and heterozygous “GA”  genotypes of the 23; in patients with PD, pain and depression are extremely common and frequently interrelated: chronic pain can lead to depression, and patients with depression tend to experience pain that is more intense and refractory to analgesia than do non-depressed individuals24. Our results corroborate previous results that patients with PD and with depression have significantly more severe pain than those without depression25. Neuropathological studies have shown that the depression-related serotonin-producing neurons in the brainstem raphe nuclei—which have the largest and most complex efferent system in the human brain—overlap with the descending inhibitory pathway relaying pain-inhibiting messages from the brain to the spinal cord through the dorsolateral and ventrolateral funiculi26. Notably, these raphe nuclei and locus coeruleus containing the brainstem regions are also areas where Lewy body pathology are present in the course of PD, even from the prodromal stage according to Braak’s pathology findings27. This pathological evidence can partially explain the strong correlation between the severities of depression and pain in patients with PD.In this study, we also identified depression to be a significant risk factor for pain vulnerability in patients with PD: a significant correlation was noted between BDI and KPPS scores, a correlation which persisted even after adjustments for onset age, disease duration, and genotypes of candidate genes. The mechanisms of comorbid pain and depression are well establishedCOMT rs4680 p.V158M polymorphism is associated with not only pain but also a higher risk of depression29. Depressed individuals display a higher frequency of COMT rs4680 Met/Met and Met/Val genotypes than do controls29. Our results were also in line with previous findings that A allele of COMT rs4680 p.V158M were modestly higher in PD patients with depression than those without depression , although the difference did not reach the significance level after Bonferroni correction. Furthermore, COMT haplotypes did not play a major role in the susceptibility of either pain or depression in our study population. We hypothesized that the relationship between depression, COMT polymoprphisms, especially rs4680, and pain susceptibility are complex and interrelated. To further clarify the contribution of depression and COMT SNPs to pain susceptibility and perception intensity in PD patients, we stratified the analyses by participants’ status of depression. After stratified by depression status, the association between COMT rs6267 GT genotype still remained significant in PD patients without depression. Notably, pain severity was only significantly higher in participants homozygous for COMT rs4680 “GG” and heterozygous for “GA” genpotypes than participants homozygous for “AA” genotype in PD patients without depression. These findings suggest that, although depression per se is a contributor to pain, COMT rs4680 and rs6267 also affect pain vulnerability in PD patients. Future studies are warranted to investigate the biological mechanisms of COMT acitivity in the pain susceptibility in PD animal models.Paradoxically, several studies have reported that COMT variant, COMT rs6267 , is significantly correlated with pain intensity, defined by KPPS scores, among patients with PD with pain. COMT rs6267 is a missense variant that encodes serine instead of alanine, resulting in changes in the RNA secondary structure such as decreased COMT enzymatic activity, leading to a high sensitivity to pain30. A study enrolling 100 patients with PD (57 with pain) also revealed that the COMT rs6267 T allele is associated with pain 31. Although our results did not demonstrate an association of COMT rs6267 with the risk of pain in patients with PD, the mean pain score was significantly higher in the COMT rs6267 “GT” genotype than wild-type “GG” among patients with PD with pain. Moreover, the COMT rs6267 “T” allele is significantly correlated with KPPS scores after the effects of onset age, disease duration, and severities of motor symptoms and depression are considered. These findings suggest that low COMT enzymatic activity contributes to increased susceptibility and intensity of pain in patients with PD.Our results showed that another COMT in variable chronic pain syndrome.A strength of our study is that we included a relatively large and ethnically homogeneous sample. All our patients received regular long-term follow-up and were evaluated and diagnosed as having pain by movement disorder specialists. In addition, the confounding factors potentially influencing susceptibility to PD pain, such as age, sex, disease duration, depression symptoms, dopaminergic agent treatment, motor symptom severity, and comorbidities, were considered in the analysis. However, our study also has some limitations: although anxiety is also strongly correlated with both depression and pain, we did not include anxiety symptoms in the analysis. Second, KPPS combines scores from seven domains of PD related pain, which captures pain ranging from wearing off related pain to central, orofacial, and radicular pain. Each domain may have different genetic causes. However, because of the limited patient number in each pain domain of KPPS, we did not perform regression analysis to evaluate the association between genetic factors and the individual pain subtypes in our PD patients for the concern of statistical power. Studies with larger sample number of PD patients with different pain characters are needed to clarify the genetic risk factors for specific subtypes of PD pain in the future. Finally, our study was only focused on the PD-related pain and did not compare the results with other chronic pain syndrome, such as fibromyalgia or