Opioids are routinely prescribed for postoperative home pain management for most patients in the United States, with limited evidence of the amount needed to be dispensed. Opioid-based treatment often adversely affects recovery. Prescribed opioids increase the risk of chronic opioid use, abuse, and diversion and contribute to the current opioid epidemic.To evaluate whether after hospital discharge, postsurgical acute pain can be effectively managed with a markedly reduced number of opioid doses.In this case-control cohort study, an ultrarestrictive opioid prescription protocol (UROPP) was designed and implemented from June 26, 2017, through June 30, 2018, at a single tertiary-care comprehensive cancer center. All patients undergoing gynecologic oncology surgery were included. Patients undergoing ambulatory or minimally invasive surgery (laparoscopic or robotic approach) were not prescribed opioids at discharge unless they required more than 5 doses of oral or intravenous opioids while in the hospital. Patients who underwent a laparotomy were provided a 3-day opioid pain medication supply at discharge.Total number of opioid pain medications prescribed in the 60-day perioperative period, requests for opioid prescription refills, and postoperative pain scores and complications were evaluated. Factors associated with increased postoperative pain, preoperative and postoperative pain scores, inpatient status, prior opioid use, and all opioid prescriptions within the 60-day perioperative window were monitored among the case patients and compared with those from consecutive control patients treated at the center in the 12 months before the UROPP was implemented.P < .001). For patients who underwent laparoscopic or robotic surgery, the mean (SD) number of opioid tablets given at discharge was 38.4 (17.4) before implementation of the UROPP and 1.3 (3.7) after implementation (P < .001). After ambulatory surgery, the mean (SD) number of opioid tablets given at discharge was 13.9 (16.6) before implementation of the UROPP and 0.2 (2.1) after implementation (P < .001). The mean (SD) perioperative oral morphine equivalent dose was reduced to 64.3 (207.2) mg from 339.4 (674.4) mg the year prior for all opioid-naive patients (P < .001). The significant reduction in the number of dispensed opioids was not associated with an increase the number of refill requests , the mean (SD) postoperative visit pain scores , or the number of complications .Patient demographics and procedure characteristics were not statistically different between the 2 cohorts of women . The mean (SD) number of opioid tablets given at discharge after a laparotomy was 43.6 (17.0) before implementation of the UROPP and 12.1 (8.9) after implementation (Implementation of a UROPP was associated with a significant decrease in the overall amount of opioids prescribed to patients after gynecologic and abdominal surgery at the time of discharge for all patients, and for the entire perioperative time for opioid-naive patients without changes in pain scores, complications, or medication refill requests. This case-control cohort study compares the total number of opioid pain medications prescribed after gynecologic and abdominal surgery, the number of requests for opioid prescription refills, and postoperative pain scores and complications before and after implementation of an ultrarestrictive opioid prescription protocol. Can postoperative pain be appropriately managed after hospital discharge with minimal or no opioids in patients undergoing gynecologic and abdominal surgery?In this case-control cohort study of 1231 patients undergoing gynecologic oncology surgery, implementation of an ultrarestrictive opioid prescription protocol was associated with a significant decrease in the number of opioids dispensed at discharge. Using the ultrarestrictive opioid prescription protocol to manage postoperative pain was also associated with a significant decrease in the number of opioids dispensed during the entire perioperative period for opioid-naive patients without changes in postoperative pain scores, complications, or increases in the number of refill requests.A reduction in the number of opioids dispensed for postoperative pain management is safe and attainable. Thus, all health care professionals are encouraged to take appropriate steps to decrease the number of opioids dispensed and monitor their misuse, abuse, and diversion.The most recent report from the Centers for Disease Control and Prevention estimates that 116 people in the United States die per day after an opioid overdose and that 40% of all deaths due to an opioid overdose involve a prescription opioid.4 Large numbers of opioid pills, mainly oxycodone hydrochloride and hydrocodone bitartrate, are often prescribed to patients after surgery, with limited evidence of the amount necessary for adequate pain management and optimal recovery.5 Studies suggest that patients take only 28% of the prescribed doses of opioids.6 New persistent opioid use is a common and underappreciated surgical complication, which occurs among 5.9% of patients undergoing minor surgery and in 6.5% of those having major surgery.7 These findings indicate that postsurgical opioid use could also be a gateway to chronic opioid use and provide a strong justification to limit perioperative opioid use.An estimated 48 million people in the United States undergo surgical procedures annually, and opioids are still the primary modality for managing acute postoperative pain.8 These efforts attempt to minimize the adverse effects of opioids , which can negatively affect the recovery of a patient. Unfortunately, ERAS protocols often omit postdischarge patient care; thus, many surgical patients are still prescribed an excessive amount of opioid pain medications for home use.6Within the last decade in the United States, many surgical subspecialties have adopted enhanced recovery after surgery (ERAS) protocols to improve patient recovery. Enhanced recovery after surgery protocols focus on multimodal analgesia, with medications administered preoperatively, intraoperatively, and immediately after surgery that target different pain pathways to limit opioid use during hospital care.9 We also hypothesized that the postoperative pain in our patients who underwent ambulatory and minimally invasive surgery could be adequately managed with nonopioid pain medication without negatively affecting recovery. Thus, in June 2017, our department designed and implemented an ultrarestrictive opioid prescription protocol (UROPP) for all patients undergoing minor or major procedures, regardless of their diagnosis and whether they were opioid naive or chronic opioid users. Our goal was to test whether such a radical approach is safe, is sustainable, and could lead to a marked decrease in the number of opioids dispensed during the postoperative period.Prior to June 2017, the Department of Gynecologic Oncology at our large tertiary care center in Western New York (Roswell Park Comprehensive Cancer Center) routinely and liberally prescribed opioids to most patients to manage their postoperative pain, similar to other gynecologic oncology practices in the country. Our department had previously adopted ERAS recommendations to maximize nonopioid medications while patients were in the hospital, but we lacked guidelines on pain management after hospital discharge. We hypothesized that most of our surgical patients were prescribed opioid pain medication in excessive amounts despite following our state regulation for not providing more than a 7-day supply of opioids for acute pain at discharge for patients with no diagnosis of cancer.STROBE) reporting guidelines.The UROPP was developed based on patient feedback in conjunction with recommendations from surgeons and pain specialists and was implemented in June 26, 2017, through June 30, 2018, for all surgical patients at our department. Based on the comments from our postoperative patients, who claimed to use very little of the prescribed opioids and were frequently inquiring about returning the unused pills, we decided to test whether opioids were even necessary after a minor or minimally invasive procedure. We also observed that patients who underwent a laparotomy used less opioids by the day of discharge ; thus, we thought that adding an additional 3-day supply after discharge would be sufficient. Rather than relying on patients returning the unused medications to count the leftover pills, as a multidisciplinary team, we agreed to test a more radical approach and assess how much additional medication was needed after limited initial discharge medications. The steps of the UROPP are outlined in In brief, all surgical patients underwent a short preoperative counseling session conducted by the surgeon or nursing staff about management of postoperative pain, which included discussion of the expected discharge pain medications (per protocol), the adverse effects of opioid pain medications, and alternative methods of pain control. All opioid pain medications were counted for the duration of admission. Per protocol, all patients undergoing ambulatory surgery or minimally invasive surgery  were prescribed a nonopioid pain relief regimen consisting of a 7-day supply of ibuprofen and acetaminophen as needed at hospital discharge. If, while hospitalized, the patient required more than 5 opioid doses  in the 24 hours prior to discharge, then the patient was prescribed a 3-day supply of an opioid pain medication as needed, which totaled 12 tablets (hydrocodone and acetaminophen or oxycodone and acetaminophen).Patients who underwent a laparotomy were equally prescribed ibuprofen and acetaminophen with the addition of a 3-day supply of an oral opioid as needed (hydrocodone and acetaminophen or oxycodone and acetaminophen), for a total of 12 tablets. If patients in the laparotomy group displayed an increased need for opioids in the 24 hours prior to discharge , then the patient was discharged home with an additional 3-day supply of an opioid pain medication, for a maximum of 24 tablets. All telephone calls for refill requests were tracked. To ensure that the postsurgical pain was well controlled, we clarified with patients that they can request opioid refills if needed. If a refill was requested over the telephone, then the patient was triaged for an urgent postoperative visit if the pain was thought to be potentially related to evolving postsurgical complications. Only an additional 3-day supply (12 pills) was provided for refill. There were no second refills provided without a clinical evaluation . PatientAdherence to the protocol was tracked in real time by inpatient pharmacists who monitored all outgoing prescriptions for compliance. All deviations from protocol were immediately captured, and the physicians were asked to document indications for deviation. A total of 22 of 627 original post-UROPP cases were removed from analysis owing to protocol deviations because the effect of limited prescribed opioids at discharge could not be evaluated in these patients. These 22 patients  were discharged home with a higher number of opioids owing to a physician’s noncompliance with the protocol . Most (16 of 22 [72.7%]) of these deviations occurred within the first 3 months of protocol implementation. Removing these 22 patients from the analysis did not significantly change any of our findings, and the total opioid-sparing effect during the 12 months of the study with these 22 patients also included in the analysis is shown in the eTable and eFigure in the This study was designed as a retrospective control and prospective case cohort design with 626 controls  and 605 cases  of all gynecological oncology patients  undergoing major or minor surgery at a tertiary-care National Cancer Institute–designated comprehensive cancer center. Surgical cases ranged from minor outpatient resections and hysteroscopy cases to comprehensive robotic or laparoscopic