Background: Although major joint replacement surgery has a high overall success rate, postoperative cognitive dysfunction (POCD) is a common complication after anesthesia and surgery, increasing morbidity and mortality. Identifying POCD risk factors would be helpful to prevent and decrease the occurrence of POCD. We hypothesized that preoperative chronic pain increases the risk of POCD.Methods: A single-center, observational, prospective cohort study was conducted from January 2018 to March 2020. All consecutive elderly patients (>65 years) who underwent elective total hip arthroplasty or hemiarthroplasty with general anesthesia by the same surgeon were enrolled. The patients underwent neuropsychological testing preoperatively and at 7 days and 2 months after surgery. To determine POCD, a nonsurgical control group was recruited from the general community.Results: Of the 141 patients who finished the neuropsychological testing 7 days after surgery, 61 (43.2%) had preoperative chronic pain. Of the 61 patients, 17 (27.9%) developed POCD; of the 79 patients with no chronic pain, 10 (12.7%) had developed POCD by 7 days after surgery. Multivariate logistic regression analysis identified preoperative chronic pain as a risk factor of POCD assessed 7 days after surgery . There was no significant difference in the POCD incidence 2 months after surgery between patients with and without preoperative chronic pain.Conclusion: Preoperative chronic pain was a risk factor of developing POCD within 7 days after surgery in elderly patients following hip joint replacement surgery.Clinical Trial Registration: [www.ClinicalTrials.gov], identifier [NCT03393676]. Major joint replacement surgery is one of the most common elective procedures and is performed primarily in elderly adults. After major joint replacement surgery, the majority of patients experience substantial relief from both functional disability and pain. Despite the overall success of major joint replacement surgery, patients undergoing this surgical procedure still remain susceptible to cognitive decline, termed POCD, reported rates of which varied between 7% and 75% depending on the definition, assessment tools used, and the population being studied . POCD caSeveral factors have been shown to be risk factors of POCD after hip and knee surgery, including the effects of anesthetics , increasThe International Association for the Study of Pain defines pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage” . The IASIt is known that pain directly impairs cognitive function . AdditioClinicaltrials.gov: NCT03393676). Written informed consent was obtained from all patients. All investigators were well trained in neuropsychological testing and pain evaluation.A single-center, prospective, observational cohort study was conducted in Renji Hospital, School of Medicine, Shanghai Jiao Tong University , from January 2018 to March 2020. The study was conducted in accordance with the Declaration of Helsinki and was approved by the local ethics committee (RJ198K)  >65 years old, (2) speaks Chinese Mandarin, (3) planned to undergo major low limb surgery such as elective total hip arthroplasty or hemiarthroplasty with general anesthesia, (4) signed the informed consent form, and (5) assessed as ASA classifications I to II.The exclusion criteria included the following: (1) existing cerebral disease or a history of neurological and psychiatric disease, including psychosis, stroke, epilepsy, and Alzheimer’s disease; (2) existing cognitive impairment as evidenced by the MMSE scores less than 24; (3) severe hearing or visual impairment; (4) unwillingness to comply with the protocol or procedures; (5) inability to communicate in Chinese Mandarin; (6) presence of serious pulmonary, heart, liver, or renal insufficiency; and (7) had undergone anesthesia or surgery within the past 30 days.To determine POCD and cognitive decline, it is necessary to use a nonsurgical control group . The selAll patients underwent elective total hip arthroplasty or hemiarthroplasty. All clinical care followed routine clinical practice. All surgical plans were decided and performed in a standard manner by the same orthopedic surgeon.2, and end-tidal sevoflurane concentration were monitored during operation. Ephedrine was given if mean arterial blood pressure decreased to less than 75% of baseline. Systolic blood pressure was kept between 80 and 90 mmHg.All patients received general anesthesia according to routine clinical practice. Anesthesia was induced using intravenous (IV) midazolam (0.02 mg/kg), propofol (1–2 mg/kg), sufentanil (0.2–0.5 μg/kg), and rocuronium (0.6 mg/kg). Anesthesia was maintained with inhaled sevoflurane (1MAC) and intravenous propofol (2–3 mg/kg/h), remifentanyl (0.2–0.5 μg/kg/min), and rocuronium (10 μg/kg/min). During anesthesia, radial artery was cannulated for intra-arterial pressure monitoring. Electrocardiograph (ECG), PETCOAll patients received standardized perioperative care, including preoperative and intraoperative care and postoperative pain control. We recorded whether patients used nonsteroidal anti-inflammatory drugs preoperatively or not . HoweverThe visual analog scale anchored at 0 and 10 was used to measure pain intensity. Scores of 1–3 were designated as grade 2, scores of 4–7 were designated as grade 3, and scores of 8–10 were designated as grade 4. Patients with a baseline pain of at least 4 on a VAS and lasting for more than 3 months were assigned into the chronic pain group, and the patients without chronic pain were assigned to the non-chronic pain group.We carried out neuropsychological testing, including a battery of six neuropsychological tests at baseline (the day before surgery) and at 7 days and 2 months after surgery. The neuropsychological tests consisted of the MMSE, Visual Reproduction Test, Digit Span Test , Digit Symbol Test, Color Trail Tests (1 and 2), and Stroop Color and Word Test . All tests were conducted in the same order at each time point. These measures not only are highly sensitive to the types of cognitive impairments but also have no cultural bias.The MMSE was only used to exclude patients with existing cognitive impairment (MMSE scores < 24) at baseline. The remaining neuropsychological battery of tests addressed three cognitive domains: attentional capacity, executive function, and memory. In the neuropsychological tests including the Visual Reproduction Test, Digit Span Test (forward and backward), Digit Symbol Test, and Stroop Color and Word Test , the higher scores reflected better performance. The Color Trail Tests (1 and 2) provided estimates of attentional capacity and executive function, where a shorter time reflected better performance.Since these tests are prone to the test–retest practice effect, an age-matched control group was tested at the same intervals, providing an indication of practice effect with this test battery for the given time intervals between sessions.Z-score. The Z-score was calculated according to the methods of Rasmussen control was SD for the changes in test results in the community control group. A combined Z-score was calculated as the sum of Z-scores divided by the SD for this sum of Z-scores in the community control group. Data from the healthy control group were used to gain information on the practice effect and normal distribution in the test results for this age group, and the Z-scores were calculated (△X was obtained from the postoperative score (7 days or 2 months) to the subtracted preoperative score. △Xlculated .U test for nonnormal distributions or the independent samples t-test for normally distributed continuous variables and the chi-square test for categorical variables to compare differences between the group with postoperative POCD and that without postoperative POCD (7 days and 2 months after surgery). All clinically relevant and statistically significant preoperative variables were then entered into a multivariate logistic regression analysis using a forward entry method to identify independent preoperative risk factors for POCD. The Hosmer–Lemeshow goodness of fit test was performed to evaluate model fitting of the logistic multivariable model. Data are presented as the odds ratio and 95% confidence intervals (CIs). Values of P < 0.05 were considered to be indicative of statistical significance.Continuous data are reported in the tables as mean and SD or as median and interquartile range, and categorical data were reported as frequency and percentage. We examined the demographic and health characteristics per dichotomous pain variable (“chronic pain” vs. “non-chronic pain”). Between-group differences were analyzed by using the analysis of variance or the Mann–Whitney rank sum test for continuous measures and the chi-squared test or Fisher’s exact test for categorical measures. For univariate analysis, we used the Mann–Whitney Pass  software was used for the sample size calculation. Logistic regression tests for odds ratios with one binary X procedure were performed. With α = 0.05, a power of 80%, and an odds ratio = 3.0, the POCD incidence of major joint replacement was approximately 20%, and chronic pain prevalence in such patients was at nearly 50% . We thenA total of 155 consecutive patients were enrolled in this study. The trial profile is shown in Among the 104 age- and education-matched community adults enrolled for the POCD calculations in this study, nine refused to sign the informed consent, three did not complete the baseline neuropsychological testing, three underwent operations after baseline cognitive evaluation, five declined to continue, and two had lost data. Finally, 82 subjects were included in the statistical analysis .P < 0.05). The BMI of patients with chronic pain was significantly higher than that of those without chronic pain (P < 0.05). There was a significant difference in the surgery type, surgery time, and length of hospital stay between patients with chronic pain and patients without chronic pain (P < 0.05) ( < 0.05) . No sign < 0.05) . Table 2P < 0.05) before surgery and 7 days after surgery. Patients had similar VAS scores after surgery (3 days and 2 months), regardless of whether they had chronic pain or not  higher scores on the Visual Reproduction Test in patients without chronic pain than in patients with chronic pain before surgery (P < 0.05) higher in patients without chronic pain than in patients with chronic pain (P < 0.05) higher in patients without chronic pain than in patients with chronic pain 2 months after surgery  was 27 (19.1%) per 141 patients. The incidence of late POCD (2 months postoperative) was 10 (7.5%) per 134 patients. Among the 141 patients, 61 (43.2%) had chronic pain preoperatively. Of the 61 patients, 17 (27.9%) developed POCD; of the 79 patients without chronic pain, 10 (12.5%) developed POCD at 7 days after surgery .Among the 134 patients who finished the neuropsychological testing at 2 months after surgery, 60 (44.8%) had chronic pain preoperatively. Of the 60 patients, 4 (6.7%) developed POCD; of the 74 patients without chronic pain, 6 (8.1%) developed POCD at 2 months after surgery.P = 0.030), VAS score at 3 days after surgery (P = 0.042), postoperative tramadol use (P = 0.049), the rate of intraoperative hypotension (P = 0.003), and intraoperative ephedrine use (P = 0.001) were risk factors of POCD within 7 days after surgery. For multivariable analysis, all the covariates with P ≤ 0.10 in the univariate analysis were entered into a backward stepwise logistic regression model for prediction of the primary outcome: incidence of POCD. BMI, diagnosis, surgery type, surgery time, and length of hospital stay were forced into the multivariable model. These variables were selected to account for possible confounding, as there was significant difference in the BMI, diagnosis, surgery type, surgery time, and length of hospital stay between patients with chronic pain and patients without chronic pain (P < 0.05)  . HoweverP = 0.037), the rate of intraoperative hypotension (P = 0.034), intraoperative ephedrine use (P = 0.004), and nonsteroidal anti-inflammatory drug use 2 months postoperation (p = 0.035) were risk factors of POCD within 2 months after surgery. In the multivariate logistic analyses, no risk factor for POCD was found within 2 months after surgery  for POCD within 7 days postoperatively in elderly patients who had undergone major joint replacement surgery but not for POCD at 2 months after surgery. Previous study showed that chronic preoperative pain impaired recovery of attention after surgery in non-elderly patients . To the P < 0.05)  .P < 0.05) higher in patients without chronic pain than those with chronic pain, which indicated that patients with chronic pain had poorer of attention and executive function skills, psychomotor processing speed, and concentration. Many studies have demonstrated that chronic pain impaired memory  were significantly . Since there was no difference in the anesthesia treatment, surgery type, surgery time, blood loss, blood transfusion, and PCIA use between the patients with POCD and the patients without POCD (7 days and 2 months after surgery) in our study, it is still unclear whether generalized anesthesia influences the ability of memory and attention in elderly population.Many factors might contribute to the easier development of POCD in patients with chronic pain. Although there was no difference in major cognitive functioning between patients with and without chronic pain before surgery, cognitive reserve was lower in the patients with chronic pain . This fiA systematic review of the influence of anesthesia and pain management indicated that general anesthesia may be associated with early POCD, with no effect seen beyond 7 days after joint arthroplasty . And a mChronic pain is very common in patients who undergo major joint surgery. Since patients with chronic pain before surgery are more likely to develop POCD, more attention should be given to this group of patients. Pain management starting in the preoperative period and high-quality anesthesia should be implemented if possible.This study had some limitations. Individuals with significant cognitive impairment (MMSE < 24) were excluded from our research cohort. Therefore, our results cannot be generalized to elderly persons with moderate to severe cognitive impairment. We did not assess several other factors, such as low postoperative oxygen saturation and inflammatory mediators in blood. Inflammation plays a central role in osteoarthritis pathogenesis. Those factors potentially could have diluted the effect of preoperative chronic pain on the incidence of POCD. In this study, there were more osteoarthritis patients in the chronic pain group than in the non-chronic pain group. Osteoarthritis is a type of autoimmunity disease; thus, it can potentially affect the occurrence of POCD , 2014. IIn conclusion, our study revealed that preoperative chronic pain was associated with an increased risk of early POCD in elderly patients after major joint replacement surgery. High-quality perioperative pain management might be helpful to reduce POCD.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 Renji Ethics Committee. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.WY, DS, and HX conceptualized the study. YJ, WY, and DS designed the study. XH, LC, HZ, and YF conducted the study and collected the data. XH and XG analyzed the data. XH, XG, and DS drafted the manuscript. All authors revised the manuscript, contributed to 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.


Objectives: So far, the strong link between neuroticism, chronic pain, and depression has been well-documented in literatures. Some suggested that they might share etiological factors, thus resulting in overlapping constructs. However, such effect has never been tested in burning mouth syndrome (BMS) patients, a complex phenomenon influenced by both neuropathic and psychopathological factors. We aim to clarify how personality affects individual's pain and pain-related experiences.Methods: Two hundred forty-eight patients with BMS provided demographic information and psychiatric history; completed Ten-Item Personality Inventory, a Visual Analog Scale of pain, and McGill Pain Questionnaire; and provided adequate parameters of depressive state, catastrophizing thinking, and central sensitization.Results: BMS patients with depression history suffered more severe clinical symptoms and scored higher in neuroticism and less in openness and extraversion than did those without psychiatric diagnoses. After age, sex, and duration of pain were controlled, neuroticism in BMS patients with depression correlates with affective dimension of pain. Instead, if psychiatric history is absent, neuroticism correlates with sensory dimension and pain intensity. In both groups, higher neuroticism, unlike other personality facets, contributed to a more severe clinical condition.Conclusion: Of the five traits, neuroticism appears to be the most crucial dimension associated with the pain symptoms and patient's conditions. This study implies that management of pain must extend beyond solely providing pain-relieving medication and must require a holistic and multidisciplinary approach. Burning mouth syndrome (BMS) is referred to as the most well-documented chronic oral pain. Its origin is largely multifactorial, with clinical symptoms ranging from simple burning pain of tongue to uncomfortable dysesthesia of other oral mucosal without evident signs , 2. GiveIn terms of personality, this multifaceted combination reflects individual differences in thoughts, behaviors, and ability to cope with life stressful events. Whereas, previous studies suggest a relation between specific pain-prone personality characterized by a high level of neuroticism [one of the five factors in the five-factors model (FFM)] and BMS, its effects on pain perception are still controversial –7. ThereAmong psychiatric comorbidities in BMS, depression is the most common, with reported prevalence from 27.2 to 56.7% , 13. So Hence, our objectives were as follows: (1) compare pain characteristics, depressive state, pain-related catastrophizing, central sensitization, and personality features among BMS patients with and without a history of depression; (2) determine the extent to which personality traits influence pain , depressive state, pain-related catastrophizing, and central sensitization.Participants of the study were recruited among patients who visited the Psychosomatic Dentistry Clinic at Tokyo Medical and Dental University in Tokyo, Japan, for the first time between July 2018 and April 2020. Inclusion criteria were as follows: (1) age over 18; (2) had no difficulty communicating in Japanese; and (3) had a diagnosis of BMS. The diagnosis was based on the definition of “a chronic intraoral burning sensation that has no identifiable cause either local or systemic condition or disease,” proposed by the International Association for the Study of Pain . The uneDiagnostic and Statistical Manual of Mental Disorders, 5th ed.) were then excluded, leaving the final two groups of BMS patients: one with a history of depression and the other without any history of psychiatric disorder.The following sociodemographic information was collected: age, sex, and duration of illness. Psychiatric history was obtained from referral letters from the patients' psychiatrists. At the first visit, we required all patients to submit referrals if they had experienced any history of psychiatric disorder. The diagnosis was then adopted as given by their attending psychiatrists. In case the patients reported such history but could not provide referrals (for any reason), we then directly contacted their psychiatrists to inquire further details. Patients with different psychiatric diagnoses other than depression  . It contPatients also completed a 20-item assessment tool known as Zung's Self-Rating Depression Scale (SDS) for the current depressive state . ResponsPatients' feelings and attitudes toward the painful situation  were examined using the Pain Catastrophizing Scale (PCS). Patients answered 13 items in total, each of which is rated on a 5-point Likert scale  . In totaTo assess central sensitization severity levels in patients with BMS, we used a high reliability and validity screening instrument named Central Sensitization Inventory (CSI) . It consp <0.05 were accepted as statistically significant. Missing values were imputed  in accordance with the precondition that they comprise <5% of total dataset and are random. We applied the chi-square test and the Kruskal–Wallis test to compare clinical characteristics , central sensitization severity level, and personality between the two BMS patient groups. A correlation matrix of Kendall's rank coefficients τ showing pairwise associations between personality and clinical characteristics was built. All the p-values were then adjusted for multiple tests, using the Holm–Bonferroni method . Probability values of i method . AfterwaData of 343 patients were reviewed. Ten patients were excluded due to conditions that could affect the reliability of their self-reports . Eighty-five with history of psychiatric disorders other than depression were omitted . After the application of all criteria, data for 248 patients were available for analysis. The patients' mean age was 62.07 ± 13.53 years, and 81.5% of them were female. Patients had experienced pain for average 35.56 ± 46.63 months. The demographic characteristics, comorbid psychiatric disorders, and symptom-related parameters of 248 patients with BMS are shown in p-values > 0.05), BMS patients with history of depression score higher in every aspect of clinical characteristics  and central sensitization level than those without psychiatric history (p < 0.05). Other traits had differences, but no statistical significance was detected , VAS , SDS , PCS , and CSI . In contrast, a higher level of agreeableness was negatively associated with SDS  and CSI . Interestingly, SDS is the only psychological parameter that was associated significantly with all five traits . None of the associations between pain characteristics and traits other than neuroticism were statistically significant. For details, see In group of BMS patients without psychiatric history, after sex, age, and duration of illness were controlled, significant associations were found between the following: neuroticism and sensory component of SF-MPQ , whereas it has no relation with either sensory component of SF-MPQ or VAS , the results in parts A and B in Among many types of chronic pain, those without obvious pathology like BMS are the most difficult to deal with, thus inducing recurring expenses. As long as the dilemma of the origin BMS remains unsolved, the key to any successful treatment is still a puzzle. So far, this