Aim of this multicenter, observational, cross-sectional study was to evaluate health-related quality of life (HRQoL) and treatment satisfaction of current medications in Chinese knee OA patients.Brief Pain Inventory (BPI), Treatment Satisfaction Questionnaire (TSQM-1.4), and HRQoL (EQ-5D-5L) were assessed in total of 601 OA of knee patients. Impact on QoL (EQ-5D-5L) and treatment satisfaction (TSQM-1.4) by BPI-Severity score (< 4 and ≥ 4) were presented using mean standard deviations (SDs) and were compared using a t-test. For each of self-assessed health EQ-5D-5L and TSQM, a linear regression model was used to estimate the regression coefficient along with corresponding 95% confidence interval (CI) for BPI-Severity.Mean score of EQ-5D-5L of patients with BPI-Severity ≥4 was significantly lower than those with BPI-Severity < 4. All the scores of TSQM in 4 dimensions were lower in patients with BPI-Severity ≥4 than in those with BPI-Severity < 4. Both HRQoL scores and TSQM scores showed a statistically significant decreasing trend with increasing BPI-Severity pain score.Chronic knee OA pain has a significant impact on patients’ HRQoL. More severe patients with OA were less satisfied with current treatments.The online version contains supplementary material available at 10.1186/s12891-021-04012-2. Osteoarthritis (OA) is one of the most prevalent chronic musculoskeletal disorders and a leading cause of disability worldwide, especially among the elderly . GloballChronic pain is one of the most common health issues that exerts a significant social and financial burden on the individual and society. Patients with inadequate pain relief are more likely to have worse quality of life (QoL), greater function loss, and greater pain interference with daily activities . OA is aPatient-reported outcome is an important consideration in the treatment of patients with OA. All aspects of QoL are compromised when pain is inadequately treated, and effective pain relief has been shown to improve health-related quality of life (HRQoL) , 13. WhePatient satisfaction is an important indicator of the quality of care provided to patients with OA . PatientLittle is known about the impact of chronic knee OA pain on HRQoL and treatment satisfaction in a real-world setting in China. Therefore, the cross-sectional survey presented in this article has been designed to understand the impact of chronic knee OA pain on HRQoL and to evaluate treatment satisfaction of current medications among Chinese patients with knee OA.This site-based, multicenter, observational, cross-sectional study in China enrolled 601 outpatients with knee OA from 2 orthopedics, 2 rheumatology, and 1 pain department in 5 tertiary hospitals from March to October 2018. Written informed consent was obtained from each patient before they participated in any study-related procedures.Chinese adult patients (aged ≥40 years) with diagnosed knee OA experiencing chronic pain for at least 3 months and receiving oral medications during the past 12 months were eligible for the study. Patients with rheumatoid arthritis or other inflammatory arthritis; knee pain caused by other diseases ; mental illness, including cognitive disorders such as Alzheimer’s disease, schizophrenia; and bedridden patients who were undergoing knee replacement surgery were excluded. Patients with pain level higher than knee pain due to cancer or other reasons such, as gout and chondrocalcinosis, were also excluded. Socio-demographics, disease characteristics, Brief Pain Inventory (BPI), treatment information, and patient responses to HRQoL  and Treatment Satisfaction Questionnaire for Medication (TSQM-1.4) interviews were also assessed.The characteristics measured were age, sex, body mass index, ethnicity, employment status, education status, insurance status, and comorbidity  for the conditions of worst, least, and average pain, as well as “pain right now”. The 5-level Chinese Quality of Life-5 Dimensions version (EQ-5D-5L)  compriseP value of 0.05 was considered statistically significant.Demographic and clinical characteristics were assessed using frequencies and percentages for categorical variables and mean values and SDs for continuous variables  in the whole patient population. Impact on QoL (EQ-5D-5L) and treatment satisfaction (TSQM-1.4) by BPI-Severity score (< 4 and ≥ 4) were presented using mean (SD) and were compared using a t-test. For each of self-assessed health, EQ-5D-5L, and TSQM, a linear regression model was used to estimate the regression coefficient along with corresponding 95% confidence interval (CI) for BPI-Severity, adjusting for age (continuous), sex, body mass index (BMI), number of pain sites (continuous), and comorbidity (yes or no). We assessed the effect modification of comorbidity on a multiplicative scale by including interaction term between BPI-Severity and comorbidity in linear regression models. Additionally, we conducted the same analysis for the association between BPI-Pain interference and self-assessed health, EQ-5D-5L, and TSQM. Missing data were not analyzed. Statistical analyses were conducted using SAS 9.4 , and a 2-sided A total of 601 patients met the eligibility criteria and completed this survey Fig. . More thP < 0.0001) (Table P < 0.0001). There were statistically significant differences in all 4 domains of TSQM-1.4 between both patient subgroups (BPI-Severity ≥4 and < 4) (Table P < 0.0001), side Effects , convenience , and global Satisfaction . As shown by the TSQM score, treatment satisfaction was significantly lower in patients with BPI-Severity ≥4 than in those with BPI-Severity < 4.The mean score of EQ-5D-5L of patients with BPI-Severity ≥4 was significantly lower than those with BPI-Severity < 4  Table . A similP < 0.0001] and EQ-5D-5L ) showed a significant decreasing trend with each unit increase in BPI-Severity pain score, indicating that reduction in knee pain was statistically significantly associated with improvements in HRQoL scores , indicated that comorbidity does not modify the association between BPI-Pain and HRQoL scores , indicating that comorbidity does not modify the association between BPI-Pain and TSQM scores,  in patients with BPI-Interference ≥3 were lower than those with BPI-Interference < 3 Table S. SimilarThe cross-sectional survey presented in this article is the first large-scale, multicenter real-world study to explore the impact of OA pain on HRQoL and treatment satisfaction among Chinese patients with OA]. The results of this study, show that chronic pain has not been well managed since 78% of Chinese patients with OA who were treated with pharmacological therapy combined with other therapies still experienced moderate-to-severe pain (BPI ≥ 4) and significantly lower HRQoL and treatment satisfaction. Moreover, more than 35% of patients self-reported that they lost more than 4 days/week of work due to OA pain. These observations indicate that the patients with OA were not satisfied with current treatments. The cross-sectional survey results suggest that patients with moderate-to-severe OA pain had significantly lower HRQoL and treatment satisfaction scores as compared to patients with mild OA pain. Overall, pain severity plays an important role in predicting HRQoL and treatment satisfaction in Chinese patients with knee OA. Also, the study results suggest that increased pain severity is associated with a decrease in the levels of HRQoL and treatment satisfaction among Chinese patients with OA. Reduction in knee pain was statistically significantly associated with improvements in HRQoL and treatment satisfaction among Chinese patients with OA.The analysis results suggest that pain severity plays an important role in predicting HRQoL, and our findings are consistent with the previous studies –22. A puPatient satisfaction with treatment is essential in OA and is a measure of therapeutic effectiveness , 28. In Our study does have some limitations. Since data were derived from a cross-sectional survey, the association between knee OA pain severity and HRQoL and treatment satisfaction cannot be viewed as causal. Longitudinal studies are needed to examine the relationship between knee OA pain severity and HRQoL and treatment satisfaction. For the loss of workdays due to OA pain, we could not retrieve specific data regarding the types of work involved, hence, the results need to be interpreted with caution. Moreover, the study was conducted at 5 tertiary hospitals in China, and no randomization mechanism was used in their selection; hence, it is difficult to generalize the findings.Chronic pain due to OA, especially in those patients with moderate-to-severe pain, has a significant impact on patients’ HRQoL. In our study, patients with more severe OA were less satisfied with current treatments. Appropriate pain management in China is important in improving HRQoL and the treatment satisfaction for medication.Additional file 1: Table S1. The association between BPI-Severity score and HRQoL in patients with/without comorbidity. Table S2. The association between BPI-Severity score and TSQM in patients with/without comorbidity. Table S3. Impact on quality of life assessed using EQ-5D-5L questionnaire and self-assessed health by BPI-Interference score (< 3 and ≥ 3). Table S4. Treatment satisfaction assessed using TSQM-1.4 questionnaire by BPI-Interference score (< 3 and ≥ 3). Table S5. The association between BPI-Interference score and HRQoL. Table S6. The association between BPI-Interference score and TSQM. Table S7. The association between BPI-Interference score and HRQoL in patients with/without comorbidity. Table S8. The association between BPI-Interference score and TSQM in patients with/without comorbidity