staging and extensive pelvic and upper abdominal debulking cases (including bowel operations) for advanced stage cancers. Patients’ baseline characteristics, the types of surgical procedures, and the main outcome measures are listed in the Our primary outcomes were the mean postoperative pain score 2 weeks after surgery and new requests for opioid refills within 30 days after surgery, including those prescribed by an outside health care professional. All patients at the 2-week postoperative visit were asked to report their pain on a numeric scale of 0 to 10, with 0 reflecting no pain and 10 reflecting worst possible pain. All available patient records on opioid use were cross-referenced with the I-STOP registry during the perioperative period (90 days before surgery and 30 days after surgery). The I-STOP registry was partially out of reference at the time of data extraction for 119 of 626 patients (19.0%) in the pre-UROPP group but was complete for the post-UROPP group. Patients with no I-STOP data were excluded from the respective analysis.10) (P = .98).Our secondary outcome was the number of complications within 30 days after the procedure  . Postopet test for comparing the equality of mean values, binary variables were analyzed using the Fisher exact test for independence, and categorical end points were analyzed using the Pearson χ2 test for independence. All statistical analysis was performed in R, version 3.3.0 statistical language . All statistical tests were 2-sided, and the results were deemed statistically significant at P < .05. Given 626 controls and 605 cases, we had the ability to detect a 0.16-SD unit mean difference between groups at 80% power using the 2-sample t test. Similarly, we could detect differences in proportions between cases and controls of 0.053 to 0.081 or larger using the Fisher exact test at 80% power for control proportions ranging from 0.1 to 0.5, respectively.The primary comparison was between the pre-UROPP and post-UROPP groups across binary, categorical, and continuous end points. All continuous variables were analyzed with a 2-sample During the intervention period, a total of 605 surgical patients  experienced postoperative pain that was managed using the UROPP after hospital discharge, and their outcomes were compared with those of 626 patients  from the year prior, when outpatient pain management followed no specific guidelines (controls) and thus allowed the liberal use of opioids per trainees’ and each physician’s preference. Patients’ baseline characteristics and the types of surgical procedures, which were performed by the same team of surgeons in the 2 cohorts, were not statistically different . The 2 cP = .06), and the number of patients who requested an opioid refill within 30 days after the surgery also remained the same  (P = .15)  was 605 of 627 total patients (96.5%) during the intervention period; the 22 deviations occurred mostly with ambulatory cases within the first 3 months of implementation of the protocol. The mean (SD) postoperative pain scores 2 weeks after the surgery were not statistically different between the 2 cohorts  . During P = .15) .P < .001). The mean (SD) number of opioid pills dispensed at the time of discharge decreased from the pre-UROPP period to the post-UROPP period from 43.6 (17.0) to 12.1 (8.9) in the laparotomy group (P < .001), from 38.4 (17.4) to 1.3 (3.7) in the MIS group (P < .001), and from 13.9 (16.6) to 0.2 (2.1) in the group of patients who underwent ambulatory surgery (P < .001) (P < .001) (The implementation of the UROPP was associated with a significant reduction in the mean (SD) number of opioid pills dispensed at discharge in all surgical cases in the post-UROPP group (3.5 [7.0]) compared with the pre-UROPP group (31.7 [21.0]) ( < .001) A. Reduct < .001) B. For al < .001) C. BreakiData from I-STOP showed that 85.0% of our surgical patients in the pre-UROPP group (431 of 507) and 85.6% of our surgical patients in the post-UROPP group (518 of 605) received no opioid prescriptions 30 days prior to surgery A. PreopeWhen opioid-naive patients and those who were chronic opioid users were further stratified for additional opioid prescription requests in the post-UROPP group C, we obsP < .001).Among chronic opioid users, the mean oral morphine equivalents filled 30 days before or 30 days after surgery were not statistically different in the pre-UROPP and post-UROPP groups, and patients reverted back to their baseline opioid use within 30 days after surgery. However, the oral morphine equivalents dispensed at hospital discharge were significantly reduced owing to our compliance with the protocol . These pThese data suggest that the implementation of a UROPP in a large surgical service is feasible and safe and was associated with a significantly decreased number of opioids dispensed during the perioperative period, particularly among opioid-naive patients. After the initial intervention period, the UROPP was adopted as our standard postoperative outpatient pain management protocol, and it has been maintained without alteration for more than 1 year at our cancer center. In the last 6 months, compliance with the protocol has been 98% by our health care professionals, with no issues with sustainability. These data demonstrate that we were able to safely manage postoperative pain in patients undergoing ambulatory surgery and MIS with essentially no prescription for opioids and without adversely affecting patient recovery or pain scores or increasing the demand for additional opioids. The opioid-sparing effect was also marked and statistically significant in the laparotomy group, where most patients remained physically active and recovered well with no negative sequelae or elevated pain score after surgery.The success of implementing this radical approach depended on the willingness of our health care team to change practice pattern and take time to educate patients preoperatively and at the time of discharge to set the right expectations for home pain management. Physician behavior profoundly influences patient care and drives opioid prescribing practices. Although there was consensus among our health care professionals regarding the implementation of the protocol, the gradual decrease in the number of protocol deviations shows the importance of data with regard to the effectiveness of opioid-sparing protocols in overcoming prior practice patterns and the fear of patient complaints.9 to no more than a 7-day supply. Although this regulation did not affect nearly half of our surgical patients even in the pre-UROPP group owing to a diagnosis of cancer, we generally complied with the recommendation to limit the use of opioid pain medication to no more than a 7-day supply. However, our study demonstrates that even the 7-day regulation is overly generous and that stricter guidelines could even be used for many patients undergoing surgery for cancer. Most patients undergoing a wide variety of gynecologic oncology procedures had adequate postoperative pain control with just ibuprofen and acetaminophen, with the selective addition of a 3-day supply of opioids as needed. The findings also argue that previously published opioid prescribing recommendations for other surgical procedures  could be more stringent, with few to no opioids given.12In New York State, there are strict regulations to limit the use of opioid pain medication for acute pain after noncancer surgery13 We also found that patients who were discharged home with an opioid pain medication were more likely to request a refill despite the lack of postsurgical complications and otherwise adequate recovery, suggesting that perhaps many of these patients are using opioids for emotional coping rather than for pain management.14We demonstrated no increase in the number of refill requests within 30 days after surgery, regardless of how many pills were dispensed at the time of discharge. These data are consistent with another publication that reported that the probability of refilling an opioid prescription after surgery did not correlate with initial prescription strength.15 However, using the standard definition of chronic pain (≥90 days), we realized that our patients with chronic pain were using opioids in such a high quantity and potency that by just lowering their discharge opioid tablet count, we could not significantly affect their overall perioperative opioid consumption . In the post-UROPP period, 20 of 266 patients (7.5%) who underwent MIS and 11 of 195 patients (5.6%) who underwent ambulatory surgery used more than 150 oral morphine equivalents for the total perioperative period, while 9 of 266 patients (3.4%) who underwent MIS and 8 of 195 patients (4.1%) who underwent ambulatory surgery consumed more than 300 mg oral morphine equivalents during the perioperative period. These patients were more likely to be discharged home with an opioid prescription per protocol because they used more opioids while in the hospital and also tended to call to request refills. These patients increased the mean perioperative opioid dose among the opioid-naive group C. We bel16 Studies investigating the association of sex with pain perception have also shown that women may have higher ratings of pain and lower pain tolerance, hence suggesting that extending the UROPP to male patients would be equally feasible.18 A wide range of complex pelvic and abdominal surgical procedures were performed for our patient population; thus, our results could be applied to other surgical fields. Most of our patients are elderly, are obese, and commonly present with multiple comorbidities at very difficult times in their lives, often with a diagnosis of cancer, so they may be particularly vulnerable to chronic opioid use and misuse.19An additional limitation is that, by the nature of our practice, all the patients studied were women. Prior studies have shown that 2 major factors associated with a high rate of opioid prescriptions at discharge are female sex and moderate to severe pain scores before discharge.The strengths of our study include the large control (pre-UROPP) group with similar patient characteristics to the post-UROPP group, the ability to demonstrate the change in health care professionals’ practice patterns and to maintain sustained compliance given the lack of adverse events or increase in patients’ complaints, and the use of a state opioid monitoring program, which allows for accurate statewide tracking of dispensed opioids.20(p1189) and that inadequate pain management can cause unnecessary suffering and loss of function and mobility and have deleterious psychosocial and pathophysiological effects, such as postoperative ileus, impaired wound healing, pneumonia, or cardiac complications.21 We observed no increase in the number of postoperative complications in our study. From the efficacy of ERAS regarding patient recovery, one can argue that, in larger cohorts, extending opioid-sparing ERAS principles to postdischarge pain management may enhance postoperative recovery because the adverse effects of opioids can be eliminated or reduced.Prior publications advocating for more liberal use of opioids have argued that “sometimes less is not more”It is clear that chronic postoperative opioid misuse can best be addressed by preventing the initiation of opioids. As health care professionals, our primary aim is to help our patients and eliminate unnecessary treatments that may do harm. Any medication prescribed must carry benefits that outweigh the risks. Using UROPP to manage postsurgical pain after discharge did not result in any negative health consequences; thus, we advocate for adopting radical opioid-sparing approaches for managing postoperative pain nationwide. This change in practice is expected to reduce health care costs and the number of opioids circulating in our communities and will ultimately protect our patients and their family members from opioid diversion, misuse, and abuse.