is the largest FFM-based personality observation in one population of BMS, in which we seek to address how individual traits associate with patients' clinical experiences and central sensitization level. Our main findings include (1) patients with a history of depression suffering from more severe clinical symptoms, had higher central sensitization, and scored higher in neuroticism and lower in extraversion and openness than those without psychiatric diagnosis; (2) neuroticism and the other four traits have inverse correlations with pain, depressive state, catastrophizing thinking, and central sensitization; and (3) higher neuroticism combined with a history of depression results in a higher level of affective dimension, while a higher level of sensory dimension and pain intensity is observed in those without psychiatric history.Since depression and pain share biological pathways, their overlapping presence is commonly observed. Findings from chronic pain cohort studies assessing the impact of depression are in agreement with ours. This demonstrates a comorbidity of depression significantly exacerbating pain complaint, especially pain intensity, and greater impairment . A part Despite unknown and ambiguous biological mechanism, personality is considered an independent efficient marker to predict overall health and well-being , 32, 33.Of particular interest of this study is that in BMS patients with depression and high neuroticism score profiles, pain seems to be perceived as a more affective disturbance. In contrast, patients without psychiatric disorders have the sensory component elevated by higher neuroticism. A similar result was observed by Harkin et al., in which highly neurotic patients perceived their chronic pain as more disturbing than less neurotic group did, despite no difference in the sensation magnitude. However, no impact of psychiatric comorbidity was examined . Our finAlthough there exists debate on whether the effect of neuroticism is overreported, evidences supporting its negative role in chronic conditions have been more consistent than those of four other traits , 38–40. 2 in multivariate regression models. However, this might be expected, since a combination of one personality trait, age, gender, and duration might not predict very well the variation of clinical outcomes. Nevertheless, it should be noted that our study is the first one to assess the relationship of personality, pain, and depression, with the largest sample of patients among personality-related research on BMS so far.This current study was limited in three main facets. The retrospective design without a control group is unable to define whether neuroticism affects chronic pain patients differently. Another potential bias is that the data were collected from a specific clinic of academic dental hospital where patients are likely to have more complex, multiple chronic conditions and suffer from more severe burning pain. Such sample might not represent the general population of BMS. Moreover, factors related to the history of depression  were not fully addressed in the current study, which limit the result interpretation. The final concern is with regard to the low RBMS patients with history of depression appear to have personality profiles different from those of the group without psychiatric history. Of the five traits, neuroticism appears to be the most crucial dimension associated with clinical experiences in BMS patients. Notably, patients with depression comorbidity and a high neuroticism score profile seem to perceive pain as affective disturbance. This study reinforces that management of pain must extend beyond solely providing pain-relieving medication and require a holistic and multidiscipline approach. Further study needs to address the role of personality in predicting patients' adherence and treatment outcome in a long-term follow-up.tu.ompm@tmd.ac.jp.The datasets presented in this article are not readily available due to ethical concerns and security requirements of patients-related data. Requests to access the datasets should be directed to Dr. Trang Thi Huyen Tu, The studies involving human participants were reviewed and approved by Ethical Committee of Tokyo Medical and Dental University. The patients/participants provided their written informed consent to participate in this study. The study protocol was approved by the Ethical Committee of Tokyo Medical and Dental University (D2013-005) and conformed to the provisions of the Declaration of Helsinki. All patients had been informed about the possibility of their data being used for study purposes at their first visit and had provided written informed consent.TT, HM, and AT were involved in study design, data collection, data analysis, and manuscript drafting. MW, TS, CH, CT, and MT contributed in data collection, results interpretation, and manuscript revision. All authors read and approved the manuscript.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.


Chronic pain and breakthrough cancer pain (BTcP) have a high prevalence in all cancer types and cancer stages, combined with a significant physical, psychological, and economic burden. Despite efforts to improve appropriate management of cancer pain, a poor assessment and guilty undertreatment are still reported in many countries. The purpose of this expert opinion paper is to contribute to reduce and clarify these issues with a multidisciplinary perspective in order to share virtuous paths of care.Common questions about cancer pain assessment and treatment were submitted to a multidisciplinary pool of Italian clinicians and the results were subsequently discussed and compared with the findings of the published literature.Despite a dedicated law in Italy and effective treatments available, a low percentage of specialists assess pain and BTcP, defining the intensity with validated tools. Moreover, in accordance with the findings of the literature in many countries, the undertreatment of cancer pain is still prevalent. A multidisciplinary approach, more training programs for clinicians, personalised therapy drug formulations, and virtuous care pathways will be essential to improve cancer pain management. BBTcP varies according to the stage of the tumour, with >70% in the advanced stages , and to High intensity of BTcP was described by 75.5% of the patients , and theIf cancer pain may be inadequately controlled, specific types of pain, such as BTcP, is more likely to be underestimated and undertreated ; clinicaIt is therefore essential to carry out an individualised and very comprehensive initial assessment to provide the best management approach in patients with cancer pain; cancer pain treatment has to comply with the guideline’s recommendations, taking advantage of modern technologies in drug formulations, and always considering the tailoring to the patient, with careful monitoring of pain relief.2This study is an expert opinion approach in the evaluation of the management of cancer pain by Italian clinicians and comparing the results with the recommendations of the literature.The scientific board developed seven main questions for use in cancer pain assessment and decision analysis to treat; the questions were submitted as anonymous branching survey that utilises skip patterns to ensure that respondents are asked only those questions that apply to them, guiding respondents based on their profile. The invitation to the survey declared the content of the study and gave the clinicians an opportunity to join the project or deny the involvement; all the clinicians have indicated their willingness to voluntarily take part in the study. Ethics committee approval is not required for this anonymous survey.The branching survey focusing on the approach to chronic cancer pain and BTcP was submitted to 13 oncologists (41%), 9 algologists (28%), and 10 palliativists (31%) from different Italian regions and institutions and from different care settings: oncology departments, pain centres, hospice, and palliative home care. The survey questions are detailed in Participants declared to visit more than 20 patients per month (53%) or 15–20 patients per month (38%) with chronic cancer pain, and from 10 to more than 20 patients per month (34%) or from 5 to 10 patients per month (66%) with BTcP. Ninety-two percent believe they have adequate training to easily recognise the BTcP and only 8% would like better training.The results of the survey were subsequently discussed together by the participants in two mixed focus group meetings held in October and November 2020, to ensure a multidisciplinary view of cancer pain management.The meeting was recorded by Sanitanova S.R.L. and a medical writer provided a meeting report to all the participants for approval of the contents and to allow the authors to proceed to the comparison with the data of the literature.For resource supporting the search and retrieval of medical literature, the authors opted for the PubMed database using the keyword “cancer pain” in the title of the article; the research has been restricted to the period 2009–2019, because most of the articles on cancer pain were published only in this decade; previous publications were left only if particularly significant on the topics. Among the 1,728 articles in English language only clinical trials, meta-analysis, randomised control trials, and reviews or systematic reviews were taking into consideration. More keywords  have been added to further narrow the bibliographical research in the different chapters. A further selection was made on the best matches or based on the journal impact factor or notoriety of the authors on the topic “cancer pain”Ethics statement: The conducted study is not related to either human or animals use. Ethical committee approval is not required for this anonymous survey study.33.1Pain assessment tools should be used routinely in monitoring patients with cancer, beginning in the early stages of cancer, always over the course of treatment and certainly in cancer survivors ,24.Since pain is a subjective perception, patients should be actively involved in the evaluation process and individual characteristics including age, cognitive function, psychological aspects, patient’s ability to cope, and all components of distress or suffering must be considered during pain assessment ,27,28,29Intensity is one of the most relevant standards for pain assessment. The intensity of pain and the treatment outcomes should be assessed regularly and consistently using the visual analogue scale (VAS) or the numerical rating scales (NRS). In elderly patients, or when cognitive deficits are severe, observational scales are alternative strategy for assessing the presence of pain ,31. PainIn palliative care setting or in dying patients, pain intensity is moderate to severe ,36 and iIn Italy, in order to guarantee pain care, a proper law  was enacted in 2010 . The lawIn our survey, only 26% of respondents expect that pain is a dimension to be investigated both during hospitalisation and at any outpatient access, and to be measured every day by the doctor or the nurse (17%). In 22% of the cases, voters believe that on the first visit the patient is encouraged to report the appearance of pain during care; only if the pain is reported by the patient or if the specialist believes that there is evidence to suspect it, then it is appropriate for a specific assessment. Only 