Objective: Recent advances in brain imaging have deepened our knowledge of the neural activity in distinct brain areas associated with acupuncture analgesia. However, there has not been conclusive research into the frequency-specific resting-state functional changes associated with acupuncture analgesia in patients with chronic pain. Here, we aimed to characterize changes across multiple frequencies of resting-state cortical activity associated with ankle acupuncture stimulation (AAS) in patients with chronic low back pain (CLBP) and healthy controls.Methods: Twenty seven patients with CLBP and Twenty five age- and gender-matched healthy volunteers were enrolled in the study. Participants received tactile sham acupuncture (TSA) and AAS, respectively. The whole-brain amplitude of low-frequency fluctuation (ALFF) in the range 0.01–0.25 Hz was assessed for changes associated with each intervention. Further, a visual analog scale (VAS) was used to collect subjective measures of pain intensity in patients. Linear mixed-effect modeling (LME) was used to examine the mean ALFF values of AAS and TSA between patients and healthy controls.Results: The ALFF was modulated in the default mode network  in both patients and controls. Decreased ALFF in the bilateral insular was frequency-dependent. Modulations in the cerebellum and right insular were significantly correlated with VAS pain score after AAS (P < 0.01).Conclusion: Hence, frequency-specific resting-state activity in the cerebellum and insular was correlated to AAS analgesia. Our frequency-specific analysis of ALFF may provide novel insights related to pain relief from acupuncture. Chronic low back pain (CLBP) affects 60–80% of people at some point in their lifetime and has become one of the most common reasons for visiting a physician . Nearly A growing body of evidence supports the use of acupuncture as an effective treatment for acute and chronic pain, including headaches, neck pain, osteoarthritis pain, and LBP . The effFrequency-specific blood oxygen level dependent (BOLD) signal oscillations measured using resting-state fMRI (rs-fMRI) are of increasing interest, and the nature of this frequency-specificity has many biological interpretations. Studies reporting specific frequencies of BOLD signal oscillations indicated that each different frequency band contributes uniquely to brain network integration in terms of physiological and pathological activities . OscillaIn the present study, we explored the contribution of different frequency bands to changes in resting-state BOLD fMRI associated with the administration of acupuncture in LPB patients. To detect the frequency-specific functional changes that may play an important role in acupuncture analgesia, we assessed BOLD oscillations in frequency bands  to compare resting-state activity in LBP patients with that of healthy controls. A painless acupuncture technique, ankle acupuncture stimulation (AAS), was used as the intervention method. AAS is a type of subcutaneous acupuncture that was developed in the 1970s . It has www.chictr.org.cn (Identifier: ChiCTR1800020029). Participants gave written informed consent before undergoing screening.The study protocol was formulated in accordance with the Declaration of Helsinki and approved by the ethical committee of the Center of Cognitive and Brain Disorders of Hangzhou Normal University (20190102). Our present study was registered on Patients were assessed by an experienced rehabilitation physician according to the following criteria. The inclusion criteria of patients were as follows: (1) right-handed adults of any gender aged 18 to 65 years; (2) a history of low back pain for 6 months or more; (3) an initial self-reported pain intensity evaluated using the visual analog scale  of at least 4 points; (4) able to understand and complete the consent form and clinical assessment questionnaires without assistance. The inclusion criteria of healthy subjects were as follows: (1) right-handed, age- and gender-matched adults; (2) no history of pain or relevant serious disease; (3) able to understand and complete the consent form without assistance.The exclusion criteria of patients and healthy subjects were as follows: (1) the presence of another cause of pain unrelated to LBP; (2) having taken any medication or undergone physical therapy in the past week; (3) any other serious illnesses or neuropsychiatric diseases; (4) any contraindications for undergoing MRI, including the presence of metal implants, cardiac pacemakers, or claustrophobia; (5) any contraindications for undergoing acupuncture, such as pregnancy or a tendency to bleed easily; (6) a history of sleep deprivation or women who were experiencing their menstrual period; (7) having consumed coffee or alcohol in the 10 h prior to the MRI scan. Participants were free to withdraw at any time. To ensure data quality, any individual who moved their head by more than 1 mm or 2° during the scan was excluded from the analyses.The order of AAS and TSA runs was pseudo-randomized across subjects to reduce order effects. In order to maximize washout of acute stimulation effects, these two runs (AAS or TSA) were separated by structural scans which lasted 15 min. In the present study, participants were acupuncture naïve and were informed that there would be “different forms” of acupuncture during fMRI. In addition, the needles used for AAS and TSA were identical. Our preliminary test showed that the sensations of AAS and TSA were similar. The locations of needle stimulation were taped with medical adhesive tape. Participants lay supine in the scanner with their vision of distal body regions blocked by the MRI head coil, preventing them from viewing the intervention occurring at their periphery. Participants could be blinded to the order of AAS and TSA. Blinding success was validated at the end of the study.AAS and TSA were performed by the same experienced acupuncturist using disposable silver acupuncture needles . The left lower 5th AAS zone was selected as the needle insertion point, with the exact location about three-finger widths above the lateral malleolus, near the posterior edge of the fibula and adjacent tendons . The acuDuring TSA, participants exposed the skin on the lateral side of the left leg, and the stimulus was administered to the same location as in AAS. Instead of inserting a needle into the skin, the needle was gently placed against the skin and held there for 5 s without penetrating the skin. All other procedures were identical to those used in AAS.The study was conducted in the MRI room of the Center of Cognitive and Brain Disorders, Hangzhou Normal University. Participants were scanned on a GE-750, 3 T MRI system with an 8-channel head coil. The participants wore earplugs and lay in a supine position on the scanner bed. Sponge padding was used to minimize head movement. During the scanning process, participants were told to keep their eyes closed, stay awake, and try not to think of anything.1. A total of 240 whole-brain volumes were obtained. A 3D T1-weighted structural image was acquired using a spoiled gradient echo (SPGR) sequence, as follows: number of slices = 176, matrix size = 256 × 256, TR = 8,100 ms, TE = 3.1 ms, FA = 8°, slice thickness = 1 mm, voxel size = 1 × 1 × 1 mm3, inversion time = 450 ms, and bandwidth = 31.25 Hz. Each participant received one functional image scan following administration of either the TSA or AAS . The structural image was acquired between the two functional runs.The fMRI acquisition used a gradient echo (GRE) echo-planar imaging (EPI) sequence with the following parameters: number of slices = 43, acquired interleaved, matrix size = 64 × 64, repetition time (TR) = 2,000 ms, echo time (TE) = 30 ms, flip angle (FA) = 90°, slice thickness = 3.2 mm, voxel size = 3.4 × 3.4 × 3.2 mmfMRI scanning paradigm is shown in A self-reported VAS was used to evaluate the current pain intensity experienced by each participant immediately after the TSA and AAS of the scan session. VAS rating was accomplished by the use of a custom-built MR-compatible handheld rotating knob, which was connected to a visual display projecting an intensity scale. The knob was set to traverse the entire rating range with minimal thumb finger twisting. The device was held in the right arm of participant. The VAS took < 1 min to complete. The scale was comprised of a 10 cm horizontal line, extending from “0” on the left indicating no pain, to “10” on the right indicating the most severe pain imaginable. Participants were instructed to mark a “×” on the line according to the pain intensity they experienced currently. The length (in centimeters) from”0” to the mark was recorded as their pain score.2 and RESTplus3. The raw data were preprocessed as follows: the first 10 brain volumes were removed, slice timing and head motion correction were applied, functional and structural images were realigned, the structural image was segmented, and all data were spatially normalized into Montreal Neurological Institute (MNI) space, resampled at 3 × 3 × 3 mm, and spatially smoothed using a Gaussian kernel of 6 mm full-width half-maximum (FWHM). Finally, the statistical model included regression of covariates  and removal of the linear trend.MRI data were processed in MATLAB (R2014), using SPM12All BOLD signal fluctuations below the Nyquist frequency (0.25 Hz in the present study) were delineated into six frequency bands: norm-1 (0.01–0.1 Hz), norm-2 (0.01–0.08 Hz), slow-5 (0.01–0.027 Hz), slow-4 (0.027–0.073 Hz), slow-3 (0.073–0.198 Hz), and slow-2 (0.198–0.25 Hz) . The who4. Descriptive statistics were presented as mean ± standard deviation. Here we used a linear mixed-effect modeling (LME) to examine the mean ALFF values of AAS and TSA between patients and healthy controls. LME is a flexible modeling approach that handles complex experimental designs and has been widely used in fMRI statistical analysis  and condition (AAS vs. TSA), and any interaction between the two were determined using a mixed-effects analysis in DPABI (V4.1)3 toolbox. Results were corrected based on Gaussian random field theory (GRF) . Post hoc analyses were performed when a significant interaction effect was detected. Associations between zALFF at the cluster peak coordinates and VAS scores were explored by calculating the Pearson correlation coefficient.Demographic data and VAS pain intensity scores were visualized using Graphpad prism 8analysis . The difn = 12 men) patients and 19 (n = 11 men) healthy subjects comprised the final dataset for analysis. All the participants reported no obvious needle sensation during acupuncture. The basic characteristics of patients with CLBP were as follows (P > 0.05), but duration of lower back pain in patients was 9.0 ± 7.7 years.Fifty two participants (27 patients with CLBP and 25 volunteers) were recruited from Zhejiang Integrated Traditional and Western Medicine Hospital. 