Pain after hemorrhoidal surgery bothers both clinicians and patients. Somatosensory stimulation treatments have shown promising effect on the pain after hemorrhoidal surgery, but the comparative effectiveness between them has not been studied. We aim to determine the relative effectiveness among these treatments on pain relief after hemorrhoidal surgery by using network meta-analysis.P score, which is the mean probability of a treatment ranking the best in all treatments. Meta-regression will be performed to assess the impact of surgery type, anesthesia methods, and funding source on the treatment ranking. The quality of the eligible RCTs will be evaluated by the Cochrane risk of bias tool.We will search the following electronic databases: MEDLINE, EMBASE, the Cochrane library, Chinese Biomedicine database (CBM), China National Knowledge Infrastructure (CNKI). We will include randomized controlled trials (RCTs) that examine the effect of somatosensory stimulation treatments on pain after hemorrhoidal surgery. The primary outcome will be the responder rate after treatment. The secondary outcomes will include the assessments with pain intensity scales  on day 1 to 7 after surgery. Two independent reviewers will extract needed information from eligible trials using standardized electronic forms. Network meta-analysis will be performed using a frequentist framework based on electrical network theory. The relative effectiveness of the treatments will be ranked by using The result of this network meta-analysis will clarify which is the relatively best somatosensory-stimulation treatment in relieving postoperative pain caused by hemorrhoidal surgery, and the review will, therefore, guide the management of postoperative pain after hemorrhoidal surgery for clinicians and patients. This review does not require ethical approval and will be reported in a peer-reviewed journal.PROSPERO CRD42018115558. A peak in prevalence is noted between 45 and 65 years of age; 1 in 3 Americans has hemorrhoids on screening. Hemorrhoids are highly prevalent in general population; 38.9% of the adult population suffered from hemorrhoids, and about 8% of them were classified with grade III or IV hemorrhoids. Among the patients with anorectal diseases, 98% of them had hemorrhoid symptoms. Conservative treatments are first-line treatments for hemorrhoids,,6 but surgeries should be performed for patients with grade III or IV hemorrhoids. The evidence of surgical interventions for grade III or IV hemorrhoids are convincing.,8,9 The pain after the surgical interventions bothers patients, especially those receiving hemorrhoidectomy. Several treatment options are provided for pain management after hemorrhoid surgery, which includes local suppositories, limited injection of long-acting analgesic drugs, oral administration or intramuscular injection of non-steroidal anti-inflammatory drugs (NSAIDs) or opioid medications.–13 These treatments are either with inconclusive evidence,13 in their effectiveness or with known adverse events ; in addition, a recent systematic review shows that unsatisfactory control of postoperative pain is a major problem in Ambulatory hemorrhoidal surgery. These factors urge physicians to find therapeutics with better pain-relief effect and less adverse events.Hemorrhoids are common and frequently-occurring diseases in clinical practice, which seriously affect people's normal life and often manifest as hematochezia, escape, anal pain, heaving pain, discomfort, and so on. Hemorrhoids are cushions of vascular tissue located within the submucosal space and are considered part of the normal anatomy of the anal canal.–18 These treatments include acupuncture-related techniques, transcutaneous electrical nerve stimulation (TENS), moxibustion (heat stimulation), and cupping (mechanic stimulation). These treatments have the advantages of lower adverse events, and they were reported to be effective in the management of postoperative pain after hemorrhoidectomy.–21 Owing to the large number of somatosensory-stimulation treatments, head-to-head comparisons of all the treatments through randomized controlled trials (RCTs) are time-consuming and financially impossible. Network meta-analysis allows the combination of head-to-head comparisons and indirect comparisons and generates treatment rankings based on currently available evidence. Therefore, we will conduct a network meta-analysis to determine the comparative effectiveness of somatosensory-stimulation treatments in treating postoperative pain after hemorrhoidal surgery.Somatosensory stimulation treatments are nonpharmacological treatments that apply stimulation  to sensory system; they are beneficial for pain management.22.1 The procedure of this review is shown in Figure The study protocol is reported in line with the Preferred Reporting Items for Systematic reviews and Meta-Analyses Protocol (PRISMA-P).2.22.2.1We will include RCTs and exclude cohort studies, case series, case reports, reviews, experimental studies focusing on treatment mechanism, in vitro experiments, or animal studies.2.2.2We will include trials recruiting patients with postoperative pain following hemorrhoidal surgery. We will not set restrictions on age, gender, region, course of disease, degree of illness, and type of surgery or anesthesia.2.2.3We will include trials examining the effectiveness of somatosensory treatments  in the management of postoperative pain following hemorrhoidal surgery. These treatments are used alone or in combination. The control group is other somatosensory treatments, usual care, analgesics, NSAIDs, placebo, or waiting-list control. We will exclude trial examining the effectiveness of somatosensory treatments combined with herbal medicine since the effect and its related mechanism of herbal medicine are not clearly elucidated.2.2.4The outcomes of eligible RCTs should include pain intensity assessment or responder rate.2.3We will search the electronic databases MEDLINE, EMBASE, the Cochrane Library, Chinese Biomedicine Database (CBM), and China National Knowledge Infrastructure (CNKI) for RCTs examining the effectiveness of the interventions recommended for postoperative analgesia of mixed hemorrhoids. The databases will be searched from inception to May 2018. To ensure that the most recent trials will be listed, we will also search RCTs testing interventions for postoperative analgesia of mixed hemorrhoids in the databases in the year 2018. An experienced librarian will serve to develop a search strategy to find out systematic reviews that examined the effectiveness of the somatosensory stimulations. A combination of terms of medical subject headings (MeSH), keywords will be utilized in the search strategy. The MeSH and keywords contain “hemorrhoid”, “acupuncture analgesia”, “randomized controlled trial”, and synonymous words. If there is any lack of research information, contact the original author to obtain the original information. Language restrictions will not be used in this review. Details of the search strategy are shown in Table 2.4Two independent reviewers selected RCTs according to the eligibility criteria mentioned above, and they determined sample articles to test the data extraction table in pre-extraction period. Any discrepancy in study selection will be solved by team discussion and arbitrated by a third reviewer. Retrieved articles will be imported into Note Express software(version 3. 0) for screening titles and abstracts; full-text articles will be acquired for further screening when the 2 reviewers are unable to decide based on titles and abstracts.2.5After identification of eligible RCTs, 2 independent reviewers will extract the necessary information from the included RCTs using a standardized form. The form will be developed by a consensus of all the reviewers. Extraction items in the form are shown in Table 2.6,23,24 most of the trials report pain assessment at 1 to 7 days after randomization; so we will record data of the outcomes collected during 1 to 7 days after randomization.Responder rate will be the primary outcome of this review. A responder is defined as a patient who has at least 30% improvement in pain intensity scales or is being judged as markedly improved according to the following criteria: a visual analog scale (VAS) score ranges from 0 to 3 cm; the average VAS score of the patients on the 3rd or 7th day after the operation is significantly reduced by 4 cm. Secondary outcomes are the pain intensity scales that including VAS, numeric rating scale (NRS), or other scales. According to a previous review of postoperative analgesia of mixed hemorrhoids,2.7 to evaluate the methodological quality of RCTs. The risk of bias tool consists of 6 domains: sequence generation, allocation concealment, blinding, incomplete data, selective reporting, and other bias. Two independent reviewers will independently assess the risk of bias of eligible RCTs. Sequence generation will be considered as adequate if central randomization or tables of random numbers are used. Allocation concealment will be considered as tolerable if central randomization or sealed envelopes are used. We will consider blinding as adequate if participants, outcome assessors and statisticians are blinded from the group assignment. Other domains will be assessed exactly as the criteria of the risk of bias tool. A summary of risk of bias of all the 6 domains will be given for each trial. We will consider the sequence generation, allocation concealment and blinding as the essential key domains to score the overall quality of a trial. For each study, all 6 domains will be evaluated and displayed . Effect size of a treatment will be presented as standardized mean differences (SMDs) for continuous outcomes  or relative ratio (RRs) for categorical outcomes (responder rate), and the 95% confidence intervals (95% CIs) of the SMD and RR will be calculated. Consistency of the network will be evaluated by comparing direct evidence with indirect evidence through z test. We will use the comprehensive Cochrane Q test to evaluate heterogeneity between and within trials. We will also use a net-heat plot to determine the source of heterogeneity owing to different trial designs. We will use P score to describe the mean probability of each intervention being the best measure and to rank the treatments according to the P score.The network meta-analysis will be conducted using the NetMeta package in the