13% of the oncologists and palliativists require the expertise of a pain specialist for pain assessment.Despite background pain being adequately controlled, patients frequently experience episodes of acute pain exacerbation known as BTcP. Diagnosis of BTcP needs a well-controlled basal pain with a therapy round the clock, able to provide analgesia to a mild pain intensity for most hours of the day. At the end of life, BTcP becomes an even worse distressing issue with a daily occurrence and high intensity involving almost all cancer patients ,42. FourThe lack of validation of BTcP tools has been a limitation; however, some assessment tools for BTcP have been successfully used, from the first Breakthrough Pain Questionnaire (BPQ) in 1990 ,43 to thThe Edmonton Classification System for Cancer Pain is a classification tool that evaluates different dimensions of pain and investigates the existence of factors that could add clinical complexity , even thCamps Herrero et al. reported a prevalence of 91% of BTcP using the Davies algorithm  and in a3.2mixed pain syndrome with a substantial overlap of nociceptive and neuropathic symptoms. The combination of different pain is not only directly linked to the tumour (by compression or infiltration) or due to metastasis or cancer therapies [The management of cancer-related pain is based on three steps of the WHO analgesic ladder, according to pain intensity ,49; howeherapies ,53 but eherapies ,54. Alsoherapies ,56.Strong opioids are the mainstay of analgesic therapy in treating cancer-related pain. WHO cancer pain ladder recommends, for mild to moderate pain, weak opioids such as tramadol and codeine in combination with non-opioid analgesics, but low doses of strong opioids could be an option as an alternative to weak opioids ,57,58.The guidelines ,57,59 reTransdermal fentanyl can be useful in opioid-naïve patients with nausea, vomiting, and problems with swallowing and is usually a good option in head and neck cancers, due to safety and tolerability profiles to control baseline pain . FentanyThanks to new technologies, the transdermal drug delivery systems are designed to ensure increasingly more simple and non-invasive methods of drug delivery and provide additional benefits for patients, enhancing their compliance. Technology of transdermal system can further improve the effectiveness of the device. A modern and innovative transdermal fentanyl five layers patch contains a rate-controlling membrane designed to control a constant release of drug over 72 h. Fifteen percent of the drug loaded in the adhesive layer immediately in contact with the skin allows to overcome the long delay that precedes the onset of the drug in the plasma after the first administration and good adhesion properties to the skin, avoiding that the patch comes off ahead of time .Patients with specific conditions that prevented the administration of oral opioids  or dying people should be considered to receive intravenous continuous infusion of morphine which will ensure a rapid-onset time for background pain control due to a complete bioavailability. The subcutaneous route can be considered as a safe and valid alternative to the intravenous and transdermal fentanyl may be the better choice to ensure a suitable alternative analgesic therapy for outpatients and for end-of-life home patients ,69,70,71The combination of opioid oxycodone/naloxone for oral administration represents the main choice of experts (75%) invited to the survey for the management of cancer patients with pain. Transdermal fentanyl is also widely used by the clinicians surveyed and represents the second most voted option (63%) among multiple choice answers .In our survey, 19% of the voters prefer transdermal fentanyl in some target patients such as young people or cancer patients under active therapy, with good performance, and work activity, so as not to interfere with their daily activities and reduce perceived medicalisation. Elderly patients with poor renal function are also a target where the transdermal route is preferable.Fifty-three percent of experts do not use transdermal fentanyl in opioid-naïve patients. Twenty-two percent of clinicians choose the transdermal route in multi-treated patients for comorbidity, to improve compliance by reducing oral administrations.When dose increases do not provide analgesia due to tolerance development or adverse intolerable and unmanageable side effects appear, chronic pain patients frequently need to be switched to alternative opioid or alternative route of administration ,73,74,75In this survey, 6% of experts chose transdermal fentanyl mainly in opioid switching, also known as opioid rotation, for improving pain relief or reducing the intensity of adverse effects.3.3A recent national, multicentre study  involvedThe most frequent sites of pain are vertebrae (36.7%), abdomen (29.5%), extremities (19.5%), chest wall (18.7%), and pelvis (10%). Pain mechanism was mixed (61.8%), nociceptive (30%), and neuropathic (8.1%) .Time to maximum pain intensity was ≤10 min (fast-onset BTcP) in 68.9% of patients and >10 min (slow-onset BTcP) in 31.1% of patients; those with fast-onset BTcP had a higher number of BTcP. The mean intensity of BTcP was 7.5 (SD 1.3) in 31.1% of patients. The mean duration of untreated BTcP episodes was 43.3 min .Considering the characteristics of BTcP  it is clear that slow-onset oral drugs cannot provide an adequate pain relief ,76,78.Intravenous or subcutaneous morphine injections provide effective and very fast treatment of BTcP episodes without producing relevant adverse effects or adding risks ,80. DataHowever, invasive routes of administration are unpleasant for the patient and intravenous opioids administration require expertise and appropriate setting.Different fentanyl formulations have been developed to provide, by non-invasive routes, fast pain relief, such as transmucosal fentanyl formulations, called rapid-onset opioids (ROOs), provide a rapid effect after drug administration, with a shorter titration period, significantly lower the impact on quality of life and result in better satisfaction scores ,84. As tSeveral placebo-controlled randomized controlled trials have demonstrated the efficacy of all available transmucosal fentanyl formulations for BTcP such as oral, transmucosal buccal tablet, sublingual tablet, buccal soluble film, and sublingual and intranasal spray ,86,87,88There are at least two important factors that should always be considered when choosing BTcP pharmacological treatments: baseline opioid regimen and breakthrough pain’s characteristics and patient preferences. Furthermore, other clinical conditions such as oral mucositis, integrity alteration of the nasal mucosa, presence of vascular access device, patients’ self-ability and dexterity in taking medication, and patient preference should be assessed for a tailored BTcP pharmacological treatment ,90,91.Each formulation of rapid-onset fentanyl, according to the summaries of product characteristics, should be carefully titrated to an optimal maintenance dosage that provides satisfactory analgesia for ongoing treatment of breakthrough pain episodes and acceptable level of adverse effects. Moreover, because of the considerable differences in absorption profiles and bioavailability among various ROOs, switching to other formulation of the dose should always be titrated.Adverse reactions attributed to BTcP medications are rare and their intensity is mild. There is a strong consensus for pharmacological treatment with transmucosal fentanyl with “start low and go slow” dosage method even for the older population . Indeed,In our survey many experts choose BTcP treatment based on fast analgesic action to provide rapid pain relief, making “fast-onset effect” the main choice (69%) among multiple answers; the safety (19%) and duration of the analgesic effect (19%), which limit the administration of the next dose of opioids, are also important characteristics .Ninety-one percent among 32 voters who responded to question 6 also believe it is an advantage to use the same molecule (fentanyl) to control basic pain and episodes of BTcP for easier management of opioid side effects; sixty-nine percent believe it was an advantage to have the availability of different dosages of ROO in order to adapt the therapy to the patient’s characteristics and type of pain.Finally, all participants agreed that a multi-professional and multidisciplinary approach is necessary for the assessment and early treatment of cancer pain. Uncontrolled or undertreated pain may become physically and emotionally disabling, leading to increased suffering and reduced quality of life in every person living with a diagnosis of cancer, whether receiving treatment or not ,94 and pDiagnosing BTcP depends on the presence of well-controlled background pain, adequate control of baseline pain is an essential prerequisite to begin specific treatment for BTcP.All clinicians including specialists and primary care physicians, who interact with cancer patients, will require the knowledge and the skills to implement best practices in the management of chronic pain and the education is one of the most important routes to enhance a new integration ,98. Nurs4The availability of new cancer-directed treatments for advanced cancer reshapes cancer into a chronic illness and points to a basic challenge in cancer care. In every stage of illness, pain profoundly impacts individual functional status and quality of life, extending to families and community.Many efforts have been made in Italy by Law 38/2010 to guarantee pain relief for citizens and to regulate opioid prescribing. New technologies provide drug formulations that respond to the need for personalised therapies and ensure efficacy and safety for the patient; however, resistance to opioid use remains, and low adherence to guidelines and recommendations on cancer pain management persists.A disease-oriented approach to treatment is still prevalent, instead of an overall assessment, global, tailored care, and palliative care are often late and ineffective. Temel et al.  demonstrOncologists have more opportunities to make an early diagnosis of BTcP, as they see patients early and more often through the course of disease. Palliativists need to be aware of the high incidence of cancer and BTcP pain in their setting and pain therapists can offer valid invasive approaches in refractory pain, in selected cases. An effective integration of disciplines and close cooperation between oncologists, surgeons, pathologists, radiologists, palliativists, and pain specialists should increase a multidisciplinary psycho-socio-pharmacological approach in every setting and stage of disease trajectory, irrespective of whether treatment intention is curative, life-prolonging, or palliative. We hope that the Italian health care system will enhance well-planned, patient-centred care pathways for people with cancer in order to strengthen and ensure the practice of supportive and/or early palliative care for better symptom-management strategies and novel communication techniques. Similarly, changing the paradigm of referral palliative care to the end of life would ensure a more dignified path for the patients in advanced stage of illness.Modern technologies can also strive to offer new drug delivery systems making opioid administration effective and safe for patients with cancer pain who need it.