12 patients dropped out during the experimental period. Three participants could not tolerate the scanning session. Two participants were not imaged during acupuncture stimuli due to claustrophobia. Three participants terminated the study due to excessive fear. One subject was removed for suspected sub-clinical neuropathy. Three participants voluntarily withdrew. A final total of 40 patients  completed all the clinical assessments and imaging scans. In addition, one patient and one control were excluded because of severe head movement during fMRI. Therefore, data from 19  lower after AAS (3.50 ± 2.23) in comparison to after TSA (5.64 ± 1.98). Duration of experiencing lower back pain was negatively correlated with the degree to which the VAS pain intensity score differed between the two conditions . All of healthy subjects were scored with VAS ≤ 1 at the two observation points. There was no significant difference noticed in the VAS scores of pain after AAS in comparison to after TSA (P > 0.05).At a group level, the VAS scores of pain in patients were significantly  and cerebellum/posterior cingulate cortex (PCC) . The peak coordinate of the overlap between all frequency bands except the slow-5 band was found to be in the right insula . Individual zALFF values for all frequency bands in mPFC, cerebellum/PCC, and right and left insula  are presented in p < 0.001 at the whole brain level. Clusters with smaller size located in the medial frontal cortex, cerebellum and the right insular cortex passed the correction threshold. The peak MNI coordinates of them were almost the same as that of clusters reported using threshold of a voxel level of p < 0.01 , and negatively correlated with the change in VAS score between the two treatments . Meanwhile, slow-3 frequency band zALFF in the cerebellum was also positively correlated with VAS score after AAS . The zALFF within the norm-2  and slow-4  frequency bands in the right insula showed negative correlations with changes in VAS score after AAS.As shown at the top of AAS is a form of acupuncture therapy that does not produce any needle sensation. Its stimulation is mild and mimics a tactile sensation on the skin. Therefore, AAS may be useful in the investigation of brain responses associated with acupuncture analgesia due to the ability to exclude or minimize the confound from forms of traditional acupuncture that are associated with stimulation from Deqi needle insertion. The current study used rs-fMRI to investigate whole-brain ALFF changes following AAS, and further explored the relationship between these changes and self-reported VAS pain intensity scores. Previous functional brain imaging studies investigating acupuncture have focused its effects either in healthy subjects or in patients with a specific diagnosis. To our knowledge, the present study was the first to collect and analyze functional brain imaging data following AAS in both patients and healthy subjects. The main results showed that in contrast to tactile sham acupuncture (TSA), self-reported pain intensity in patients with CLBP significantly decreased after AAS. Meanwhile, ALFF in sub-band frequencies ranging from 0.01 to 0.25 Hz was consistently modulated within nodes of the DMN  in both patients and healthy subjects. Decreased ALFF in the bilateral insular cortex  showed frequency-specific modulations. Furthermore, pain intensity experienced by patients showed a close relationship with the functional responses within specific bands in the right insula and cerebellum.Acupuncture stimulation induces widespread responses within DMN . ResultsOur study provides the characteristics of multi-band BOLD signal oscillation with ALFF as the index for the central response of AAS analgesia. In present study, frequency-specific resting-state activity correlated to AAS analgesia focused in the cerebellum and insular. It is shown that plasticity changes in the insular cortex have been frequently observed in patients with chronic back pain . StudiesIn present study, we identified frequency-specific resting-state activity in the cerebellum during the AAS stimulation. Notably, we found that norm-1 and norm-2 band ALFF patterns following acupuncture was very similar, but they did not completely overlapping, especially in the cerebellum. Only norm-2 band ALFF correlated to pain-relief effect of acupuncture. ALFF was originally defined based on norm 2 (0.01–0.08 Hz) band BOLD signal oscillation . HoweverIn summary, the central mechanism underpinning the effects of AAS requires further explanation. This study has demonstrated a relationship between frequency-specific BOLD oscillations in the brain associated with ankle acupuncture analgesia and pain intensity scores in CLBP patients. The characteristics of BOLD signal oscillations across multiple frequency bands following AAS analgesia were demonstrated. Further work is necessary to further elucidate the mechanisms behind the effects of AAS through a combination of multi-scale, multi-modal neuroimaging, animal models, and electrophysiological techniques.With regard to the study design and protocol, there are some limitations that need to be taken into account. Firstly, our results were observed in a small cohort of subjects. Therefore, further testing in clinical populations is warranted. Given that each different frequency band contributes uniquely to brain network integration in terms of physiological and pathological activities, the present studies of smaller size have yielded more information to help interpret localized BOLD changes associated with acupuncture analgesia and provided impetus to further investigations. These preliminary results may be of importance for the design of further confirmative studies. Secondly, washout period for AAS’s effects remains unknown, although stimulus runs were separated by structural scanning for 15 min in present study.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the Ethical Committee of the Center of Cognitive and Brain Disorders of Hangzhou Normal University. The patients/participants provided their written informed consent to participate in this study.AX, XS, and SL conceived the study design. AX, MC, CQ, JR, and CW collected the data. AX analyzed the data. AX, MC, CQ, XS, and SL helped to draft and revise the manuscript. All authors contributed to write the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Over 3 million people lost their lives across the globe due to the COVID-19 related pandemic. The unprecedented restrictions on mobility have imposed in the form of isolation, quarantines, and lockdowns to curb the profound effects of the pandemic and retain physical health. This study examined the relationship between various pain levels, demographic variables and patient satisfaction with COVID-19 during isolation.The primary data in this study were collected from isolated patients during their isolation and treatment in a public hospital. We obtained information from patients with COVID-19 (N = 100) about their demographic characteristics, varying levels of pain, and satisfaction with the services provided during the isolation period. We computed the descriptive statistics to explain the profile of participants, ANOVA was used to find out the difference between various groups on patient satisfaction, and structural equation modeling was performed to examine the link between pain levels, demographic factors, and patient satisfaction. This analysis was performed with STATA and SmartPLS-3.p = 0.003), assets such as possession of a house , perception of income adequacy during the lockdown , and negligence in prevention  significantly affects patient satisfaction during the isolation period. Moreover, satisfaction with life, physicians and medicine, income adequacy, and fear of the participants was significantly linked to the pain level . Patients who were satisfied with their treatment had significantly lower odds of having pain . Patients who had enough income to meet their basic necessities were found to have significantly lower odds of having pain (OR 0.155, 95% CI [0.032–0.740].The findings of this study ascertained that respondent’s education (Beta, β = 2.961, We conclude that a higher level of education, low income, and living in a rented house contributes significantly to the feeling of more satisfaction with the provided services. This implies that people with more affluent backgrounds are less likely to be satisfied with the provided services as low-income and living in rented house groups are more satisfied during isolation than others. The pain level is also affected by subjective factors such as fear and satisfaction which need to be considered while doing patient management. This study can be helpful in improving the delivery of public services of isolation centers by considering various characteristics and demographic factors of patients. The COVID-19 pandemic has jolted the whole world. The outbreak started in China in late 2019 and turned into a pandemic due to its highly transmittable nature . In PakiIt is often argued that quarantine and isolation are two sides of the same coin, but there are two folds of dissimilarity in terms of definition. Quarantine means isolating the persons who have been potentially exposed to the virus and are not sick yet to observe the virus’s symptoms and reduce the potential spread of the disease. On the contrary, isolation is the separation of confirmed infected patients . The incQuarantines and isolations of patients have played a vital role in controlling the spread of the disease. On the one hand, they facilitate in reducing the infection, but, on the other, cause many side effects, which is recently argued as shadow pandemic. The psychological side effects of isolation include anger, depression, anxiety, loss of patient satisfaction and mental wellbeing, and loss of self-control . QuarantDeveloping countries are already struggling with the scarce health facilities and services to combat the disease. Where a patient in isolation experiences fear, anxiety, and depression . Due to •Does patient’s satisfaction during COVID-19 isolation differ among demographic groups?•What are the factors affecting the pain level (subjective) of the COVID-19 patient during isolation?