R software , quality of evidence , course of disease, and mean age of the participants, main points, number of the points, diagnostic criteria, background therapy, and financial support. Meta-regression models will be used to quantify the difference between subgroups and test for statistical significance.3We will use network meta-analysis to integrate the direct and indirect evidence of somatosensory treatments in the management of postoperative pain and rank the treatments according to the probability and select the best somatosensory treatment and analgesia plan, so as to provide a reference for the application of somatosensory treatments after the operation of clinical mixed hemorrhoids. Clinicians can make the most appropriate choice according to patients, hospitals and their own conditions. It can also enable doctors to improve the treatment methods according to the shortcomings of these methods and conduct further research.The authors would like to thank Tao-Hong He in colorectal department of the Teaching Hospital of Chengdu University of Traditional Chinese Medicine for advice in the treatment of postoperative pain.Contributors: AMZ, MC, TCT, DQ, and HZ contributed to the conception and design of the study protocol. The search strategy was developed and run by AMZ and HZ, who will also screen the title and abstract of the studies after running the search strategy. HZ and MC will also screen full copies of the remaining studies after title and abstract selection, while MC and TCT will extract information of the identified studies; MC will check the data entry for accuracy and completeness. DQ and HZ will give advice for data analysis and presentation. All the authors drafted and revised this study protocol and approved it for publication.Conceptualization: An-Mei Zhang, Hui Zheng.Writing – original draft: An-Mei Zhang.Writing – review & editing: An-Mei Zhang, Min Chen, Tai-Chun Tang, Di Qin, Ling Yue, Hui Zheng.Data curation: Min Chen.Funding acquisition: Min Chen, Hui Zheng.Methodology: Min Chen, Tai-Chun Tang, Ling Yue.Formal analysis: Di Qin, Hui Zheng.Hui Zheng orcid: 0000-0002-0494-1217.


Aim. To evaluate the effects of acupuncture and transcutaneous electric nerve stimulation (TENS) applications on the quantitative electroencephalography (qEEG) changes and to evaluate their therapeutic effects in patients with fibromyalgia syndrome (FMS). The study included 42 patients with FMS and 21 healthy volunteers. The patients were randomly assigned to two groups (n=21 in each) to undergo either TENS or acupuncture application. In both acupuncture and TENS groups, baseline electroencephalography (EEG) recording was performed for 10 min and, then, TENS or acupuncture was performed for 20 min, followed by another 10 min EEG recording. Baseline qEEG findings of FMS patients in the TENS and acupuncture groups were similar. Delta and theta powers over the frontal region of FMS patients were lower than controls. Theta powers of right posterior region were also lower than controls. In the TENS group, after the treatment, an increase was observed in the alpha power of the left anterior region as well as a decrease in pain scores. In the acupuncture group, an increase was determined in the alpha power of the right and left posterior regions as well as a decrease in pain score after the treatment. The power of low- and moderate-frequency waves on resting EEG was decreased in the patients with FMS. Decreased pain and increased inhibitor activity were found on qEEG after TENS and acupuncture applications. In conclusion, both TENS and acupuncture applications seem to be beneficial in FMS patients. Fibromyalgia syndrome (FMS) is a complex chronic pain syndrome accompanied by widespread pain with the presence of tender points, fatigue, sleep disorder, and cognitive disorders. Its pathophysiology still remains unclear. Although the theories on the pathophysiology of FMS have initially underlined the pathologies of muscular origin, the origin of pain has recently turned toward processing disorders . It has Effects of TENS on pain and the gate control mechanism have been known for a long time. Following high-frequency stimulation, increased enkephalins and gamma-aminobutyric acid concentrations, which are endogenous opioids, have been shown, whereas following low-frequency stimulation in the central nervous system, increased beta-endorphin and serotonin concentrations have been demonstrated and the analgesic effect is eliminated, when antagonists are given, suggesting that analgesia is partially provided by these mediators , 5.The history of acupuncture dates back to 3,000 years ago. Currently, it is used as a solution for many health problems. In recent times, its use in diseases with pain symptoms has been gradually increasing. The pain control system is activated as the acupuncture needle is inserted into the point, and an increase is determined in endogenous opioids such as beta-endorphin –8, enkepQuantitative EEG is a neurophysiological method frequently used to evaluate central pain processing –14. In tThe study protocol was approved by the Başkent University Institutional Review Board and Ethics Committee (no.: KA 11/238). All patients were informed about the study and their consents were obtained prior to their participation in this study. The study was conducted in accordance with the principles of the Declaration of Helsinki.The study sample consisted of 42 patients in the age group of 21-65 years who were diagnosed with FMS according to the American College of Rheumatology Classification System among those who were admitted to Başkent University, Faculty of Medicine, Department of Physical Therapy and Rehabilitation outpatient clinic, between January 2012 and July 2013. The control group consisted of 21 healthy volunteers. In order to compare the EEG findings of patients with fibromyalgia and healthy individuals, we formed the control group of healthy individuals. Patients with endocrine disorders , neurological disorders , and chronic renal insufficiency and those receiving antidepressant-antiepileptic drugs were excluded. In addition, patients who were contraindicated for TENS  were excluded. Age of all participants and time to the onset of symptoms were recorded.In the patients diagnosed with FMS, severity of pain and fatigue was assessed using Visual Analog Scale (VAS), whereas pain threshold levels of tender points were determined by algometry. Severity of depression was assessed using Beck Depression Inventory (BDI). Severity of disease and quality of life were evaluated by Fibromyalgia Impact Questionnaire (FIQ).Tender points were detected using digital palpation method, which corresponds to the application of approximately 4 kg pressure at an intensity that would turn the thumb white. Pressure pain threshold (PPT) measurement was performed bilaterally in the tender points using pressure algometry device . To obtain the total PPT score, PPT values were summed after measurement of PPT in 18 tender points, which are characteristic for FMS.Current pain and fatigue levels of the patients who were assigned to TENS or acupuncture group were evaluated using VAS prior to EEG. Change in the level of pain was reevaluated using VAS after TENS and acupuncture applications.Acupuncture was applied on the Houxi (SI 3), Wangu (SI 4), Shenmai (UB 62), Jinggu (UB 64), Shugu (UB 65), and Yintang points for 20 min using a steel needle. We used Kingli sterile acupuncture needles (0.25 mm x 25 mm) in the present study. In addition, TENS was applied using the Endomed CV 405 device . We placed electrodes of TENS at the T2 and T6 paravertebral level in the upper thoracic region. 70 Hz 100 ms conventional TENS was applied for 20 min. Current intensity of TENS was finely adjusted to create a mild tingling sensation in the patients without causing contraction or discomfort.A total of 42 patients were randomly assigned to two groups of 21 each to receive either TENS or acupuncture application. Procedures were performed after all participants in these two groups and control group were allowed to rest for 10 min. In the TENS and acupuncture groups, EEG was recorded for 10 min following resting and, then, TENS or acupuncture was performed for 20 min, and EEG was recorded again for 10 min after the application. In the control group, EEG was recorded for 20 min following resting. The EEG recording was performed at Başkent University, Faculty of Medicine, Acupuncture Therapy Unit, Umitkoy, Ankara, using the NicoletOne v32 device . The electrodes were placed via a cup electrode in accordance with the international 10/20 electrode system, and each electrode area was filled with electro gel. The electrodes used were Fp1, F3, C3, P3, O1, F7, T3, T5, A1, Fz, Cz, Pz, Fp2, F4, C4, P4, O2, F8, T4, T6, and A2. While placing the cups, the electrodes Fp1 and Fp2 were enabled to be on the correct position. The position of Cz electrode was checked. Electrodes were placed in accordance with the three-point principle. During recording, the device was adjusted at sampling frequency of 500 Hz, band-pass filter interval of 0.5-35 Hz, and amplitude of 100 microvolts. Attention was paid to keep all electrode impedances to be under 5 KOhms. Procedures were performed with closed eyes. The temperature of the room where the EEG recordings and applications were made was 24°C. This room is 35 square meters. Attention was paid to prevent factors such as sound or light which might distract the patients' attention, and each subject was checked to see whether she/he was awake. Five-minute EEGs without artifacts were used for the spectral analysis.EEG data recorded from each electrode were filtered to obtain frequency components of delta (0.5–4 Hz), theta (4–8 Hz), alpha (8-13 Hz), and beta (13– 30 Hz) EEG bands after removing linear trends. For obtaining powers of EEG bands, the power spectral densities of these filtered signals were calculated by using Fourier transform with 0.25 frequency resolution for each electrode. U test. The Mann-Whitney U test was also used for multiple comparisons (post hoc) with Bonferroni correction. The electrodes and regions that showed differences in terms of EEG powers and pre- and posttreatment values of the TENS and acupuncture groups were evaluated using the Wilcoxon signed-rank test for abnormally distributed data and using Student's paired test for normally distributed data. The relation between regional alpha, beta, delta, and