Knowing the International Classification of Orofacial Pain helps pain specialists to differentiate types of orofacial pain. It is important to select the best treatment or intervention for the patients based on the diagnosis. As part of our study, we reviewed the article published in BMC Oral Health, titled “Clinical characteristics and associated factors of trigeminal neuralgia: Experience from Addis Ababa, Ethiopia” by Ayele et al. :7, 2020). For patients suffering from Classical Trigeminal Neuralgia taking a suitable dose of Carbamazepine or Gasser Ganglion radiofrequency could be helpful. Patients complaining Trigeminal neuralgia who had a history of a dental extraction in the painful region should be categorized in other group as Complex Regional Pain Syndrome type 1, who need larger dose of carbamazepine with anticonvulsant or tricyclic agent drugs  or intervention (PPG radiofrequency). Definitive diagnosis for facial pain is a complicated task, and requires expertise and meticulousness. Misdiagnosis can result in incorrect treatments. Especially incautious description of symptoms can negatively affect scientific conversations, training of physicians and patients’ treatments.In their published article at BMC-Oral Health, Ayele et al. suggested that there was a significant association between higher doses of Carbamazepine and history of tooth extraction . TherefoSpecial care is required with examining symptoms and diagnosis of patients with facial pain caused by dental-related traumas. Some patients complain of constant burning, and irregular tingling and stabbing pain. In combination of trophic changes, edema, and redness, a possible diagnosis for this condition could be reflex sympathetic dystrophy. However, if patients report significant burning pain, a treatment such as sympathetic blockade of the stellate ganglion could be considered. -p.296 claim thAyele et al.  mentioneTable 4 of Ayele et al. article, showed that 10, 16.4%) of their patients had burning pain  and 13, 21.3%) of them had a feeling similar to being injected with a red hot needle. According to the International Classification of Headache Disorders (ICHD-3) (13.1.1) these two forms of pain quality are not included in diagnostic criteria of Trigeminal Neuralgia; meanwhile, the last criterion in diagnostic criteria of TN (D) is, “not better accounted for another ICHD-3 diagnosis” [, 21.3% o0, 16.4% A possible diagnosis for patients with unusual pain in a tooth extraction site will be PTTN that has different pain quality . In moreTrigeminal Neuralgia is usually responsive, at least initially, to pharmacotherapy  , 5. TreaWe believe that such a nonchalant approach to a complicated pain can lead to wrong diagnoses and consequently wrong treatment plans. Burning pain would be a clue to other diagnoses than TN.


Osteoarthritis is one of the most common musculoskeletal problems. Pain is the most common complaint and the most significant cause of decreased health-related quality of life (HRQOL) among osteoarthritic patients. The objectives of this study were to assess the impact of pain on quality of life among patients with osteoarthritis and to assess the association of sociodemographic and clinical factors with HRQOL.Using a cross-sectional study design, we collected data from osteoarthritis patients in orthopedic outpatient clinics from four hospitals in the Palestine-West bank between November 2020 and March 2021. We used the Brief Pain Inventory (BPI) scale to assess pain and the Quality of Life scale five dimensions (EQ-5D) with the visual analog scale of the European Quality of Life (EQ-VAS) to assess HRQOL.p <  0.001, and − 0.554, p <  0.001, respectively. Similar associations were found between pain interference score and both EQ-5D  and EQ-VAS scores . Multiple regression analysis showed that participants with higher educational level (p = 0.028), less diseased joints (p = 0.01), shorter duration of disease (p = 0.04), and lesser pain severity and interference scores (both with p < 0.001) had significantly higher HRQOL scores.In our study, 196 patients composed the final sample, with an average of 60.12 ± 13.63 years. The medians for the EQ-5D score and EQ-VAS score were 0.72 (0.508–0.796) and 70 (55–85), respectively. The pain severity score was found to have a significant negative association with both the EQ-5D and EQ-VAS scores with r of − 0.620, We found that many variables have a significant negative impact on HRQOL among patients with osteoarthritis. Our finding provides a well-founded database to use by clinicians and healthcare professionals who work with patients with osteoarthritis, as well as educational and academic institutions. Osteoarthritis (OA) is an age-related disease characterized pathologically by areas of focal damage and loss of articular cartilage in synovial joints , is one However, pain is not the only symptom of osteoarthritis. Patients may also suffer from joint stiffness, especially in the morning , and joiOsteoarthritis is classified into two main types based on previous abnormalities in the affected joint. The first type is primary osteoarthritis, which occurs in joints without a previous abnormality and an inciting trauma or agent. The second type is secondary osteoarthritis, which is more common than the primary type. It is usually due to a previous joint abnormality, such as trauma, rheumatoid arthritis, avascular necrosis, hemoglobinopathy, Paget disease, Ehlers-Danlos syndrome, or Marfan syndrome , 9.There are many risk factors for osteoarthritis, some of which are modifiable, and some are nonmodifiable. The most important modifiable factors are obesity, occupational status, comorbidities, and physical activity that can be managed to improve joint function. Nonmodifiable risk factors include age and genetic or hereditary mutations that increase the susceptibility to osteoarthritis , 11.In Europe, it was reported that a large percentage of OA patients (59.6%) complained of moderate to severe pain and had a significant impact on several aspects of health . It was According to an extensive review, OA has a significant effect on the quality of life . KnowledWe conducted a cross-sectional study over 6 months, between November 2020 and March 2021, in the orthopedic outpatient clinics of four main hospitals; three of them were governmental and included Rafidia Governmental Hospital, Qalqilia Governmental Hospital, and Tulkarem Governmental Hospital, and the fourth was an academic hospital, which was An-Najah National University Hospital (NNUH).http://www.raosoft.com/samplesize.html). Convenient sampling was used to select 196 patients, distributed as the following: 100 patients were recruited from the Rafidia Governmental Hospital, 35 patients from the Qalqilia Governmental Hospital, 20 patients from the Tulkarem Governmental Hospital, and 41 patients from the NNUH. We relied on the availability in these hospitals to decide the number of participants from each hospital, such as the fraction of patients in each hospital was somewhat representative of the percentage of patients who counseled the outpatient clinic of the whole number of patients counseled in all selected hospitals.To carry out our study, we chose four hospitals in northern Palestine. We calculated the size of our sample using the Raosoft Inc. sample size calculator. , duration of osteoarthritis, number of affected joints, any previous trauma to the affected joint, pain medications used, and number of chronic diseases of any type. For analysis purposes, the BMI was categorized into normal weight (18.5–24.9), overweight (25–29.9), and obese (30 or more), and pain medications were classified as acetaminophen, NSAIDs, or both.In the third section, we included a tool for pain measurement, the Arabic version of the Brief Pain Inventory (BPI), which is an accepted and widely used tool for the assessment of pain in terms of intensity (sensory dimension) and interference with the patient’s life (reactive dimension) . We compFor the last part of the questionnaire, we used an assessment tool for health-related quality of life (HRQOL), which is the European Quality of Life Scale 5 dimensions 5 levels (EQ-5D-5L). The EQ-5D-5L is a widely used tool to evaluate the overall quality of life , 22, andTo evaluate its understandability and simplicity and how much time is needed to complete it, we tested the questionnaire in a pilot study on ten patients who were not