•What are the factors affecting patient’s satisfaction during COVID-19 isolation?The introduction section is followed by the Materials and Methods section, which explains data collection, sample, and data analysis technique. The third section includes descriptive statistics, patient satisfaction among patients, factors affecting pain level, and factors affecting patient satisfaction. Results are followed by discussion and conclusion.This study relies on primary data collection for making inferences. We conducted a cross-sectional survey to collect the information from the COVID-19 patients who were isolated in the government centers. The study focused on the investigation of patient satisfaction and their pain perception of isolated patients. The variable of fear comprises of seven dimensions. The questionnaire adopted the fear scale from the study conducted by The sample was collected from COVID-19 patients who were isolated in COVID-19 isolation wards. The sample data was collected from the patients during their isolation using purposive sampling. Purposive sampling is a selective sampling where the population with certain characteristic is selected. Based on the objective of the study, only the COVID-19 patients were purposively selected for the study. However, at next stage, the COVID-19 patients to be included in the sample were selected randomly  using the partial least squares (PLS) path modeling method. The benefits of the PLS approach consist of measurement settings, theoretical settings, practical attention, and distributional attentions . The PLSTo analyze various factors affecting the level of pain, an ordered logistical regression was used. Due to the orderly nature of the responses of the pain variable, that technique was chosen.The general model of ordered logistic regression is: Substituting the value of B zj are the cut points of the distribution. The independent variables include fear, age, satisfaction with medicine during isolation, sufficiency of income, satisfaction with life and satisfaction with the doctors.where “i” is the number of observations. “j” is 1,…,5 and represent the values for y. “X” is the vector of independent variables, “Ø” is the coefficient vector and Structural equation modeling was applied to see the relationship of factors with patient satisfaction.For the analyzing patient satisfaction, structural equation modelling (SEM) was used. The underlying model of SEM is linear model. The general linear model in vector form is given below: yi” is a vector of outcome variable and “Ω” is a matrix of parameters constrained according to the association of variables. The independent variables for the pain satisfaction model are age, number of dependants, household size, education, house ownership, marital status, income adequacy, negligence and pain level. PLS software was used because it provided reliable results even with a small sample size and is suitable for predicting. Following t-values in the research model among latent constructs. In addition, Hair and colleagues (2013) have also suggested ways of determining effect size (f-square). The predictive power of the research model was determined by the R-square value of the dependent variable, while the trajectory coefficients assess the strength of the hypothetical relations.where “n = 31) or postdoctoral (n = 23) in full-time employment (n = 62).As illustrated in Patient satisfaction is the perception of medical facilities and paramedic care . We haveIn the next section, we will see the factors affecting the pain level, whereas pain and other factors also affect the patient satisfaction of individuals.t-test and the model through F-test. The robustness of the model is checked through adding and dropping of variables and the final model was selected based on Akaike Information Criteria (AIC) and Bayesian Information Criteria (BIC). The AIC and BIC criteria suggests Model 1 as the final model and is significant which is tested through F-test. According to the findings, when the respondent is neutral with respect to fear rather than disagreeing, there is a higher probability of having a higher level of pain. This suggests that patients being neutral about fear raises the likelihood of having a higher level of pain. In addition, as satisfaction with the medication supplied in the isolation facility increases, the probability of experiencing pain decreases. This indicates that if a person is satisfied with the treatment, then the sensing of pain will also be less as the patent will be anticipating to get better before long. The probability of having higher pain reduces if a person can afford some necessities compared to the situation where the income is not adequate. Income adequacy suggests the affordability of treatment and better, treatment may reduce pain and pain perception. An interesting result came out of the data, suggesting that patients with COVID-19 who are more satisfied with their lives are more likely to have more pain. People having contended life are more likely to report a higher level of pain subjectively. COVID-19 is known to be lethal. People with higher life satisfaction might fear the loss of life, and thus these emotions might interpret as higher pain. If the COVID-19 patients are neutral about satisfaction with the doctors as compared to disagreeing, the probability of perceiving higher pain is lower.The level of pain is a subjective phenomenon and therefore affected by subjective factors beyond objective reasons. We examined the effect of fear and other factors on the level of pain and attempted to model the subjective component of pain. The respondents were asked about the pain level on a five-point scale ranging from no pain to unspeakable. The results have been analyzed using ordered logistic regression and shown in Based on the literature, the pain level, and other demographic variable factors, significantly affect patient satisfaction. Results indicated that the model fits the data . Bootstrapping is used to test this hypothesis. Results in The results indicate that patient satisfaction decreases with the increase in age. It was found that people with higher education were more satisfied with the isolation facilities. With the increase in the level of education, awareness can increase, and so the realization of the efforts of doctors and staff and the facilities provided make people more satisfied. Furthermore, people possessing their own home have lower satisfaction from isolation centers than people living in a rental home. People feel better about isolating themselves at home. In addition to this, the results illustrated that those individuals who had enough income to meet their expenses during lockdown reported a low level of satisfaction while having inadequate money increase isolation centers’ satisfaction. Those who perceived that they were suffering from COVID-19 due to their negligence displayed a high level of satisfaction. Neglect has been operationally defined as the carelessness in taking steps to protect themselves from COVID-19. People whose income is adequate are less satisfied with patients. Similarly, having a high level of pain enhances the level of satisfaction at the isolation center. They feel satisfied when they get medical facilities and other services in public isolation centers, which otherwise was not possible at home while facing a high level of pain. On the other hand, several dependents, household size, and marital status are not significantly related to the satisfaction of isolation centers. As a result, the second assumption is partially supported. The COVID-19 pandemic has jolted the whole world with infectious disease by spreading the sickness and causing mortalities. According to WHO guidance, quarantine and isolation are among the primary methods to reduce the spread of the disease. The literature has shown that isolation may have negative effects on the patients , so it iPain is a subjective experience . The subThis study has far-reaching implications for the health care system and patients. The healthcare system needs to improve their isolation facilities though struggling with scarce resources. It will help them to reduce the pain level of patients and improve their experience. With closed borders and a ban on foreign travel, local treatment is the only option for COVID-19 patients. The improved isolation experience will help patients to spread good word of mouth, which will help regain the nation’s trust in doctors, paramedic staff, and the health care system despite having scarce resources. This will also help them ensure that the best is being provided to them. They will eventually enjoy the isolation experience, which will not help them recover, but their safe isolation will also protect others from the spread of the disease. Other countries can also derive lessons from this study by focusing on the factors identified to improve isolated patients’ experience in isolation centers.The data collection from isolated COVID-19 patients during isolation was a big hurdle. We did not want to ask patients about their experience after isolation to avoid the bias of forgetting affecting our results. Due to the stated hurdle of access to patients isolated in centers, we could not collect large data. Further research can be done with a large data sample and in different countries to investigate individuals’ isolation experience and see the country-specific factors.The novelty of COVID-19 has not only brought issues in the disease treatment and management, but also the overall medical care and related services. We cannot ignore the importance of treatment, recovery and prevention in this pandemic. The patient experience is extremely important in isolation centers to build patient confidence in paramedics and physicians. A better experience will also contribute to reducing pain for patients. The factors affecting the pain level of patients are satisfaction with doctors and medicine, satisfaction with life, income adequacy, and fear. An improved isolation facility with quality of doctors and medicine can help to reduce the pain level of the patients.It is important to maintain isolation facilities for patients by providing a comfortable environment to patients where they can recover and feel satisfied and perceive less pain. Improving the patient experience may improve the overall quality of hospitals and, as a result, hospitals will face fewer complaints. Being a developing country, income adequacy is also an important factor affecting pain and patient satisfaction. Satisfaction with medical care helps the individual to perceive less pain.Creating public isolation facilities and equipping them with the latest available facilities is a great initiative, especially in developing countries where masses cannot afford these facilities at an out-of-pocket expense. The focus on the provision of services can improve their experience and thus patient satisfaction. However, patient satisfaction is not significantly different between the distinct groups of the population. Improving overall facilities may help to increase the patient satisfaction of patients. Reduction of fear through proper counseling and media awareness may help to bring down the perceived pain of patients. Improving isolation experience will also help decrease negligence in other patients about their diseases and approach the hospitals for isolation, believing that they are in trusted hands.10.7717/peerj.11859/supp-1Supplemental Information 1Click here for additional data file.10.7717/peerj.11859/supp-2Supplemental Information 2Click here for additional data file.10.7717/peerj.11859/supp-3Supplemental Information 3Click here for additional data file.


