Endometriosis is a complex disease with a spectrum of pain symptomsfrom mild dysmenorrhea to debilitating pelvic pain. There is no concrete evidence in theliterature whether endometriotic cyst per se, causes pain spectrum related to the disease.The aim of the present study was to evaluate the effect of surgical removal of endome-triomas on pain symptoms.In this prospective, observational, before-after study, whichwas conducted between March 2012 and January 2013 in Training and ResearchHospital,Adana, Turkey, a total of 23 patients including 16 sexually active and 7 vir-gin symptomatic women were questioned for non-cyclic pelvic pain (NCPP), intensityof the NCPP, presence of cyclic dysmenorrhea, and dyspareunia before and after theendometrioma operation. Participants who were sonographically diagnosed and laterpathologically confirmed as having endometrioma without sign and symptoms of deepinfiltrative endometriosis (DIE) were also questioned for pain symptoms before and afterthe laparoscopic removal of cyst wall. Patients with intraabdominal adhesions, history ofpelvic inflammatory disease, and pathological diagnosis other than endometrioma wereexcluded. No ancillary procedures were applied for pain management, but if pain waspresent, pelvic peritoneal endometriotic lesions were ablated beside the removal of ovar-ian endometriotic cysts.Out of 23 cases with endometrioma, 91 and 78% reported to have NCPPand dysmenorrhea, respectively, before the operation, while 60 and 48%, respec-tively, after the operation . Among thesexually active cases, 31% (5/16) had dyspareunia before the operation and only 1case reported the pain relief after the operation . Intensity ofNCPP were reported to be none (8.7%), moderate (21.7%), severe (56.5%) and un-bearable (13%) before the operation and decreased to none (43.5%), mild (43.5%),moderate (4.3%) and severe (8.7%) after the operation .In symptomatic cases with ovarian endometrioma, without sign andsymptoms of DIE, laparoscopic removal of the cysts with/without ablation of theperitoneal endometriotic lesions yields relief of NCPP and cyclic dysmenorrhea, butnot dyspareunia. Endometriosis is the most common gynecologicalpathology causing cyclic or non-cyclic pelvicpain (NCPP) accounting for 12-32% of womenof reproductive age and for 45-70% in adolescents because Microscopic studies have documented nerve fibresin endometriotic peritoneal lesions -9, deepIn a prospective, observational, before-after study,was conducted between March 2012 and January2013 in Adana Numune Training and ResearchHospital, Adana, Turkey. Twenty three cases including16 sexually active and 7 virgin women  who were sonographicallydiagnosed and later pathologically confirmed ashaving unilateral endometrioma (3-8 cm in diameter)without sign and symptoms of deep infiltrativeendometriosis (DIE), as dyschezia, hematuria,rectal bleeding, constipation, diarrhea and bloating,formed our study group. The patients whose rectal/rectovaginal examination, imaging studies [ultrasoundand magnetic resonance imaging (MRI)],and intraoperative findings suggested DIE as wellas the patients who had intra-abdominal adhesions,history of pelvic inflammatory disease, and pathologicaldiagnosis other than endometrioma were allexcluded. Women completed a preoperative questionnairethat collected demographic characteristicsand data on presenting problem as full menstrualhistory, medical and surgical history and characteristicsof pain symptoms. Pain was assessed using averbal scale which has good correlation with visualanalogue scale and higher compliance in clinicalsettings . The verAll patients were operated using stripping methodby the same operator. No ancillary procedures as presacralneurectomy, uterosacral interruptions of sensorynerves and uterine suspension were applied forpain management, but if pain was present, pelvic peritonealendometriotic lesions were ablated beside theremoval of ovarian endometriotic cysts. The diagnosisof endometrioma was confirmed by histologicalexamination of specimens removed at surgery.Pain relief was analyzed by the McNemar’s testfor pre- and post-operative symptoms. Analyses ofpain scores were performed using the Wilcoxon signed-rank test for paired non parametric data.Analyses was undertaken Statistics Package forthe Social Sciences  version 15. A P value of <0.05 was acceptedas statistically significant. Qualitative data are expressedin percentage (%) and quantitative data areexpressed as the means ± standard deviation (SD).The study protocol was elaborated according tothe revised Declaration of Helsinki and was approvedby the Local Research and Ethics Committeeof Adana Numune Training and Research Hospitalin Adana, Turkey. All subjects were provideda written informed consent.Average age of women at the time of surgerywas 31.9 (range 20-43). Out of 23 subjects, 