Patients who reported significant medication-related side effects reported greater activity interference, negative affect, catastrophizing, and opioid misuse risk compared with those with fewer side effects. There is increasing concern among primary care practitioners about the use of opioids for chronic pain, including their adverse effects, but little attention has been given to how reports of side effects from prescription medication can contribute to outcomes among patients with chronic pain. The aim of this study was to investigate the impact of frequently reported side effects on mood, disability, and opioid misuse in patients with chronic pain prescribed opioids within primary care.Two hundred (N = 200) patients with chronic pain taking opioids for pain were recruited into the study. All patients completed baseline measures and a monthly side effects checklist once a month for 6 months. Patients were divided evenly based on a median split of the number of endorsed side effects over 6 months. The subjects repeated the baseline measures at the end of the study period.P < 0.01). In addition, those patients with pain who reported more side effects showed significantly higher scores on opioid misuse risk (P < 0.001).Over time, reports of medication side effects tended to decrease, but differences in frequency of reported side effects from baseline to follow-up (6-month time) were not significant, and the order of the frequency of the reported side effects remained similar. Patients who reported significant medication-related adverse effects reported significantly greater activity interference, negative affect, and catastrophizing compared with those with fewer side effects (This study demonstrates the important role of monitoring medication-related side effects among patients with chronic pain who are prescribed opioid medication for pain within primary care. However, there are also ongoing concerns about misuse, abuse, and addiction related to use of opioids for chronic noncancer pain. With increased availability of opioids over the past decade, prescription drug abuse has been perceived to be a fast-growing problem,13 and the co-occurrence of prescription opioid misuse and chronic pain has become very common.32 Fear of regulatory scrutiny about improper prescribing practices associated with opioids is also a primary concern among prescribing physicians. This has resulted in tension between the need to treat legitimate medical conditions, such as postoperative pain and failed surgery, while also minimizing the risk of opioid abuse and addiction. According to provider survey studies, more than one-half of physicians surveyed reported that they were worried about scrutiny regarding opioid prescribing,19 and potential professional sanctions.27 The safe use of opioids for treatment of chronic pain has become a particular concern among health care providers and a high priority had been place on the identification of those who are at the greatest risk of opioid misuse.25Chronic pain is a significant public health–related problem that negatively impacts quality of life among millions of individuals and costs society an estimated $560 to $635 billion annually.28 but few studies have investigated the influence of medication side effects on pain-related outcomes among patients with chronic pain. The bulk of previous studies conducted in this area primarily examined the influence of medication side effects on patients' daily functioning or quality of life. Martel et al.29 showed that medication side effects were associated with heightened pain-related activity interference among patients treated in specialized, tertiary care pain clinics. To our knowledge, such studies have yet to be conducted among patients with pain seen in primary care settings.All prescription medications have the potential for associated side effects, and the monitoring of side effects is clinically important. Ingesting medications can add to risk of unintended consequences, which can be mild without any long-term effects  or, in some situations, quite severe . Although certain medication side effects may have perceived beneficial qualities , most are unwanted and can interfere with overall quality of life including headaches, nausea, dizziness, constipation, and weakness. Also, some medications, that are proven to be helpful in treating a certain medical condition, are discontinued because they cannot be tolerated because of their side effects. Studies have examined the effect of medication-related side effects among patients with chronic pain on treatment satisfaction,The aim of our study was to extend previous work by exploring the influence of medication side effects on mood disorder, negative affect, and opioid misuse among primary care patients with chronic pain. We hypothesized that patients who reported experiencing many medication-related side effects would show greater pain intensity and pain-related disability, higher emotional distress, and possibly higher risk of opioid misuse compared with those who reported fewer medication-related side effects.This study was approved by the institutional review boards (IRBs) of each of the participating health care organizations and centers, and informed consent was obtained from all the participants before any study procedure.27 Subjects were included if they (1) had chronic pain for >6 months' duration, (2) averaged 4 or greater on a pain intensity scale of 0 to 10, (3) were able to speak and understand English, (4) had been prescribed or were eligible to be prescribed opioid therapy for pain based on the practitioner's personal criteria for eligibility for chronic opioid therapy, and (5) were under the care of a primary care physician.We identified and recruited patients who had a diagnosis of chronic pain from primary care centers located within the Metropolitan Boston area as part of a larger study.26 that would interfere with study participation.Patients were excluded from participation if they meet any of the following criteria: (1) diagnosis of cancer or any other malignant disease, (2) acute osteomyelitis or acute bone disease, (3) present or past DSM-IV diagnosis of schizophrenia, delusional disorder, psychotic disorder, or dissociative disorder that would be judged to interfere with study participation, (4) pregnancy, (5) any clinically unstable systemic illness judged to interfere with treatment, (6) a pain condition requiring urgent surgery, and (7) an active substance use disorder, such as cocaine or IV heroin use ,www.nidcr.nih.gov) as a research participant and that personal identifiable information would be protected from disclosure.Patients were recruited through flyers placed in the centers and were invited to participate by their treating physicians. Patients were followed up with a letter describing the study and an informed consent form that they were instructed to complete and mail back to the research assistant assigned to this study. All patients received a $50 gift card for completing the packet of questionnaires at the start of the study. Patients were informed that they would be called each month to obtain information about their health status over 6 months, to track their medication use, and to determine the presence of any side effects related to their medication. They were informed that information from the study would be shared with their practitioners, but that their information was protected through the guidelines of a confidentiality certificate through the National Institutes of Health 11 The questionnaire provides information about pain history, intensity, and location as well as the degree to which the pain interferes with daily activities, mood, and enjoyment of life. Scales (rated from 0 to 10) indicate the intensity of pain in general, at its worst, at its least, and pain “right now.” Test–retest reliability for the BPI reveals correlations of 0.93 for worst pain, 0.78 for usual pain, and 0.59 for pain now. Research suggests that the BPI has adequate validity.11The Brief Pain Inventory (BPI) is a well-known measure of clinical pain.35 Patients respond to each item on 0- to 10-point scales anchored with descriptors ranging from “no disability” to “total disability.” This measure has adequate internal consistency  and test–retest reliability (0.91) and is a valid measure of disability.35This inventory consists of 7 questions designed to measure the degree to which patients believe that their pain interferes with their functioning in family and home responsibilities, recreation, social activities, occupation, sexual behavior, self-care, and life-support (eating and sleeping) activity.37 Seven items assess anxiety, and 7 items measure depression, each coded from 0 to 3. The HADS has been used extensively in clinics and has adequate reliability (Cronbach Alpha = 0.83) and validity, with optimal balance between sensitivity and specificity.2 It has been translated into many languages and is widely used around the world in clinical and research settings.The Hospital Anxiety and Depression Scale (HADS) is a 14-item scale designed to assess the presence and severity of anxious and depressive symptoms.34 It has good psychometric properties with adequate reliability and validity and is associated with levels of pain, depression, and anxiety.The Pain Catastrophizing Scale (PCS) is a 13-item instrument that examines 3 components of catastrophizing: rumination, magnification, and helplessness. The PCS is found to predict levels of pain and distress among clinical patients, and scores have been related to thought intrusions.7 used to help determine risk potential for aberrant drug-related behavior. Items are rated from 0 = never to 4 = very often, and their sum is the total SOAPP-R score. The SOAPP-R has been shown to have good predictive validity, with an area under the curve ratio of 0.88 . Test–retest reliability was 0.71 with a coefficient alpha of 0.74. A cutoff score of 18 shows adequate sensitivity (0.86) and specificity (0.73) and has been cross-validated.4The Screener and Opioid Assessment for Patients with Pain-Revised (SOAPP-R) is a 24-item, cross-validated, self-administered screening instrument revised from the original SOAPP v.1Current Opioid Misuse Measure (COMM).5 The COMM is a 17-item self-reported questionnaire designed to assess current aberrant medication-related behaviors during opioid treatment. All items are rated from 0 = never to 4 = very often, with a total maximum score of 68. Construct validity has been shown to be adequate, with positive correlates with urine toxicology results (P < 0.05). Test–retest reliability was 0.86 with a 95% CI ranging from 0.77 to 0.92. The overall accuracy of the COMM for predicting current aberrant drug-related behavior, as measured by the area under the curve ratio, was 0.81 , and coefficient α (0.86) for the 17 items suggests adequate reliability. A cutoff score of 8 yielded a sensitivity of 0.75 and specificity of 0.65.Each month, patients were called and asked to complete the same items from the SEC over the phone. After 6 months, all subjects were asked to repeat the baseline measures of the BPI, HADS, Pain Disability Index and the Patients were paid $50 once the completed follow-up packet of questionnaires was received. Packets were resent if they were not received within a month of the mailing, and all patients were called to verify that they had received the second packet of questionnaires.t test) and nonparametric analyses (χ2 or Wilcoxon Signed Rank tests) were used to compare results depending on the variables, with 2-sided P values set at P < 0.05.Analyses were conducted using SPSS . Descriptive data for continuous variables were presented as mean values and SDs, and data for categorical variables were presented as percentages. Total scores and average values were