theta powers before treatment and disease duration, total PPT score, and VAS pain and fatigue scores before treatment were assessed using Spearman's correlation analysis. Clinical data were evaluated by parametric independent two-sample t-test for normally distributed data and nonparametric Mann-Whitney U test for abnormally distributed data. The age of participants in all groups was evaluated using parametric one-way analysis of variance (ANOVA) and Tamhane's T2 multiple comparison test. The BDI scores were evaluated using chi-square independence test (Yates chi-square). Pre- and posttreatment VAS pain scores were evaluated using nonparametric Wilcoxon t-test. A p value < 0.05 was considered statistically significant.Statistical analysis was performed using the SPSS version 16.0 statistical software . Descriptive data were expressed in mean ± standard deviation (SD) for normally distributed data and median (min-max) for abnormally distributed data. Whether the data were suitable for normal distribution was analyzed by Shapiro-Wilk normality test, while the homogeneity of the variances was evaluated by Levene's test. Delta, theta, alpha, and beta frequencies of each electrode and the four regions were compared using the nonparametric Kruskal-Wallis test and Mann-WhitneyIn the present study, the mean age of FMS patients in the acupuncture group was 44.6±10.34 years, the mean age of FMS patients in the TENS group was 38.05±11.3 years, and the mean age of the control group was 30.24±6.5 years. The control group was younger than the acupuncture and TENS groups (p<0.05).The mean FIQ and fatigue scores showed no significant difference between the acupuncture and TENS groups (p>0.05). The mean total PPT score was significantly lower in the TENS group compared to the acupuncture group .The presence of depression in the acupuncture and TENS groups was assessed using the BDI. According to the Turkish validity and reliability study of this scale, the cut-off value was considered as 17 . AccordiThe median duration of the disease was five (1-20) years in the acupuncture group and four (1-8) years in the TENS group, suggesting no statistically significant difference (p>0.05). The median pain score of FMS patients assessed by VAS before treatment was 5 (1-7) in the acupuncture group and 5 (1-10) in the TENS group, indicating no statistically significant difference (p>0.05).Electroencephalography data were analyzed by dividing the brain into four quadrants. Accordingly, “Fp1+F3+F7” formed the left anterior region, “Fp2+F4+F8” formed the right anterior region, “P3+T3+T5+O1” formed the left posterior region, and “P4+T4+T6+O2” formed the right posterior region. The sum of the alpha, beta, theta, and delta powers obtained from these regions formed the regional power.For delta power, evaluation of pretreatment EEGs of the patients in the acupuncture and TENS groups and the bands from four regions in the healthy controls showed a statistically significant difference between the groups for left anterior and right anterior regions p<0.05, . A decreFor theta power, pretreatment EEGs of the patients revealed a decrease in theta power of the left anterior, right anterior, and right posterior regions in the acupuncture and TENS groups compared to the healthy control group p<0.05, .For alpha power, when the alpha power obtained from pretreatment EEGs of the patients in the acupuncture and TENS groups was compared with the control group, a decrease was observed in the alpha power of the left and right anterior regions in the acupuncture group p<0.05, . Beta poWe investigated the correlation of regional alpha, beta, theta, and delta powers obtained from pretreatment baseline EEGs of patient groups with the total PPT score, disease duration, and VAS pain and fatigue scores. In the acupuncture group, a negative correlation was found between pretreatment theta power of the left posterior region and pretreatment pain score , whereas a positive correlation was found between pretreatment alpha power of the left anterior region and the disease duration . In the TENS group, a positive correlation was found between pretreatment alpha power of the left anterior region and disease duration . However, no significant correlation was found between other regional powers and clinical data.Pain scores using VAS were 5 (1-10) (mean±SD: 5.19±2.20) before TENS application and 3 (0-8) (mean±SD: 2.86±2.01) after TENS application in FMS patients, indicating a statistically significant decrease (p=0.001). The median VAS pain scores in FMS patients were 5 (1-7) (mean±SD: 4.62±1.56) before acupuncture application and 2 (0-9) (mean±SD: 2.60±2.28) after treatment, indicating a decrease in the pain scores after treatment (p=0.003).When the regional theta power obtained in the qEEG which was recorded after TENS in FMS patients was compared with pretreatment theta power, an increase was observed in the right posterior region p<0.05, .When the regional alpha power obtained in the EEG which was recorded after TENS in FMS patients was compared with its pretreatment alpha power, an increase was observed in the left anterior region and a decrease was observed in the right posterior region p<0.05, .When the regional theta power obtained in the qEEG recorded after acupuncture application was compared with pretreatment theta power in FMS patients, an increase was observed in the right posterior region p<0.05, .When the regional alpha power obtained in the qEEG recorded after acupuncture application was compared with pretreatment alpha power in FMS patients, an increase was observed in the right posterior and left posterior regions p<0.05, .When the regional beta power obtained from EEG recorded after acupuncture application was compared with the pretreatment beta power, an increase was observed in the right posterior and left posterior regions p<0.05, .In the current study, we investigated the association between disease duration, different clinical symptoms of FMS including pain, fatigue, depression, pressure pain threshold, and resting state qEEG brain activity, and effects of TENS and acupuncture treatments. Our study results showed that the main PPT scores were significantly lower in FMS patients in the TENS group compared to the acupuncture group. However, disease duration and other clinical symptoms of FMS were not significantly different in the TENS and acupuncture groups.In our study, delta and theta powers over the frontal region of FMS patients in TENS and acupuncture groups were lower than controls. Theta powers of right posterior region in both FMS patient groups were also lower than controls. Beta and alpha powers of frontal region in the acupuncture group were lower than the controls. These findings are consistent with previous results obtained by Hargrove et al. , indicatAnother study showed that FMS patients exhibited increases in the frontal theta power during resting EEG. Furthermore, theta power was associated with increased tenderness and tiredness score in FMS patients . In our Transcutaneous electrical nerve stimulation is frequently used by health professionals for pain control. The effects of TENS for pain control are explained by the gate control theory, which suggests that electrical stimulation of large diameter afferent fibers inhibits second-order neurons in dorsal horn and prevents impulses carried by small-diameter fibers from being transmitted . StimulaIn the present study, we found that TENS treatment resulted in a significant decrease in pain intensity and alpha power over right posterior region of FMS patients, compared to pretreatment level. Alpha waves theoretically reflect the activities of inhibitor neurons . ChangesIn recent years, many studies have been conducted to explain the mechanism of action of acupuncture. Studies on humans and animals have demonstrated that pain control system is activated, as the acupuncture needle is inserted into the point and analgesic, anti-inflammatory, anxiolytic, and sedative efficacies are enabled by increasing endogenous opioids , 28, 29 In the present study, we used Houxi (SI 3), Wangu (SI 4), Shenmai (UB 62), Jinggu (UB 64), Shugu (UB 65), and Yintang points. It is known that Houxi (SI 3) and Shenmai (UB 62) are the eight confluent points and they are affective in diseases with pain symptoms in the neck, shoulder, thoracic, and lumbar regions. The Wangu (SI 4) point is used for painful conditions in the Yuan-Primary point of SI meridian and shoulder-neck region. The Jinggu (UB 64) point is used for painful conditions in the Yuan-Primary point of UB meridian and the neck-lumbar region. The Shugu (UB 65) point is used for painful conditions in the neck-lumbar region and lower extremities . The YinIn the present study, in the acupuncture group, increased alpha power of the right and left posterior regions, increased theta power of the right posterior region, and increased beta power of the right and left posterior regions were observed after treatment. According to the pain scores before and after acupuncture in this group, a decrease was observed in pain score, but an increase was found in the alpha-wave power. Increased alpha power may be related to the suppression of pain sensation by activation of inhibitor neurons in the central nervous system due to the stimulation of pain control system, which was excited by acupuncture application . The litIncreased delta and theta activities in acute pain were attributed to the negative emotional response to cold compress, whereas increased beta activity was attributed to hypersensitivity to tonic pain . In addiThere are some limitations to this study. Small sample size and young mean age of the control group can be regarded as the main limitations. In addition, we were unable to assess for how long altered EEG activity following TENS and acupuncture applications was maintained. Therefore, further large-scale, randomized, prospective studies are required to confirm these findings.In conclusion, our study results showed a decrease in the power of low-medium-frequency waves in the EEGs of FMS patients with high pain scores. Decreased pain scores and increased alpha power over anterior region after TENS and acupuncture application in FMS patients can be associated with augmented activities of inhibitor neurons. Considering pain scores and EEG findings, we suggest that both TENS and acupuncture applications seem to be beneficial in FMS patients.