temporomandibular joint disorder. Future studies enrolling patients with different chronic pain syndromes are warranted to compare the effects of genetic variants of COMT rs4680 and rs6267 contribute to both pain susceptibility and severity in patients with PD. Additional experimental studies are required to investigate the role of COMT in the nociceptive processes in patients with PD.In conclusion, our results reinforce previous findings that depression is a strong risk factor for pain in patients with PD. The 32 and were having regular follow-up at the movement disorder clinics of National Taiwan University Hospital and Chang Gung Memorial Hospital in Taiwan. Patients were excluded if their Mini–Mental State Examination scores33 were <24. All patients were receiving L-dopa or a combination with dopamine agonists and showed favourable clinical responses. L-dopa equivalent doses were calculated34. Patients maintained their regular anti-PD medications and were examined while in the “on” status. Each patient was examined using the Unified Parkinson’s Disease Rating Scale (UPDRS)35, modified Hoehn-and-Yahr staging36, Mini-Mental Status Evaluation (MMSE)33 and Beck depression inventory (BDI)37. Informed consent was obtained from all participants, and the study was approved by the institutional ethics board committees of National Taiwan University Hospital (201505003RIND) and Chang Gung Memorial Hospital (201600356A3). All methods in this study were performed in accordance with the relevant guidelines and regulations.We recruited patients who fulfilled the clinical diagnostic criteria of the United Kingdom PD Society Brain Bank38, and visual analogue scale were applied to describe the characteristics and severity of pain. The KPPS is a scale based on interviews conducted with patients and has seven domains with a total of 14 items39. The scale includes musculoskeletal pain (domain 1), chronic neuropathic pain (domain 2), motor fluctuation-related pain (domain 3), nocturnal pain , orofacial pain (domain 5), limb edema- or swelling-related pain (domain 6), and radicular pain (domain 7). Each item is scored by severity  multiplied by frequency [0 (never) to 4 ], resulting in a subscore of 0–12, the sum of which gives the total score, with a theoretical range of 0–168. Patients who have multiple overlapping pain reports are collapsed into the major domain in the KPPS. The KPPS is currently the only validated PD-specific pain scale and is recommended by the rating scales development committee of the Movement Disorders Society for pain intensity rating36.Two movement disorder specialists (Drs CH Lin and YR Wu) interviewed the patients by using a structured questionnaire that included demographic and clinical data, such as onset age, disease duration, and medication. In addition, patients were asked whether they experienced pain; if yes, a PD-specific pain scale, King’s PD pain scale (KPPS)40. The rs6267 , rs6269 (intronic variant G > A), rs4633 , rs4818  and rs4680  of COMT, rs6746030  of SCN9A, and rs1799971  of OPRM1 were genotyped by real-time polymerase chain reaction (PCR) using TaqMan® Genotyping Assays on the StepOnePlus Real-Time PCR machine (Applied Biosystems). Primer sequences and PCR conditions are available on request. The NCBI SNP databases were used to assign SNP numbers.DNA was extracted from venous blood according to standard protocolst test. We used either the Pearson product-moment correlation coefficient or Spearman rank correlation coefficient to evaluate the correlations among variables. The correlations were explored using multivariate linear regression analysis; the covariance of the model (R2) and the standardized correlation coefficient were presented. The potential risk factors associated with the susceptibility and severity of pain in patients with PD were examined using multivariate stepwise logistic regression analysis. Logistic stepwise regression is designed to find the most parsimonious set of predictors that are effective in predicting the dependent variable. The dependent variable in the model was the existence of symptoms of pain or KPPS score. The independent variables included in the model were age at motor symptoms onset, disease duration, sex, BDI scores, UPDRS part III scores, individual candidate genotypes and COMT haplotypes. The method of forward stepwise selection method with the criteria for entry of the variable is 0.05 and removal is 0.1 has been used to select the most optimal subset of independent variable. We also performed stratified analyses to evaluate potential effect modifications of depression in the susceptibility and severity of pain in patients with PD. Participants were classified according to the comorbidity of depression. A two-sided P < 0.05 was considered significant.We tested each genetic variant for the Hardy–Weinberg equilibrium. Allele and genotype frequencies were compared between PD patients with and without pain by using the chi-squared test; alternatively, we used the Fisher exact test when the number was less than five. Numerical variables were expressed as means ± standard deviations of the means. For variables following a Gaussian distribution, data were compared using a two-tailed P value was considered significant after Bonferroni correction with conservative P was 0.05/7 = 0.007.We performed all analyses by using Stata . A Supplementary Information