Spinal deformity corrections in paediatric patients are long-lasting procedures involving damage to many tissues and long pain exposure; therefore, effective pain management after surgical treatment is an important issue. In this study, the effect of inclusion of local infiltration analgesia, as an integral part of the scheme in postoperative pain control, in children and adolescents, subjected to the spinal deformity correction procedure, was assessed. Thirty patients, aged 8 to 17 years, undergoing spinal deformity correction were divided into a study group, receiving a 0.25% bupivacaine solution before wound closure, and a control group . Morphine, at the doses of 0.10 mg/kg of body weight, was administered to the patients when pain occurred. Pain scores, morphine administration, and bleeding were observed during 48 postoperative hours. The pain scores were slightly lower in a 0–4 h period in patients who received bupivacaine compared with those in the control group. However, no differences were observed in a longer period of time and in the total opioid consumption. Moreover, increasing bleeding was observed in the bupivacaine-treated patients (study group) vs. the control. Bupivacaine only modestly affects analgesia and, due to the increased bleeding observed, it should not to be part of pain control management in young patients after spinal deformity correction. Only 0.1%. of paediatric patients suffering from scoliosis need surgical treatment; however, posterior spinal deformity corrections are long-lasting procedures, which require an extensive surgical approach, involving damage to many tissues and long pain exposure. They also carry the risk of many problems and complications . The emep = 0.92). Before the surgery, the patients were classified as I–III groups, according to the American Society of Anaesthesiologists (ASA) categorisation. The data about the patients and surgery are provided in The prospective cohort study involved patients treated for spinal deformity in the Paediatric Orthopaedics Department at the Children’s University Hospital in Lublin  in 2015. The study was approved by the Bioethics Committee (consent no. KE-0254/105/2015). The oral and written consent was obtained prior to the surgery from all participants and their parents. Patients that (1) had allergies to bupivacaine, acetaminophen, or opioid, (2) had coagulation disorders, (3) were not fully responsive for physical, intellectual, and emotional reasons were excluded from the study. In collaboration with an anaesthesiologist team, the extended pain management protocol in spine surgery has been studied. Finally, the study involved 30 patients, including 13 children who followed standard perioperative protocol (control group) and 17 children who followed modified pain management protocol. The majority of subjects were patients with idiopathic scoliosis (23 persons), Scheuermann’s disease (4 persons), and congenital scoliosis (3 patients). The average number of segments involved was 11 in the study group and 12 in the control group . A Kruskal-Wallis multiple comparison test, a T-distribution test, a chi-squared test, Mann-Whitney test, and Yule’s Q measure were used to analyse the differences between the control and the study group. The statistical significance was set at α = 0.05.The effect of bupivacaine on postoperative pain was investigated based on the pain scores according to the 10-point NRS scale, in which the child rates the pain from 0 (no pain) to 10 (worst imaginable pain). From 1 to 3, the pain was regarded as mild, and opioids were administered when the pain was described as 4 and above. The results were expressed as a percentage of patients who declared pain sensation at particular NRS values . As can be seen in p = 0.059) was close to the critical point of 0.05. No statistically significant differences were noted in the other periods of observation.The analgesic effect was also assessed based on the number of patients who needed opioid administration. The observations were conducted in the recovery room, and in the ward, in the period of 0–6 h, 6–24 h, and 24–48 h after the surgery. Generally, the chi-squared test did not show clearly significant differences between the patients in the control group and the study group within the tested periods. However, in the first 6 h in the ward, a slight effect of bupivacaine on the pain sensation was visible . In thisp = 0.54).The total consumption of opiates in both groups  did not p = 0.0299). The increased bleeding was not reflected in the frequency of packed red-blood-cell transfusion in the postoperative course, amounting to 30% and 35% in the study and control groups, respectively (p = 0.1766). The amount of blood in the drain and the time after which it was removed were also assessed. The average blood loss in the study group was 815 mL and 590 mL in the control group . The valp = 0.1235) and no correlations between the number of fixed segments and increased bleeding (p = 0.35) were observed.No significant differences in the wound drainage time (Local injections of postoperative wounds, as part of postoperative pain management, have proven to be effective in some orthopaedic, neurosurgical, and cardiothoracic surgical procedures . The benHowever, some researchers do not observe the expected beneficial effects of LIA. As reported by Zmora et al., the intraperitoneal administration of bupivacaine does not lead to pain alleviation after laparoscopic cholecystectomy . The resThere are not many papers presenting the use of LIA with regards to spinal surgeries, or they usually involve adult patients that are most frequently subjected to less extensive surgeries. Greze et al. evaluated the impact of ropivacaine, administered through a catheter, on pain experienced by patients undergoing posterior fixation, which included various numbers of segments. The authors did not obtain any satisfactory analgesic effects of LIA . In turnIn the majority of papers, authors did not consider the impact of LIA on postoperative bleeding. Only Niemeläinen et al. mentioned this aspect of the performed procedures; however, in contrast to our findings, he did not observe increased blood loss after the surgery . The incThe number of patients involved in our study was relatively low; however, an interim analysis revealed that bupivacaine infiltration was not effective to support control of postoperative pain in paediatric patients undergoing spinal surgery; thus, we decided to discontinue the study and not to extend the research with a larger group of patients.This study aimed to assess the effectiveness of local injections of bupivacaine as part of postoperative analgesia in children undergoing surgical corrections due to spinal deformities. The investigation showed that the pain sensation was moderately reduced up to 4 h after the surgery in patients treated with bupivacaine; however, the study and control groups did not differ significantly in the time up to the first morphine administration in the ward and in the total amount of opiates administered during 48 h. Moreover, increased postoperative wound bleeding was observed in the study group. It may have been related to the fact that, besides their effect on fibres responsible for pain conductivity, the local anaesthetics led to the dilation of sympathetic fibres to skeletal vessels. Therefore, local infiltration analgesia with bupivacaine should not constitute a routine procedure in the group of young patients subjected to spinal deformity corrections. However, this observation did not exclude the effectiveness of LIA with bupivacaine in the case of surgeries with, potentially low, postoperative bleeding. Moreover, the addition of other analgesics and/or vasoconstrictors might increase the analgesic effects of treatment without an adverse effect on the amount of bleeding. Another idea worth considering, to improve postoperative pain control, can be Erector Spinae Plane Blockade. This could be a starting point for further studies.


To evaluate whether periapical surgery affects oral health-related quality of life (OHRQoL) within the first postoperative week.The primary outcomes in 133 patients  undergoing periapical surgery were the Oral Health Impact Profile-14 (OHIP-14) score and postoperative sequelae, including pain, analgesic intake, swelling, limited mouth opening, chewing difficulties, and postoperative infection.We found a significant effect on OHIP-14, pain, and analgesics, which decreased throughout the week. We found no significant differences in mean OHIP-14, pain scores, or analgesic use for gender, medical history, surgical flaps, operation time, or location of the operated teeth. Younger patients had a higher OHIP-14 score in the first 2 days after surgery and more pain on the first postoperative day. Women experienced more pain during the first 3 days. Smokers had a higher OHIP-14 score on the first postoperative day and greater pain during the first 3 days compared to non-smokers.We identified a low incidence of pain and reduced OHRQoL following periapical surgery. The postoperative reduction in OHRQoL and pain were of short duration, with maximum intensity in the early postoperative period and rapidly decreasing with time. Periapical surgery is a therapeutic surgical procedure to treat teeth with periapical inflammation, particularly when orthograde retreatment is problematic or fails to lead to regression of the apical pathology , 2. As wThe aim of the present study was to investigate whether periapical surgery affects oral health-related quality of life (OHRQoL) during the first postoperative week. Patients were surveyed using the Oral Health Impact Profile-14 (OHIP-14) questionnaire. In addition, we assessed postoperative pain, analgesic intake, and infection in the first postoperative week.Patients referred by their dentists for periapical surgery at the Department of Oral and Maxillofacial Surgery of Amstelland Hospital in Amstelveen, the Netherlands, during 2017 and 2018 were eligible for inclusion in this prospective study. The study was reviewed and approved by the institutional Medical Ethics Committee of the Academic Medical Centre of the University of Amsterdam and conducted in accordance with Good Clinical Practice and the Declaration of Helsinki, as amended in Somerset West, Republic of South Africa, in 1996. Patients were fully informed about the surgical procedure, postoperative care, follow-up examinations, and alternative treatment options. Each patient was informed that they could withdraw from the study at any time without consequences regarding their treatment.Patients with apical periodontitis in a root canal-treated tooth were included in this study. Asymptomatic patients aged ≥ 18 years and in good health (American Society of Anesthesiologists (ASA) I or II) who were willing to participate and able to read, understand, and answer the questionnaire were considered for inclusion if they had periapical periodontitis with no possibility of root canal retreatment or the ability to achieve better results with a nonsurgical approach. Patients underwent a clinical and radiographic examination, and a panoramic radiograph and periapical radiograph were taken. The tooth to be treated had to have an adequate final restoration without clinical evidence of coronal leakage. No acute symptoms were present, and the diameter of the periapical lesions had to be < 10 mm as measured on the periapical radiograph.Exclusion criteria were other causes related to root pathology other than apical re-infection, such as root fractures, teeth with an inadequate coronal restoration, perforations and bone loss , and defects of the buccal and lingual cortical bone, as suggested by Zuolo et al. . Other eThe surgery was performed by two surgeons (JT and JL). Patients received local anesthesia with 40 mg of articaine/hydrochloride and 0.01 mg epinephrine . The surgical technique consisted of a midlevel, rectangular or triangular, full-thickness mucoperiosteal flap. The surgical flap was reflected, and bone removed by a round burr with continuous sterile distilled water irrigation to expose the root apex. After