Acne vulgaris is a chronic inflammatory disease affecting the pilosebaceous unit. Isotretinoin is an effective treatment option for severe acne. The aim of this study was to evaluate musculoskeletal side effects of systemic isotretinoin treatment.Ninety-four patients with acne vulgaris and 100 sex- and age-matched controls were enrolled in this study. Only the patients who had musculoskeletal symptoms were evaluated in this study. All participants were firstly assessed by a dermatologist. The patients were asked whether they had any musculoskeletal symptoms after isotretinoin treatment, if so, the feature and duration of the symptoms were recorded. The dosage of the drug, treatment duration, incidence of arthralgia, myalgia, low back pain, sacroiliitis and tendinopathy and laboratory test results were noted. The severity of pain was assessed by visual analog scale (VAS). The severity of acne vulgaris was evaluated by Global Acne Grading Scale (GAGS). Sacroiliac radiography, magnetic resonance imaging (MRI) and rheumatologic blood tests were requested from the patients meeting Assessment of Spondyloarthritis International Society (ASAS) criteria.p = 0.014). There was no significant correlation between cumulative dose of drug, treatment duration and VAS with ESR and CRP (p > 0.05). Also no correlation was found between GAGS scores and musculoskeletal symptoms (p > 0.05).Of the 94 patients, 71 were female and 23 were male. 47.9% of the patients had arthralgia, 53.2% had myalgia, 70.2% (66) had low back pain, 11.7% had sacroiliitis and 4.3% had tendinopathy. 37.8% of 66 patients with low back pain had inflammatory pain and 62.2% had mechanical pain. Bone marrow edema consistent with sacroiliitis was detected by sacroiliac MRI in 11 patients with inflammatory back pain. The median total cumulative dose of isotretinoin was significantly higher in patients with low back pain than in patients without low back pain (Low back pain is one of the very common complications of isotretinoin. It can be mostly mechanical or inflammatory. Isotretinoin-induced low back pain is dose-related, and inflammatory back pain without sacroiliitis is also frequent. The clinicians should be aware of the back pain may be a reflective of sacroiliitis during isotretinoin usage. Acne vulgaris is a chronic inflammatory disease affecting the pilosebaceous unit with multifactorial etiology . IsotretIn the literature, there are only a few original studies investigating the musculoskeletal side effects of isotretinoin , 9, 10. The primary aim of this study was to evaluate and emphasize the musculoskeletal side effects of systemic isotretinoin treatment in patients with acne vulgaris and to compare them with healthy controls. The second aim was to elucidate clinicians regarding with isotretinoin-induced musculoskeletal symptoms.A total of 94 patients with moderate to severe acne vulgaris treated with systemic isotretinoin and 100 sex- and age-matched controls who were admitted to Ankara Training and Research Hospital, Department of Dermatology, between September 2018 and April 2019 were enrolled in this cross-sectional study. The local ethics committee approved the study. All participants were informed about the study and their written consent form was obtained.The patients with moderate to severe acne vulgaris who receiving no other treatment modalities, no history of low back pain, ankylosing spondylitis and spondyloarthropathy, and aged over than 18 years were included in the study. Isotretinoin group included the patients under isotretinoin treatment for acne vulgaris, but had no history of rheumatologic syndromes. The control group was selected from among health professionals who had received a routine medical checkup in the hospital.Exclusion criteria for this study were the presence of any chronic rheumatological, dermatological diseases or any patients with a history of mechanical back pain, inflammatory back pain, sacroiliitis, enthesitis, before starting isotretinoin, history suggestive of spondyloarthropathies , or systemic autoimmune disorders. We did not include the patients who had musculoskeletal symptoms such as low back pain before isotretinoin usage in the patient’s anamnesis. Also, the patients with depression or similar psychiatric diseases, had renal and liver function disorders, those who were pregnant or using any systemic drugs for other diseases, were not included.All participants were firstly evaluated by a dermatologist and questioned carefully about the musculoskeletal symptoms. Only the patients who had musculoskeletal symptoms such as myalgia, arthralgia, back pain were determined and enrolled in the study. They were referred to the physical medicine and rehabilitation department and examined by a specialist. Sociodemographic information, including age, sex, history of drug use (dose and duration), history of chronic diseases were recorded. A detailed anamnesis was obtained and a careful dermatological and physical examination was performed by both of the specialists. It was queried that whether myalgia, arthralgia and low back pain occurred after starting isotretinoin treatment. Data were recorded on a standardized pre-prepared evaluation form. The pain severity of the participants was evaluated by visual analog scale (VAS) based on a chart numbered from 0 (no symptom) to 10 (maximum severity).The severity of acne vulgaris was assessed by using Global Acne Grading Scale (GAGS). According to GAGS, the body was divided into six regions -forehead, nose, each cheek, chin and back. In each region, each type of lesion is given a number: zero for no lesion, one for comedones, two for papules, three for pustules and four for nodules. Acne severity based on the GAGS score is considered as mild (1–18), moderate (19–30), severe (31–38) and very severe (≥39).It was investigated that whether there was a enthesitis by a detailed clinical examination. The presence of enthesitis was assessed with detecting tenderness by pressure to each enthesis until blanching of the examiner’s nail bed , 22. TheInflammatory low back pain was evaluated by Assessment of Spondyloarthritis International Society (ASAS) criteria . The ASAG*Power sample size calculation program  was usedp < 0.05 was considered as statistically significant.Data were analyzed using SPSS software version21.0 . The normality of the data was tested by Kolmogorov-Smirnov test. Categorical datawere presented as the number (percent), and continuous data were expressed as the mean ± standard deviation or as the median (interquartile range: IQR) as appropriate. For the comparison of the paired groups, the independent samples t-test  and the Mann-Whitney U test  were used for the quantitative data. Chi-squared test was used to evaluate whether there was a difference in terms of musculoskeletal symptoms between the study groups. The relationship between the non-normally distributed variables was analysed with Spearman’s correlation analysis and between the normally distributed variables with the Pearson’s correlation analysis. Linear regression analysis test was used to evaluate the relationships between arthralgia, myalgia, lumbalgia, sacroiliitis and tendinopathy/entesopathy complaints and age, drug dose (isotretionin), duration of use. In all tests, This case-control study included 94  patients with acne vulgaris receiving isotretinoin and 100 age- and sex-matched controls. The age and sex distributions of the study and control groups are presented in Table p < 0.001). The flow chart of the participants was presented in Fig. 47.9% (45 cases) of the 94 patients had arthralgia, 53.2% (50 cases) had myalgia, 70.2% (66 cases) had low back pain, 11.7% (11 cases) had sacroiliitis and 4.3% (4 cases) had Achilles tendinopathy, in isotretinoin group. All of the tendinopathies were mechanical feature, swelling or erythema was not observed. In the control group, 8% of the subjects (8 cases) had arthralgia, 7% (7 cases) had myalgia and 10% (10 cases) had low back pain and there was no sacroiliitis and tendinopathy. There was a statistically significant difference in terms of musculoskeletal symptoms between the groups (39 (41.5%) of the 94 patients had severe acne vulgaris, 55 (58.5%) had moderate acne vulgaris according to the GAGS scores. The median cumulative drug dose was 2400  mg. The median duration of treatment was 3 (min.-max:1–10) months.p = 0.03). The clinical characteristics of both isotretinoin group and healthy controls can be seen in Table There was a total of 66 patients 70.2%) with low back pain in the isotretinoin group. 25 of them (37.8%) had inflammatory back pain according to ASAS criteria, while 41 of them (62.2%) had mechanical back pain. In control group, none of the patients had inflammatory back pain, however 10 patients (10%) had mechanical back pain. Median VAS score was 6 (IQR:7) in isotretinoin group and 4 (IQR:6) in control group. There was a statistically significant difference between the VAS scores in the groups (% with lon = 45); 3  months in patients with myalgia (n = 50); 3  months in patients with back pain; 3  months in patients with sacroiliitis and 3.5  months in patients with tendinopathy.The median duration of treatment was 3  months in patients with arthralgia (p = 0.40). There was no statistically significant difference in terms of total cumulative dose of isotretinoin in patients with myalgia compared to patients without myalgia (p = 0.33). Also, we found no statistically significant difference in total cumulative isotretinoin dose in patients with sacroilititis compared to the patients without sacroiliitis (p = 0.11) and in total cumulative dose of isotretinoin in patients with tendinopathy compared to patients without tendinopathy (p = 0.75).No statistically significant difference was detected in terms of total cumulative dose of isotretinoin in patients with arthralgia compared to patients without arthralgia (p = 0.014). There was no statistically significant difference between the total cumulative isotretinoin dose in patients with inflammatory back pain and mechanical back pain . The comparison of the patients who had musculoskeletal symptoms or not in isotretinoin group regarding as total cumulative dose of drug were given in Table The median total cumulative dose of isotretinoin was 2700 mg in patients with low back pain and the median total cumulative dose of isotretinoin was 1800 mg in patients without low back pain. The median total cumulative dose of isotretinoin was statistically significantly higher in patients with low back pain than in patients without low back pain . There was a significant relationship between myalgia and gender (p = 0.01), and it was twice as high as in women (43/71 (60.6%) versus 7/16 (30.4%), respectively). There was a significant and linear relationship between the low back pain with cumulative dose of isotretinoin (p = 0.02) and no significant relationship between the compared parameters with tendinopathy (p > 0.05). The results of linear regression analysis between the age, sex, duration of treatment and cumulative dose of drug with musculoskeletal side effects were shown in Table In linear regression analysis, a significant and linear relationship was found between age and arthralgia, sacroiliitis and tendinopathy  patients. Nine of the 11 patients had bilateral and 2 had unilateral bone marrow edema on iliac and/or sacral wings. There was hyperintense signals on STIR images consistent with sacroiliitis . Also no significant relationship was found between GAGS scores with musculoskeletal symptoms (p > 0.05).There was no correlation between the cumulative dose of isotretinoin, treatment duration and VAS with ESR and CRP  and continued a lower dose of isotretinoin. These symptoms were decreased dramatically within the first month and improved within the 3 months. In patients who were diagnosed as sacroiliitis, the drug was discontinued immediately and a NSAID was prescribed. We observed that the complaints of these patients were resolved within a month after cessation of the drug and VAS scores were also decreased dramatically. The symptoms were mostly disappeared by the third