Recent experimental research has suggested that spinal manipulative therapy (SMT) may reduce pain through modulation of the ascending pain signals and/or the central pain-regulating mechanisms. People with persistent neck pain (NP) have also been found to have disturbances in autonomic nervous system (ANS) regulation. A common way to study the ANS is to measure heart rate variability (HRV). It is not known whether deviations in HRV are related to changes in pain perception or to the treatment response to SMT.Commonly, an individual in pain will experience pain reduction when exposed to a second pain stimulus, a mechanism known as conditioned pain modulation (CPM). Patients with persistent pain have been found to have a reduced CPM reaction. It is not known whether this is predictive of treatment response to SMT.The aim of the study is to examine the effects of SMT on HRV and pain. Further, a secondary aim is to test whether a CPM test can be used to predict treatment response in a population of patients with recurrent and persistent NP.A multicentre randomized controlled clinical trial will be carried out in multidisciplinary primary care clinics. This setting is chosen to minimize bias resulting from patient preference for the treatment modality and provider.The subjects are either self-referred or referred from other health care practitioners locally. The treatment modalities are two well-known interventions for NP; SMT and stretching exercises compared to stretching exercises alone.HRV will be measured using a portable heart monitor. The subjective pain experience will be investigated by assessing pain intensity and the affective quality of pain. CPM will be measured with a standardized cold pressor test. Measurements will be performed three times during a 2-week treatment series.The study will utilize normal clinical procedures, which should aid the transferability and external validity of the results. The study will provide knowledge regarding the underlying mechanisms of the effects of SMT. Furthermore, the study will examine whether a CPM test is predictive of treatment outcome in a population of patients with recurrent and persistent NP.NCT03576846. Registered on 3 July 2018.ClinicalTrials.gov, The online version of this article (10.1186/s13063-019-3678-8) contains supplementary material, which is available to authorized users. Musculoskeletal pain is a global burden due to a high prevalence and substantial costs worldwide . The mosChiropractic care including spinal manipulative therapy (SMT) has been found to be a safe, effective and cost-effective non-invasive treatment for some types of spinal pain –7. SMT hSMT is thought to decrease pain by mechanically affecting muscular and joint function . However, recent experimental research has suggested that SMT may also be influencing the incoming/ascending pain signals  and/or the excitability of the central pain regulating mechanisms , 10. A sDifferences in ANS activity have been found between healthy controls and people with NP . In healStretching is used both as a passive treatment intervention and as active home exercises for several conditions relating to the musculoskeletal system. The rationale behind stretching is to improve the range of motion and to reduce pain and perceived stiffness . The effA pure placebo trial is not indicated either when an evidence-based treatment options exists or when the patients taking part in the study are actively seeking care . Due to As already mentioned, chiropractic treatment is considered non-invasive and safe –7. CommoThe research in the area so far suffers from some limitations: small group sizes, possible patient bias (positive expectations) towards the therapist and treatment method, short follow-up time and lack of a reasonable comparator treatment. A randomized design with a standardized control treatment would distinguish treatment effects from contextual effects. In order to study the neurological effect of SMT and stretching exercises compared to stretching alone in patients with persistent and recurrent NP in a clinical setting, a sufficiently large sample and a randomized design should be used. In order to study long-term HRV responses, measurements over 2 weeks will be conducted.Interestingly, when exposed to pain, a different noxious (painful) stimulus can be used as a conditioning (inhibitory/facilitatory) stimulus. The normal reaction is a reduction in pain perception known as “pain inhibits pain” or inhibitory conditioned pain modulation (CPM). In patients with chronic pain, a reduced CPM response may prevent the normal reaction to a painful stimulus from occurring, and patients will not experience the normal “pain inhibits pain” reaction .In this study, a tool previously described in the literature  will be The study aim is to determine the effects of a treatment series consisting of stretching and SMT versus stretching alone on HRV and pain in a clinical setting in a population of patients with recurrent or persistent NP. A secondary aim is to test CPM as a predictor of treatment outcome in terms of pain.This multicentre randomized controlled clinical trial will be carried out in multidisciplinary primary care clinics where physiotherapists and chiropractors are consulted for musculoskeletal pain. These types of clinics are selected to minimize bias from patients having expectations towards a specific treatment modality.A total of six clinics will take part in this study, and each clinic will include 20 subjects, resulting in 120 subjects in total (60 in each treatment arm).Two research trained clinicians will conduct all of the measurements.The treatments (both intervention and control) will be delivered by clinicians (licensed chiropractors) in the participating clinics.Inclusion criteria: minimum 18 years old, able to read and understand Swedish, presence of recurrent (at least one previous episode) and persistent (duration more than 6 months) NP, and no chiropractic treatment during the previous 3 months. This interval was chosen as research has shown that similar treatments seem to have little effect beyond 3 months .Exclusion criteria: conditions or medications that will affect the HRV measurements, such as cardiovascular disease, hypertension, diabetes, pregnancy, obesity (BMI > 30), currently using pain-reducing medication on a daily basis, steroids, β-blockers or antidepressants. All contraindications to SMT—that is, anything that could seriously aggravate the pain (e.g. inflammatory conditions) or be indicative of cerebrovascular injuries (previous drop attacks or a recent episode of a new headache or dizziness)—will exclude the patient from the study.The study procedure is shown in the flow chart and SPIRIT figure Figs.  and 2.FPatients in this study are self-referred after hearing about the study from another health care provider or reading about the study in an advertisement or newsletter. A research assistant calls the patient and assesses their eligibility using a standardized form. The patients are informed about the aim of the study and the study procedures. If eligible, the patient is scheduled for all study visits during this call. Logistical details of this recruitment stage will be adapted to individual clinics as some clinics have newsletters and some use social media to inform their patients about clinic news. Different local newspapers are also used to recruit patients, as the individual clinics are located in and around the Stockholm area.On their first visit, patients will sign an informed consent form and have their baseline measurements taken. They will then be randomized to one of the treatment arms and treated accordingly. On the day of the study visit, the participants will refrain from caffeine, nicotine and alcohol, and from performing strenuous exercise.https://www.artologik.com/en/SurveyAndReport.aspx).A standardized protocol is followed on the day of the first study visit. After consenting to participate, the subjects will start by filling out a baseline questionnaire for demographic information. They will also answer questions concerning their NP  as well as questions regarding pain levels and the affective quality of pain using the NRS-11 scale , 26, STahttps://www.firstbeat.com/en/). The monitor is applied by the research clinician, and the participants will rest quietly for 5 min with the equipment attached before baseline resting values are ascertained over a period of 5 min. After this, CPM will be tested with a structured CPM test [The equipment used to measure HRV is called FirstBeat  to ascertain the type and level of reactions to the interventions [Data on normal treatment reactions (tiredness/fatigue and pain/tenderness) are collected the day after the first treatment using SMS , the clinicians are free to select any other treatment modality for the patients. However, patients will be monitored with questionnaires every other week (via email) regarding their affective quality of pain and pain levels for 2 months after their final measurement at the clinic. The clinicians will also report what treatment modalities were used after the initial 2 weeks of the study.Patients who do not complete the full treatment plan will be asked to complete all measurements in order to study attrition and to complete a drop-out analysis.Consecutively numbered opaque envelopes containing the group allocation are created off-site at the research centre by a statistician. A 1:1 allocation ratio in randomly permuted blocks of different sizes according to a randomization schedule is used. The envelopes are arranged in batches of 20 and distributed to the clinics at the start of each data collection period. SPSS version 20 is used to generate the randomization code. The envelopes are opened consecutively by the treating clinician.The subjects will be unaware of what treatment the other group is receiving, as they will be told that the study is testing two different treatment modalities with similar clinical benefit to examine the effect over 2 weeks on physiological parameters and pain. Subjects in both treatment arms should feel that complying with their treatment plan during 2 weeks is a necessity for their improvement.It will not be possible to blind the clinicians performing the treatments. The research clinicians who will collect the data in the experiment will be blinded to the treatment allocation. The statistical analysis will be performed with the treatment allocation blinded.Log root-mean-squared successive differences in RR intervals (RMSSD) are the primary measurement of HRV. We will also explore other aspects of HRV according to Task Force Standards  to gain SMT in this study is defined both as a high-velocity, low-amplitude (HVLA) thrust applied to the target