included in the final study.Institutional Review Board (IRB) of An-Najah National University (# 21 October 2020) approved the study. Permission was obtained from selected hospitals to allow researchers to interview their patients.The p-values of < 0.05 to be significant. Furthermore, we used multiple regression analysis to determine the specific variables that were independently associated with quality of life. All variables that are significantly correlated with quality of life, including sociodemographic, clinical, as well as pain severity and interference, in the bivariate analysis were entered into the regression model. We also checked the internal consistency of the Pain Severity Score, Pain Interference Score, and HRQOL scale using the Cronbach alpha test.We analyze the data in our study using the IBM-SPSS version 26. Frequencies and percentages were used to present the qualitative variables, while means and standard deviations or medians and interquartile ranges were used to describe the continuous variables. We used the Kolmogorov-Smirnov test to evaluate the normality of continuous variables. Then, Mann-Whitney and Kruskal-Wallis tests were applied to assess the significance of correlations between patient characteristics and their scores on the scales used in this study. We considered Two hundred twenty-one participants were invited to participate in this study; 196 of them agreed to participate, resulting in a response rate of 89%. Table Regarding the characteristics related to osteoarthritis, 41.3% had the disease for 5 to 10 years, and 38.8% had the disease for less than 5 years. Of all 196 subjects, 67.3% reported no history of trauma to the affected joint, 44.4% had two affected joints, and 42.3% had only one affected joint. Approximately half (51%) of the participants had mild pain, while the majority of them (66.8%) had a low pain interference score. Table In our study, the mean pain severity score was 4.23 ± 2.09 with a median of 4 (2.75–5.5), while the mean pain interference score was 3.94 ± 2.33 with a median of 3.85 (2.0–5.68). Furthermore, the Cronbach alpha of the pain severity score was 0.906, and that of the pain interference score was 0.881, which indicates that these scores have good internal reliability.We found that the median of the EQ-5D score of our sample was 0.72 with the interquartile range (0.51–0.80) and it is mean was 0.65 ± 0.19. Cronbach’s alpha was used to measure internal consistency, and our result was 0.867, indicating good internal reliability. Regarding the EQ-VAS score, the median score of our study was 70.00 (55.00–85.00), while its mean score was 70.43 ± 19.14.The worst health status in all dimensions of the EQ-5D was reported as follows: mobility 2%, self-care 1%, usual activity 2%, pain and or restlessness 3.1%, and anxiety and/or depression 4.1%. Furthermore, the worst condition in any dimension was reported by 7.7% of the sample  with age, educational level, occupation, previous trauma to the joint, number of joints affected, number of comorbidities, duration of the disease, and severity and interference pain scores of the patients. In addition, in our study, a significant negative association was found between the EQ-5D score and both the pain interference score  and the pain severity score .Table p = 0.028), less diseased joints (p = 0.01), shorter duration of disease (p = 0.04) and lesser scores of pain severity (p < 0.001) and pain interference (p < 0.001) had significantly higher HRQOL scores.Table r = − 0.554, p < 0.001) and the pain interference score , while it was positively correlated with the EQ-5D score .Table p = 0.007), lower number of comorbidities (p = 0.007), lower number of affected joints (p = 0.002), lower severity of pain severity (p = 0.008) and pain inference (p = 0.001) had significantly higher VAS scores.The results of the multiple linear regression analysis of the correlation with the EQ-VAS score are summarized in Table This cross-sectional study conducted a thorough analysis of HRQOL in OA patients on pain management in four hospitals in the north of the Palestinian West Bank. We quantified HRQOL using the EQ-5D-5L scale and its VAS component, in addition to the Brief Pain Inventory (BPI) scale to assess the severity of pain and its interference in our sample. Different sociodemographic and clinical factors are correlated with HRQOL. We found that HRQOL was lower in patients with demographic characteristics, such as older age, lower educational level, and unemployment.Patients with OA suffer from various clinical manifestations, such as pain, which have an impact on HRQOL . TherefoThe mean of the EQ-5D score among participants was 0.65 ± 0.19. This is nearly the same as what was found in some previous studies, which reported scores of 0.66 ± 0.24 and 0.67 ± 0.3 in Sweden , 36 and Multiple factors were associated with HRQOL in Palestinian patients with OA, which confirmed the findings of the previous studies , 38–43. We have also found that educational level and occupation were significantly associated with HRQOL; with lower HRQOL in uneducated and unemployed patients. This is quite similar to a previous study in Brazil . This coWe found a significant association between a higher number of comorbidities and a lower HRQOL, a finding comparable to the results of a previous study . AlthougRegarding the EQ-VAS score, our study showed a mean of 70.43 ± 19.14, higher than similar studies in Spain , 34. FurThe strengths of our study include the fact that it is conducted in multiple hospitals in the West Bank in Palestine. This study was the first study in Palestine to evaluate HRQOL among OA patients and examine its association with pain control, in addition to various clinical and sociodemographic variables. Moreover, the information was gathered through face-to-face interviews, making our data complete and reliable. However, since data collectors performed face-to-face interviews with patients, this might have negative outcomes because it could influence participants’ answers to the main questions. Moreover, this study has some limitations that include using convenience sampling techniques that may reduce the generalizability to our study population. We also use a cross-sectional design that does not clarify the cause-effect relationship. Additionally, as our study was carried out in the outpatient clinics of hospitals, that might overestimate the severity of the pain. Notably, only one specific system is applied, which may be not convincing and reliable as there are several score systems of assessments of function and quality of life. Furthermore, specific clinical data, such as classification and severity of OA were not determined and some sociodemographic variables, such as educational level and occupation are a potential risk of bias since it is a kind of multi-factor issue. In this study, we did not conduct a subgroup analysis or test the correlations between the type of comorbidities or the site of the affected joint with the HRQOL. These analyses may give a greater understanding of OA patients’ quality of life. Finally, due to the COVID-19 epidemic, the number of patients available for participation in this study was somewhat limited, which could further reduce the generalizability of the results.We found that many variables can remarkably lower the HRQOL in patients with OA. Patients who were older, unemployed, with a lower educational level, a higher number of affected joints, a longer duration of osteoarthritis, and those with multiple comorbidities were at increased risk of having lower HRQOL. The results of our study provide a well-founded database that helps clinicians and healthcare professionals who work with and consult OA patients to achieve higher degrees of pain relief, and therefore, higher quality of life. In addition, it can be useful for educational and academic institutions. Healthcare professionals should pay special attention to the HRQOL in patients with OA, especially those who are risky for worse HRQOL. It is of great importance to advocate standard recommendations and guidelines for the care, treatment, and follow-up of these patients, including pain management as a cornerstone for improving quality of life. However, there is a need for further work on a larger case series. Therefore, we recommend further studies on OA among Palestinians because it is a neglected health issue in previous national investigations.