month. All the patients with sacroiliitis were completely symptom free at the sixth month of the discontinuation of the drug.Isotretinoin, or 13-cis retinoic acid, is a vitamin A derivative used for severe recalcitrant acne since 1982. Although isotretinoin is a very effective drug, it may have many side effects. It is essential that the clinician should be careful about the various side effects of the drug .In this study, we focused on the musculoskeletal side effects of isotretinoin. Ninety-four patients treated with isotretinoin suffering from musculoskeletal pain were included. The patients were then examined in detail. They were also compared with 100 healthy controls.Isotretinoin has been associated with various musculoskeletal side effects in the recent literature. Some of these are original studies, while most of them are sporadic case reports , 11–20. p = 0.01). This was one of the most important results of this study. Other musculoskeletal side effects were not found to be statistically significantly related with the total cumulative dose of isotretinoin. The patients with low back pain using isotretinoin should be asked about the dosage and duration of their drug, and if necessary, the dose should be reduced. On the other hand, it is an interesting finding that sacroiliitis is not related with the total cumulative dose of the drug.Selçuk et al. evaluated 73 patients receiving isotretinoin due to moderate or severe acne vulgaris and asked all patients about their inflammatory back pain and musculoskeletal complaints. They have found myalgia in 42.5% and low back pain in 49.3% of the patients. Acute sacroiliitis was determined in 8.2% of them following a sacroiliac MRI. The authors concluded that the incidence of sacroiliitis in patients receiving isotretinoin is quite high . In our In their study, Alkan et al. compared two acne vulgaris group receiving either isotretinoin or tetracycline. In the isotretinoin group, 23.1% of the patients were found to have spondyloarthropathy-related symptoms. No inflammatory back pain was observed in tetracycline group (32 patients). They found unilateral sacroiliitis only in one patient in the isotretinoin group that included a total of 42 patients. They also emphasized that all rheumatologic symptoms of the patients disappeared after the discontinuation of the drug and the complaints were drug related [In another study, the effect of isotretinoin on Achilles tendinopathy was investigated. The authors divided a total of sixteen rats into two groups and administered isotretinoin for the first group and soy oil for the second group. After 6 weeks, Achilles tendons were excised and evaluated histopathologically. In the isotretinoin group, a biomechanical and histopathological negative effect on Achilles tendon was detected. Therefore, the authors recommended asking the patients with tendinopathy about their use of isotretinoin in their medical history . EnthesiThe exact pathogenesis of sacroiliitis in isotretinoin use is unclear. Isotretinoin induces some alterations in the lysosomal membrane structure of cells due to it’s detergent-like effects. This leads to a degeneration process in the synovial cells. Retinol and retinoic acid derivatives such as isotretinoin can also stimulate MMP-2 activity and cause membrane damage in the joints , 32, 33.The limited extent bone marrow edema of sacroiliac joints is quite unspecific and can occur in various conditions, not related to axial spondyloarthropathy. Winter et al. reported that sacroiliitis on MRI according to the ASAS definition was found in postpartum women, healthy individuals, and runners as 57, 23, and 13%, respectively. The only one MRI finding that differentiated the HLA B27+ axial spondyloarthropathy patients from asymptomatic individuals, runners, and women with postpartum back pain was a deeper (extensive) bone marrow edema . In our Taheri et al. conducted a study in military personel to evaluate whether trauma or more physical activity can affect the incidence of sacroiliitis. In this cross-sectional study, 113 military personnel who receiving isotretinoin at least 3 months for acne vulgaris were investigated. The authors reported that 46.9% of the patients had low back pain. Of the patients with back pain, 54.7% (29 cases) had inflammatory back pain and 45.3% (24 cases) had mechanical back pain. Sacroiliitis was determined only in 5 patients . This stIn healthy control group, only a few of the volunteers had musculoskeletal pain symptoms such as myalgia, arhtralgia and back pain. None of them had sacroiliitis or tendinopathy. The statistically significant high prevalence of musculoskeletal findings in drug users in the same age group was considered as an important indicator that current symptoms were significantly drug dependent.This study has some limitations. There is a limited number of patients in total, so the results of the study should be interpreted carefully. Another limitation was that the MRI images of the patients with sacroiliitis were not scored. Furthermore, MRI follow up may be recommended for sacroiliitis positive patients to confirm resolution after drug cessation. Enthesitis was not evaluated and scored by an imaging method such as ultrasonography or MRI in our study. The diagnosis of enthesitis was depended on solely clinical evaluation. Further randomized controlled studies are needed with wider patient groups in order to elucidate the musculoskeletal side effects of the isotretinoin.Low back pain is a very common side effect of isotretinoin and it is dose-related. Although sacroiliitis is a rare complication of isotretinoin, inflammatory back pain without sacroiliitis can be seen frequently. The patients suffering from back pain should be asked for drug usage. Considering that musculoskeletal complaints are mostly temporary, they can be often overlooked by clinicians. For this reason, we recommend the clinicians to perform a more careful and close follow-up in order to carry out the most proper approach to these patients.


Background: Pain and vitamin D deficiency are common in inflammatory bowel disease (IBD). Disease activity, fatigue, frequent relapses, prior surgery and psychological factors all seem to influence the experience of pain in IBD. Vitamin D deficiency has been associated with muscle and skeletal pain. This study aimed to determine whether there is an association between vitamin D deficiency and severity of pain in patients with IBD, and to investigate the influence of other socio-demographic and psychological variables on the experience of pain. Methods: Patients with IBD were recruited from nine hospitals in Norway in a multicenter cross-sectional study. The Brief Pain Inventory (BPI) questionnaire was used to measure pain. Disease activity was assessed using clinical disease activity indices, C-reactive protein (CRP) and fecal calprotectin. Regression models were fitted to explore a possible association between 25-hydroxyvitamin D and pain severity. Results: Of 407 patients included in the analyses, 229 (56%) had Crohn’s disease (CD) and 178 (44%) had ulcerative colitis (UC). Vitamin D deficiency was present in half (203/407) of patients. Presence of pain was reported by 76% (309/407). More severe pain was associated with female gender and increased disease activity scores, but not with increased CRP or fecal calprotectin. In CD, patients without prior intra-abdominal surgery reported more severe pain. In multivariate analyses, there was no association between 25-hydroxyvitamin D and pain severity. Conclusions: In this study, no significant association between pain severity and vitamin D deficiency was revealed in patients with IBD. Inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), are long-term conditions that involve the inflammation of the gastrointestinal tract ,2,3. SymA relapsing course of IBD is seen in many patients, which may cause the intermittent exacerbation of abdominal pain . FurtherModulating factors, including different psychological factors, may significantly contribute to the clinical manifestation and severity of pain ,8,9. EmoIn addition to abdominal pain, many IBD patients report lower back pain and other sites of chronic pain that do not always correspond to disease activity . AbdominVitamin D receptors are expressed in many tissues including skin, bone, muscles, endocrine tissues and the immune system, and thus many organs require vitamin D for optimal function and, accordingly, vitamin D may influence mechanisms of pain . SeveralThe primary aim of this study was to determine whether there is an association between vitamin D deficiency and severity of pain in patients with IBD. The secondary aims were to investigate the influence of selected socio-demographic and psychological variables on the experience of pain.The study was approved by the Regional Committee for Medical and Health Research Ethics (2012/845/REK). All the study participants gave written, informed consent before their inclusion in the study, and the study was performed in accordance with the Declaration of Helsinki.Patients were recruited between March 2013 and April 2014 from nine hospitals in south-eastern and western Norway for this observational, multicenter cross-sectional study. The inclusion criteria were: age ≥ 18 years, a verified diagnosis of IBD based on endoscopic, biochemical and histological findings according to the Lennard-Jones criteria , and theData were collected using patient interviews, medical records, and laboratory tests. All data were collected at inclusion.Serum 25-hydroxyvitamin D [25(OH) D] was analyzed by one central accredited laboratory using liquid chromatography tandem mass spectrometry (LC-MS/MS). The method used has been compared to the LC-MS/MS method used in the vitamin D standardizing program, where it showed good compliance . VitaminAll other biochemical analyses were performed at the local laboratories at the participating hospitals. C-reactive protein (CRP) level of ≥5 mg/L was set as a cut-off for active inflammation ,26.The stool samples for the measurement of fecal calprotectin were sent by post and analyzed with Calpro Easy Extract . A fecal calprotectin level of ≥100 mg/kg was used to indicate mucosal inflammation .Clinical disease activity was measured with the Simple Clinical Colitis Activity Index (SCCAI) for UC, and the Harvey Bradshaw Index (HBI) for CD ,29. For Pain was measured using the Brief Pain Inventory (BPI) . The BPIDepressive and anxiety symptoms were measured with the Hospital Anxiety and Depression Scale (HADS), which has been translated into Norwegian and validated . HADS ist-test when normally distributed, otherwise a non-parametric test was used . The associations between pairs of categorical variables were analyzed with a Chi-square test, and for associations between continuous variables, the Pearson correlation test was used. To explore possible associations between the