43.5%(10/23) were nulliparous and 56.5% were parous.Average endometrioma cyst diameter were 43.7± 21.7 mm. Twenty two women had no previousabdominal procedure; only one woman had a laparoscopicendometrioma ablation before .Out of 23 cases with unilateral endometrioma,91% (21/23) reported to have NCPP before theoperation, but this ratio decreased to 60% afterthe operation (McNemar’s test P=0.016). Thefrequency of dysmenorrhea was also felt by 30%after the operation had dyspareunia before the operation and only 1case reported pain relief after the operation , moderate (21.7%), severe (56.5%) and unbearable(13%) before the operation and decreasedto none (43.5%), mild (43.5%), moderate (4.3%)and severe (8.7%), after the operation  , asymptoThere have been very few studies in the currentliterature evaluating the effect of removal of endometriomaon pain symptoms. The efficacy ofsurgical management of endometriosis was demonstratedby a randomized trial, comparing theoutcome of women after therapeutic laparoscopywith the outcome of women who underwent diagnosticlaparoscopy alone. Laparoscopic excisionof implants led to symptomatic improvement in80% of patients at six months compared to 32%of controls undergoing diagnostic laparoscopy .According to a review by Jadoul et al.  inwhichThere were some limitations in our study. Dueto small number of participants, we were unableto categorized the subjects according to the sizeof endometriomas, although no larger study wasconducted on this subject yet.One hundred and fifty years after endometriosiswas first described, we are still debating both itsetiology and management. Although main questionsremain unanswered, solid evidence showsthat laparoscopic surgery appears to be the mostlogical approach to treatment. As a result of ourstudy, we want to emphasize that in cases of symptomaticendometriosis, without sign and symptomsof DIE, laparoscopic removal of the cystswith/without ablation of the peritoneal endometrioticlesions may relive NCPP and cyclic dysmenorrhea,but not dyspareunia.


IL1A (rs1800587 C>T), IL1B (rs1143627 T>C) and IL1RN (rs2234677 G>A) influenced the clinical outcome the first year after disc herniation. Patients (n = 258) with lumbar radicular pain due to disc herniation were recruited from two hospitals in Norway. Pain and disability were measured by visual analogue scale (VAS) and Oswestry Disability Index (ODI) over a 12 month period. The result showed that patients with the IL1A T allele, in combination with the IL1RN A allele had more pain and a slower recovery than other patients . However, regarding the IL1B/IL1RN genotype, no clear effect on recovery was observed . The data suggest that the IL1A T/IL1RN A genotype, but not the IL1B T/IL1RN A genotype, may increase the risk of a chronic outcome in patients following disc herniation.Previous studies indicate that lumbar radicular pain following disc herniation may be associated with release of several pro-inflammatory mediators, including interleukin-1 (IL1). In the present study, we examined how genetic variability in  Studies of patients with lumbar disc herniation verified by MRI suggest that mechanical compression of the nerve-roots may induce lumbar radicular pain. However, disc herniation is also associated with an inflammatory response, with increased levels of pro-inflammatory mediators, such as interleukins (ILs), matrix metalloproteinases (MMPs) and prostaglandines (PGs) IL1A may reduce the pain threshold after disc herniation Several genetic variants may affect such processes and influence pain sensitivity. These might involve genetic variants important for the expression of GTP cyclohydrolase close to the nerve roots IL1RN). This naturally occurring antagonist binds to IL1 receptors in competition with IL1, but does not elicit an intracellular response upon binding.The IL1 gene family includes IL1α and IL1β, as well as the interleukin-1 receptor antagonist (IL1Ra). The former two are strong inducers of inflammation and one of the first cytokines produced by stress. They are secreted by a variety of cells, including monocytes, endothelial cells and disc cells IL1A, or IL1B, and IL1RN genotypes in recovery after disc herniation.IL1α, IL1β and IL1Ra and their composite genotype have previously been linked to disc degeneration and low back pain in the general population Patients aged 18–60 years, with confirmed lumbar disc herniation by magnetic resonance imaging (MRI) with corresponding sciatic pain and positive Straight Leg Raising (SLR) test were recruited from Oslo University Hospital, Ullevaal, Norway and Haukeland University Hospital, Norway, for details see All participants received written information and signed an informed consent form. The study was approved by the Norwegian Regional Committee for Medical Research Ethics and the Norwegian Social Science Data Services.After