debridement of the pathological tissue, the root was resected approximately 3 mm from the apex using a cylinder burr with minimal or no bevel. Using glasses with 5.0 magnification loupes and a PureLight Headlamp with 140 mm spot size , the root end was prepared using ultrasound to a 2–3-mm depth with ultrasonic retro-tips . Intermediate Restorative Material  was placed into a dried cavity after adequate hemostasis. Before wound closure, the bone cavity was cleaned with 10 ml of 0.9% NaCl solution . The wound was closed by re-approximating the soft tissue to the original position and sutured with Vicryl 4/0  before taking final radiographs.After surgery, patients were given verbal and written instructions, including information about swelling, using an ice pack for cooling the cheek to reduce swelling and pain relief, avoiding mouth rinsing and spitting, practicing caution when eating and drinking hot food and beverages, and avoiding physical activities. Patients < 50 years of age with an ASA I classification were prescribed 600 mg ibuprofen  three times a day postoperatively, whereas patients ≥ 50 years old or with an ASA II classification were prescribed 1000 mg paracetamol 3–4 per day postoperatively. No antibiotics were prescribed. The day after surgery, patients began using a 0.12% aqueous chlorhexidine mouth rinse twice a day for 1 min for 7 days. Patients were informed to contact the surgeon if they experienced severe pain, swelling, fever, bleeding, or any concerns after surgery.One week after surgery, patients were examined by an independent assessor to assess surgical site wound healing and to check for wound infection. Remaining resorbable sutures were removed. Infection was defined as the presence of purulent discharge and/or excessive swelling with fluctuation, with or without pain; presence of a local abscess; or onset of facial or cervical cellulitis plus other signs suggesting infection, such as pain, increased heat, temperature, erythema, and/or fever . In patiThe primary outcome measures were the OHIP-14 questionnaire and pain score based on the numeric rating scale (NRS). Each patient was asked to complete a questionnaire in the first 7 days postoperatively. The questionnaire was translated into Dutch, comprising 14 questions to evaluate the OHRQoL on a 5-point scale ranging from 0 (“never”) to 4 (“very often”) , 21. HigData were collected and imported into a database. Variables included patient age, gender, medical history, and smoking habits. Age at surgery was computed in years as the difference between the date of operation and the patient’s date of birth. Furthermore, the location of the treated tooth, surgical flap design, and operation times were recorded.α = 0.05. To obtain the overall mean OHIP-NL14 score, all 14 questions were averaged for each day, and this score was used to compare changes over time and between groups. Repeated measures ANOVA within subjects was performed to assess the change over time (day 1–7). Additional analyses were conducted to determine the relationship between OHRQoL and the other study variables  over time by means of univariate analysis of variance. Between-group comparisons were performed by means of independent t-tests.Data were analyzed using SPSS version 25 . Significance was set at A total of 133 patients (54 (40.6%) males and 79 (59.4%) females) participated in this study, and all questionnaires were included in the study. The mean patient age was 50.8 years (SD 14.7) for the whole population, 50.7 years (SD 14.8) for the males, and 51 years (SD 14.7) for the females. Surgery was performed in 22 maxillary anterior teeth (16.5%), 29 maxillary premolars (21.8%), 37 maxillary molars (27.8%), 3 mandibular anterior teeth (2.3%), 5 mandibular premolars (3.8%), and 37 mandibular molars (27.8%).p < 0.001). Subsequent pairwise comparisons indicated that the mean OHIP-14 scores decreased significantly throughout the week. Only the mean scores from day 5 and day 6 did not differ significantly (p = 0.11), whereas all the mean scores on the other days differed significantly from each other (p < 0.05). No significant differences in mean OHIP-14 scores were found for gender, ASA score, surgical flaps, or operation time. Smokers had a significantly higher OHIP-14 score on the first postoperative day than non-smokers. Patients who had a postoperative infection had a significantly higher OHIP-14 score on the fifth postoperative day. Younger patients had a significantly higher OHIP-14 score on the first 2 postoperative days compared to the older patient groups. Figure p = 0.84; day 2, p = 0.34; day 3, p = 0.27).Of the 133 returned questionnaires, the mean overall OHIP-14 score was determined for postoperative days 1 to 7 (Table p < 0.001). Subsequent pairwise comparisons showed that the mean NRS scores decrease significantly throughout the week. Only the mean scores from day 3 and day 4 did not differ significantly (p = 0.15), whereas all the mean scores on the other days differed significantly from each other (p < 0.05).Repeated measures were used to determine mean scores over time for pain from postoperative days 1 to 7. Repeated measures ANOVA was used to analyze mean NRS scores collected each day during the first postoperative week Table . We founp = 0.30; day 2, p = 0.32; day 3, p = 0.29). Figure Women and smokers experienced significantly more pain during the first 3 days. Younger patients had a higher pain score compared to older patients on the first postoperative day. We found no significant interaction effect during the first postoperative week for pain scores and ASA group, surgical flaps, location of teeth, or operation time. Comparing the second molar region with the other locations, we found no significant differences during the week for the NRS pain scores, or even during the first 3 days . Subsequent pairwise comparisons show that the mean analgesic use decreased significantly throughout the week. Only the mean scores from days 4 and 5 and days 6 and 7 did not differ significantly (p = 1.00), whereas all of the mean scores on the other days differed significantly from each other (p < 0.05). We found no significant interaction effect during the first postoperative week for mean analgesic intake and gender, ASA group, smokers, surgical flaps, operation time, or location of teeth. Figure Repeated measures were used to determine mean scores over time for pain from postoperative days 1 to 7. Repeated measures ANOVA was used to analyze mean analgesic intake each day during the first postoperative week Table . We founTables A significant difference in mouth opening was found on days 2, 3, and 4 for teeth surgically treated in the lower jaw. Postoperative swelling persisted longer in mandibular locations, especially the molars, and was significant on days 5, 6, and 7. Limitations in mouth opening were reported significantly more in females on the first postoperative day and in the ASA I group on the third postoperative day.Seven (5.3%) patients with a postoperative infection presented with increasing swelling at the surgical site on postoperative day 6. The abscess was drained, followed by a 5-day oral course of 500 mg amoxicillin three times a day. The patients with a postoperative infection had a significantly higher OHIP-14 score on the fifth postoperative day and a significantly higher pain score on the sixth postoperative day, which corresponded with the day that the abscess was drained Tables .In the present study, we assessed how periapical surgery affects postoperative OHRQoL and found the greatest effect of periapical surgery on OHRQoL and NRS pain scores during the first postoperative day, gradually decreasing through the first postoperative week. Compared to earlier studies on postoperative OHRQoL and pain after third molar surgery, periapical surgery only had a mild to moderate effect during the first postoperative week –21. ThisPostoperative pain is not uncommon following periapical surgery, and is usually of short duration, with a maximum intensity either on the day of the surgical procedure or the next day , 9, 14. The postoperative mean pain score is influenced by the analgesics taken by patients and, as such, does not truly reflect the real pain caused by the surgery. To obtain a real measurement of the pain after periapical surgery, patients should refrain from taking analgesics; however, as pointed out by Seymour et al., this approach would be unethical .The NRS pain score exhibited a significant gender difference in the first 3 days, with women experiencing more pain, but this did not affect the OHRQoL. The mean differences in OHIP-14 score were not significantly different between males and females; however, the slightly higher pain with less impact on OHRQoL observed in women may be explained by women being better at managing pain than men . TherefoIn the present study, the younger age group < 25 years) experienced a greater effect of periapical surgery during the first 2 days and more pain during the first postoperative day. This finding is in contrast to other studies that did not find any significant effect of age on postoperative symptoms after periapical surgery  years ex, 9, 10. In the present study, ibuprofen was used as an analgesic in younger patients and paracetamol in the ASA II group and older patients. No significant differences were found in the use of analgesics between gender, age groups, smokers or non-smokers, flap design, or location. In the present study, 85.7% of the patients reported using analgesics on the first postoperative day. This decreased during the week and, on the seventh postoperative day, 23.3% of the patients used analgesics. Earlier studies reported that 63–67% of the patients took analgesics, which meant that some patients did not take them even though pain was reported , 7.Surgical operation time, ASA classification, and flap design did not significantly impact OHRQoL and NRS pain scores during the first postoperative week. Seymour et al. also failed to find a correlation between operating time and postoperative pain. Studies have reported great variety in operation time, from a mean of 25 min to a time of 140 min for a single-rooted tooth , 12, 14.We found that smokers had a significantly higher OHIP-14 score on the first postoperative day than non-smokers. In addition, smokers experienced significantly more pain during the first 3 days. Garcia et al. also found that smokers experienced greater pain throughout almost the entire first postoperative week .In the present study, the operation site had no significant influence on postoperative OHRQoL or pain. This finding is in agreement with other studies , 12, 14.Swelling is common following surgical periapical treatment. In the present study, swelling was significantly different between genders on postoperative days 1 and 4, with women reporting more swelling. Postoperative swelling persisted longer in mandibular locations and was significant on days 5, 6, and 7. Previous reports found that the maximum swelling is experienced on the first postoperative day  and patiSeveral earlier studies used some form of antibiotic prophylaxis for periapical surgical procedures , 12, 17.This study has some limitations. First, only asymptomatic cases were included; therefore, no conclusions can be drawn about the impact on OHRQoL in cases of acute periapical surgery. Second, we did not use an operating microscope in the periapical procedure. An operating microscope is used for optimal identification of root canals, fractures, and isthmuses , and somAnother limitation of the present study is that, although the OHIP-14 is a reliable and validated tool to measure OHRQoL, data acquired from the patients are self-reported. The usual disadvantage with questionnaires is that data acquisition is subjective, and the data cannot be controlled. As such, some bias may be present , 24. FacWe identified a low incidence of postoperative pain and reduced OHRQoL following periapical surgical treatment. The postoperative reduction in OHRQoL and pain were of short duration, with maximum intensity in the early postoperative period and decreasing with time.