selected variables and severity of pain, ordinal logistic regression models were fitted, using pain severity as the dependent variable. The variables with a p-value < 0.1 in the univariate analyses were entered into the final multivariate models. Those variables with p-values < 0.05 were considered statistically significant in the multivariate analyses. All tests were two-sided. The study was considered exploratory, so no correction for multiple testing was done. IBM SPSS Statistics for Windows version 25.0  was used for all statistical analyses.Normally distributed continuous variables are presented with means and standard deviation, while variables with skewed distributions are described with medians and ranges. Crude differences between pairs of continuous variables were analyzed using Student’s The main outcome variables were severity of pain and vitamin D deficiency. For the statistical analyses, three patient groups were formed: (i) no pain, (ii) mild pain and (iii) moderate or severe pain. These groupings were considered the most relevant approach from a clinical perspective, but also statistically, as relatively few patients reported moderate and severe pain. Additional outcomes included selected socio-demographic and psychological variables. The guidelines of the STROBE statement have been adopted.p < 0.01). Furthermore, more CD patients were receiving treatment with biologics . Approximately half (203/407) of the patients had vitamin D deficiency, and around one-third (135/407) were using low-dose vitamin D supplementation. Furthermore, vitamin D deficiency was shown to be associated with increased clinical disease activity, a relapsing disease course, and higher inflammatory activity [In total, 452 patients were invited to participate; of these, 414 (92%) gave written consent. Seven patients were excluded due to missing data from questionnaires. Thus, 407 patients were available for the analyses, of which 229 (56%) had CD and 178 (44%) had UC. There were no statistically significant differences between the UC and CD patients in terms of age or gender. The CD patients had significantly longer disease duration than UC patients . Current smokers reported more pain, but this was not statistically significant, and the number of daily smokers in this sample was low. In univariate analyses, increased symptoms of depression and anxiety were associated with pain severity in UC patients, but not in patients with CD.Presence of pain was reported by 76% (309/407) of the patients, most commonly in the abdomen, back and joints . The meaIn the multivariate analysis, adjusted for gender, vitamin D level, and symptoms of depression and anxiety, pain severity was associated with elevated disease activity scores in UC and in CD. However, pain severity was not associated with objective inflammatory markers CRP or fecal calprotectin. CD patients with no prior intra-abdominal surgery reported pain that was significantly more severe than pain reported by those who had undergone surgery. Pain severity was significantly associated with the female gender in UC and in CD. The analyses are summarized in p = 0.96). More severe pain was associated with increased pain interference in daily activities in both UC  and CD . There was no significant association between vitamin D deficiency and pain interference in daily activities in either UC  or CD .The mean scores for pain interference were similar in patients with UC and those with CD . With self-reporting of symptoms, there is also a risk of recall bias.Pain is commonly reported in IBD patients and is associated with clinical disease activity and the female gender. Our study did not reveal any significant association between vitamin D deficiency and pain severity, supporting a bio-psycho-social approach to the understanding of pain in IBD patients. Further studies are needed to explore whether better pain management may improve outcomes, and to further elaborate on the possible importance of coping mechanisms and psychological factors beyond depression and anxiety.


Approximately 2–10% of patients with varicocele complain of pain. Varicocelectomy for testicular pain is a surgical choice when conservative therapy fails to relieve the pain. Different variables have been reported as prognostic factors for pain relief following varicocele ligation. Moreover, the success rate of varicocelectomy for testicular pain has varied among studies. This retrospective study aimed to investigate the predictors and success rate of microscopic subinguinal varicocelectomy performed for the treatment of painful varicocele.P < 0.0001); no other factors were predictors of pain relief.Among the 132 patients, 83.3% reported pain relief. A significant association was identified between varicocelectomy for unilateral testicular pain and pain resolution (Microscopic subinguinal varicocelectomy for testicular pain is an effective surgical alternative. Varicocelectomy for unilateral testicular pain may predict postoperative pain relief in appropriately selected patients. Varicocele is an abnormal dilatation of the gonadal veins within the pampiniform plexus of the spermatic cord . The preThis retrospective study was performed by reviewing medical records of the patients. From March 2016 to February 2019, 984 patients underwent microscopic subinguinal varicocelectomy at the Prince Sultan Military Medical City, Riyadh, Saudi Arabia. Of these men, 689 were operated for infertility and 118 for military purposes . Additionally, 45 patients who had varicocele associated with other findings that cause testicular pain, such as sexually transmitted disease, urinary tract infection, prostatitis, testicular torsion, trauma, or history of scrotal surgery, were excluded from the study. The study involved 132 patients who did not have infertility concerns and underwent microscopic subinguinal varicocelectomy for only varicocele-associated testicular pain following failed conservative treatment  for 3 months . Descriptive statistics were used to report the demographic and clinical characteristics. Continuous variables are presented as the mean with standard deviation or median. Categorical variables are expressed as absolute numbers with frequencies or percentages. One-way analysis of variance was used to compare the preoperative patient conditions and postoperative outcomes. Univariate analysis was performed using the Chi-square test and logistic regression analysis to evaluate the relationship between possible predictive factors and pain relief. P < 0.0001) (Table The present study included 132 patients. The average patient age at the time of surgery was 29.7 ± 6.6 years (range 18–26 years). Pain duration before surgery was 10.7 ± 4.5 months (range 3–18 months) with 85 (64%) patients describing the preoperative pain as dragging and 47 (36%) as dull pain. Bilateral varicocelectomy was performed in 48 (36.4%) patients and unilateral varicocelectomy in 84 (63.6%). No intraoperative complications were reported. Postoperative complications, including wound infection and hematoma, were documented in two (1.5%) patients. All patients were followed up (13.5 ± 4.9 months) with a range of 12–24 months. Of the 132 patients, 110 (83.3%) patients reported pain relief with a score of 0 on the 11-point NRS, whereas 22 (16.7%) reported persistent pain with either no change or very mild, insignificant change on the 11-point NRS for pain   and low complication (1.5%) rates when performed in selected patients after failed conservative treatment. Patients with unilateral testicular pain have a higher chance of pain relief after varicocelectomy. A prospective randomized study with a large sample size and long-term follow-up covering all the different prognostic factors for a painful varicocele is essential to validate the findings of the present study.


Botulinum neurotoxin is widely used for the treatment of central and peripherical neurological conditions. Initially used to treat strabismus, over the years its use has been expanded also to spasticity and other neurological disorders. This review summarizes the evidence from the published literature regarding its effect on neuropathic pain. Almost all investigations were performed using onabotulinum toxin type A (BoNT/A). Most studies provided positive results, even though toxin formulation, dose, dilution, injection techniques, and sites are heterogeneous across studies. Future larger, high-quality, specifically designed clinical trials are warranted to confirm botulinum neurotoxin efficacy in neuropathic pain. Neuropathic pain (NP) is a pain caused by a lesion or a disease affecting the somatosensory nervous system and encompasses common neurological pain syndromes such as trigeminal neuralgia (TN), postherpetic neuralgia (PHN), diabetic neuropathic pain (DN), and postsurgical neuralgia.NP is caused by pathological changes involving the peripheral  and the central nervous system (CNS). The pathologies responsible for tissue specific symptoms of NP comprise viral infections , metabolic disorders with mitochondrial dysfunctions , stroke, mechanical injuries to the CNS or peripheral nerves , 2, and Nociceptor activation is one of the most relevant NP peripheral mechanism, causing abnormal neuronal hyperexcitability, hyperalgesia, and allodynia –6.Nociceptors consist of free nerve endings related to unmyelinated C-fibers and small-myelinated Aδ-fibers; they are activated by different mechanical, thermal, and chemical stimuli and a variety of endogenous substances  –6. IncreThe activity of second-order neurons is modulated by the descending brainstem inhibitory noradrenergic, serotonergic, and opiatergic pathways, spinal GABAergic and glycine inhibitory inputs, as well as by the cannabinoid system –10.Current pharmacological and non-pharmacological treatment of NP is still unsatisfactory , 11, 12.BoNT is a potent neurotoxin produced by Clostridium botulinum, which blocks acetylcholine release at neuromuscular junctions causing muscle relaxation. The mechanism of action of BoNT in NP is related to the inhibition of the release of neurotransmitters and neuropeptides involved in pain mechanisms and inflammation  , 17. MorThe aim of the present paper is to systematically review the evidence on BoNT usefulness in the management of NP, to highlight scientific certainties and doubts, addressing research progresses, and suggesting directions for future investigations.We searched the electronic database MEDLINE, PubMed, and the Cochrane Database for published papers and extracted data for (1) pain, (2) neuropathic pain, (3) botox, (4) botulinum toxin, (5) neuralgia, and (6) neuropathy. We considered randomized controlled trials (RCT), open label (OL) studies, retrospective/prospective case-control (CC) studies, case reports (CR), and case-series (CS) on adult patients with neuropathic pain. Our search also included meta-analyses with no language restrictions and all