calculated for the baseline measures and follow-up measures. Both parametric , 60.0% were women, and most were Caucasian (72.4%). Although most subjects had back or neck pain, only 8 percent reported having low back pain alone. A great majority of the patients (74.5%) reported having multiple pain sites. One hundred ninety-four (97.0%) of the patients reported taking prescription opioids at the start of the study. Six patients, who were initially not taking prescription opioids, were prescribed opioids for pain during the 6-month study trial. Of those patients prescribed opioids at baseline, 59.2% were prescribed short-acting opioids alone , 16.0% were prescribed extended-release, long-acting opioids alone , 24.5% were prescribed both short-acting and extended-release, long-acting opioids, 7.5% were prescribed tramadol, and 2.1% were prescribed buprenorphine and naloxone alone. Other nonopioid prescription medications and the number of subjects taking them included anticonvulsants , nonsteroidal anti-inflammatory drugs , antidepressants , muscle relaxants , and anxiolytics and sedatives . Four subjects were using lidocaine, one was using benadryl, and one was taking Marinol. We did not track intake of nonprescription medication.The frequency of reported medication side effects was averaged, for each patient, across the 6-month period. All patients were then grouped as “high” or “low” in medication side effects based on a median split (median = 2.33). The mean number of side effects was 2.85  over a 6-month period. Patients were divided based on a median split, and those reporting less than an average of 2.33 side effects were classified as having few side effects , and those reporting equal to or greater than 2.33 side effects each month were classified as having many side effects . As can be seen from Table Over time, reports of medication side effects tended to decrease, but differences in frequency of reported side effects from baseline to follow-up  were not significant. Dry mouth, constipation, sweating, headache, and weakness continued to be associated with taking prescription medication. The order of the frequency of the reported side effects remained similar between those with many side effects and those with few side effects, although those classified as having few side effects reported experiencing weakness, headache, and dizziness much less often.P < 0.05), disability (P < 0.05), catastrophizing (P < 0.01), and on the HADS anxiety subscale (P < 0.05) compared with those with low side effects. Patients with a higher frequency of self-reported side effects also scored significantly higher on the SOAPP-R , pain catastrophizing (P < 0.001), disability (Pain Disability Index P < 0.001), and opioid misuse , and most continued to report above average activity interference . At 6-month follow-up, those patients with chronic pain who reported a higher number of average side effects again tended to report significantly more activity interference compared with those who reported a lower number of side effects Table . Signifi30 However, all patients in this study had been taking opioids for over 6 months and would likely not report any euphoria related to taking pain medication. Instead, these findings seem to support an association of sensitivity to medications with functional limitations, mood disorder, and opioid misuse. These results also emphasize the importance of attending to patient reports of adverse effects from taking prescription medication as a prediction of future problematic outcomes. These findings are in agreement with studies using quantitative sensory testing which show that those who are hyperalgesic also are prone to misuse opioids.15 This study suggests that those with opioid misuse risk are sensitive to reactions of medications as well.This prospective secondary data analyses study was designed to determine how reports of medication-related side effects over 6 months were associated with disability, mood, and opioid misuse among patients with chronic pain on opioid therapy within primary care. Our main findings showed that patients who reported experiencing many side effects from their medication showed greater activity interference, negative affect, and greater catastrophizing than those reporting a lower number of side effects. Another important finding of this study was that patients who were more prone to misuse opioids reported more adverse effects of the medication. It might be predicted that those who would overuse or misuse opioids would report fewer side effects of opioids because they would like taking opioids, which is in agreement with past studies that show that opioid liking predicted misuse.29 those who report more medication-related side effects present with a disposition toward future problems. Patients with pain who have a significant mood disorder, who catastrophize, and who are more disabled due to their pain tend to ruminate about pain and may tend to focus on symptoms and experience helplessness when in pain. There is evidence that patients who demonstrate the most emotional distress are prone to be prescribed opioids for pain.24 It should also be pointed out that despite taking opioids for pain, many of the patients reported significant pain and disability. Past research indicates that those with greater negative affect tend not to benefit from opioids.36 Thus, the long-term benefit of prescribing opioid therapy for any patient who presents with high levels of medication-related side effects should be examined. However, contrary to our hypothesis, no differences were found in pain intensity between those who reported experiencing more medication-related side effects and those with fewer side effects. Thus, reports of side effects are not just related to reports of general hypersensitivity. Future studies are needed to help understand this negative finding.Most prescription medications have associated adverse effects, and it is common for users of opioids to report dry mouth, constipation, and itching, among other symptoms. However, these findings have clinical implications for assessment and treatment of patients with chronic pain in primary care. In agreement with findings among patients in specialty pain centers,14 there is support to suggest that these individuals may also have a heightened sensitivity to adverse reactions to medication. Future research may focus on objective assessment of differences in physical reactions to medications based on the level of catastrophizing.It is interesting that, in general, those who scored higher on the PCS reported a higher incidence of adverse effects to prescription medication. By definition, those who catastrophize and have recurrent worried thoughts tend to focus on symptoms and be hypervigilant to new sensations. Whether the higher incidence of reported side effects was related to heightened attention to physical symptoms or whether persons who tend to catastrophize have a physical predisposition that may make them more susceptible to adverse effects of medication needs to be addressed in future investigations. Because those who catastrophize have been found to be hyperalgesic based on quantitative sensory testing,27 Recent guidelines have encouraged increased emphasis on educating PCPs on issues of chronic pain and substance abuse.31 Although opioids will continue to be offered for acute pain management, there is less willingness to sustain patients on chronic opioid therapy. Centers for Disease Control (CDC) guidelines encourage risk assessment, periodic urine screens, consultation with prescription monitoring programs, opioid agreements, and frequent monitoring of all patients prescribed opioids for pain.9 As this study suggests, assessment of medication-related side effects would also be valuable as a predictor of future opioid misuse.1 Regular adherence monitoring by clinicians may further assist in preventing physical and psychological toxicity such as drug abuse and addiction.17There has been a recent change in attitudes among providers toward the use of chronic opioid therapy to treat noncancer pain. This has been particularly notable among younger primary care practitioners (PCPs).12 and by obtaining side effect reports before the subjects are prescribed opioids. Second, although this is a longitudinal study, we also cannot assume that the outcomes at 6 months followed a progression from baseline. Close monitoring with daily assessments might help to address this study limitation. Third, this study was conducted in an urban area in the northeast region of the United States, and it is uncertain whether these results might be affected by selection bias based on willingness to participate or by regional differences. Although some patients dropped out before completing the study, which could have contributed to selection bias, we did not find differences among those who completed the 6-month trial and those who did not. Fourth, the assessments were all self-report measures and objective measures of function or opioid compliance were not included. We did not capture the participants' duration of pain and the duration of using opioids. Although validated measures were used to assess opioid risk and misuse, the results were based on self-report. Future studies would benefit from results of urine toxicology screens and provider ratings of compliance. Also, many measures were included in the study, and it is possible that some results would be significant by chance alone. Finally, it should be noted that these results are correlational and do not assume causation.This study has a number of limitations that should be highlighted when interpreting these results. First, we did not relate the specific side effects to the specific drugs taken for pain, and we did not collect medication dosage. It is possible that those who reported more side effects were taking higher doses of medication. We also monitored side effects as either present or absent, and did not assess the intensity of each of the side effects that were experienced. It might be shown that the severity of the side effects may have more predictive power than the total number of the side effects experienced. It is also possible that some of the reported side effects may have already been present before taking opioids, and scores on the SEC may not represent adverse reactions only to prescription medications. Most of the items on the SEC represent somatic symptoms, and this checklist may well be measuring somatic complaints. Future investigations might consider teasing out this relationship by including measures that assess multiple physical symptomsDespite these limitations, the results of this study emphasize the importance of monitoring adverse effects of prescription pain medication and provide some insight into possible psychosocial risk factors of poor outcome in treating patients with chronic pain. This study is also notable because it is the first to demonstrate that primary care patients who report a greater number of side effects, possibly related to opioid use, may be at greater risk of medication misuse. Our study is one of the few that have been conducted to assess the relationship between opioid use, side effects, and psychosocial factors in primary care. Managing complex pain patients in primary care settings can be extremely challenging. PCPs typically have limited time, training, and resources to effectively evaluate patients with chronic pain. These findings have clinical implications that support the benefits of carefully monitoring reports of side effects of patients who are prescribed opioids in primary care centers. This might have a positive effect in reducing opioid misuse, although additional controlled trials are needed to empirically establish this effect.The authors have no conflicts of interest to declare.