Most hemophilia patients experience pain in their lives. Some complementary interventions might affect pain belief.This study aimed to determine the effect of Benson’s relaxation technique on pain intensity, pain belief and perception, and pain acceptance in hemophilia patients. In this clinical trial study, 80 hemophilia patients were divided into an intervention (relaxation technique)and a control (routine care) group based on block randomization. This study was conducted in the hemophilia centerof Shahid Dastgheib hospital affiliated to Shiraz University of Medical Sciences from October to December 2018.The intervention group listened to a voice containing relaxation technique twice a day for eight weeks.Numeric rating scale, pain belief and perception inventory, and chronic pain acceptance questionnaires werecompleted at the beginning and eight weeks after the intervention. Data were analyzed by SPSS 21 using independentt-test, Paired-t-test, Chi-square, Mann-Whitney U test, and ANCOVA. P-value <0.05 was considered as significant. After the intervention, the mean scores of pain intensity, pain belief and perception inventory, and painacceptance in the intervention group were 4.26±2.17, -13.35±1.50, and 67.24±9.49 and in the control groupswere 5.85±2.61, -2±1.70, and 56.57±11.04, respectively. After the intervention, a difference was found betweenthe groups regarding the mean score of pain intensity (P=0.007), pain belief and perception inventory(P<0.001) and its subscales (P<0.05) as well as total pain acceptance (P<0.001). This study showed relaxation technique can be applied to reduce these patients’ pain intensity, improve theirpain belief and perception, and enhance their pain acceptance. IRCT20180311039037N1. One of the importantconsequences of joint hemorrhage in hemophilia patients is pain that more than one third of them suffer from chronic pain. 3Chronic pain exists in all body parts throughout the patients’ lives. Among the adult hemophilia patients referred to thehemophilia center in Shiraz, 71% suffered from pain. 4Pain exists in various body organs, including knees, ankles, shoulders, thighs, elbows, and wrists. Additionally, pain may startand continue at any time even when the patient is asleep. 5Pain not only impacts the patients, but also might affect the patients’ social and family environment and health care systems. 6Hemophilia is a bleeding disorder caused by congenital deficiency of coagulation factors. 7It is also associated with increased stress, anxiety, and depression in hemophilia patients. 4Pain can also lead to problems in the patients’ social activities, change their social relationships, 7and decrease the health-related quality of life in adult hemophilia patients. 8It was reported that belief of pain affects compatibility with and reaction to it. It was stated that positive pain beliefs andpain acceptance were effective in reduction of pain intensity. 9However, negative beliefs could increase the intensity of chronic musculoskeletal pain. 10Hence, identifying pain beliefs and pain-related behaviors is of utmost importance in management of pain,particularly in patients suffering from chronic pain. 11Pain acceptance is also a key phenomenon in changing the behavior of patients with chronic pain. 12A review of the literature indicated that individuals with high pain acceptance levels reported significantly lower levelsof pain, mental disorders, and pain-related disabilities. 13Pain can result in hopelessness, discomfort, and suffering. 15massage therapy, 16reflexology, 17yoga, 18and coping skill training. 4Relaxation techniques are among CIH interventions, which have been considered as psychological interventions. 19Additionally, various nursing measures are being used as complementary treatments to help relieve pain, eliminate thespectrum of damages, and decrease complications. 21Recently, evidence has indicated that CIH techniques could reduce the intensity of pain among patients. 22Recently, researchers have paid special attention to Complementary and Integrative Health (CIH), including relaxation, 19Relaxation, as a part of nursing practice, is effective in reduction of mild to moderate pain.It is also an appropriate method for decreasing severe pain and consumption of analgesics. 23The positive outcomes of relaxation include reduced anxiety, supply of energy, reduction of pain resulting from muscular pressure,reduction of pain-related anxiety, and improvement of sleep quality. 24Relaxation techniques as examples of nursing-accessible therapies are among CIH interventions, which have received much attention recently. 25This technique had positive effects on reduction of anxiety and mood disorders, promotion of physical activity, 21and improvement of sleep quality, 14quality of life, pain intensity in hemodialysis patients, 21and cardiac surgery. 26This technique may also be effective in pain intensity, acceptance, and belief in hemophilia patients. However, in recent literature review,no published studies have been conducted on this regard. Nurses are responsible for pain evaluation, using pain measures,and assessment of therapeutic efficacy. The present study aimed to determine the effect of Benson’s relaxation technique on pain intensity,pain belief and perception, and pain acceptance in hemophilia patients.Benson’s relaxation technique was introduced by Herbert Benson (1970), as a simple method for elimination of tension. This randomized controlled clinical trial was conducted in the hemophilia center of Shahid Dastgheib hospital affiliated to ShirazUniversity of Medical Sciences (SUMS), Shiraz, Iran from October to December 2018. The participants included hemophilia patientswho were willing to participate in the study, had the ability to read and write, and had not participated in similar interventionalstudies including relaxation, massage therapy, and other complementary and alternative integrative medicine during the past three months.The exclusion criteria were not completing the study questionnaires; suffering from known psychological diseases such as depression,anxiety, and psychosis based on their self-report; suffering from other bleeding disorders such as Von Will brand disease,factors I, XII, V, and VII deficiency; not performing the interventional program for three consecutive days; being hospitalized duringthe study period, and encountering crises such as bereavement or divorce (because these factors could affect the patients’ concentrationand the correct performance of Benson’s relaxation technique) based on their self-report. 1-µ2) and δ as 3 and 2.76 for pain intensity,the sample size was estimated 80 subjects. Moreover, by using that study and α=0.05, and power=80%, the (µ1-µ2) and δ as 2.5 and3.73 for pain belief, 12.26 and 18.83 for pain acceptance, 70, and 72 subjects were determined for the study.Therefore, the highest sample size  was considered for the study.Based on a pilot study, α=0.05, power=80% and following formula, and considering the (µn=[(zα2+zβ)2×{2(δ)2}](μ1-μ2)2=[(1.96+0.841)2×{2(2.76)2}](3)2≈40 ubjects in each groupAt the beginning of the study, 96 subjects were assessed. Eighteen subjects were excluded as a result of not meetingthe inclusion criteria (n=13), declined to participate (n=2) and other reasons (n=3). Therefore, 80 subjects were allocatedto the intervention and control groups. However, during the study period, six participants were excluded from the interventiongroup due to traveling (n=2), hospitalization (n=1), suffering from major depression (n=1), death of one of the close ones(n=1), and forgetting the performance of Benson’s relaxation technique for more than three days (n=1) .https://www.sealedenvelope.com/simple-randomiser/v1/lists). Then, the two groups were required to complete allthe questionnaires. After that, Benson’s relaxation program was performed in the intervention group, while the control groupreceived routine care. The two groups completed the questionnaires again at the end of the eighth week. It should be notedthat the individuals who collected and analyzed the data were blind to the study groups.After explaining the research objectives and obtaining written informed consents, we divided the patients into two groups usingblock randomization with block sizes of four. This block was created with a blocked randomization list, each time lasting for 20 minutes. They were asked to performthis intervention for eight weeks. A self-report form was given to the patients to record their daily performance.In this form, their compliance to Benson relaxation technique  and the times that intervention was done were assessed.The patients had to take the forms to the center at the end of each week for collection by the researcher.Patients were reminded to perform the relaxation technique via telephone contacts through the week. In case the patients forgotto do the technique, they were asked to do so when they remembered. Based on these reported forms, the patients who did notperform the technique for more than three consecutive days were excluded from the study. It should be noted that the researchergave her phone number to the patients, so that they could ask their possible questions and problems.Benson’s relaxation technique was performed by the second author of this study under the supervision of the correspondingauthor who had previous experience in performance of the technique. The relaxation technique was taught to the patientsverbally in a quiet room in the hemophilia ward. An audio file including Benson’s relaxation technique together with instrumentalmusic was played for the patients who were requested to practice the technique as they were listening to the file.In doing so, the patients were required to stay in relaxed position with closed eyes, relax their muscles from the solesof their feet upwards, breath through the nose, pay attention to the sound of their breathing, and say “one” at the time of exhalation.The patients had to practice the technique for 20 minutes and stay in the same position for some minutes after the end of the practice.They were also reminded that they did not have to use alarm rings for checking the end of the 20 minutes. The control group received the routine care including factor injection training, control of reaction to pharmacological treatments,control of bleeding and the related pharmacological measures, periodical assessment of laboratory tests, dental care,physiotherapy for the injured joints and muscles, and periodical examinations by physicians. However, they underwent no relaxationinterventions. To prevent bias, we provided the control group participants with no information regarding the interventionand the subjects in the intervention group were asked not to provide or give the CD containing Benson’s relaxation techniqueto the control group or others until they were told. Yet, the control group subjects were given a CDcontaining Benson’s relaxation technique at the end of the eighth week. The study data were collected using a demographic information form information about age, educational level, marital status,occupation, type of hemophilia, history of hemophilia in the family, absence from work due to bleeding and hemophilia problems,severity of hemophilia, having hepatitis, number of bleeding area during the past six months, bleeding areas during the past six months,and pain zones within the past six months; a Numeric Rating Scale (NRS); pain belief and perception inventory;and Chronic Pain Acceptance Questionnaire (CPAQ). 