the titles and abstracts identified by the search were evaluated for eligibility .We considered all the articles on human studies providing abstract and full-text published in English language, regardless the year of publication.www.clinicaltrials.gov.We also searched clinical trials on BoNT and NP on The search and selection of the articles were made independently by two evaluators  and then discussed with the third author (PB).www.clinicaltrials.gov documented 17 experimental trials: nine completed, four terminated, two ongoing, and one withdrawn. One study actually focused on migraine and was therefore exclude. Complete results are available only for one of the above trials included in our review.Among the numerous pharmacological studies on BoNT for NP treatment in adults, we identified 22 RCTs, 20 CR, and 10 OL studies including a total of 1,543 patients. Eighteen studies focused on the effect of botulinum toxin in TN, nine in traumatic, compressive and post-surgical causes of NP, six in PHN, five in complex regional pain syndrome (CRPS), four in post-stroke pain (PSP), four in spinal cord injury (SCI), three in painful diabetic neuropathy (PDN), two in occipital neuralgia, two in phantom limb pain (PLP), two in neurogenic thoracic outlet syndrome (NTOS), and four in chronic pelvic pain syndrome (CPPS) see . The seaidiopathic (without any reliable organic substrate), classic , and secondary   .Indisputably, carbamazepine  and oxcarbazepine  represent the first-choice TN medical treatment . Howevern = 7) (n = 8) (n = 4) (Diverse investigations provided encouraging data on the efficacy of onabotulinum toxin type A (BoNT/A) in reducing pain severity and attack frequency in TN , 26. It'n = 7) –33, OL s (n = 8) –41, and  (n = 4) –45 (Tabl (n = 4) .p < 0.01), showing sustained efficacy and good tolerability  or saline (20 pts) in the skin and/or mucosa of affected pain areas. BoNT/A significantly reduced pain intensity at week 2 and pain attack frequency at week 1 compared to the placebo  and acute medication intake and increasing quality of life (QoL) functioning scale at week 12. Each point injection, detected using a “follow the pain” method, received BoNT/A (5 U) or 0.1 ml placebo subcutaneously. In patients with mandibular root involvement, a larger toxin dose was injected posteriorly in the masseter to avoid undesired cosmetic effects (BoNT/A (100 U) has been demonstrated to be effective also in intractable TN in a randomized, single-blinded, placebo-controlled study on 20 patients, significantly reducing pain intensity  in a RCT on 36 patients (20 randomized to active and 16 to placebo) affected by idiopathic TN. Injections were delivered subcutaneously in the affected area and also in the masseter muscle in patients with the involvement of the third branch of the trigeminal nerve  outperformed placebo in pain severity reduction at 3 months post-dosing , BoNT/A 25U (n = 27), or BoNT/A 75U (n = 29) and found that both toxin doses were equally significantly more effective than placebo in reducing VAS scores as early as week 1, showing higher response rates at week 8 . The proportion of patients reporting their pain symptoms as “much improved” or “very much improved” at Patient Global Impression of Change was comparable at both 25U (66.7%) and 75U (75.9%) doses and clearly superior to placebo (32.1%).The efficacy of BoNT/A in the treatment of classical TN is not dose-dependent. Zang et al.  randomizp < 0.0001) and frequency of attacks (p < 0.0001), documenting a benefit duration up to 3 months and mild–moderate and self-limiting adverse events ..47).Herpes zoster results from reactivation of varicella zoster virus which lies dormant in sensory dorsal roots, cranial nerves, and autonomic ganglia. It presents as a painful maculopapular or vesicular rash in a dermatomal distribution, most commonly in thoracic and cranial distributions. The PHN is its most common complication, occurring in 10–50% of patients , and it BoNT/A may represent an effective therapeutic option for PHN. Some case-reports documented the efficacy of the toxin in patients with PHN refractory to conventional treatments in term of VAS score reduction at a mean dose of 100 U, with an analgesic effect duration ranging from 52 to 64 days and a good tolerability –52.p < 0.01). The improvement of sleep time in the BoNT/A group was also significantly greater compared with the other groups (P < 0.01) , lidocaine (20 pts), or placebo (20 pts). The volumes of administration varied according to the area of tactile allodynia, but fewer than 40 mL volumes (200 units for the maximum BoNT/A dose) were used. BoNT/A reduced pain more effectively than both lidocaine and placebo at day 7 and after 3 months compared to baseline ( < 0.01) , 53.P < 0.001). Notably, BoNT/A improvement in pain and sleep scores persisted for 16 weeks  the mean pain intensity over 24 weeks after the first treatment administration compared with placebo. The study, which included six subjects with PHN, confirmed the role of BoNT/A in reducing pain severity, evidencing that it was particularly efficacious in participants with preserved nociceptive input. Moreover, the authors suggested that at least two administrations of BoNT/A might be necessary in non-responders before deciding to withdrawing the treatment , 34 subjects were randomized to receive two subcutaneous administrations of BoNT/A (up to 300 U) or placebo, 12 weeks apart. Two successive BoNT/A administrations significantly decreased  , 59. As p = 0.05) reduction in neuropathic pain scale (NPS) scores for all items—except cold sensation—in VAS (p = 0.01) and DN4 scores (p < 0.05) compared to placebo in a study performed on 40 patients affected by PDN aged <70 years. One third of patients in the treatment group showed bilateral pain reduction 3 weeks after injection  induced a significant reduction in VAS score at weeks 1, 4, 8, and 12 compared to placebo with a reduction of VAS ≥3 within 3 months after injection in 44% of patients receiving the active drug. A transient sleep quality improvement was also described . Using tnjection .The use of BoNT/A in DN is promising although the studies are scarce and carried out on small populations –63. LargPSP is a heterogeneous clinical entity caused by neuropathic and nociceptive mechanisms, which affects from 10 to 70% of patients with stroke and includes central PSP, pain related to spasticity, muscle-skeletal pain, complex regional pain syndrome, and post-stroke headache , 65.PSP is one of the factors contributing to patients' disability and interferes with daily activities, sleep, walking, physiotherapy, greatly affecting their quality of life.p < 0.05) compared to patients treated with placebo plus standard care .–69.66–69ard care  (69).ad hoc designed RTCs.The usefulness of BoNT/A in the management of PSP deserves to be investigated in further p = 0.0315)   71)..p = 0.03ARCT with botulinum toxin type B (BoNT/B) in 20 outpatients affected by CTS did not confirm the positive findings reported in an open label trial on five women  72, 73), 7372, 7PTPS is a traumatic neuropathy that can affect as many as 50% of patients undergoing thoracotomy, is often refractory to conservative management and may require multiple analgesics for adequate pain control. BoNT/A may represent an alternative or adjunct treatment to improve symptom management in patients with PTPS  79). Tw. Tw79). The prevalence of chronic post-surgical pain in cancer patients ranges from 20 to 70% according to different studies. Chronic post-surgical pain pathophysiology is likely to include both peripheral and sensitization mechanisms , 81.p < 0.0001) and pain during both initial and final expansion (p = 0.009), greater volume of expansion per session (p = 0.010), reduced number of expansion sessions (p = 0.025), and lower narcotic use compared to standard procedures (p= 0.012) (A prospective study on 48 post-mastectomy patients demonstrated that BoNT/A (100 U) administration in the pectoralis major, serratus anterior, and rectus abdominis muscle followed by immediate insertion of tissue expander leads to a significant reduction of post-operative pain (= 0.012) .p < 0.0001) and diazepam (p < 0.0001) and an increase in the expansion volume per visit in the active group compared to placebo (p < 0.05) , demonstrated a reduction in the use of oxycodone ( < 0.05) .BoNT/A  proved effective in reducing pain and improving quality of life in eight out of 12 female cancer patients who had surgery or radiation for local cancer and failed >2 analgesic treatments  Table 7Table 7.CRPS is characterized by disabling chronic-relapsing burning pain, vasomotor changes, and occasionally trophic or motor function changes .p < 0.02) and greater reduction in pain intensity (p < 0.0001) in those receiving BoNT/A compared with local anesthetic alone  in almost all individuals (97%)  to 37 patients with severe local pain at baseline induced a significant pain reduction  . Lumbar ls (97%) . The stuP < 0.0001)  or placebo revealed a more marked reduction in VAS score, compared with placebo, at 2, 4, 6, 8, 10, and 12 weeks post-injection ( 0.0001)  88)..P < 0.00The long-term treatment of PLP using BoNT/A administration  in the stump muscles of a lower limb amputee led to almost complete pain freedom .A prospective RCT on 14 patients randomized to receive BoNT/A (250–300 U) or lidocaine plus depomedrol at the focal tender point demonstrated that both treatments were equally effective in PLP relief  90)..90).Pain often complicates SCI. Neuropathic pain after SCI is generally severe, refractory to treatment and persistent over time, reducing quality of life and interfering with cognitive, emotional, and physical functioning. Its prevalence rate ranges between 75 and 81% , 92.p < 0.01) and in improving quality of life  , 94. The of life  96)..p < 0.01NTOS is a complex entity characterized by different neurovascular signs and symptoms involving the upper limb due to a compression of the brachial plexus trunks or cords, including nerves which comes from the C5-T1 spinal levels. According to some studies, BoNT may be useful to reduce NTOS symptoms in those patients who did not benefit from physical therapy –99 Tabl.CPPS is defined as “a chronic pain and inflammation in the pelvic organs lasting >6 months” . Its treThe majority of the studies were performed using BoNT/A, two studies using BoNT/B. VAS score reduction was the primary endpoint in all the studies. A positive effect of BoNT/A on NP was documented in 19 out of 21 RCT studies. The only RCT performed with BoNT/B provided negative results. Negative results emerged in two RCTs, (one in PSP and one in CTS) , 73 whilIn all the studies, BoNT/A had been used as a second line treatment in patients who had had previous pharmacological therapeutic failures. Prior unresponsiveness to standard of care did not affect patient's responsivity to BoNT/A. The overall tolerability of