Shoulder pain and pain in the upper abdomen are common complaints after laparoscopy, sometimes surpassing the pain at incision sites. The incidence of shoulder pain ranges from 35 to 80%. Post-laparoscopic pain is caused by retention of carbon dioxide in the abdomen, which irritates the phrenic nerve and diaphragm, causing referred pain in the shoulder and in the upper abdomen. A promising strategy to reduce this post-laparoscopic pain is the pulmonary recruitment maneuver, which indirectly increases intraperitoneal pressure and thereby facilitates removal of residual carbon dioxide. An alternative strategy is the infusion of intraperitoneal normal saline. With normal saline infusion, carbon dioxide rises and escapes through the port sites. In addition, normal saline offers a physiologic buffer system to dissolve excess carbon dioxide.2O. The trocar sleeve valves will be left open, so carbon dioxide can escape the abdominal cavity. With the patient in a neutral position the instruments are removed from the abdomen. In the control group, carbon dioxide is removed from the abdominal cavity at the end of surgery, with gentle abdominal pressure and passive exsufflation through the port sites, with open sleeve valves.This multicenter randomized controlled trial is conducted in two teaching hospitals in the Netherlands. Women between 18 and 65 years of age, with an ASA classification of I-II who are scheduled to undergo an elective laparoscopic procedure with benign gynecologic indication can participate. Following informed consent, participants are randomly allocated into two groups at the end of the surgical procedure. In the intervention group, the upper abdomen is filled with normal saline infusion with the patient in the Trendelenburg position. Then the anesthesiologist performs a standardized pulmonary recruitment maneuver with a pressure of 40 cm HThe primary outcomes are the incidence and intensity of post-laparoscopic pain in the shoulder, upper abdomen and at the operation sites, at 8, 24 and 48 h after surgery. Secondary outcomes are postoperative use of analgesics, nausea, vomiting and pulmonary complications.This study may reduce post-laparoscopic pain in women undergoing laparoscopy.NTR4812.Dutch trial register, number  Laparoscopic surgery has become a common surgical practice. It is associated with a shorter hospital stay, earlier return to daily activities and work and improved cosmetic results compared with open procedures . DespiteSometimes this post-laparoscopic shoulder pain surpasses the pain at the incision site . NowadayThe cause of post-laparoscopic pain is not fully understood. Several factors may contribute to this pain. Rapid distention of the peritoneum may result in traumatic traction on blood vessels and nerves with inflammatory mediator release and phrenic nerve neuropraxia –11. TherTwo promising strategies to reduce post-laparoscopic pain after gynecological surgery are mentioned in the literature , 19, 20.We propose a randomized controlled trial to study the effect of a combination of intraperitoneal saline and the pulmonary recruitment maneuver on the incidence and intensity of post-laparoscopic pain in Dutch women.The aim of this study is to assess the incidence and intensity of post-laparoscopic pain in the shoulder, upper abdomen and at the operating site 8, 24 and 48 h after elective gynecologic laparoscopic surgery with benign indication. This study will also evaluate postoperative use of analgesics, occurrence of nausea and vomiting and pulmonary complications.This study is a randomized controlled trial and will be performed at the Maastricht University Medical Center, a university hospital in the Netherlands, and at Máxima Medical Center Veldhoven, a tertiary teaching hospital in the Netherlands.The study is conducted according to the principles of the Declaration of Helsinki and in accordance with the Medical Research Involving Human Subjects Act (WMO) and has been approved by the ethics committee of Máxima Medical Center . The protocol is registered in the Dutch Trial register, number NTR4812.The trial will be conducted without any funding sources.Women between 18 and 65 years of age with an American Society of Anesthesiologists physical status classification of I-II (ASA classification) who are scheduled to undergo an elective laparoscopic procedure, with a benign gynecologic indication, can participate in the trial.The first exclusion criterion is daily use of analgesics because postoperative use of analgesics is a secondary outcome. The next exclusion criterion is allergy/intolerance to nonsteroidal anti-inflammatory drugs (NSAIDs), as these are the standard postoperative analgesics used. Emphysema and chronic obstructive pulmonary disease (COPD) are also exclusion criteria for the pulmonary recruitment maneuver is used. A midline laparotomy in the medical history is another exclusion criterion, as this is often a reason to perform an open laparoscopy and it increases the risk of conversion to laparotomy. The last exclusion criterion is poor understanding of the Dutch language. This was deemed necessary because we make use of questionnaires written in Dutch.Eligible patients are identified by the gynecologist or the resident in one of the two participating hospitals. Women eligible for the trial will be counseled by experienced research nurses or researchers. They will be informed about the aims, methods, reasonably anticipated benefits and potential hazards of the study. After a week patients will be asked if they want to participate and informed consent will be collected. By giving written informed consent, patients agree to participate and agree that their anonymous data may be used for publication.Randomization will be performed by using sealed envelopes and will take place just before the end of the surgery.The study is blinded for patients, but not for the gynecologist, as the gynecologist is the one who will leave normal saline intraperitoneal when necessary. Because this study is a multicenter trial, randomization will be stratified by hospital to get an equal distribution of patients between the two groups (control and intervention) per hospital. For randomization we used an Excel sheet that randomly assigned 200 patients  to either the intervention or control group. Data handling will be done anonymously and the date code is only available to the local investigator. The baseline data and follow-up data collection at both hospitals is the responsibility of the two local investigators. Data will be stored in a sealed, anonymous files.The dataset supporting the conclusions of this article will be available upon request. In accordance with the guidelines of the Dutch Federation of University Medical Centers (NFU), the data will be kept for 15 years.2O (pulmonary recruitment maneuver) will be given. The fifth positive pressure inflation will be held for 5 sec. The trocar sleeve valves will be left fully open during this procedure, so the carbon dioxide can escape the abdominal cavity. Hereafter the patient is placed in a neutral position and the instruments are removed from the abdomen.In the intervention group, the patient will be placed in the Trendelenburg position of 30 degrees at the end of the laparoscopic procedure. An intraperitoneal saline infusion of 15–20 ml/kg will be administered evenly and bilaterally by the operating gynecologist. The anesthesiologist will perform the pulmonary recruitment maneuver after the saline infusion. Five pulmonary insufflations with a pressure of 40 cm HIn the control group, the carbon dioxide is removed from the abdominal cavity at the end of surgery, with gentle abdominal pressure and passive exsufflation through the port sites with the sleeve valves open.Primary outcomes are the incidence and intensity of post-laparoscopic pain in shoulder, upper abdomen and at the operating site at 8, 24 and 48 h after surgery, which are measured using the Visual Analogue Scale (VAS). Secondary outcomes are postoperative use of analgesics, nausea, vomiting and pulmonary complications. We will record patient characteristics ) and operative details .The two primary outcomes of our study are the incidence of pain and the intensity of pain using the VAS score. In accordance with Tsai et al. , we haveData will be analyzed according to the intention–to-treat principle. Statistical analysis will be performed using the software Statistical Package for the Social Sciences 22.Categorical variables will be described as frequencies and percentages. Continuous variables will be described in terms of means with standard deviation if normally distributed, and otherwise as a median with an interquartile range (IQR). Significance will be tested two sided with an α-level of 0.05. Patients will be classified as either having pain or not having pain using the questionnaires the patients fill in after surgery. To compare the incidence of pain between the intervention and control groups, the Pearson’s Chi-squared statistic will be used. For those patients experiencing pain, the average pain scores between groups will be compared. T-tests for pain scores will be used when the scores are normally distributed.After randomization we included 56 patients in the control group and 71 patients in the intervention group. The unequal randomization was caused by using the incorrect method, as we should have used a block randomization method. To correct the unequal distribution, we requested an amendment which was approved by the ethics committee. We wanted to include 200 women, resulting in 100 women in each arm. To reach this number of inclusions, we had to include an additional 29 women in the intervention group and an additional 44 women in the control group.In light of the increasing number of laparoscopic interventions , the sho