Chronic pain has been not recognized as a chronic illness, and its far-reaching impacts are often ignored. Chronic noncancer pain (CNCP) is a chronic disease and health care professionals need recommendations on how to monitor treatments, patients and long-term side effects of the different medications used to control CNCP.CNCP patients make up a vulnerable population due to the various associated pathologies and the challenging socio-economic conditions experienced by many of these patients. CNCP is more common among older adults, females, cancer survivors, indigenous peoples, veterans, and populations affected by social inequities and discrimination. These social determinants can lead to a complex interplay between chronic pain, mental illness, and substance use disorders. Given these realities, long-term pharmacological and side effect surveillance is more complex.Follow-up of patients with CNCP is a challenge for physicians, and thus it is important to provide recommendations on how to monitor treatments and long-term side effects of the different medications used to control CNCP. Pain continues to be one of the main reasons for medical consultation worldwide. Chronic noncancer pain (CNCP) is a common condition considered to be an epidemic with major social and economic impacts -4. AccorMultimodal analgesia includes the use of two or more drugs that act via different mechanisms to provide analgesia. The aim of multimodal analgesia is to reduce opioid requirements, improve pain relief, and decrease side effects. As physicians move away from an opioid-centric model in pain management, the focus has shifted to multimodal analgesia.Considering its multifactorial etiology, the treatment of CNCP requires a comprehensive, integrated, and multifaceted model of care. Most treatment guidelines recommend multimodal therapy -8. The pThe objective of this update was to gather appropriate monitoring parameters for the long-term management of patients suffering from CNCP and provide family physicians with a practical and comprehensive overview to help guide follow-up.Quality of evidenceThis article is a literature review and presents an approach for monitoring the potential side effects of medications used in the long-term treatment of patients with CNCP. The relevance of the article was identified after an internal audit of 85 medical charts at a tertiary care center pain clinic  revealed that only 16% of the patients had received adequate screening for hypogonadism. This result led us to consider the likelihood that, if physicians working in a tertiary care university center are not carrying out adequate monitoring for long-term side effects of pharmacological treatments used to control CNCP, other medical specialists and family doctors are probably not carrying this out either.Unfortunately, at this time there is a lack of evidence-based recommendations for the monitoring of patients being treated for CNCP. This article presents a concise summary of the essential elements that should be monitored for all patients receiving treatment for CNCP to help palliate this lack of guidelines.Long-term treatment regimens that combine co-analgesics such as antidepressants and anticonvulsants with opioids, even at lower doses, require long-term surveillance. Indeed, this patient who receives small doses of three or more drugs must be monitored for possible alterations in cognitive function, mood, concentration, gastrointestinal function, hypothalamic-pituitary-adrenal-gonadal axis (HPAG axis), sexual function, and osteoporosis.Taking into consideration that multimodal analgesia is the most used for the treatment of CNCP, we propose that the most important factors to monitor from the pharmacological point of view in the long-term follow-up of patients treated for CNCP are the following: oral hygiene, chronic constipation, and narcotic bowel syndrome (NBS), cardiovascular opioids effects, effects on the immune system, sleep and somnolence, respiratory depression, substance use disorders, and addiction, HPA axis and hypothalamic-pituitary-gonadal axis (HPGA) axis dysregulation, mental health and lack of exercise Figure .Oral hygieneMost medications used to treat pain decrease saliva production and the oral mucus can, therefore, be very dry. Physiologic amounts of salivary secretions are essential for oral health. Saliva influences various processes in the oral cavity such as protection from cavities, as well as digestive and immunologic functions .Opioid use increases the risk for a variety of oral health conditions, including dental caries and periodontitis. Furthermore, opioids have been shown to directly induce heightened cravings for sweet carbohydrates . It is iChronic constipation and NBSThe multimodal approach also introduces multiple potential sources for constipation since many drugs used as coanalgesics can cause constipation. Chronic constipation is defined as having two or more of the following symptoms in the last 12 months: lumpy or hard stools, fewer than three defecations per week, the sensation of incomplete evacuation, and/or anorectal obstruction/blockage and need for manual maneuvers to facilitate defecation .NBS is characterized by chronic or frequently occurring abdominal pain that worsens with continued or escalating doses of opioids . This paIn addition, the lack of regular physical activity often observed in patients with CNCP is another factor that can contribute to constipation.Cardiovascular opioid effectsAlthough opioids have been used in the treatment of CNCP for decades, only a few studies have looked specifically at the relationship between opioid use and cardiovascular effects . SeveralInteraction with other medicationsWhen treating patients with multiple comorbidities, the use of different medications increases the potential for drug interactions. Pharmacological treatment in CNCP, therefore, requires vigilance regarding potential drug interactions. Noting that this is not meant to be a comprehensive review of all possible interactions, some of the most frequent interactions seen in the follow-up of patients treated for CNCP are highlighted here.Drug-drug interactions are well recognized and are classified into three types: pharmacokinetic, pharmacodynamics, and pharmaceutical. Certain antidepressants combined with opioids can increase the risk of serotonin syndrome . Other mIt is important to note that methadone, meperidine, and fentanyl inhibit the reuptake of serotonin and their use with certain antidepressants can contribute to serotonin syndrome. Furthermore, methadone plasma concentrations can be increased by concurrent use of certain antimicrobials , certain antidepressants (fluoxetine and amitriptyline) as well as certain antipsychotics such as quetiapine.The most frequent interactions between medications commonly used for pain management and other medications involve opioids, SSRIs, benzodiazepines, phenothiazine, dexamethasone, imidazole, thyroxine, furosemide, and anticonvulsants.Effects on the immune systemGiven that many chronic pain patients tend to be elderly and present multiple comorbidities, potential immunosuppression in these patients needs to be considered.It has been well documented that with chronic stress (and chronic pain as a variant) and chronic inflammation, the interaction of the nervous, endocrine, and immune systems can contribute to potential depressive symptoms. In addition, depression and the use of antidepressants can negatively impact the immune system ,19.Opioids directly affect the μ-opioid receptor on all immune cells. They may also modulate the immune function indirectly through glucocorticoids released by the hypothalamic-pituitary-adrenal (HPA) axis and norepinephrine released by the sympathetic nervous system.Sleep and somnolenceA large majority of patients with CNCP suffer from insomnia and sleep disorders. In addition, several studies report an alarming relationship between sleep apnea and opioid use, as well as instances of death due to opioid overdose.Orally administered opioid drugs, even at low doses, decrease time spent in the deep stages of sleep, with an accompanying increase in stage 2 sleep. The change in deep sleep is remarkable, as it represents a 30% to 50% decrease in stage 3 and stage 4 sleep .There is evidence to support the benefits of antidepressants and anticonvulsants with improvements in pain scores, sleep, and quality of life. However, these benefits come at the expense of increased daytime somnolence as well as possible alterations in HPGA function with long-term use.Respiratory depression Respiratory depression remains the most serious potential side effect of opioids with an ultimate risk of death. The mechanism of opioid-induced respiratory depression involves Mu opioid receptor inhibition of the brainstem respiratory control centers impacting both rate and depth of respiration, eventually resulting in increased arterial partial pressure of carbon dioxide and reduced partial pressure of oxygen . This riAll opioids combined with benzodiazepines, antidepressants, anticonvulsants, and muscle relaxants can lead to serious side effects including respiratory distress.HPA axis and HPGAThe HPA axis is involved in the neurobiology of mood disorders, including depression and bipolar disorder, posttraumatic stress disorder, anxiety disorder, ADHD, borderline personality disorder, and addictions including alcoholism. The HPA is implicated in other functional diseases like irritable bowel syndrome and chronic fatigue among others ,23.All opioids, endogenous and exogenous, modulate gonadal function primarily by acting on opioid receptors in the hypothalamus. Hypogonadism can lead to irregular menstrual cycles or amenorrhea in women, erectile dysfunction in men, infertility, and decreased libido in both sexes. Symptoms like flushing, sweating, lethargy, sleep disturbance, loss of body hearing, decreased muscle mass, osteopenia or osteoporosis, and depression are also common in both sexes. Hypogonadism secondary to opioids is more prevalent in men than in women and opioid-induced hypogonadism in CNCP is underrecognized and undertreated. According to some authors, the prevalence may be higher in patients receiving high doses of opioids, especially via the intrathecal route ,23.The HPA axis is also affected by many other medications used to control CNCP including antidepressants, and anticonvulsants  which arMental healthAccording to the World Health Organization (WHO), mental health is a “state of well-being in which the individual realizes his or her own abilities, can cope with the normal stresses of life, can work productively and fruitfully, and is able to contribute to his or her community” .Co-morbidities that can accompany chronic pain include depression, anxiety, borderline personality disorder, and adult attention-deficit/hyperactivity disorder (ADHD) among others. CNCP pain is a significant risk factor for the development of a mental health disorder in the adult general population -27.There are an increasing number of patients with chronic pain who present with symptoms of ADHD. Recent studies suggest that up to 80% of adults with ADHD have generalized pain, as compared to 17.4% in a control population .Substance use disorders and addictionThe abuse of opioid prescriptions has been in the media spotlight in recent years. This attention has contributed to the stigmatization and social isolation of patients who require these drugs to help control their CNCP. While it remains imperative that we avoid being opiophobic or opiophilic, opioids can be used to treat chronic pain responsibly by providing adequate information to our patients -31. TherThe inappropriate use of opioids will always exist, and it is our duty to inform our patients of this risk and establish guidelines for use. Despite popular belief, the majority of patients followed in pain centers for CNCP are not at high risk of misuse/abuse, nor are they taking inappropriate amounts of opioids .Lack of exerciseAccording to the WHO “Regular physical activity is proven to help prevent and treat noncommunicable diseases (NCDs) such as heart disease, stroke, diabetes and breast, and colon cancer. It also helps to prevent hypertension and obesity, and can improve mental health, quality of life and well-being.”Numerous articles highlight exercise as an important part of long-term pain management. Current evidence suggests physical activity and exercise is an intervention with few adverse events that may improve physical function, decrease pain severity, and enhance the quality of life -35.Finally, Table Chronic pain sufferers make up a vulnerable population of patients, often presenting multiple health challenges that must be monitored and treated accordingly to improve quality of life.Within an integrative approach, rigorous surveillance of the medium and long-term side effects of the medications used to control the CNCP needs to be implemented.We consider this article to be important, an opportunity to present and summarize the parameters to be monitored when treating a patient with CNCP. Unfortunately, to date,, there are no evidence-based recommendations to support monitoring strategies in patients treated for CNCP.