joint and also as spinal mobilization (MOB) where the application of manual force to the spinal joints is within the passive range of joint motion and does not involve a thrust . The typAs the participating chiropractors have similar educational backgrounds and have received the same instructions concerning their limited choice of treatment techniques, we expect that they will have a similar approach to SMT. Data on the specific interventions will be collected.The common modality used in both treatment arms is a programme of home stretching exercises. Both groups will receive verbal and written instructions describing the home stretching exercises that have been recommended as a low-cost, first-instance intervention for NP . The variation in the beat-to-beat heart rate is an indicator of parasympathetic and sympathetic modulation of the heart rhythm. Deviations in HRV have been found in patients with both acute and chronic pain. Patients with various chronic pain conditions show reduced parasympathetic activity at rest, the proposed mechanism behind central sensitization . Thus, vIn this study, conditioned pain modulation (CPM) consists of the evaluation of a painful test stimulus followed by a second evaluation after the painful conditioning stimulus has been withdrawn  . CMP is There is a growing body of evidence suggesting that CPM may be an important biomarker of chronic pain and a predictor of treatment response . One mayOur study will use a structured CPM testing protocol with a standardized clamp pressing on the thumb nail for 10 s as the test stimulus, and cold water (0–2 °C) as the conditioning stimulus, previously tested and validated by O’Neill and O’Neill . An NRS-The neck disability index is an instrument designed to measure disability, and has been shown to be reliable and valid in Swedish .Pain intensity is measured with a validated NRS-11 where the subjects grade their perceived pain level using the anchors “no pain” and “worst possible pain” , 26.Measures of self-rated health are assessed by the EQ-5D, a translated (Swedish) and validated questionnaire with five domains and three answer options in each domain , 48.To assess the affective quality of pain, the Swedish version of the short-form McGill Pain Questionnaire-2 will be used. This is a validated questionnaire , 30 usedSecondary measurements such as disability and health-related quality of life will be collected. The subjective pain experience will also be evaluated, as this is important when considering chronic pain . The outThese questionnaires will be given at baseline, and again at the second and third measurements. In addition, they will be administered every other week during the following 2 months after the study period has ended. Pain intensity (NRS-11) , 26 willThe most common side effects following SMT are local tenderness and tiredness of a short duration . In thisThe data collection commenced in January 2019 and is expected to be finished by February 2020. Intention-to-treat analysis will be applied.Univariate multiple regression analysis (one outcome) and/or multivariate multiple regression analysis (more than one outcome) will be used to analyse the primary and secondary outcomes of the trial.If appropriate, age and sex will be included as covariates and controlled for in the model.To investigate whether CPM is a predictor of treatment outcome we will look at the statistical interaction between CPM and SMT with regards to their effects on the primary outcome.SMT is applied clinically in musculoskeletal health care and has been examined in a variety of research studies. Serious complications are very rare , 50. Thehttps://www.lkr.se/) (Nordic Insurances). Thus, the subjects are insured in case of adverse events from treatment.The clinicians (chiropractors) who perform the treatment all have an academic degree, are licensed by the Swedish National Board of Health and Welfare  and have personal liability insurance through their professional federation , replacing their personal identity number and name, to which all measurement data and patient reported data will be linked. The key that matches the subject ID with their personal identity number and name will be securely stored in a locked fireproof cabinet at Karolinska Institutet in accordance with the National Board of Health and Welfare’s requirements for storage of journal documents.During the data collection, data are recorded and processed by the research clinicians, and all entries in the databases are recorded using the subject ID only. During the analyses, data will be completely anonymized and only the involved researchers will have access to the data, which will be stored electronically at Karolinska Institutet in accordance with local rules and European GDPR regulations.All reporting will be done at the group level without the possibility of identifying any individual study subjects. The results of the study will be published in open access journals, and will be communicated through several professional channels nationally and internationally.Central ethical approval has been confirmed by the Regional Ethical Review Board in Stockholm  and has approved participation of all individual centres in the trial.The pain-reducing effects of SMT on certain spinal pain conditions are well established, as are the normal reactions to such treatment –7. HowevThe development of CPM as a clinical prediction tool could potentially inform clinicians on what to expect in terms of treatment response concerning stretching and manual treatment. The knowledge gathered will inform future clinical studies regarding useful outcome measures, minimally clinically relevant change values and necessary sample sizes in this type of research.There are some challenges to consider with the current design. The data collection demands effective recruitment to ensure a sufficient number of subjects to adequately power the trial. As mentioned, the study will utilize an existing practice-based research network, where chiropractors have participated and successfully recruited patients in previous studies, and thus we believe that it is feasible to include the required number of subjects.Based on previous experience with multi-centre clinical trials, procedures are in place to minimize the burden on the subjects in the study. However, attrition is to be expected to some degree. Reminder functions have been included in the email and text-message measurement protocols, some of which are automatic, but some will require monitoring and individual follow up. As subjects deal with only one research clinician and one treating clinician, we believe that the personal contact will be optimal, thus reducing attrition.The testing methods require a highly structured testing protocol as the testing equipment is highly sensitive. However, we believe that this is achievable considering the experience of the research group members.A pilot study was conducted prior to commencing the full-scale study. This resulted in changes to the recruitment strategy with regards to the use of newspapers and advertising. The responsibility of booking eligible patients was transferred to a research assistant from the local receptionist.Patient recruitment began in January 2019, and is expected to be completed by February 2020. Additional file 1:Stretching exercises, daily for 14 days. (DOCX 341 kb)Additional file 2:SPIRIT Checklist. (DOC 123 kb)Additional file 3:Protocol for measurements procedures . (DOCX 13 kb)


Marfan syndrome (MS) is a multisystem disorder caused by a mutation in FBN1 gene. It shares some phenotypic features with hypermobile Ehlers-Danlos syndrome (EDS) such as joint hypermobility. EDS is a group of inherited heterogenous multisystem disorders characterized by skin hyperextensibility, atrophic scarring, joint hypermobility, and generalized tissue fragility. Hypermobile EDS (hEDS) is thought to be the most common type. Recent studies have suggested an association between connective tissue hypermobility and functional gastrointestinal disorders (FGDs). The aim of this study is to determine the prevalence of gastrointestinal symptoms in patients with Marfan syndrome and hypermobile EDS.  Patients with a diagnosis of either MS or hEDS attending cardiology or rheumatology outpatients at our hospital were asked to complete SF36 RAND and Rome IV Diagnostic questionnaires. Questionnaires were also completed by patients who are members of Marfan Association UK. The same questionnaires were also completed by age- and gender-matched controls attending fracture clinic without existing diagnoses of MS or hEDS.  Data were collected from 45 MS patients  and 45 hEDS patients . None had a previous organic gastrointestinal diagnosis. The control group was matched for age and sex . Both MS and hEDS groups showed a higher prevalence of abdominal symptoms compared to the control group; however, the hEDS group not only showed a higher prevalence but more frequent and severe symptoms meeting Rome IV criteria for diagnosis of FGIDs. Nearly half of the hEDS patients met the criteria for more than one FGID. The hEDS group also scored lower on quality of life (QOL) scores in comparison to either of the other groups with a mean score of 48.6 as compared to 54.2 in the Marfan group and 78.6 in the control group.  