Post-treatment pain has been suggested as an important indicator for health-related quality of life (HRQOL) in patients with breast cancer. Therefore, this study was performed to examine the association between pain and its impact on HRQOL among breast cancer patients in Palestine. Also, this study aimed to determine the QOL profile for breast cancer patients and stated the factors associated with QOL.A correlational cross-sectional study was conducted from May 2016 to November 2016 at Al-Watani Hospital and An-Najah National University Hospital in the Nablus district in Palestine. The five-level EuroQol five-dimensional instrument (EQ-5D-5L) was used to examine HRQOL. Pain severity and interference were assessed using the Brief Pain Inventory (BPI). Multiple linear regression analysis was performed to determine the most important variables related with HRQOL.p value < 0.001), and pain interference score . Furthermore, univariate analysis showed that age, marital status, employment status, income, current condition of cancer, and post-treatment pain were associated with quality of life . Regression analysis revealed that patients with high income , patients with lower pain severity score , and lower pain interference score  were independently associated with high QOL.One hundred and seventy patients were involved in this study. Overall, all participants were female, with a mean ± SD for age of 51.71 ± 11.11 years. The reported HRQOL of this study was measured by using the median EQ-5D-5L index score, which was 0.67 (interquartile range: 0.51–0.84). There were moderate negative correlations between EQ-5D-5L index score and pain severity score (r = − 0.58, This is the first study to present important data regarding QOL by using the EQ-5D-5L instruments that may help healthcare providers to identify patients at risk of low QOL. Healthcare providers and health strategy makers should be alerted to low level HRQOL among breast cancer patients with low income level, patients with post-treatment pain, especially in the state of severe pain, and the state of pain interfering with daily life to improve their HRQOL. Breast cancer refers to a malignancy in women and in a small percent in men, which arises from the epithelial tissue of the breast tissue, representing approximately 10% of the total volume of the breast . Breast In Palestine, cancer is the second most common cause of death, accounting for about 14.2% of all deaths in 2014, meaning that they are very common . AccordiThis cross-sectional study was conducted by using standardised and validated assessment tools in women with breast cancer from May 2016 to November 2016.This study was conducted in Al-Watani hospital and An-Najah National University hospital, Nablus, West Bank, Northern Palestine. These two hospitals serve as the main referral hospitals for the northern districts of West Bank-Palestine and receive most cases of breast cancer patients from all northern West Bank districts.The medical records of both hospitals in 2015 showed that the number of breast cancer patients in both hospitals was around 600 patients in 1 year and around 300 patients during the period of study. Each of both hospitals where study was conducted gave us a list with the names of breast cancer patients in order to assess their comfort for this study.http://www.raosoft.com/samplesize.html) was used for sample size calculation. We assumed that 50% of women with breast cancer had a high QOL, which would give the maximum sample size. Furthermore, we used a 5% margin of error at a 95% confidence interval as recommended; the required sample size was calculated to be 170 women. Convenience sampling was used to recruit participants.The Raosoft sample size calculating tool .The second section contained patient clinical data such as type of breast cancer, stage of breast cancer, duration of disease, and the types of management that the patient had undertaken.The third section was based on the assessment of post-treatment pain and discomfort among breast cancer patients by using a well-known pain-measuring scale which is called the Brief Pain Inventory scale (BPI); . The BPIThe fourth section consisted of the EQ-5D instrument to assess HRQOL. EQ-5D is a widely used instrument for evaluation of the generic quality of life . EQ-5D iThe data collection form consisted of four sections:Academic experts  reviewed and evaluated measurement items for face and content validity, and clinical accuracy. Data collection forms were administered to participants face-to-face by two medical students. These researchers received training in investigation skills and research ethics at the College of Medicine and Health Sciences and from epidemiologists with expertise in quality of life research. In order to insure interviewer consistency, both of the interviewers interviewed the participants closely with each other. The data collection form was piloted on 15 patients  to assess questionnaire comprehension, clarity, and completion time. The results of the pilot study were evaluated critically and some minor modifications were made accordingly for socio-demographic and clinical data.The Institutional Review Board (IRB) of An-Najah National University (#20Mar2016) approved the study. Permission was obtained from the two selected hospitals for allowing researchers to interview their patients.Analysis of data was done with the IBM Statistical Package for Social Sciences . Continuous variables were presented mainly as mean ± SD or medians (lower–upper quartiles), and categorical variables were both expressed as frequency and percentage. Normality of continuous data was checked by the Kolmogorov–Smirnov test. Continuous variables such as the EQ-5D-5L index score was tested for intra-individual differences by using the Kruskal–Wallis or Mann–Whitney test, as required. In addition, the Spearman correlation coefficient was used to assess the degree of association between all scales. The significance level was determined at a p-value < 0.05. Multiple linear regression analysis was also used to determine independent associations with HRQOL. Variables  that were significant in bivariate analysis were entered into regression models. Cronbach’s alpha was assessed for each scale to check the scale’s internal consistency reliability.One hundred and eighty-three patients were interviewed, and the response rate was 92.9%. In total, 170 patients  with breast cancer were recruited for the study. Of these, 67 (39.4%) patients were aged between 50 and 59 years old. Ninety-one (53.5%) participants lived in villages and 132 (77.6%) were married. More than 80% of the participants were housewives, and 75 (44.1%) participants lived in families with a moderate income level. The socio-demographic data of the study participants are listed in Table As shown in Table The median pain severity score was 14.50 (interquartile range: 8.00–21.25), and the median pain interference score was 17.00 (interquartile range: 9.00–30.00). Reliability values for these two subscales were good .The reported HRQOL of this study was measured by using the median EQ-5D-5L index score, which was 0.67 (interquartile range: 0.51–0.84). Cronbach’s alpha for the EQ-5D-5L scale was 0.824, indicating satisfactory internal consistency. The distribution of participants with answers of no problem across the dimensions of EQ-5D was as follows: mobility 66 (38.8%), self-care 107 (62.5%), usual activities 87 (51.2%), pain/discomfort 44 (25.9), and anxiety/depression 81 (47.6%); . Also, there was significant moderate negative correlation between pain interference score and EQ-5D-5L index score . This study showed a moderate negative correlation between EQ-VAS score on the one hand with pain severity score  and pain interference score  on the other. Also, the study showed a moderate positive correlation between EQ-5D-5L index score and EQ-VAS score .Regression analysis, using QOL score as a dependent variable and the covariates of age, marital status, employment status, income, current condition of cancer, pain severity score, pain interference score, and post-treatment pain as independent variables revealed that patients with high income , patients with lower pain severity score , and lower pain interference score  were independently associated with high QOL. The factors significantly associated with QOL according to multiple linear regression analyses are summarised in Table This study provided an inclusive measurement of HRQOL between breast cancer patients in Nablus, Palestine. In our study, EQ-5D QOL instrument was applied to measure HRQOL. Overall, the main socio-demographic factors related to breast cancer HRQOL were old age, being a housewife, low income, being single, an active or recurrent tumour and post-treatment pain. According to the literature, EQ-5D was also used to assess HRQOL among breast cancer patients in different countries –35. EQ-5In our study, the EQ-5D score median among breast cancer survivors in Palestine was 0.67 (interquartile range: 0.51–0.84); this compared to other studies which used the same instrument in Iran, Holland and Sweden, with the following results: 0.69 ± 0.22 , 0.72 ± According to our results, increased age was associated with lower HRQOL among breast cancer patients. Similarly, many previous studies concluded the same findings . One of One possible explanation is that older patients age, as the disease progresses, and will experience a poor social life with an increased rate of depression and physical inactivity, which could lead to high pain and fatigue level and thus lower QOL scores . This obOur data showed in relation to marital and financial status that being single and having a low income level were significantly associated with poor QOL (i.e. lower EQ-5D scores). Low income level was also confirmed as being an important factor related to impaired HRQOL among breast cancer patients in other studies . AnotherAccording to our study, current breast cancer condition was significantly related to impaired HRQOL in breast cancer patients. Patients experiencing recurrent cancer or undergoing active cancer treatments reported a lower HRQOL than those who are cancer-free. These findings could be explained by the suggestion that receiving breast cancer treatment will induce post-treatment pain which interferes with patients’ functioning and quality of life , 46, 47.Post-treatment pain in breast cancer patients remains clinically especially during the first few years following treatment , 49. ManIn this study, we found that post-treatment pain was significantly associated with low levels of HRQOL. Patients who experienced pain after breast cancer treatment reported lower EQ-5D scores. These findings were confirmed by the results of Kroenke and Theobald . Many stThis study has many strong points in that it is the first study about HRQOL among breast cancer patients conducted at West Bank in Palestine; also, the information was gathered by face-to-face interviews to get more reliable and complete data. Also, the current study measured the impact of pain on HRQOL by using the global BPI and EQ-5D scales. However, in our study, we found a number of limitations that should be focused on. One of these limitations, the cross-sectional study type of this study, may prevent us from developing a good cause—effect relationship between post-treatment pain and HRQOL. Another limitation is that this study was held in Nablus city, which represents only one section of the entire Palestinian West Bank. Lastly, gathering study data via a face to-face interviews may have a negative outcome as the researchers can influence participant’s answers, leading to less reliable data.This is the first study to present important data regarding QOL by using the EQ-5D-5L instruments that may help healthcare providers to identify patients with breast cancer who are at risk of low QOL. Our current study identified a number of significant associated factors that should be considered when dealing with breast cancer patients. Breast cancer patients with high pain severity, higher degrees of pain interference, and low income levels all reported with poor HRQOL. Our findings are likely to be important for educators, doctors, and clinics dealing with breast cancer patients. Healthcare providers and policy makers have to be alerted to the low QOL in patients with a low income level, and in patients with post-treatment pain, especially those in a state of severe pain and state of pain interfering with daily life, in order to improve their HRQOL.