IntroductionTesticular pain is one of the common conditions in patients visiting the emergency department. The causes of acute testicular pain vary from non-urgent inflammatory conditions like epididymo-orchitis to testicular torsion which is a surgical emergency. Early diagnosis of testicular torsion with early initiation of appropriate surgical intervention helps in salvaging the testes. There is a need for a simple, rapid bedside diagnostic tool for the evaluation and triaging of subjects with acute testicular pain in the emergency department. The aim of this study is to determine whether hand-held Doppler (HHD) examination by the emergency department (ED) physician can safely rule out testicular torsion in a case of acute testicular pain.Materials and MethodsA prospective pilot study was conducted in the emergency department of Alkhor Hospital, Hamad Medical Corporation, Qatar. The subjects between 18 to 50 years of age who presented to the ED with testicular pain were included. Subjects with recent trauma to the scrotum, or recent genitourinary surgery and those who had pain for more than 48 hours were excluded. Point-of-care HHD was done by a single ED physician who was blinded for the Doppler study results done by the radiologist. The results of the HHD performed by the ED physician and Doppler study performed by the radiologist were compared and analyzed.Results Forty-five patients were included in the study. The mean age was 28 years and the mean duration of pain was 20 hours. HHD ruled out testicular torsion in 44 subjects with a specificity of 97.8%. In one subject, HHD was reported as torsion testis which was ruled out by the radiologist. The radiologist Doppler ruled out torsion in all 45 subjects.ConclusionThe diagnostic performance of HHD by the ED physicians was almost equal to that of radiologists in ruling out testicular torsion. HHD can be used as a first-line triaging tool by the ED physician to rule out torsion of testis in patients presenting with acute testicular pain. We conclude that patients with testicular pain with a negative HHD for torsion testis can be safely discharged from the emergency department. Acute testicular pain is a common condition encountered by emergency physicians. Testicular torsion is a surgical emergency that needs to be considered in the differential diagnosis of acute testicular pain. Early diagnosis and appropriate intervention will help to salvage the organ. The estimated yearly incidence of testicular torsion was 5.9 per 100,000 between the age group one to 17 years and 1.3 per 100,000 in those older than 18 -6. TheseThis study was conducted to determine the usefulness of HHD as a triaging tool for acute testicular pain by ED physicians, and the results were compared with those of Doppler examinations performed by a radiologist . The objStudy design and settingsA prospective pilot study was conducted in the emergency department of AlKhor Hospital, Hamad Medical Corporation, Qatar. Patients were enrolled from April 2018 to January 2020.Study patientsThe study included patients between 18 and 50 years of age who presented to the ED with testicular pain as a primary complaint. Patients who had pain for more than 48 hours, recent trauma to the testes, or recent genitourinary surgery were excluded from the study.Study protocolPatients presenting with acute testicular pain to the ED were triaged to the observation room by a triage nurse and assessed by an ED physician. The research protocol was initiated when the ED physician requested Doppler ultrasound by the radiologist to further evaluate acute testicular pain. The patients were screened by a research team member for the eligibility criteria. If eligible, they were enrolled in the study after obtaining informed consent. All patients were evaluated for a brief history, and a clinical examination was performed. History included duration and site of pain, fever, associated scrotal swelling, urinary complaints, and recent scrotal trauma or surgery. Clinical assessment included the area of tenderness, position of the testes, local erythema, and swelling. Laboratory investigations included urine analysis and complete blood cell counts.HHD was performed by a single investigator who was an ED physician, and the findings were recorded. After the Doppler examination was performed by the radiologist and the results were documented, the HHD report was compared with that of the radiologist.The investigatorsThe HHD study was performed by a single ED physician who was trained and certified in a point-of-care ultrasound course conducted by Hamad Medical Corporation. Since the HHD was performed and documented in the patient’s electronic file before the Doppler examination by the radiologist, the investigator was blinded to the radiology Doppler report. The device (HHD)A BISTOS Hi-dop BT 200 Vascular Doppler  with an 8-MHz probe was used for the study.Study methodologyHHD examination of the testes was performed with the patients in the supine position with the thighs abducted, and the testes were appropriately supported. The HHD examination was first performed on the unaffected side. The probe was initially placed over the upper pole of the testis and epididymis and then moved from medial to lateral to identify the testicular artery Doppler signals. In each of these regions, Doppler audio signal intensity was observed. The affected side was then examined similarly, and the audio signal intensity was compared with that of the normal side.InferenceAn increase in the Doppler audio signal intensity indicated increased blood flow to the region, suggesting inflammatory conditions such as epididymitis, orchitis, or epididymo-orchitis. On the contrary, diminished or absent Doppler audio signals indicated decreased or absent blood flow to the region, which is strongly diagnostic of testicular torsion.The findings of HHD were documented in the patients’ electronic file to indicate possible testicular torsion or an inflammatory condition. The HHD results were compared with the radiologist's Doppler report, and the statistical significance was analyzed.Ethical considerationThe study protocol was approved by the Institutional Review Board of Medical Research Center, Hamad Medical Corporation A total of 45 patients were included in the study. The mean age was 28 years (range 18-50 years), and the mean duration of pain was 20 hours. The majority of the patients had pain on the left side. Barring one patient, HHD performed by the ED physician was negative for testicular torsion. In contrast, the radiologist found all of the patients to be negative for testicular torsion Table .The mean duration of performing and reporting the results of HHD was 20 minutes, whereas it was 2 hours and 40 minutes for the Doppler examination performed by the radiologist.Forty-four patients were discharged with medication. One patient was admitted for further workup because the radiology Doppler indicated a possible testicular tumor which was subsequently diagnosed as testicular malignancy.By detecting the audible testicular artery signal at the level of the spermatic cord and upper level of the testis, HHD correctly excluded torsion in 44 cases with a specificity of 97.8%. Since testicular torsion was not encountered in the present study, other statistical variables could not be measured.Our findings revealed that HHD, by detecting the audible testicular artery signal at the level of the spermatic cord and in the region just above the testis, excluded testicular torsion with a specificity of 97.8%. Although very few studies have been conducted on this subject, our results confirmed the results of previous studies. Shaikh et al., who studied the role of HHD in patients with testicular pain lasting less than 24 hours, had found that HHD had a sensitivity and specificity of 100% in diagnosing and excluding testicular torsion . In anotOne patient in the present study who was diagnosed with testicular torsion by HHD was found to be negative for torsion by the radiologist. On reviewing this patient, it was found that a thickened and edematous spermatic cord was likely the reason for the failure of HHD to detect the artery signal.Point-of-care examination of the testes by HHD in the ED, for patients with acute testicular pain, has a wide range of clinical implications. Firstly, in routine practice, most of the patients with acute testicular pain are referred to the radiology department for Doppler ultrasound by ED physicians, despite relative certainty that the given condition is not testicular torsion on clinical examination. Referring all patients with testicular pain to the radiology department for Doppler ultrasound is not feasible and might delay the disposition of such patients from the ED. Hence, in patients with a positive testicular artery signal by HHD, unnecessary referral to the radiologist for Doppler ultrasonography can be avoided, which not only reduces the burden on the radiology department but is also cost-effective. Secondly, by ruling out testicular torsion, decisions about the management and disposition of patients with testicular pain can be made early. If HHD signals are clear, it most likely rules out testicular torsion, and these patients can be discharged from the ED with conservative management and outpatient clinic referrals -12. On tSignificance of the studyThe uniqueness of this study is that only limited studies have been conducted on the use of HHD for acute testicular pain, and no study has compared HHD with the Doppler ultrasound performed by the radiologist.LimitationsThe main limitation of the study was that none of our patients had testicular torsion; hence, the sensitivity of HHD in diagnosing torsion testes could not be ascertained. This could be due to the very low incidence of testicular torsion in this region. Another reason could be that the research was conducted in the adult ED, which excluded patients below 18 years of age. The incidence of testicular torsion is much higher in younger patients than in adults. Moreover, HHD was performed by a single researcher, and most of the cases were recruited during his work shifts. This further reduced the likelihood of recruiting cases of testicular torsion. Another limitation was the subjective nature of this investigative modality.HHD can be used as a first-line triaging tool by the ED physician to rule out testicular torsion in patients presenting with acute testicular pain. In addition, with minimal training required for the physicians, it can be a valuable tool to rule out testicular torsion in centers with poor healthcare resources. However, more extensive multi-center studies are needed to validate whether HHD can be used in day-to-day clinical practice to augment bedside clinical examination. Further studies with larger populations are also needed to ensure that an adequate number of testicular torsion cases are included to determine the usefulness of HHD.