At the end of the study, we had improved to 1st activity-related pain and to 2nd in patient satisfaction. Although benchmarking started and finished with the same standardized pain management concept, results were initially pure. Beside pharmacological treatment, interdisciplinary teamwork and benchmarking with direct feedback mechanisms are also very important for decreasing postoperative pain and for increasing patient satisfaction after TKA.Perioperative pain reduction, particularly during the first two days, is highly important for patients after total knee arthroplasty (TKA). Problems are not only caused by medical issues but by organization and hospital structure. The present study shows how the quality of pain management can be increased by implementing a standardized pain concept and simple, consistent benchmarking. All patients included into the study had undergone total knee arthroplasty. Outcome parameters were analyzed by means of a questionnaire on the first postoperative day. A multidisciplinary team implemented a regular procedure of data analyzes and external benchmarking by participating in a nationwide quality improvement project. At the beginning of the study, our hospital ranked 16 In addition, a major factor for patient dissatisfaction, prolonged hospital stays with delayed recovery, and immobility after surgery is severe postoperative painThe 40 surgical procedures with the highest pain scores  6 or 7) include 22 orthopedic interventions on the extremities. Total knee arthroplasty (TKA) is in 5To improve postoperative pain and patient satisfaction, many studies tried to optimize techniques and drugs42678Therefore, it is very important to find new ways to improve postoperative pain management. In a present study Chughtai showed that patients are of the opinion that postoperative pain control after TKA is mainly the responsibility of the treating orthopedist1214Our hypothesis was that pain management can also be improved by continuous benchmarking and implementation of a pain management concept including feedback from and to educated staff. Such improvements subsequently reduce postoperative pain and improve patient satisfaction. Our specific pain management concept was agreed on by an interdisciplinary pain council. Although postoperative pain is multifactorial, this study was not aimed at discussing the concept itself but at finding out whether the manner in which the concept is implemented by the medical team may make a difference.The present prospective cohort study included the registry data of 256 patients who had undergone total knee replacement surgery at our university medical center between 2014 and 2015. The data were collected for the project ‘Quality Improvement in Postoperative Pain Treatment’ (QUIPS), a benchmark initiative for comparing pain outcome parameters among participating hospitals. This project has been supported by the German Society of Anesthesiologists and the German Society of Surgeons16The validated 15-item questionnaire asked for worst and least pain intensities since surgery using a numeric rating scale The project was approved by the Ethics Committee as well as the Data Security Board of the Jena University Hospital, Jena, Germany, as well as by the Ethics Committee of the University of Regensburg. The study is registered in the German Register of Clinical Studies (DRKS) under the number DRKS00006153 (WHO register). The study was carried out in accordance with the ethical standards of the Declaration of Helsinki of 1975. Patients were informed in written form as well as orally by the study personnel. An informed consent was obtained from all subjects. Participation was voluntary, and withdrawal was possible at any time.Our standard pain management concept for patients undergoing TKA was used for each patient in this study.1 h before surgery, patients receive oral benzodiazepine premedication followed by ischiadic nerve and psoas compartment blockage with 20 ml of ropivacaine 0.75% and 20 ml of prilocaine 1.0% for each block. Patients are sedated with propofol during surgery. During the first 12 h after surgery, the nurse in the intermediate care unit administers 3 mg of piritramid on demand in intervals. 0.375% of ropivacaine set at 6–10 ml/h is used for nerve blockage and Ibuprofen 600 (3×) as standard analgesic on a regular daily basis. At the normal ward, oral controlled analgesia (OCA) is administered. Depending on the NRS, patients may get additional analgesics if required: Tramadol 100 mg (40gtt) with the possibility of a repeated dose after 30 min if NRS 3–6 and oxycodone 20 mg and a repeated dose after 1 h if NRS 7–10. In the case of persisting or increasing pain, the nurse will notify the physician. In addition, patients are advised on how to avoid pain by self-activation and are asked to report any occurrence of pain as well as its characteristics, also during night time. Cool packs for the affected knee are also provided.A multidisciplinary team of anesthetists, orthopedic surgeons, and nurses implemented a regular procedure of data analyzing and internal benchmarking. Beside the main parameters mean NRS max. pain, min. pain, activity-related pain and patient satisfaction, side effects like nausea, dizziness, tiredness and postoperative nausea and vomiting (PONV) prophylaxis were evaluated. In addition functional parameters were analysed, that means patients were asked how much pain affected their ability to move in bed, their ability to cough or deep breath, their ability to sleep and their mood in the last 24 h hours after surgery. The healthcare team was informed on any results and suggested improvements. Every staff member involved in pain management had educational lessons every 3 months, and a special pain nurse was trained in each ward. The data shown here were internally analyzed for each ward to be able to give a direct feedback to the ward of the respective patient. Additional lessons were given in the case of deteriorating standards or a turnover in staff because of ward restructuring.Nurses received lessons in general pain management, in pain treatment required by patients after TKA, and pharmacological training according to our