Serum anti-HBc levels increased significantly along with the increasing histology activity index (HAI) score. After antiviral-treatment, patients with HAI score reduction had significant decline in serum anti-HBc level. Multivariate analysis showed that anti-HBc was independently associated with moderate-to-severe hepatic inflammation in patients with normal ALT level. Furthermore, serum anti-HBc showed a high diagnostic accuracy for predicting moderate-to-severe inflammation in both hepatitis B e antigen (HBeAg)-positive and HBeAg-negative CHB patients with normal ALT levels . Thus, anti-HBc may be a strong indicator for assessing the hepatic inflammatory degree and used for antiviral treatment decisions in CHB patients with normal ALT levels.Our previous studies unexpectedly indicated that the level of serum hepatitis B core antibody (anti-HBc) was positively correlated with the serum alanine aminotransferase (ALT) level. The aim of this study was to determine whether anti-HBc could serve as a potential biomarker for the detection of liver inflammation in chronic hepatitis B (CHB) patients, especially in patients with normal ALT levels. Serum anti-HBc levels were quantified in 655 treatment-naïve CHB patients, including 45 patients who underwent two liver biopsies (baseline phase and the 78 In the progression of chronic hepatitis B (CHB), the persistent inflammation burden of the liver is not only the main risk factor for the development of liver cirrhosis and hepatocellular carcinoma (HCC), but it also leads to ineffective HBV clearance5. Clinically, serum alanine aminotransferase (ALT) has been widely used for evaluating the severity of hepatic inflammation in liver disease. However, numerous studies have reported that some CHB patients with normal ALT levels have severe liver damage and require antivirus treatment according to current guidelines7. Therefore, the accurate assessment and monitoring of the severity of liver inflammation plays an important role not only in the control of disease progression, but in the therapy decision for patients with normal ALT levels.HBV is not cytopathogenic and is indirectly involved in the occurrence of hepatocyte damage and necroinflammation by immune-mediated responses10. Patients with high baseline anti-HBc levels had a significantly higher response than patients with low baseline anti-HBc level. Furthermore, our previous studies also suggested that the anti-HBc level was positively correlated with ALT and that the proposed serum anti-HBc level could be a potential biomarker for hepatic inflammatory activity in CHB patients9. However, no direct evidence has reported.Recently, quantitative antibodies to hepatitis B core antigen (anti-HBc) levels have been reported to predict the treatment response for CHB patients receiving antiviral therapiesTherefore, we aimed to determine whether serum anti-HBc could serve as a potential biomarker for the detection of the severity of liver inflammation, and used for antiviral treatment decisions CHB patients with normal ALT levels.655 CHB patients were enrolled in the cohort study, which included 404 hepatitis B e antigen (HBeAg) -positive (HBeAg [+]) and 251 HBeAg-negative (HBeAg [+]) CHB patients. In 98 HBeAg (+) patients with normal ALT levels, 35 (35.7%) patients had at least moderate inflammation, and 33 (33.7%) had significant fibrosis. In 95 HBeAg (−) patients with normal ALT levels, 35 (36.8%) patients had at least moderate inflammation, and 30 (31.6%) had significant fibrosis. The CHB patient’s characteristics at the time of liver biopsy are summarized in Table P < 0.001 by ANOVA)  .In the HBeAg (+) CHB patients, serum anti-HBc levels increased significantly along with the increasing histology activity index (HAI) score  Fig. . In the 05) Fig. . SpearmaP < 0.001), whereas there was no significant difference in the anti-HBc level between fibrosis stage score more than 2  and HBeAg (−) patients  undergoing second liver biopsies after 78 weeks of antiviral-treatment were further analyzed. The levels of serum anti-HBc decreased in accordance with the alleviated histological inflammation, and the levels were significantly different between the baseline and 78th week) , suggested that serum anti-HBc levels were positively correlated with severity of hepatic inflammation in the longitudinal cohort study.As shown in Fig. P = 0.01 and 0.311 P < 0.01; respectively), whereas that was no significance in patients with normal ALT levels  and patients with 1 × ULN < ALT ≤ 2 × ULN . Nevertheless, in both HBeAg (+) and HBeAg (−) CHB patients, the correlation between serum anti-HBc and HAI score in patients with normal ALT levels  and patient with ULN < ALT ≤ 2 × ULN  were much better than that in patients with ALT >2 × ULN   and HBeAg (−) patients, serum ALT levels were significantly correlated with HAI score in patients with ALT >2 × ULN  and HBeAg (−) CHB patients , HBV DNA  and TBil  could be used to independently predict moderate-to-severe inflammation  CHB patients, the serum levels of HBsAg, HBV DNA, anti-HBc, AST, GGT, TBil and platelet counts were significantly correlated with moderate-to-severe inflammation based on the univariate analysis, whereas the multivariate logistic regression analysis indicated that the anti-HBc  was an independent predictors of moderate-to-severe inflammation (Table In HBeAg (−) CHB patients, the univariate analysis identified anti-HBc, AST and GGT were significantly associated with moderate-to-severe inflammation. The multivariate analysis indicated that only anti-HBc  CHB patients, the AUC of anti-HBc for the prediction of moderate-to-severe inflammation was 0.75. The optimal cut-offs of anti-HBc was 4.47 log10 IU/mL with a maximizing the sum of sensitivity and specificity and 5.00 log10 IU/mL with a specificity of 95%.ROC curves were created to evaluate the diagnostic efficiency of serum anti-HBc for differentiating between mild or no inflammation and moderate-to-severe inflammation in CHB patients with normal ALT levels. As shown in Fig. 10Anti-HBc IU/ml) − (0.345 × log10HBV DNA IU/ml) + (0.134 × TBil IU/ml) −9.008. However, the addition these variables to anti-HBc did not improve its diagnostic efficiency.It is worth noting that the AUCs of AST and GGT were significantly less effective than anti-HBc for differentiating mild or no inflammation from moderate-to-severe inflammation. Furthermore, the combination index was constructed to explore whether considering HBV DNA and TBil to anti-HBc levels in addition to anti-HBc would lead to a better diagnosis of HBeAg (+) CHB patients with moderate-to-severe inflammation using binary logistic regression. The best formula for predicting moderate-to-severe inflammation was  and HBeAg (−) CHB patients with normal ALT levels .4. The latest guidelines suggested that early control of developing liver inflammation should be the priority for the detection of liver fibrosis11. Thus, accurate evaluation of the initial stage of liver inflammation and progression over time represents a high priority and growing medical need. To date, percutaneous liver biopsy followed by histological analysis remains the gold standard for evaluating the severity of liver injury. Because it is a costly and invasive procedures with inherent risks, the clinical use of this diagnostic method has been restricted13. Over the past decades, several non-invasive methods have been developed or are being validated, especially the diagnosis of liver fibrosis15. However, there have been few novel markers for assessing the severity of liver inflammation. In clinical practice, serum ALT is an easily accessible surrogate parameter and is commonly used for monitoring the state of liver inflammation16. The present study indicated that approximately 36.6% (70/193) of CHB patients with normal ALT levels have moderate-to-severe hepatic inflammation  should be considered for antiviral therapy immediately11. Thus, use of ALT could be weakness in assessing liver injury and may underestimates the proportion of patients who urgently need antiviral therapy in patients with normal ALT levels. Recent studies have noted the possibility of lowering ULN to 30 IU/L for men and 19 IU/L for women18. However, the majority of countries in Asia including China, still use an ALT of 40 IU/ml as ULN19. The results of our study may provide support for decreasing the ULN of ALT in Chinese patients, and reducing the portion of patients with moderate-to-severe hepatic inflammation.Active significant hepatic inflammation is the main risk factor for developing cirrhosis and HCC in CHB patients21. In this study, serum anti-HBc levels were not only correlated positively with the severity of liver inflammation in baseline of total patients, but decreased along with alleviated histological inflammation in CHB patients receiving antivirus treatment. Furtherly, we analyzed the correlation between HAI score and serum anti-HBc, ALT in CHB patients, and the results indicated that serum anti-HBc was better than ALT in correlation with severity of liver inflammation in patients with ALT ≤2 × ULN, especially in patients with normal ALT levels  based on the multivariate analysis  is the most immunogenic HBV antigen, and its antibody, anti-HBc secreted via the activated antibody-secreting B cells directly play an important role in the severity of chronic hepatitis B by hepatocytotoxic response22. Furthermore, Li et al. found that circulating CXCR5+CD4+ T cells can help naïve B cells to produce anti-HBc via IL-21 in patients with chronic HBV infection24. The percentage of circulating CXCR5+CD4+ T cells was positively correlated with serum levels of ALT and AST, suggesting that the frequency and phenotype of CXCR5+CD4+ T cells is associated with HBV-related liver damage25. Therefore, we hypothesized that the anti-HBc could play an important role in liver inflammation of CHB patients through the hepatocytotoxic effects of anti-HBc-secreting B-lymphocytes. Anti-HBc may be a strong indicator for liver damage during a certain cellular immune response in CHB patients, and further studies on the mechanism of anti-HBc involvement hepatocellular injury will be worthwhile.In the present study, we are first to report that increasing levels of serum anti-HBc were independently associated with moderate-to-severe hepatic inflammation in both HBeAg (+) and HBeAg (−) CHB patients with normal ALT levels (odd ratio = 4.78 s Tables  and 4. T10 IU/mL (which was established by maximizing the sum of sensitivity and specificity). And using anti-HBc specific high cut-off of 4.67 log10 IU/mL (which established by obtaining a specificity of at least 95%), 95.24% of the patients with mild or no inflammation (PPV 85.71%) were correctly excluded. In HBeAg (+) patient with normal ALT levels, using anti-HBc specific low cut-off value of 4.47 log10 IU/mL, 67.47% of the patients with moderate-to-severe inflammation were correctly distinguished. 