27Patients mark their pain intensity on this scale. The test-retest reliability of the scale was reported to be 0.96 and 0.95 inliterate and illiterate rheumatoid arthritis patients, respectively. 27Besides, the validity of NRS with Visual Analogue Scale was reported to be 0.86-0.95 in patients with rheumatism and other chronic diseases. 28The reliability of Persian version of NRS was assessed by Rambod et al. in a study conducted on hemodialysis patientsin Shiraz in 2014 using test-retest method (r=0.94). 21NRS was used to assess the intensity of pain. NRS is a 10-cm scale ranging from 0 (no pain) to 10 (the worst possible pain). 29The validity of the Persian version of the pain belief and perception inventory were demonstrated by Asghari Moghadam et al.using factor analysis. This analysis showed four factors. They reported Cronbach’s alpha coefficient of these factors between 0.70 and 77.0. 30In the present study, also, the reliability of the pain belief and perception inventory was confirmed by Cronbach’s alpha=0.76.Pain belief and perception inventory was designed by Williams and Thorn (1989). It consisted of 16 items and could bescored via a 4-point Likert scale ranging from -2  to +2 . This inventory consistedof four subscales, namely belief about duration of pain, belief about the stability of one’s pain, belief in pain self-blame,and belief in pain as mysterious and unexplained. Higher scores in this inventory represented the individuals’ deeper belief in pain.Williams and Thorn approved the validity of the inventory by factor analysis. Based on this factor analysis,three factors including “self-blame, perception of pain as mysterious, and beliefs about the duration of pain” were fit to the data,and these factors accounted for 94% of the total variance. Moreover, the reliability of self-blame, perception of pain as mysterious,and beliefs about the duration of pain subscales were approved by Cronbach’s alpha coefficient as 0.65, 0.80, and 0.80, respectively. 31Then, McCracken, Vowles, and Eccleston reduced the items to 20 in 2004. CPAQ items assess pain acceptance.This questionnaire consists of two subscales, namely activity engagement (11 items) and pain willingness (9 items).The items were scored via a 7-point Likert scale ranging from 0 (never true) to 6 .The scores of the two subscales were summed up and the total score could range from 0 to 120, with higher scoresrepresenting higher chronic pain acceptance. The validity of CPAQ was approved by factor analysis, and four factorsaccounted for 46.8% of the total variance. In addition, the reliability of this questionnaire was approved by Cronbach’s alpha=0.78. 32The reliability and validity of this questionnaire with 20 items were confirmed by Mesgarian et al. in an Iranian study published in 2010. 33Accordingly, its reliability was confirmed with Cronbach’s alpha coefficient of 0.85 and test-retest coefficientof 0.71. The validity of Persian version of this questionnaire was determined using factor analysis.Firstly, the data of 245 subjects were collected; it was shown that these participants were suitable for conducting factorial analysis.Based on this analysis, 40.5% of the variance of CPAQ was determined by these items. Additionally, its convergent validity withpain self-efficacy questionnaire was proved. Its divergent validity was also verified by computing the correlation with physicaldisability, depression, anxiety, pain intensity, and catastrophe. 33In the present study, the reliability of the CPAQ was approved by Cronbach’s alpha=0.86.CPAQ which was developed by Geiser in 1992 and contains 34 items. This study was approved by the Ethics Committee of Shiraz University of Medical Sciences (Code: IR.SUMS.REC.1396.15274).The study was explained to patients who were required to sign written informed consent for taking part in the research.They were reassured about the confidentiality of their information and the voluntary nature of the study.Permission to use the Persian version of the study questionnaires was also obtained from its designers (Asghari Moghadam and Mesgarian).The data were analyzed using SPSS statistical software, version 21. Independent t-test and chi-square testwere used to assess differences between the two groups regarding demographic characteristics.Additionally, independent t-test and Mann-Whitney U test were used to compare the study groups’ pre-and post-intervention.Paired t-test also was used. Moreover, ANCOVA was used to control the effect of the confounding variables on the post-test. P<0.05 was considered to be statistically significant.The mean age of the participants was 29.87±8.01 years; the mean age of the intervention participants was 30±9.16 and29.73±7.05 years in the control groups. All patients were male. Half of the subjects in the control group were singleand half of those in the intervention group were married. Moreover, most participants in the two groups were employed.Indeed, more than half of the participants in the control and intervention groups had diploma and below educationallevels, respectively .Most of the patients in the two groups suffered from severe hemophilia and were absent from work due to bleeding during the past six months.Nearly two thirds of the patients in both study groups suffered from hemophilia A and had the family history of the disease.In addition, approximately one-eighth of the patients in the control group and one-fifth of those in the intervention group had hepatitis.The two groups’ demographic and clinical characteristics are presented in The participants of this study had experienced bleeding in their knees, elbows, ankles, femur, and pelvis in the past six months.They had also experienced gastrointestinal, muscular, and mucosal bleeding. Almost half of the participants in both study groupshad pain in more than two areas, with nearly one third of the patients in the two groups reporting pain in their knees.Before the intervention, the mean intensity of pain was 5.82±2.63 in the control group and 6.26±2.56 in the intervention group.No significant difference was observed between the two groups with regard to pain intensity before the intervention .However, after the intervention, the mean intensity of pain was 5.85±2.61 in the control group and 4.26±2.17 in the intervention group.A significant difference was found between the two groups regarding the mean score of pain intensity after the intervention .There was no significant difference between the two groups regarding pain belief and perception inventory and its subscalesbefore the intervention (P>0.05) . HoweverThere was a significant difference between the two groups regarding the mean score of pain acceptance before the intervention(P=0.02) . Therefo26It seems that Benson’s relaxation technique helps hemophilia patients accept their illness as well as their unchangeablelife conditions. It reduces negative thoughts and emotions associated with pain and, consequently, decreases pain intensity. 34Similar to meditation, relaxation increases attention on the present moment, declines tension by preventing thetransfer of pain to the spinal cord, and relaxes the muscles. Indeed, stimulation of endorphin secretion in the brainas the result of performing relaxation leads to muscle relaxation followed by decreased pain intensity among patients. 21The study showed that Benson’s relaxation technique decreased the pain intensity and improved the pain belief, perception,and acceptance in hemophilia patients. In this study, the hemophilia patients who performed Benson’s relaxation techniquereported lower pain intensity compared to the control group. Similarly, it was shown that Benson’s relaxation techniquereduced pain intensity in acute or chronic conditions. 35Based on the researcher experience (second author) and considering the chronic and continuous nature of pain in hemophilia patients,they imagine that there is no definite treatment for their disease and that they have to stand the pain all through their lives.Relaxation therapy probably helps hemophilia patients put aside their previous beliefs about pain and form new positive beliefs.These positive beliefs promote the individuals’ compatibility and daily functions 30and play a critical role in pain coping strategies. 36Strategies for coping with pain, such as massage therapy and relaxation techniques can decrease the intensity of pain anddisability and increase compatibility by reducing fear and catastrophizing thoughts about pain. 36In the current study, Benson’s relaxation technique improved the scores of the pain belief and perception inventoryand its subscales in hemophilia patients. It has been reported that psycho-education/physiotherapy interventions couldaffect the pain belief and attitude. 37It was indicated that modified mindfulness-based cognitive therapy was effective in acceptance of pain in patients with fibromyalgia. 34Overall, pain acceptance interventions were effective in reduction of pain experience. 38The present study revealed a significant difference between the two groups with respect to the mean scores of chronicpain acceptance and its subscales after the intervention. It has also been reported that acceptance- and mindfulness-basedinterventions might help the patients cope with pain. One of the strengths of this study was that performance of Benson’s relaxation technique improved the pain intensity, belief,perception, and acceptance. Thus, this technique can be recommended as a complementary method of pain intensity reductionand increase in pain belief and acceptance in hemophilia patients. One of the limitations of this study was that the participants were selected from a single center, so the results cannotbe generalized to other regions of the country. Another study limitation included short intervention and follow-up periods.Further longitudinal studies are suggested to be conducted on the issue. In assessment eligibility stage of the trial, 13 participants were declined as a result of the study inclusion criteria.As this decline was inevitable, it is suggested that this intervention should be used for all of the hemophilia patients.The study results indicated that Benson’s relaxation technique reduced the pain intensity and improved the pain belief,perception, and acceptance in hemophilia patients. Further studies are suggested to be conducted on the issue to improveevidence-based practice. This study failed to assess the predictors of pain intensity, belief, perception, and acceptancein hemophilia patients; therefore, another study in this regard is recommended. Moreover, the effect of Benson’s relaxationtechnique on hemophilia patients’ outcomes such as stress and anxiety levels, quality of life, physical activities, and qualityof sleep is suggested to be assessed in another study. In addition, the effect of Benson’s relaxation technique on illness perceptionand usage of painkillers or opium is recommended to be investigated in future study.