FGIDs are reported in both Marfan syndrome and hypermobile Ehlers-Danlos syndrome but appear to be more common and severe in hEDS. These patients score lower on quality of life scores as well despite hypermobility being a common feature of both conditions. Further work is needed to understand the impact of connective tissue disorders on gastrointestinal symptoms. Marfan syndrome (MS) is a multisystem disorder caused by a mutation in FBN1 gene . EDS is Gastrointestinal symptoms are reported to be common in patients with hypermobility; however, much of the recent interest in this area is focused only on patients with hEDS. No previous study has compared the prevalence of gastrointestinal symptoms in patients with MS and compared to patients with hEDS. The aim of our study is to use standardised definitions for all gastrointestinal symptoms using Diagnostic Rome IV questionnaire as well as look for the overall perception of health and well-being using RAND SF36 questionnaire. We have also investigated the use of the most commonly used medications which affect gastrointestinal function in these groups.Patients attending outpatients at St. George's Hospital who had an existing diagnosis of MS or hEDS were asked to complete SF36 RAND and Rome IV Diagnostic questionnaires. Some patients were recruited with the help of Marfan Association UK. All patients completed the questionnaires by themselves, either in the Outpatients Department or at home, and returned them by post.Controls were recruited from outpatients attending the fracture clinic at St. George's Hospital, one control being recruited for each MS and hEDS patient, matched by gender and age (±10 years). Hypermobility was assessed in these controls using Beighton criteria, and scores of 4 or less were included. All patients completed the questionnaires themselves while attending clinic. No financial or other inducements were given.All recruited subjects completed the SF36 RAND and Rome IV Diagnostic questionnaires. Additional questions regarding ethnicity, smoking and alcohol use, use of medicines, and other medical conditions were added using previously validated questionnaires. All participants were asked if they had used antisecretory/antacid therapy or laxatives, either regularly or on as required basis in the last six months. The scoring algorithm for Rome IV Diagnostic questionnaire for adults was used, and a functional gastrointestinal disorder was said to be present if the criteria were met. The presence of abdominal pain, constipation, and diarrhoea was investigated separately even if criteria for FGID were not met.Oesophageal disorders Gastroduodenal disorders Bowel disorders (irritable bowel syndrome (IBS), functional constipation, functional diarrhoea, functional abdominal bloating/distension, and unspecified functional bowel disorder)Centrally mediated abdominal pain syndromeFunctional biliary painAnorectal disorders The Rome IV classification was followed for various gastrointestinal symptoms and diagnoses including the following:Functional chest pain was defined as retrosternal chest pain or discomfort at least weekly with no heartburn or dysphagia. Functional heartburn was defined as burning retrosternal discomfort or pain with no relief from antisecretory therapy. Globus was defined as persistent or intermittent, nonpainful sensation of a lump or foreign body in the throat with the absence of dysphagia or heartburn. Functional dysphagia was defined as sense of solid and/or liquid foods sticking, lodging, or passing abnormally through the oesophagus in the absence of organic disorders.Functional dyspepsia was defined as postprandial fullness, early satiation, epigastric pain, or burning, severe enough to impact on usual activities or prevent finishing a regular size meal. Functional belching was defined as belching, severe enough to impact on usual activities, from the oesophagus or stomach more than 3 days a week. Nausea and vomiting disorders were defined as weekly nausea or vomiting episodes, severe enough to impact on usual activities. Rumination syndrome was defined as persistent or recurrent regurgitation of recently ingested food into the mouth with subsequent spitting or remastication and swallowing.IBS was defined as recurrent abdominal pain related to defecation and associated with a change in frequency or form of stool. IBS subtypes  were classified based on patient's perception of the usual consistency of abnormal stools, according to Bristol stool scale. Functional constipation was defined as bowel opening associated with two or more of straining, type 1-2  stools, sensation of incomplete evacuation, sensation of anorectal obstruction, manual manoeuvres to facilitate defecation, fewer than three spontaneous stools per week, and absence of loose stools. Functional diarrhoea was defined as the presence of loose, watery stools  without predominant abdominal pain or bloating. Functional abdominal bloating/distension was defined as recurrent bloating or distension at least weekly where bloating predominates all other symptoms. Unspecified functional bowel disorder was defined as the presence of symptoms of abdominal pain, constipation, diarrhoea, or bloating which do not meet criteria for other conditions.Centrally mediated abdominal pain syndrome was defined as continuous or nearly continuous abdominal pain with no  relationship of pain to physiological events such as eating, defecation, or periods. Functional biliary pain was defined as pain in the epigastrium and/or right upper quadrant that builds up to a steady level, lasts 30 minutes or longer, occurring at different intervals, severe enough to interrupt usual activities and not related to bowel movements, posture change, or acid suppression.Faecal incontinence was defined as recurrent uncontrolled passage of faecal material. Functional anorectal pain was defined as chronic or recurrent rectal pain or aching with episodes lasting 30 minutes or longer.All participants completed the SF36 Quality of Life questionnaire. Mean scores out of 100  for all groups were calculated for each of the eight domains, that is, physical functioning, role limitations due to physical health, role limitations due to emotional problems, level of energy/fatigue, emotional well-being, social functioning, pain, and general health.t-test values were used to compare the mean scores in different modalities of SF36 questionnaire. As multiple comparisons were made, probability values of <0.05 were thought to be statistically significant.Statistical analyses were performed using the IBM Statistical Package for the Social Science (SPSS) software version 25 . The Fisher's exact test and Chi-squared test were used for comparing categorical variables. Independent sample The study protocol was approved by the South West-Central Bristol Research Ethics Committee and NHS Health Research Authority UK.90 patients and 90 controls were included in this study. Data was collected from 45 MS patients  with no organic gastrointestinal diagnosis. Data was collected from 45 hEDS patients  with no organic gastrointestinal diagnosis.Combining the MS and hEDS patients together, these patients were more likely to report a wide range of gastrointestinal symptoms compared to controls .Abdominal pain, bowel symptoms, heartburn, dyspepsia, and dysphagia were all significantly more common in the combined hypermobile group compared with controls. Medication use was also significantly more common in this group.More Marfan patients reported abdominal pain, diarrhoea, and constipation than controls; however, only symptom of abdominal pain was thought to be statistically significant. The use of antisecretory therapy and laxative was also reported in more MS patients than controls, but this did not reach statistical significance .All GI symptoms and use of medicines were considerably higher in the hEDS group meeting statistical significance for all three symptoms and use of medicines. FGIDs were also more frequently found in hEDS group meeting statistical significance for functional heartburn, functional dysphagia, functional dyspepsia, irritable bowel syndrome, functional constipation, functional diarrhoea, functional abdominal bloating, and unspecified bowel disorder .The SF36 Quality of Life questionnaire generates a mean score out of 100  for eight domains: physical functioning, role limitations due to physical health, role limitations due to emotional problems, level of energy/fatigue, emotional well-being, social functioning, pain, and general health. The mean scores across all domains of MS patients were compared with controls showing statistical significance in most domains . SimilarThis is the first study of its kind showing that connective tissue hypermobile syndromes are associated with a significant number of gastrointestinal symptoms compared to control patients. Despite the many phenotypic similarities, MS and hEDS exhibit different symptom complexes. The burden of functional gastrointestinal symptoms in MS in comparison with hEDS has never been studied and compared. Individuals with hEDS suffer a greater impairment to general well-being than MS patients.Marfan syndrome is a spectrum of heritable disorders of connective tissue with a high degree of clinical variability. It has an autosomal dominant mode of transmission mainly affecting the connective tissue protein fibrillin. The defect itself has been isolated to the FBN1 gene on chromosome 15, which codes for the connective tissue protein fibrillin . The mosA variety of large surgical publications have highlighted the anatomical or structural complications involving the gastrointestinal tract in patients with Marfan syndrome –32; howeEhlers-Danlos syndrome is described as a group of inherited noninflammatory connective tissue disorders primarily caused by a defect in the synthesis of collagen. The syndrome derives its name from clinical case reports presented by 2 physicians: Edvard Ehlers, a Danish dermatologist in 1901, and Henri-Alexandre Danlos, a French physician in 1908. The types of EDS have traditionally been classified according to the Revised Villefranche Nosology presented in 1997 .The current classification of EDS is based on the 2017 international classification of Ehlers-Danlos syndrome which includes the traditional six types as well as other rarer types . All theOne of the first descriptions of gastrointestinal involvement in EDS was an observational study published in 1969 . HoweverSymptoms of functional gastrointestinal disorders appear to be more prevalent in the hypermobility subtype of Ehlers-Danlos syndrome. A comparison of patients affected by joint hypermobility syndrome/hypermobile Ehlers-Danlos syndrome with matched controls showed that all gastrointestinal symptoms were more common in this group and affected the quality of life adversely . The assIn this study, patients with hypermobility reported a wide range of gastrointestinal symptoms, frequently met the criteria for the diagnosis of functional gastrointestinal disorders, and showed increased use of medications for gastrointestinal symptoms. These appear to be more common in hypermobile Ehlers-Danlos syndrome patients than in Marfan syndrome patients. Both groups scored lower than controls on quality of life indicators; however, hEDS patients had lower mean scores as compared to MS patients.However, our study does have some limitations. The sample size is small, and although individuals with a known organic gastrointestinal diagnosis were excluded, undiagnosed conditions may have been present. Finally, although it would be expected that all MS patients are under secondary or tertiary care, it is likely that only the severe hEDS would be under rheumatology specialist care. This selection bias might explain the more severe symptoms in this group compared to the MS group.A greater understanding of functional gastrointestinal symptoms in patients with connective tissue disorders may give further understanding to the aetiology of gastrointestinal symptoms in individuals not formally diagnosed with connective tissue abnormalities and may give insight into the causes of functional gastrointestinal disorders and irritable bowel syndrome.