95% of the patients with mild or no inflammation (PPV 75%) were correctly excluded using the cut-off of 5.00 log10 IU/mL. Therefore, to evaluate liver inflammation caused by HBV infection, the measurement of serum anti-HBc levels may provide accurate evidence to determine the antiviral choice in patients with normal ALT levels.In HBeAg (+) CHB patient with normal ALT levels, 81.63% of the patients with moderate-to-severe inflammation were correctly identified using anti-HBc specific low cutoff value of 4.47 logIn conclusion, we are the first to demonstrate that serum anti-HBc is significantly corrected with hepatic inflammation in CHB patients with normal ALT. Serum anti-HBc is a promising noninvasive clinical biomarker that exhibits a high diagnostic accuracy for moderate-to-severe hepatic inflammation in patients with normal ALT levels.A total of 655 consecutive treatment naïve patients with chronic HBV infection who underwent liver biopsy in 24 teaching hospitals located in mainland of China were enrolled into this study between October 2013 and February 2016. Patients recruited in the cohort study met the following criteria: (1) age 18–75 years; (2) HBsAg seropositive status beyond 6 months; (3) treatment naïve; (4) negative serum levels of anti-HAV IgM, anti-HCV, anti-HEV IgM/IgG, anti-EBV IgM, and anti-CMV IgM; and (5) off potential transaminase-lowering agents such as bicyclol for at least 2 weeks prior to blood sampling biochemistries. Exclusion criteria for this study included overlapping etiologies for hepatitis including HCV, human immunodeficiency virus (HIV), alcohol abuse, autoimmune, genetic, drug-induced and nonalcoholic fatty liver disease. Patients with decompensated cirrhosis or hepatocellular carcinoma were also excluded.Additionally, of the aforementioned 655 patients, 45 CHB patients who underwent second liver biopsies after 78 weeks of antiviral-treatment were also enrolled.clinicaltrials.gov (NCT01962155) and chictr.org (ChiCTR-DDT-13003724).All patents provided written informed consent for the scientific use of their clinical data and sample. The study was approved by the local ethics committee of Peking University First Hospital, and all methods were performed in accordance with the relevant guidelines and regulations. The complete protocol for the clinical trial has been registered at 26. Disease activity grade was staged using the modified histology activity index (HAI), and hepatic fibrosis was assessed using the Ishak fibrosis score. For analysis, HAI ≥ 5 was considered moderate-to-severe inflammation, and F ≥ 3 was considered significant fibrosis28.Ultrasonographic-guided liver biopsies with a length ≥20 mm were routinely performed on all patients according to a standardized protocol after receiving the patient’s written informed consent. Pathological assessments were conducted in the Department of Pathology at the You-An Hospital affiliated with Capital Medical University. Each section was blindly and independently assessed by 2 pathologists. When discrepancies occurred, the samples were reviewed by experienced pathologists who were also responsible for reassessment in a randomly selected 10% of samples1–1.7 × 108 IU/ml) were measured via a COBAS AmpliPrep/COBAS TaqMan method as previously described29.At the time of liver biopsy, biochemical tests, blood cell and coagulation tests were performed using routine automated analyzers. Serum levels of hepatitis B surface antigen (HBsAg) and hepatitis B e (HBeAb) were quantified using commercially available enzyme immunoassays . Serum HBV DNA levels . Quantitative variables were expressed as the mean ± standard deviation (SD). The chi-square test was used to analyze relationships between categorical variables, and Student’s P < 0.05 (two-tailed).The diagnostic abilities of anti-HBc and combination between anti-HBc and different variables were evaluated based on the estimated ROC curves and by calculations of the sensitivity, specificity, positive predictive values (PPV) and negative predictive value (NPV) for cut-off values. Statistical significance was defined as Supplementary Information


Traditionally, laparoscopic procedures have been performed under general anesthesia. Spinal anesthesia is an effective alternative to general anesthesia. However, one of the intraoperative complications of performing laparoscopic surgery under spinal anesthesia is shoulder pain. This study aimed to compare the effect of transcutaneous electrical nerve stimulation (TENS) with fentanyl on pain relief in patients who underwent gynecologic laparoscopy under spinal anesthesia.  We conducted a prospective randomized clinical trial from May 2016 to March 2017. A sample of patients who underwent gynecological laparoscopy under spinal anesthesia was recruited. If they had shoulder pain, they randomly received either transcutaneous electrical nerve stimulation (TENS) or 50 mg of fentanyl. Pain intensity was measured using the single item visual analogue scale (VAS-10 cm) immediately before and 5, 10, 20, and 30 minutes after treatment. Also, the effect of higher doses of analgesia on pain relief was analyzed. P = 0.80). Repeated measures analysis of variance indicated that there was no significant difference on overall pain scores between the two treatment groups adjusted for age, BMI, total analgesia used, and baseline pain score  = 1.44, P = 0.23). The use of analgesic drugs in the TENS group was significantly higher than the fentanyl group (P = 0.01). In addition, we found that nine patients (22.5%) complained of nausea/vomiting in the TENS group compared to thirteen patients (32.5%) in the fentanyl group (P = 0.31).  In all, 80 patients (40 patients in each group) were entered into the study. The mean pain intensity score was 9.02 ± 1.32 in the TENS group and 8.95 ± 1.33 in the fentanyl group at baseline (IRCT2016031216765N3. The findings indicated that TENS was not superior to fentanyl for pain relief in laparoscopic surgery. It seems that the correct use of TENS parameters might merit further investigation. This trial is registered with:  Although general anesthesia is a choice for laparoscopic surgeries, regional anesthesia provides more benefits over general anesthesia , 2. SpinDifferent procedures have been evaluated in several studies to relieve shoulder tip pain in laparoscopy under spinal anesthesia . A numbeCurrently, there are several treatment procedures for relieving acute pain during gynecologic laparoscopy. These include nerve blocking, drug therapy (narcotic medication such as fentanyl), and bioelectric therapy . Of these, nerve blocking is an invasive approach and is difficult to perform; using narcotics is associated with some complications. Yet, TENS is a safe and effective technique and could reduce postoperative analgesic consumption , 20, 21.IRCT2016031216765N3).A prospective open parallel group randomized clinical trial was conducted at a teaching hospital, affiliated to Tehran University of Medical Sciences from May 19, 2016 to March 19, 2017. The study was approved by Ethics Committee of Tehran University of Medical Science (ID: 1394.2139) and was registered at Iranian Registry of Clinical Trials . Written informed consent was obtained from all participants.The surgical procedures included gynecological laparoscopy under spinal anesthesia. Spinal anesthesia was performed with a 25G spinal needle and after free flow of cerebrospinal space fluid. 4 ml (20 mg) of bupivacaine 0.5% was injected into L2-L3/L3-L4 subarachnoid at a rate of 0.1 ml/s. We operated all patients with pneumoperitoneal pressure up to 10 mmHg. In preoperative visit, the anesthesiologist explained the patients that any pain or discomfort occurring during surgery would be treated with intravenous medications or TENS. Patients were asked to inform the nurse anesthetist when they experience pain. The extra analgesic drug was 50 mg fentanyl and was administered intravenously.In the TENS group, 4 pads of the device with size of 4 × 10 cm and at the distance of 5 cm are adhered in the zone of scapula and behind both shoulders. TENS parameters were pulse frequency of 16 Hz and pulse width of 150 microseconds . After spinal anesthesia, TENS device was turned on for 20 minutes for patients who complained of pain. Pulse amplitude was increased and adjusted according to patient's tolerability by the nurse (the highest level that did not make patients uncomfortable). The electrical impulse was applied up to 20 minutes for patients who complained of pain.In the fentanyl group, 50 milligrams (mg) of intravenous fentanyl was injected.TENS or fentanyl were administered during surgical procedures when patients experienced unbearable pain and requested pain relief.The primary outcome of the trial was shoulder pain relief. Pain was measures using a visual analogue scale (VAS). The pain VAS is a continuous scale comprised of a horizontal (HVAS) or vertical (VVAS) line, usually 10 centimeters (100 mm) in length, anchored by 2 verbal descriptors, one for each symptom extreme . A nurseThe secondary outcome was amount of extra analgesic use and nausea and vomiting. The former was measured on the basis of total usage of fentanyl (mg) while the latter was indicated by the patients.Patients were randomized in 1 : 1 ratio to receive TENS or fentanyl. Allocation sequence was done using a computer-generated randomization chart by the coordinating investigator of research center at hospital. Permuted block randomization with a block size of six was used.Sample size was estimated according to the VAS score as a primary outcome. A repeated measures design with one between-subjects factor (intervention groups) and one within-subjects factor (times of recording) needed 40 patients per each intervention groups  in order to achieve 80% of power to detect average differences of 1 score in VAS in two treatment groups (an effect size of 0.23). The standard deviation of the VAS score in each treatment groups was assumed to be 4 and equal in both treatment groups. All above calculation assumed