BoNT/A in the different clinical setting was good, and adverse events were usually transient and mild. No safety concerns emerged. The treatment of the face for trigeminal neuralgia or post-herpetic neuralgia was burdened by a greater number of side effects compared to limb or thorax districts due to potential facial asymmetry induced by the muscle relaxant effect of BoNT/A.NP is a chronic, highly disabling condition caused by a lesion or disease of the somatosensory nervous system which affects from 1.5 to 6.9% of individuals aged 50–64 years , 11.There is a stringent need for innovative and alternative NP treatments because the current standard of care—including antidepressants, anticonvulsants, opioids, topical capsaicin, and lidocaine as well as non-pharmacological approaches—is still unsatisfactory due to the low responder rate (<30% of patients), the frequency and severity of adverse events , and the relevant proportion of patients with treatment discontinuation (30–50%) , 13.Botulinum toxin could represent a promising therapeutic tool for NP for its documented efficacy and tolerability in a wide range of NP conditions. BoNT/A is the toxin most extensively studied, having being investigated in 21 RCTs. BoNT/A seems helpful in particular in TN, PHN, PDN, occipital neuralgia, post-surgical pain and in SCI-related pain. However, the quality of evidence is low overall due to the paucity of RCT in some NP types, the small number of patients studied and methodological heterogeneities. One major limitation is the use of different toxin serotypes and preparations which hampers the comparison of studies' results. Most studies specified the use of the common BoNT/A brand (Botox®) , 93, 101No major safety issue emerged in the studies reported in the present review. Adverse events were rated as mild or moderate and included local skin reaction (swelling), pain at the injection site, muscles weakness, flu symptoms, nausea, and vomiting. However, there is a need for a specific evaluation of this aspect in human trials as, at present, only data on experimental animal models have been provided , 106.The cost of the toxin and the need of specific injection expertise may represent a restriction for its widespread use.Bearing in mind these limitations, we deem that the use of botulinum toxin should be carefully considered in patients with NP not responsive to current standard of care and to avoid undesired adverse events and safety concerns. BoNT could also reduce the use of surgical or invasive procedures, often applied in patients refractory to common therapeutic strategies.Larger and specifically designed RCTs are awaited to confirm efficacy and tolerability of BoNT and also to provide standardized treatment models for the different types of NP, systematically specifying serotypes, doses, treatment sites, and the depth and number of injections. Future researches are also expected to ascertain the proportion of patients developing anti-toxin antibodies during prolonged treatment, evaluate the risk of systemic effects after local delivery and appraise the safety of the botulinum toxin in the elderly and in fragile individuals.GE and LF equally contributed to the review of the literature and to the draft of the article. PB contributed to the draft and revision of the article. All authors contributed to the article and approved the submitted version.GE has received travel grants and honoraria from Eli-Lilly, Novartis, and New Penta. LF has received travel grants and honoraria from TEVA, Eli-Lilly, and Novartis. PB has received travel grants or research support and honoraria or both for lecturing and being a consultant and scientific advisor for Merck, Lusofarmaco, Bayer, TEVA, Novartis, Eli-Lilly, Visufarma, and Assosalute.


Administration of medications such as dexmedetomidine as a topical anesthetic has been suggested in the pain control in dentistry. This double-blind randomized control trial study evaluated postoperative pain and associated factors following impacted third molar extraction surgery. Lidocaine alone was taken as the control and lidocaine plus dexmedetomidine as the intervention. μg for the intervention group while only lidocaine was used in the control group. A visual analog scale was used to measure and record pain levels at the end of the surgery and 6, 12, and 24 hours after the surgery and number of painkillers taken by the patients after the surgery was also recorded.  Forty patients undergoing mandibular third molar extraction entered the study and were randomly allocated to the control and interventional groups. 0.15 ml of dexmedetomidine was added to each lidocaine cartridge and the drug concentration was adjusted to 15 P value < 0.05). There was a nonsignificant reduction in the number of painkillers taken by the patients at 6, 12, and 24 hours after surgery .  Pain scores of the intervention group decreased significantly during the surgery and also 6, 12, and 24 hours after the surgery compared to the control group. The pain score was correlated significantly with our intervention during the surgery and also 6 and 12 hours after that (all Clinical Relevance. Compared to the injection of lidocaine alone, combination of dexmedetomidine and lidocaine can be used for a better pain control in molar surgeries. In patients undergoing molar surgery, administration of a combination of dexmedetomidine and lidocaine is beneficial for the pain control.  Despite significant advances in pain management in dentistry, pain remains a major concern for many patients . Surgicaα2-adrenoreceptor agonist which is highly selective. It triggers and also maintains the sleeping state by stimulating the densest region of α2-receptors in the central nervous system which is located in the locus coeruleus in the brain stem. Patients can be aroused by language or stimuli after sedation and respiratory depression does not occur during the surgery [Becoming aware of the need for a surgery evokes feelings of fear and anxiety in many patients. Sedatives can increase pain threshold, exert antianxiety effects, and ultimately influence and control patients' pain . Glucoco surgery , 11. Owi surgery . A compa surgery . Due to  surgery . Dexmede surgery . Some re surgery . Studies surgery . But theThe objective of this study is to see the effects of adding dexmedetomidine to lidocaine which is the routine nerve blocker for the extraction of third molar tooth, by comparing the postoperative vital signs and pain in a randomized control trial in patients referring to Torabinejad Clinic, Isfahan University of Medical Sciences , in 2018.rd molar surgery, excessive fear of surgery, and not replying follow-up phone calls after surgery. All of the cases were also examined for the nature of impaction and expected difficulty level of the surgery by a senior maxillofacial surgeon based on the anatomical and radiological variables [This double-blind clinical trial was conducted on the patients referred to dental clinics affiliated to Isfahan University of Medical Sciences for mandibular hard tissue surgery in 2018. The patients were included if they were aged 18–40 years, were ASA I-II, had no contraindication for dexmedetomidine use , and signed an informed consent form. The exclusion criteria were lack of analgesia with the administered dose, maxillary 3α = 0.05 and ratio of the cases and control = 1, the number of participants in each group was calculated as 15 by the method of sample size for comparing two means [To calculate the sample size, a preliminary study was performed on three patients in the case group and three in the control group, and the mean and standard deviation (SD) of pain score after 6 hours had been obtained to use for sample size calculation. The method of this preliminary study was the same as the main study which will be discussed later. These patients' data were not used in the main study results and analysis. In this preliminary study, the mean ± SD of the pain score after 6 hours in cases and control was 3.6 ± 2.5 and 6.35 ± 2.8, respectively. To reach the power of 80%, considering wo means . Howeverμg. An anesthetist individually prepared the mixture. Using the same method of randomization by choosing a random number between one and two, one of the groups was assigned to one of the sets of cartridges. The surgeon and the consultants were not aware of the cartridge type. All surgeries were performed by the same surgeon. To avoid consecutive surgeries in each group, by using the same method of choosing random numbers, a number between one and forty was assigned to each person for the order of surgeries. The cartridge was also labeled by that number.Two identical sets of twenty cartridges were prepared. One set was lidocaine cartridge  and for making the other set, 0.15 ml of dexmedetomidine  was added to lidocaine cartridge and the drug concentration was adjusted to 15 The eligible patients were first briefed about the study objectives and methods and asked to sign an informed consent form. They were then asked to complete a questionnaire containing demographic information, medical history, medicine use, and smoking. During the surgery, patient information  was recorded in a specific data collection form. A visual analog scale was also administered to measure and record patients' pain levels at the end of the surgery and 6, 12, and 24 hours later in the scale of 0 to 10, 0 corresponding no pain and 10 the worse pain. Patients were allowed to take nonsteroidal anti-inflammatory drugs (NSAIDs) or acetaminophen after the surgery and they were asked by telephone about the number of postoperative painkillers taken. The patient's satisfaction and the surgeon's assessment of the surgical process in regards to the pain control was recorded as 3-scale questionnaire, high, intermediate, and low, for the patients' satisfaction and 4-scale questionnaire, good, fair, poor, and impossible, for the surgeon's assessment of the surgical process and pain control. The patient is marked good if he or she is fully cooperative with optimum degree of sedation, marked fair if the minimal interference is necessary due to over/under sedation, marked as poor if the operation is difficult due to over/under sedation, and marked impossible if actions such as general anesthesia are required.All patient information was recorded anonymously and the participants were ensured about the confidentiality of the collected data. The patients paid no fees for pre- and postoperative tests. Informed consent was obtained from all subjects before the intervention. The study protocol was approved by the Ethics Committee of Isfahan University of Medical Sciences (ID = 397331).P < 0.05. After the results have been obtained, the power of the study was determined by using free online open source calculator OpenEpi, version 3, by the method of comparing two means for the pain score between the interventional and control groups [Data