standards in pain management. Nurses were encouraged to use all treatment options available and were informed about possible risks. In addition, we emphasized the importance of using non-pharmacological therapeutic possibilities such as cooling the wound and different positioning of the patients as well as of communication with the patient and between nurse and physician.Additionally, patients were asked to report pain to the nurses as early as possible and not try to bear the pain.Statistical analysis was done with SPSS . All single results were divided into intervals of 3 months (quarter of a year) to establish a timeline. Metric variables were reported descriptively as mean and standard deviation. Statistical data were not normally distributed. Non-parametric Mann-Whitney U tests were used to compare continuous variables between resulting independent subgroup pairs and the Kruskal-Wallis test to compare results between multiple subgroups. Pearson’s Chi-square tests were used to compare categorized data of independent subgroups. Analyses included the chi square test and the non-parametric Mann-Whitney U test to compare the effects. Statistical significance was set at a level of P < 0.05. With a sample size of n = 112 in 2014 compared to n = 144 in 2015, we had 80% power to detect an effect size of d = 0.35, which can be considered as small.256 patients who had undergone primary total knee arthroplasty surgery between January 2014 and December 2015 were included in this study. The mean age was 66.87 years (±10.00), and 89.1% of the patients had an ASA  status of 2 or 3. Surgery was conducted by experienced orthopedic surgeons at a center of excellence for arthroplasty (Department of Orthopedics of the University of Regensburg). The mean duration of surgery was 81.65 min (±24.16). 72.7% of patients had reported chronic pain in the affected knee for more than 3 months prior to surgery with a mean NRS of 6.95 (±1.65).  82% of tA comparison of the side effects between 2014 and 2015 showed improvement in all parameters. Nausea, tiredness, and dizziness just showed a tendency toward decrease, but other functional influences were significantly decreased. The decrease in the interference of pain with the ability to move had significantly dropped from 60.5% to 29.5% (p = 0.001). In 2014, 14.7% of patients had reported their mood being influenced by pain in contrast to only 1.2% in 2015 (p < 0.001). The number of patients receiving nausea prophylaxis (PONV) had also risen from 30.9% in 2014 to 35.4% in 2015.  Number ond quarter of 2014. This score rose to 6.81 (±2.24) in the 3rd quarter before continuously falling to the minimum of 4.64 (±1.88) in the 1st quarter of 2015. There was a massive rise to 5.83 (±1.39) before it could be reduced again to 5.44 (±1.83) at the end of the observation period (p = 0.001) (Mean NRS (0–10) were recorded for maximum pain, minimum pain, and activity-related pain (e.g. movement). At the beginning, mean maximum pain was 6.45 (±2.235), which could be decreased to 5.93 (±2.56) in the 2= 0.001) .Minimum pain started at a mean NRS of 1.25 (±1.37) and nearly permanently decreased to a value of 0 (±0) over the last two quarters of 2015, which represented significant improvement (p < 0.001) .st quarter of 2015, the score dropped to 1.91 (±1.23) and remained constant at 1.86 (±1.07) until the end of the surveillance period. This improvement was also significant (p < 0.001) , a first decrease was followed by an increase to 5.00 (±2.45). In the 1< 0.001) .After implementation of the program, an (non-significant) increase in the use of piritramid and tramadol could be noticed.st quarter of 2015 that was followed by a small bend. After that, the patient satisfaction score remained nearly constant at 1.86 (±1.07) until the end of the study (p = 0.001) , rising continuously to 9.77 (±0.56) in the 1= 0.001) .st place in activity-related pain . After a first period of collecting data, we started at rank 16 for activity-related pain and at rank 9 for patient satisfaction. Maximum pain was 6.45 (±2.235) and minimum pain 1.25 (±1.37). In another recent study Gerbershagen showed a mean max. pain of 5.56 (±2.66) postoperativelynd quarter of 2014. Patient satisfaction had also increased immediately. Because of these positive results, staff training was set back to normal because the time needed for additional training had been difficult to integrate into clinical routine in the first 6 months. This decision was perceived as negative, and all parameters worsened over the next period of data collection. Because of this relapse and the impending recertification, the decision to cut down on staff training was revised, and training lessons were again intensified. Particularly newly appointed physicians and nurses got extra lessons to perform better within our pain management concept, which significantly decreased all pain scales as well as side-effects in 2015. In this year, the educational program was driven by staff demand, resulting in a satisfactory steady state. At the end of the study, our department ranked 1st in activity-related pain and 2nd in patient satisfaction in the inter-hospital comparison. These positive results were reached without increasing the negative side-effects significantly.First positive results were seen rather soon, because the NRS for maximum and minimum pain had decreased at the end of the 2When comparing these data to other present studies, there are no similar findings in the field of orthopedics. But also using QUIPS, similar positive effects have been described in improving pain management after septorhinoplastywww.pain-out.eu) offers a similar tool for feedback and benchmarking.Outside Germany, the corresponding project PAIN OUT .Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.