significance level of 0.05.t-test and chi-square were applied to compare baseline characteristics and side effects among groups. The primary outcomes  were analyzed using repeated measures analysis of variance. The model included treatment as fixed factor and age, BMI, analgesia usage, and baseline VAS score as covariates. All statistical analysis was performed using Statistical Package for the Social Sciences  version 18, and P value of <0.05 was considered statistically significant.The analysis was by intention-to-treat and included all patients who were randomly assigned. Categorical and continuous variables were summarized as proportions and mean ± standard deviation, respectively. Student's P = 0.80). However, a significant difference was observed at 5-minute evaluation indicating that fentanyl was more effective in reducing pain severity (P < 0.001) while at 30-minute assessment the TENS showed a significant superiority (P = 0.008). The results are shown in At baseline, the mean pain intensity level was 9.02 (SD = 1.32) in the TENS group while in the fentanyl group it was 8.95 (SD = 1.33) indicating no significant differences between the two groups (P = 0.013). In addition, in the TENS group, nine patients (22.5%) complained of nausea/vomiting compared to thirteen patients (32.5%) in the fentanyl group (P = 0.31).Further analysis showed that the overall analgesia usage was significantly higher in the TENS group than the fentanyl group  = 1.44, P = 0.23).Finally, comparing pain severity in different assessment points by performing repeated measures analysis of variance indicated no significant differences on overall VAS scores between treatment groups adjusted for age, analgesia usage, BMI, and baseline pain score  reported complains of shoulder pain in five patients . In addiUsing more opioids might be both costly and harmful to patients. Thus, the current randomized trial was an attempt to either reduce the use of fentanyl or if possible replace it with TENS, although we could not show that TENS was superior to fentanyl. Several explanations could put forward to justify the results. First, we studied intraoperative pain and stimulator of pain continued up to the end of the study. Thus, TENS was not effective as expected. Secondly, it could be due to the fact that the maximum effect of TENS possibly can be obtained in long term while patients usually could not tolerate the pain and therefore ask for more analgesia. Thirdly, we compared TENS with a very powerful analgesic drug (fentanyl) and thus could not see any superiority for the TENS group. Finally, as we know, the mechanism of pain relief produced by TENS is activation of the endogenous opioid pathway, and this might be another reason for a lesser effect when compared to fentanyl. However, to see the exact effect of TENS, we propose a different study design. Perhaps a study with a group of patients receiving TENS plus narcotics and another group receiving narcotics only might indicate whether TENS could result in reduction of opium consumption while giving similar or better pain relief during laparoscopic surgery. Another suggestion is to reapply TENS more than one session.We used low-frequency electrical stimulation in order to avoid muscle contraction and to make it bearable for the patients. Such approach for using the TENS could be problematic since one might argue that the effect (benefits) of TENS depends on the correct use of its parameters .The findings indicated that patients in both groups experienced nausea and vomiting as expected , 45. HowDuring administration of TENS, although pulse amplitude was increased and adjusted according to patient's tolerability, we did not increase the intensity during the treatment every time, and thus this might make pain relief effect limited. This should be seen as a limitation of the study in addition to the short time of evaluation of the pain.The findings suggest that TENS was not superior to fentanyl. Further evaluation with a larger number of patients, using correct parameters of TENS, and more focus on opioid dosage is recommended.


To evaluate the validity and reliability of the Brazilian version of theBehavioral Pain Scale (BPS-Br) in victims of traumatic brain injury.Observational prospective study with paired and repeated measures conductedat two intensive care units  of a large generalhospital. The convenience sample consisted of adult victims of moderate orsevere penetrating or blunt craniocerebral trauma who were sedated andmechanically ventilated. A total of 432 paired observations were performedby independent evaluators simultaneously, prior to eye cleaning, during eyecleaning, during tracheal aspiration and after tracheal aspiration.Sociodemographic, clinical, trauma-related, sedoanalgesia and physiologicalparameter data  werecollected. The discriminant validity was tested using the Friedman andWilcoxon paired tests. The intraclass correlation coefficient and Cohen'sKappa coefficient were used to evaluate the reliability. The Spearmancorrelation test was used to test the association between clinical variablesand BPS-Br scores during tracheal aspiration.There was a significant increase in the physiological parameters duringtracheal aspiration, but without correlation with the BPS-Br scores. Painwas significantly more intense during tracheal aspiration (p < 0.005).Satisfactory interobserver agreement was found, with an intraclasscorrelation coefficient of 0.95 (0.90 - 0.98) and Kappa coefficient of0.70.Brazilian version of the Behavioral Pain Scale scores increased duringtracheal aspiration. The Brazilian version of the scale was valid andreliable for pain assessment of traumatic brain injury victims undergoingtracheal aspiration. The inability to report pain does not exclude the possibility of its existence, givenit is an individual, subjective and multidimensional experience related to actual orpotential damage. Mobilization, wound care, trachealaspiration (TA), and arterial puncture are some examples of procedures cited aspainful by patients interviewed after discharge from the ICU.,4Patients in critical care units (ICUs) are routinely submitted to proceduresperformed by multiprofessional teams to maintain their basic organ functions. Someinterventions are characterized as using nociceptive stimuli that, althoughnecessary, impair comfort and cause pain.delirium in patient-centeredICUs is a current concern in recent international guidelines, with the objective ofensuring better outcomes related to mortality, physiological complications, lengthof hospital stay and mechanical ventilation time.,6 Despite the expansion ofsuch knowledge, appropriate pain management in critically ill patients is still achallenge.The pain management, restlessness and  requiring the use of specific instruments in thesesituations. Studies on observational tools for pain assessment in patients unable toself-report have been continuously developed at the internationallevel.-9Sedation, a decreased level of consciousness, intubation and mechanical ventilationare some of the factors that make pain assessment via self-reportunfeasible,,6 In Brazil, only the BPS has been culturally adaptedto Brazilian Portuguese, validated with intubated patients from a generalICU,11 and in the postoperative period of heartsurgeries. However, additional validations with differentpatient populations are fundamental because of the pathophysiologicalparticularities of each situation.The Behavioral Pain Scale (BPS) and the Critical-Care Pain Observation Tool (CPOT)are scales based on pain-related behaviors, have evidence of validity andreliability and are recommended by guidelines and protocols for pain management inthe ICU.,14 Due to the severity of the condition and theassociation with multiple trauma, the situation becomes more worrisome in regard tovictims of traumatic brain injury (TBI), as there are few studies related to thistopic.,16 TBI is a serious public health problem that leadsto disability, impaired quality of life and chronic pain. Thus, the objective ofthis study was to evaluate the validity and reliability of the Brazilian version ofthe BPS (BPS-Br) in TBI victims.Although pain is an experience often associated with trauma, pain underestimation andundertreatment  are constant phenomena among careteams.We conducted an observational, prospective study with repeated and paired measures ina surgical ICU and a clinical ICU of a large general hospital in Aracaju, Sergipe(SE), Brazil, from September 2015 to June 2016.,18Sampling was non-probabilistic by convenience, with an estimated sample size ofapproximately 25 - 30 patients. The sample size calculation was based on Cronbach'salpha coefficient with precision of 0.90 ± 0.05 for a scale with threesubscales, according to previous studies.Critically ill patients over 18 years old, victims of moderate or severe penetratingor blunt TBI, sedated and mechanically ventilated for more than 48 hours wereconsidered.,18,19 Patients who hadscheduled extubation, were discharged to the ward, or died before the secondassessment were also excluded.Quadriplegia, underlying neurological disease, use of neuromuscular blockers,suspected brain death, hemodynamic instability and use of resuscitation measureswere considered exclusion criteria because they interfered with the manifestation ofpain-related behaviors and were used in previous studies.Sociodemographic and clinical data and data related to the trauma incident,prescribed analgesics and sedation were obtained from medical records and ininterviews with family members of the participants.The Acute Physiology and Chronic Health Evaluation (APACHE II) score was used todescribe the severity of the clinical condition in the first 48 hours of ICU stay.The level of sedation was measured using the Ramsay and Richmond Agitation-SedationScale (RASS) scores prior to the pain assessments using the BPS-Br. , systolic blood pressure (SBP) anddiastolic blood pressure (DBP) were recorded during the collection of BPS-Br scores.Health professionals constantly associate the fluctuation of these parameters withthe presence of pain.The collection team consisted of three nursing students and one medical student. Thestudy assistants received theoretical training, provided by the principalinvestigator, on general concepts of pain assessment and management, physiologicaland behavioral indicators of pain in critically ill patients, as well as on theBPS-Br. The pilot test was performed with three