collected through questionnaires were coded and analyzed using Fisher's exact test, ANOVA, or Mann–Whitney U test wherever appropriate. Spearman rank correlation analysis was performed by dichotomizing the pain score values using the 75 percentiles (third quartile) of the patient's pain scores as the cutoff value, between pain score and the intervention group, using the intervention group as 1 and the control group as 0. All analyses were performed using SAS version 9.4  at a significance level of l groups .From the total of 40 patients, 17 were men (42.5%) and 23 were women (57.5%). Assessment of 36 patients (901%) was good and 4 patients (10%) was fair. Satisfaction rate of 35 patients (87.5%) was high and 5 patients had moderate satisfaction. The two groups had no significant differences in the number of painkillers used at 6, 12, and 24 h after surgery. However, pain score was significantly lower in the intervention group at the time of surgery and also 6, 12, and 24 hours after that . The thiBy considering the mean pain score and the SD in the intervention and control groups, the power of the study during the surgery and 6, 12, and 24 hours after the surgery was 61.47%, 98.56%, 9.53%, and 87.75%.The findings of this study demonstrated that adding dexmedetomidine to lidocaine cartridge increased the effects of lidocaine and reduced pain scores in patients immediately and 6, 12, and 24 hours after surgery. The correlation of pain score and the intervention is negative, meaning adding dexmedetomidine to lidocaine cartridge correlates with decreasing the pain score in the patients. This significant correlation had been observed during the surgery as well as 6 and 12 hours after that. After 24 hours although the patients had lower pain scores, the difference between two groups was not significant. We also found out that, although the intervention group used fewer painkillers, there were no significant differences between the two groups in terms of the mean number of painkillers used. So, the higher pain score did not result in taking significantly more painkillers.α2-adrenoreceptor agonist, dexmedetomidine plays a key role in reducing postoperative complications. The drug's mechanism of action is by inhibiting epinephrine and norepinephrine release and thus decreasing patient stress through eliminating the feelings of confrontation and escape [Molar surgery and the associated pain lead to various complications including decreased quality of daily activities, excessive use of sedatives, and increased risk of polypharmacy . Studiesd escape , 23.Several studies have evaluated the effects of dexmedetomidine and lidocaine on pain relief. In a study on healthy individuals in 2014, Yamane et al.  showed tA double-blind study by Shetty et al. in 2016  evaluateOur study had some limitations including a relatively small sample size (due to lack of access to further facilities and time and space limitations), although the power of our study was very high, especially 6, 12, and 24 hours after the surgery, regarding the pain scores. Using only one drug dose (rather than various doses) was another limitation of this study. Given more efficiencies reported in the coadministration of other pain relievers, further studies with larger sample sizes are recommended to use combinations of dexmedetomidine and other drugs. An advantage of this study was the control of factors affecting the final results, which can provide more realistic and reliable outcomes.In patients undergoing molar surgery, administration of a combination of dexmedetomidine and lidocaine reduced pain scores to a significantly greater extent compared to lidocaine alone and decreased the number of painkillers compared to the control group. Therefore, a combination of dexmedetomidine-lidocaine is recommended for further pain relief and reducing the use of analgesics in patients undergoing such procedures.


To investigate the effect of acupuncture on reducing pain and anxiety related to hysterosalpingography (HSG).A total of 107 patients planned to undergo HSG were randomly separated into 3 groups; the acupuncture group (n=36), intramuscular diclofenac sodium group (n=35), and control group (n=37). In the acupuncture group, electro-acupuncture was applied to specified points for 20 mins before the procedure. In the intramuscular diclofenac sodium group, an intramuscular injection of 75 mg diclofenac sodium was applied 30 mins before the procedure. No analgesics were administered to the patients in the control group before intervention. Pain was evaluated with a Visual Analog scale (VAS) and anxiety with the State-trait Anxiety inventory -state (STAI-S), preoperatively and at specified times postoperatively.The VAS scores at 1 and 5 minutes after HSG were similar in acupuncture group and intramuscular diclofenac sodium group, and significantly lower than in the control group. At 30 mins postoperatively, there was no significant difference between the 3 groups in respect of the VAS scores. The STAI-S scores at 1 hour preoperatively were similar in all the groups (p=0.563). In the comparisons of the STAI-S values at preoperative 5 mins, following acupuncture in acupuncture group and the diclofenac injection in intramuscular diclofenac sodium group, and at postoperative 30 mins, the acupuncture group values were determined to be statistically significantly lower than those of the other groups .Acupuncture has similar effects on the reduction of pain as other analgesics and reduces anxiety. It can therefore be used in HSG in suitable clinics. PRECIS: Acupuncture has similar effects on the reduction of pain as other analgesics and reduces anxiety.. Hysterosalpingography (HSG) is a relaible and cost-effective method used in the determination of both tubal pathologies and tubal patency, and uterine and peritoneal pathologies in the investigations into the etiology of infertility. Although HSG is a procedure that does not require cervical dilatation or general anaesthesia, the procedure can be painful. Up to 72% of patients complain of pain from the procedure.Infertility affects approximately 15% of the general population worldwide and 40-50% is attributed to female infertility. It is caused by many factors, and fallopian tube abnormalities cause about 30-35% of cases of female infertility. Patients think that this procedure will be painful and are reluctant to have the test, which also causes anxiety. Many different randomised controlled studies have investigated many different agents and different application methods to reduce pain during HSG,6,7,8, and there are reviews in literature that have evaluated these studies,10,11. However, the majority of these studies have limitations such as heterogenity in the randomisation, lack of blinding, patient selection criteria, differences in drug doses and in the pain score measurements. Therefore, no optimal method has been found as yet, which can be recommended to alleviate pain during the HSG procedure.The mechanisms causing pain may include cervical instrumentation, and irritation of contrast medium in uterine cavity distension, and peritoneal irritation of contrast medium that has spread to the abdomen. In addition, taking the uterus into traction by holding the cervix with a tenaculum increases local prostaglandin synthesis and can lead to uterine contractions and pain and chronic pain. Kiran et al. determined that acupuncture and non-steroid anti-inflammatory drugs (NSAIDs) have similar effects in patients with primary dysmenorrhea. In recent randomised controlled studies, Smith et al. reported that acupuncture decreased anxiety and increased quality of life in patients applied with in vitro fertilization.Complementary treatments have started to be more widely used in modern medicine, and of these, acupuncture applications have shown efficacy, especially in acute pain syndromesTherefore, the aim of this study was to investigate, for the first time in literature, the effect of acupuncture in reducing pain and anxiety in patients undergoing HSG.Approval for the study was granted by the Clinical Research Ethics Committee of Kahramanmaraş Sütçü İmam University . Patients who admitted to our Assisted Reproductive Techniques clinic with the desire to have a child and planned to undergo HSG were included in our study. Informed consent was obtained from all the patients. Age, infertility duration, gravida and smoking status of all patients participating in the study were registered. At the beginning of the study, a pilot study was conducted with 10 patients from each group and the minimum number of patients in each group with α=0.05 and 90% power was found to be 27 in the power analysis. There with, 133 patients were planned to be included in the study at first. However, the study was conducted with the remaining 107 patients after excluding the ones allergic to radiopaque substance (n=1) and NSAID (n=3), those with cervical-endometrial infection (n=5), those with previously defined NSAID drug-related side effects (n=5), those with cervical surgical anamnesis (n=1), those who were found to have acute pelvic inflammatory disease (n=3) and those who did not want to participate in the study. The remainig 107 subjects were divided into three groups after computer-generated randomization; the acupuncture (ACU) group (n=36), intramuscular diclofenac sodium (IMDS) group (n=35), and the control group (n=37).. The HSG procedure was applied within 3 hours of the ACU application.For the patients in the ACU group, taking anxiety into consideration, the points selected and identified to decrease the pain and stress that can develop during the taking of HSG were those which are most widely used in the treatment of dysmenorrhea and anxiety. All the ACU procedures were applied by the same physician (A.D.) who has experience on ACU procedures for more than ten years. The H7, Du-20, Liv-3, P-6, HT-7, PC-6, LI 4, LI 10, SP-6, LR-3, ST-36, GB-26, CP-15, ST-28 and Ren-4 points were stimulated using sterile, disposable, steel needles with a single-sided point and length and diameter of 0.30x40 mm and 0.25x25 mm, placed bilaterally in a single session at a depth of 10-50 mm and angled at 45-90˚ to the skin. ACU was applied to these points for 20 minutes using Acutens SMS-205, 5-channel, 1-200 Hz, 1-10 mA, at 1-20 Hz frequency and current at maximum 10 mA intensity.For the patients in the IMDS group, 75 mg diclofenac sodium  was administered intramuscularly one hour before the HSG procedureNo medication or procedure was applied to the control group patients before HSG.The randomisation of patients to the 3 groups was performed by a single physician (M.G.) blinded to the patients. HSG was applied in the Outpatients clinic at 1-3 days after the end of menstruation, in the follicular phase of the menstrual cycle. HSG was performed under fluoroscopy guidance with the patient in the lithotomy position. A sterile speculum was placed in the vagina, and following observation of the cervix, local cleaning was applied with 3% povidone-iodine. Then, depending on the cervix position, the anterior or posterior cervical lip was held with a tenaculum, and a Rubin HSG cannula was gently placed in the cervical canal. The speculum was removed and 10-20 mL water-soluble, radio-opaque solution  was used as a contrast medium and injected slowly under spot fluoroscopy. After completion of the procedure, all the instruments were removed and the patient was transferred to a bed.A Visual Analog scale (VAS) was used in the evaluation of pain severity, and the State-trait Anxiety inventory- state (STAI-S) in the evaluation of patient anxiety. All the VAS and STAI-S scoring was performed by a single physician (A.U.) blinded to the groups. In the VAS system, the patient is instructed to place a mark on a 100 mm horizontal line corresponding to the level of pain felt, where 0 =no pain and 10 =intolerable pain. The questions on the STAI-S form were asked directly to the patients and the results were recorded. Both evaluations were applied at 1 min and 5 min before the HSG procedure and at 30 minutes after the procedure and all the results were recorded. In the evaluation of anxiety, the changes over the specified time period were evaluated.