Our objective was to evaluate the impact of multimodal analgesia based enhanced recovery protocol on quality of recovery after laparoscopic gynecological surgery.One hundred forty female patients scheduled for laparoscopic gynecological surgery were enrolled in this prospective, randomized controlled trial. Participants were randomized to receive either multimodal analgesia (Study group) or conventional opioid-based analgesia (Control group). The multimodal analgesic protocol consists of pre-operative acetaminophen and gabapentin, intra-operative flurbiprofen and ropivacaine, and post-operative acetaminophen and celecoxib. Both groups received an on-demand mode patient-controlled analgesia pump containing morphine for rescue analgesia. The primary outcome was Quality of Recovery-40 score at postoperative day (POD) 2. Secondary outcomes included numeric pain scores (NRS), opioid consumption, clinical recovery, C-reactive protein, and adverse events.P = 0.033). In the Study group, NRS pain scores, morphine consumption, and rescue analgesics in PACU  were lower, time to ambulation  and time to bowel function recovery  were shorter, C-reactive protein values at POD 2 was lower  and patient satisfaction was higher .One hundred thirty-eight patients completed the study. The global QoR-40 scores at POD 2 were not significantly different between groups, although scores in the pain dimension were higher in Study group (32.1 ± 3.0 vs. 31.0 ± 3.2, For minimally invasive laparoscopic gynecological surgery, multimodal analgesia based enhanced recovery protocol offered better pain relief, lower opioid use, earlier ambulation, faster bowel function recovery and higher patient satisfaction, while no improvement in QoR-40 score was found.ChiCTR1900026194; Date registered: Sep 26,2019. Enhanced recovery after surgery (ERAS) is a standardized, multidisciplinary protocol delivered to surgical patients aimed to reduce stress response, improve patient recovery and optimize surgical outcome after surgery. The ultimate endpoint of this program is to allow patients to restore functional capacity and resume daily activities rapidly. The ERAS protocols have been adopted for colorectal, gastric, urologic and pancreatic surgeries and improved patient outcomes including fewer complications, shorter length of hospital day and lower costs have been demonstrated –4.Laparoscopic surgery is a minimally invasive procedure and an increasing number of gynecological surgeries are performed laparoscopically. Though less trauma injury, significant abdominal and shoulder pain is common during the early postoperative period and strong analgesics including opioids are required . At the Some retrospective studies have described the implementation of ERAS program for gynecological surgery and revealed outcomes focus on length of stay, narcotic requirement, and hospital cost. No randomized controlled trials have investigated the effect of an enhanced recovery pathway on patient quality of recovery (QoR) for laparoscopic gynecological surgery –10.Thus, the primary goal of this randomized clinical trial was to investigate if multimodal analgesic regimen, as a part of enhanced recovery protocol, could improve patient recovery after gynecological laparoscopy. The Quality of Recovery 40 (QoR-40) questionnaire is a valid and reliable measurement used to assess the degree of recovery after different surgical types and anesthetic techniques. It provides a patient-assessed health status through five dimensions. We hypothesized that multimodal analgesic regimen would improve patient-reported recovery when compared with conventional pain control method. The primary outcome was QoR-40 score assessed at postoperative day (POD) 2. Secondary endpoints were morphine consumption, pain scores, time to functional recovery, serum marker of the surgical inflammatory response, and incidence of PONV during the first 48 h after surgery.This was a prospective, randomized clinical trial. This study was approved by the Ethics Review Board of Peking University First Hospital, Peking, China (No. 2019–173) in August 2019 and written informed consent was obtained from all patients before enrollment in the study. The trial was registered prior to patient enrollment at Chinese Clinical Trial Registry . This manuscript adheres to the applicable CONSORT guidelines.2) or bowel disease, current use of corticosteroid or opioid analgesic, allergy or contraindication to any drug used in the study, pregnant, breasting, or refuse to participate the study.Female patients aged 18–65 years old with American Society of Anesthesiologists (ASA) physical status I-II, scheduled for elective laparoscopic gynecological surgery for a benign indication were assessed for eligibility. Exclusion criteria were ASA physical status III or more, pre-existing hepatic , renal  were applied in both groups. All patients received general anesthesia and mechanical ventilation. Induction of anesthesia was performed with midazolam 0.03 mg/kg, propofol 1.5-2 mg/kg and remifentanil target effect site concentration 3 ng/ml. Rocuronium 0.6 mg/kg was administered to facilitate the Supreme laryngeal mask insertion. Anesthesia maintenance was achieved with continuous infusion of propofol 5–6 mg/kg/h and remifentanil 3-4 ng/ml, titrated to maintain mean blood pressure within 20% of baseline, and BIS values between 40 and 60. Oxygen and air were administered in a ratio of 1:1 and ventilation was controlled to maintain an end-tidal carbon dioxide partial pressure between 35 and 55 mmHg. The maintenance fluid was Lactate Ringer’s solution. Intraoperative fluid administration was based on change in hemodynamic parameters throughout the surgery. Dual antiemetic agents were given, including dexamethasone 5 mg after induction and tropisetron 5 mg prior the end of the surgery. All procedures were performed by two senior gynecological surgeons to ensure conformity. On completion of surgery, patients were extubated and transferred to the post-anesthesia care unit (PACU) for observation.Patients in the Study group received multimodal pain regimen, including oral acetaminophen 650 mg and oral gabapentin 600 mg 2 h before surgery, 1% ropivacaine 10 ml trocar areas infiltration after skin closure, two doses of intravenous flurbiprofen 50 mg (at the end of surgery and 6 h postoperatively), oral acetaminophen (650 mg every 8 h) and celecoxib (200 mg every 12 h) on postoperative day (POD) 1–2. Following elements of ERAS program were also applied: no mechanical and oral bowel preparation, clear carbohydrate beverage (5 ml/kg) allowed up to 2 h before surgery, fluids limited to less than 2 L of crystalloids, normothermia maintained, early oral diet and early ambulation.Patients in the Control group received our conventional analgesia. A single dose of intravenous flurbiprofen 50 mg was administered 30 min before the end of the procedure. Preoperative intervention included routine bowel preparation and no oral fluid was allowed prior to surgery.During the first 48 h, all patients were provided morphine patient-controlled analgesia (PCA) for rescue analgesia . Pain intensity was assessed using an 11-point numeric rating scale  by an investigator blinded to group allocation. Additional IV morphine was given for NRS pain score ≥ 4. Sedation levels were assessed using the Ramsay sedation scale . Over sedation was defined as a sedation score ≥ 4 ), and analyzed using the Mann–Whitney U test. Categorical variables were described as number (percentage) and analyzed using the Chi square test or Fisher’s exact test as appropriate. For postoperative cumulative morphine consumption and NRS scores, a Bonferroni correction for multiple between-group comparisons was used to control for false positive rates.The Shapiro-Wilk and Kolmogorov-Smirnov tests were used to test the hypothesis of normal distribution. Normally distributed continuous variables were described as means ± standard deviation (SD), and analyzed with a two-sided independent P value less than 0.05 was considered statistically significant. For cumulative morphine consumption and NRS scores, 4 comparisons were adjusted and P value less than 0.05/4 = 0.013 was considered statistically significant.All statistical analysis was performed using the SPSS 22.0 software . A two-sided The sample size was calculated according to data from previous studies –17. Amonn = 1 patient, Study group) or protocol violation . The CONSORT flow diagram was presented in Fig. Of the one hundred and forty-six patients assessed for eligibility, six patients were excluded because of not meeting inclusion criteria. One hundred and forty subjects were randomized and 138 completed the study. Two patients were excluded after enrollment due to lost to follow-up (P = 0.338). Nonetheless, when the five dimensions was analyzed separately, the score in the pain dimension was higher in the Study group  . In PACU, more patients in the Control group required rescue analgesics for moderate pain . Total morphine consumption throughout the study period was significantly less in the Study group when compared with the Control group .Comparing with the Control group, the NRS pain scores were significant lower in the Study group at all time points postoperatively (P = 0.507)]. In addition, the rate of rescue antiemetic medication, adverse events such as fever and dizziness were also similar between study groups (Table There was no difference between the two groups regarding the incidence of PONV  and time to return of bowel function  were shorter, CRP values on POD2 was lower , and patient satisfaction was higher  in the Study group.  h vs. 6.5 5.0–14.8) h; .8 h; P =This prospective randomized clinical trial investigated the impact of multimodal analgesia, as a part of enhanced recovery protocol, on quality of recovery after laparoscopic gynecological surgery. Our results revealed similar global QoR-40 score on POD 2 in multimodal analgesic group, although better pain relief, lower morphine consumption, earlier ambulation, and faster bowel function recovery were achieved when compared to conventional opioid analgesic group.P = 0.361) respectively. Another study also showed no significant difference in QoR-40 scores when utilizing the TAP block on laparoscopic hysterectomy patients. The overall QoR-40 score was 168 (125–195) in the transverses abdominis plane (TAP) block versus 169.5 (116–194) in the no-block group [The QoR-40 questionnaire is a valid and reliable measurement used to assess the degree of recovery after different surgical types and anesthetic techniques. It provides a patient-assessed health status through five dimensions. A negative association between the global score and duration of hospital day was demonstrated in different types of surgery . Contrarck group .Postoperative pain can potentially influence QoR-40 scores , 21. TwoMultimodal analgesic strategy with nonopioids analgesic results in better analgesia, less opioid use, and enhanced recovery. Beneficial effects after laparoscopic surgery have been shown in previous studies. Kell and colleagues  performeIn our study, we used a multimodal analgesic protocol including acetaminophen, gabapentin, ropivacaine, NSAIDs and dexamethasone in study group. Wound infiltration with local anesthetics decreased abdominal pain, and systemic inflammatory pain may be controlled by NSAIDs and corticosteroids. Consequently, we found lower pain score, less opioid use, lower CRP value, shorter time to ambulation, and faster bowel function recovery in multimodal analgesic group.However, we failed to demonstrate any improvement in QoR-40 score when utilizing multimodal analgesic protocol on laparoscopic gynecological patients. We speculated that the negative result might be attributed to overall low pain scores in minimally invasive laparoscopic surgeries. Our results showed that pain intensity was maximal in the first 6 h after surgery, and gradually declined to low levels within the first 2 days of surgery. Although one point difference in pain score was statistically significant, it was likely not clinically significant thus make difference in quality of recovery.Additionally, it is important to note that, not only nociceptive stimulus from tissue trauma, but also other factors such as socio-culture and individual characteristics may affect subjective pain perception. Wolmeister and colleagues  demonstrThere are some limitations to this study. First, this was a single-center study, and our cohort was relatively young. We excluded patients with significant comorbidities or chronic pain conditions. Hence, potentially greater benefits may have been found if more diverse patients had been included. Secondly, since preoperative QoR-40 scores may not be suitable for comparing recovery after surgery, multiple postoperative evaluations would be better for obtaining meaningful results. Future studies should focus perioperative psychological factors to further improve postoperative quality of recovery.For minimally invasive laparoscopic gynecological surgery, multimodal analgesia based enhanced recovery protocol offered better pain relief, lower opioid use, earlier ambulation, faster bowel function recovery and higher patient satisfaction, although no improvement in QoR-40 score was found.