patients for practical training andadjustment of the collection form. The data from the pilot study were discarded andwere not part of the final analysis.The BPS-Br was conducted in a paired manner, simultaneously by two independentobservers, and there was no communication between them during the assessment. Thisprocedure was repeated on a second occasion, during a different shift from the firstcollection, in order to obtain a larger number of observations. BPS-Br scores werecollected 1 minute prior to eye cleaning (EC) during EC, during TA and 10 minutesafter TA. The baseline or reference BPS-Br score was considered the score obtainedwhen the patient was resting, that is, before the non-nociceptive stimulus.All data were analyzed descriptively. Numerical variables were expressed as themean ± standard error of the mean, and categorical variables wereexpressed in absolute and relative frequencies. The symmetry of the distributionwas tested by the Shapiro-Wilks test. The Spearman correlation test wasperformed to examine the association between physiological parameters, APACHE IIscores, Ramsay scores, RASS scores, and total BPS-Br scores. The discriminantvalidity was evaluated using the non-parametric Friedman test for the fourdistinct assessment times, and the non-parametric Wilcoxon test for post hocpairwise comparisons. Reliability was assessed through interobserver agreement,with calculation of the intraclass correlation coefficient (ICC) and Cohen'sKappa coefficient.UniversidadeFederal de Sergipe  and followed therecommendations of the Declaration of Helsinki and the National Health CouncilResolution 466/2012. An informed consent form was signed by the participants'legal guardian because the participants were unable to make decisions. Trachealaspiration was performed exclusively by professionals from the physiotherapycare team according to the needs of the patients. No additional procedures wereperformed for the benefit of this study.This study was approved by the Ethics Committee of the A total of 37 patients were recruited to compose the sample. Ten were excludedbecause they were extubated, discharged to the ward, or died before the secondassessment. Thus, we obtained a final sample of 27 patients, for a total of 432observations (27 patients × 2 observers × 4 observation times ×2 assessments).In our study, severe TBI prevailed (88.9%), caused by blunt trauma mechanisms due toautomobile collisions involving motorcycles (74.1%), in which the victims did notuse the recommended safety device (66.7%) .Only one record of pain, made by the doctor and physiotherapist, was found in thechart. Midazolam and fentanyl were the drugs used to make the standard sedoanalgesiasolutions at the institution. Patients were deeply sedated in both assessments. Simple analgesics, non-steroidal anti-inflammatories and otheropioids were prescribed in an irregular manner. Infusion of the sedoanalgesiasolution was active during most assessments .For the physiological parameters the mean SBP, DBP and HR increased significantlyduring TA, returning to baseline values 10 minutes after the nociceptive stimulus.The BPS-Br scores increased significantly during TA in both assessments, which didnot occur during EC. Similar values were obtained during rest and the retestobservation, confirming the discriminant validity of the BPS-Br score increasingduring painful procedures .There was no significant correlation between clinical parameters, physiologicalparameters and total BPS-Br scores during TA. Only the Ramsay and RASS scorescorrelated with the BPS-Br scores recorded by observer 1 in the first assessment.Regarding reliability, ICC values of 0.95  and 0.89 (95%CI: 0.75 - 0.95) and Kappa coefficients of 0.45 and 0.60 wereobtained in the first and second assessments, respectively, when comparing thescores attributed by the observers during TA. Among the subscales, upper limbmovement , followed by compliance withmechanical ventilation  obtained the bestagreements . which must be ensured regardless oftheir level of consciousness. The use of valid and reliable instruments to assesspain is a key step for its proper management. TBI is often associated with multipletrauma and the need for ICU hospitalization. Thus, in addition to the painassociated with trauma, during the resting period, the use of invasive devices androutine procedures may intensify the pain experience.Pain relief is a fundamental patient right However, careful investigation of the patient'smedical history cannot be disregarded in view of its importance in the developmentof an individualized care plan for pain relief.There was no association between the clinical variables and the BPS-Br scores, whichreinforces the premise that pain is an individual experience, and its intensity andthe consequent suffering are not related to the extent of tissue injury or diseaseseverity.Regarding analgesia and sedation, deep sedation regimens still persist in theinstitution where the study was conducted. Midazolam and fentanyl solutions were themost frequently prescribed. By contrast, there is evidence that the exacerbated useof benzodiazepines is associated with negative patientoutcomes.deliriumrecommend that the critical patient's comfort is a priority. Adequate painmanagement leads to more superficial sedation, with lower doses of benzodiazepines,reduced mechanical ventilation time, lower infection rates and pulmonarycomplications, and greater patient collaboration.-27 It was found thatpost-hospitalization patients report vivid memories about experiences in the ICU.Therefore, more effective interventions are needed for the relief, treatment andprevention of pain by the multiprofessional care team.The most recent guidelines on analgesia, sedation and The use of simple analgesics, non-steroidal anti-inflammatory drugs and otheralternative drugs to opioids was inconsistent and prescribed in an irregular manner,that is, "whenever necessary". In addition, it is inferred that such drugs were notprescribed for analgesic purposes because there is no systematic pain assessment atthe study institution. Systematic prescription regimens of these substances confermany benefits, such as decreased opioid use and the subsequent onset of related sideeffects.-31 Thus, they should not be used as the only source ofpain assessment, but just as initial signs for suspecting its existence andfurthering investigation. Disease severity, hemodynamic instability, use ofvasoactive drugs, anxiety and fear are some of the factors that may alter these viathe activation of mechanisms that involve the organic response of catecholaminecascade activation and stress hormone release.Physiological parameters are readily available to intensivists and, culturally, havebeen used as indicators of the presence of pain. However, several studies have shownthat vital signs are not specific indicators for pain assessment in critically illpatients.,29,30 However, in Arbor et al., only the respiratoryrate was found to be a potential indicator for TBI victims because of itssignificantly positive correlation with patient self-report, but this necessitatesfurther investigation. We chose not to include the respiratory rate in our datacollection because its significant change is expected given the nature of the TAprocedure.In our study, there was a significant increase in SBP, DBP and HR during TA, butthere was no correlation with the BPS-Br scores. There are similar reports in theliterature regarding HR, SBP, oxygen saturation and respiratoryrate.,33The BPS-Br presented good discriminant validity, as during TA the scores increasedsignificantly. It was not possible to evaluate the validity criterion due to theunavailability of a tool that is recognized as the gold standard for painmeasurement in unconscious patients. The total scores during the nociceptivestimulus were lower than those reported in previous studies. Possibly, this findingmay be associated with the altered consciousness level in TBI victims, secondary tothe mechanisms of primary and secondary neurological injuries, as well as thesedation intensity and regimen adopted by the institution. We believe that the standardization ofdata collection, with exhaustive theoretical and practical training of researchassistants, contributed to these results. Interestingly, the facial expressionsubscale presented the lowest agreement coefficient, in contrast to previous studiesin which compliance with mechanical ventilation presented loweragreement.,34 The psychometric evaluation of the Chinese versionof the BPS presented similar high agreement in the facial expressionsubscale.With regard to reliability, satisfactory interobserver agreement results wereobtained, especially those related to the ICC. Similar results were found in aclinical validation study by Morete et al. Facial expression is the behavioral indicator mosteasily recognized by health professionals.,37 Therefore, this unique characteristic of TBIvictims can make pain assessment even more challenging.Some researchers have reported that TBI victims manifest atypical or unusualpain-related behaviors, which may explain why the change in facial expression scoreswas not as prominent.,39 In addition, the development and implementation ofprotocols and clinical guidelines for care centered on the comfort of criticalpatients are crucial for humanization and improving the quality ofcare.Tools such as the BPS should be widely disseminated in Brazilian ICUs. Although theBPS was found to be valid, reliable and easy to use, an intense awareness campaignand training for healthcare professionals is imperative for its use to beconsistent, efficient and effective.The lack of blinding of the investigators regarding the observed procedure was alimitation of this study. The principal investigators, however, were excluded fromthe data collection phase to reduce the possibility of measurement bias. Anotherlimitation was the impossibility of randomizing the inclusion of patients in thestudy. However, we increased the number of observations to enhance the power ofanalysis.The Brazilian version of the Behavioral Pain Scale is a valid and reliable instrumentfor assessing pain in traumatic brain injury victims. We suggest that it beincorporated into the routine of Brazilian ICUs and that future studies test itspsychometric properties with different painful procedures and its impact on patientoutcome after implementation, as well as use it as a measurement instrument inrandomized controlled trials.