Ø., Harper, D.A.T., Ryan, P.D. 2001. Paleontological statistics). To assess the conformity of data to normal distribution, the Shapiro-Wilk test was applied to data with single variables and the Mardia test (Dornikand Hansen omnibus) to data with multiple variables. The Levene test was used to evaluate variance homogeneity. Parametric methods were used in the analyses of variables with homogenous variance and normal distribution and non-parametric methods were used for variables not showing homogenous variance and normal distribution. In the comparisons of independent multiple groups with each other, the One-Way ANOVA (Robust test: Brown-Forsythe) and Kruskal-Wallis tests were used, and for the post hoc analyses, the non-parametric post hoc test . To examine the interaction of repeated measurements of dependent variables according to the groups, the General Linear Model Repeated Anova (Wilks Lambda) was used and the LSD test for post hoc analysis. Quantitative data were presented in the tables as mean ± standard deviation and median range (IQR or minimum-maximum) values, and categorical data as number (n) and percentage (%). The data were examined at a 95% confidence interval. A value of p<0.05 was accepted as statistically significant.Data obtained in the study were analysed statistically using SPSS 22.0 vn 22 software  and PAST 3 software    (As shown in p=0.625) . There wp<0.001) . STAI-S p<0.001) . When thp<0.001) .The results of the study showed that ACU reduced the pain scores before and after the HSG procedure as effectively as the NSAID diclofenac. It was also determined that unlike diclofenac, ACU had the effect of reducing anxiety related to the procedure.. In a review by Ahmad et al. on the subject of pain-relief in office-setting gynaecological interventions, there was reported to be no benefit of oral NSAIDs within the first 30 mins and 30 mins after the procedure, but when local anaesthetics were used, it was shown that even if not in the first 30 mins, there could be beneficial effects after 30 mins.There are many studies on the subject of pain relief in HSG that have investigated the types of pharmacological drugs used and the methods of use. A systematic Cochrane review in 2015 on the subject of pain releief in HSG analysed 23 prospective, randomised studies. Although the level of evidence was low, it was concluded that topical anaesthetics and intravenous opioids could be effective in reducing pain during the procedure, but this effect was not seen after the procedure. It was reported that there was not sufficient evidence that other analgesic methods could be effective and Varpula, it was determined that the use of flexible balloon catheters instead of a traditional metal cannula was not effective in reducing pain, while De Mello et al. reported in a study published in 2006 that the use of flexible balloon catheters resulted in less pain. Stoop et al. investigated the efficacy of fast-release orodispersible tramadol, as a different analgesic method, in cases where traditional metal cannula and balloon catheter were used, and reported that it was effective independently of the type of catheter used.The majority of studies in literature related to reducing pain with non-pharmacological methods are studies where catheters have been used. It has been suggested that catheters used during HSG could have different effects on pain. In studies by Austin et al. reported that the analgesic efficacy of ACU occurred by increasing endogenous opioids and demonstrated that this effect could be removed with naloxane, which is an opioid antagonist. Using functional magnetic imaging technology, another study showed that the stimulation of ACU points affected the the limbic system and structures in both the cortical and subcortical areas in the brain. In a clinical study, Cho et al.(24) determined activity signals in the cingulate gyrus and thalamic region with pain stimuli, and following ACU, reported a decrease both in the signals and in the pain felt by the patient.ACU is a complementary medicine application with increasingly widespread use. There have started to be wide areas of use especially in the elimination of pain symptoms. Previous studies have shown that the effect mechanisms of ACU are formed on a biological basis. Cheng and Pomeranz investigated changes in plasma adrenocorticotropic hormone, corticosteroid and platelet 5-HT levels in response to anxiety treatment. Comparisons were made of ACU, pharmacological treatment and combined treatment groups, and similar results were found in the ACU group and the pharmacological treatment group. That the side-effects seen in the pharmacological treatment group were not seen in the ACU group was emphasised as a positive aspect. The effects of ACU on anxiety were investigated by observing changes in the parameters of oxygen saturation and heart rate by Karst et al. and in heart rate and skin conductivity by Shayestehfar et al.. As ACU reduced heart rate in both groups, it was concluded to be effective on anxiety.Although there are no studies in literature examining the effect of ACU on anxiety engendered by the application of HSG, there are studies related to the effect of lowering anxiety in general. The hypotheses of some of these studies are explained by biochemical mechanisms and some by physiological parameters. Yuan et al.To the best of our knowledge, this is the first study in literature to have investigated ACU on this subject. However, there were some limitations to the study, the first of which is that the different stages of HSG  were not evaluated with VAS. In addition, the side-effects of NSAIDs and ACU were not examined, and when examining the pain scores, the HSG results were not taken into consideration.Although the use of ACU is restricted in most clinics because of the need for trained practitioners, equipment and time, as it has a similar effect to other analgesics in reducing pain, and effectively reduces anxiety, it can be used in HSG in suitable clinics.


Dear Editor,Our previous study has demonstrated non‐small‐cell lung cancer (NSCLC) patients with high tissue‐based tumor mutation burden (TMB) derived encouraging benefits from immune checkpoint inhibitor (ICI).P < .001; HR 0.67, 95% CI, 0.57‐0.78; P < .001; Figure In the whole intention‐to‐treat and EGFR wild‐type patients, compared with docetaxel, atezolizumab resulted in significantly longer OS . Of note, a previously established bTMB threshold of 16We next performed similar analysis at various MSAF cut‐points and found EGFR wild‐type patients with MSAF < 0.10 had improved OS  and PFS  when treated with atezolizumab compared with docetaxel, whereas patients with MSAF ≥ 0.10 showed no difference in OS or PFS . Additionally, a low MSAF significantly predict favorable OS and PFS among each of entire patients and atezolizumab‐treated patients . None of the tested bTMB or MSAF cut‐points could classify EGFR mutant patients into groups with different PFS or OS two treatments .R2 = 0.90) than with the bTMB (R2 = 0.68) or with the MSAF (R2 = 0.78) . The threshold of <20 gave the optimal clinical relevance, at which the lowest HRs for OS and PFS was identified .We further determined a novel bTMB‐MSAF algorithm outperforming bTMB in predicting survival with atezolizumab versus docetaxel. Patients with lower versus higher bTMB‐MSAF scores had significantly better OS and PFS in entire patients and separate OAK and POPLAR cohorts . The OS HR was more strongly correlated with the bTMB‐MSAF score (P < .001) and PFS  when treated with atezolizumab compared with docetaxel  and PFS . The blood mutation status of TP53, KEAP1, and ATM were associated with OS following ICI and were incorporated with race, sex, histology, Eastern Cooperative Oncology Group Performance Status, sum of the longest diameter, number of metastasis sites, PD‐L1 expression, and treatment response information were used to develop clinicopathologic‐genomic nomogram, which was well predictive of atezolizumab efficacy , indicating 22% predictive information was additionally provided by adding MSAF.Based on the findings above, we recommend ICI as preferred treatment for EGFR wild‐type patients with a bTMB‐MSAF score < 20, especially those in the TC3 or IC3 subgroup. Our bTMB‐MSAF score markedly enhances the degree of correlation with OS compared with bTMB , the Medical artificial intelligence project of Sun Yat‐Sen Memorial Hospital (YXRGZN201902), the National Natural Science Foundation of China , the Natural Science Foundation of Guangdong Province (2017A030313828), the Guangzhou Science and Technology Major Program (201704020131), the Guangdong Science and Technology Department (2017B030314026), the Special Funds for the Cultivation of Guangdong College Students’ Scientific and Technological Innovation (pdjh2019a0212), National Students’ Innovation and Entrepreneurship training program (201910571001), and Guangdong Medical University College Students’ Innovation Experiment Project (ZZZF001).The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request (yaoherui@mail.sysu.edu.cn).The study protocol was approved by the ethics committee of the Sun Yat‐sen Memorial Hospital of Sun Yat‐sen University. The requirement for informed consent of study participants was waived because the human data were obtained from publicly available datasets.Not applicable.The authors declare that they have no competing interests.Preliminary results of this study were presented in part as a mini–oral presentation at the ESMO Asia 2019 Congress; November 22–24, 2019; Singapore.Supporting informationClick here for additional data file.