inclusion, the patients were followed up at 6 weeks, 6 months and 12 months. Conservative treatment was received by 42%, while the remaining 58% received surgery. At inclusion all patients underwent a standardized clinical examination with assessment of sensory and motor function and tendon reflexes at the lower limbs as well as an MRI scan. At 6 weeks and 12 months follow-up the clinical examination was repeated, while at 6 months follow-up patients reported their condition by a telephone interview and answered questionnaires by mail.All patients were asked to rate their pain intensity in activity during the last week on a 10-cm visual analogue scale (VAS) with endpoints “no pain” and “worst possible pain”. The validated Norwegian version of the Oswestry Disability Index (ODI) was used to assess problems with physical function related to low back pain IL1A rs1800587 C>T, IL1B rs1143627 T>C and IL1RN rs2234677 G>A. Approximately 10 ng genomic DNA was amplified in a 5 µl reaction mixture in a 384-well plate containing 1x universal TaqMan master mix and 1x assay mix, the latter containing the respective primers and MGB-probes. The probes were labeled with the reporter dyes FAM or VIC at 5′end to distinguish between the two alleles. The reactions were performed on an ABI 7900HT sequence detection system (Applied biosystems) at the following program: After initial denaturation and enzyme activation at 95°C for 10 min, the reaction mixture was subjected to 60 at 95°C for 15 s and 60°C for 1 min. Negative controls containing water instead of DNA were included in every run. Genotypes were determined using the SDS 2.2 software (Applied Biosystems). Approximately 10% of the samples were re-genotyped and the concordance rate was 100%.Genomic DNA was extracted from whole blood cells using FlexiGene DNA isolation kit . SNP genotyping was carried out using predesigned TaqMan SNP genotyping assays (Applied Biosystems) for VAS activity score and ODI measurements over time were compared regarding genotypes by repeated measures analysis of variance (rmANOVA). When sphericity assumption was not met, a Greenhouse-Geisser correction was applied. Separate analyses were performed to check for potential confounding effects of the covariates age, gender, treatment and smoking status. Covariates with a p-value less than 0.1 were kept in the final model . FurtherIL1A or IL1B, and IL1RN genotypes were analyzed. IL1A C/T and IL1RN G/A genotypes were grouped in the following variables: 1) IL1A C/C and IL1RN G/G, 2) IL1A */T or IL1RN */C, and 3) IL1A */T and IL1RN */C. IL1B T/C and IL1RN G/A genotypes were grouped in the following variables: 1) IL1β C/C and IL1RN G/G, 2) IL1B */T or IL1RN */C, and 3) IL1B */T and IL1RN */C. Statistical analyses were performed by using the SPSS (version 20) statistical package. A p-value less than 0.05 was set as the level of statistical significance. The data are shown as mean ± SEM.The combined effect of IL1A/IL1RN genotype. In accordance with our hypothesis, patients with both rare alleles (IL1A */T and IL1RN */A) seemed to report more pain and have a slower recovery than other patients . No clear association were, however, found for the clinical outcomes, with regard to the IL1B/IL1RN genotype . The characteristics of the cohort of patients stratified by the IL1A/IL1RN genotype and the IL1B/IL1RN genotype are listed in The analysis of clinical outcome over time, i.e. from inclusion to 12 months, revealed that the progression of pain and disability after lumbar disc herniation may be associated with the patients  A, B. A IL1A */T and IL1RN */A genotype had an increased one-year risk of a negative outcome, with more pain and poorer recovery . Post-hoc comparisons confirmed the differences between carriers of both IL1A T and IL1RN A alleles compared to none-carriers at 12 months . In contrast, no significant influence of the IL1B/IL1RN genotype on the one-year outcome was observed . Mean ± SEM values at 12 months are listed in Further analyses of the data sampled at 12 months showed that patients with the IL1A rs1800587 C>T, IL1B rs1143627 T>C and IL1RN rs2234677 G>A in patients following disc herniation. As expected, all patients suffered severe pain when they first were referred to the hospitals. However, patients carrying the IL1A T allele in combination with the IL1RN A allele  reported more pain and disability during the follow-up period than the patients carrying only one or neither of these alleles. In line with previous data obtained from 131 occupationally active Finish men IL1A T/IL1RN A genotype.In the present study we investigated the clinical impact of the genetic variants IL1A T allele has been associated with an enhanced promoter activity resulting in increased gene expression, both at mRNA and at protein level, compared to the C allele IL1RN A allele, since it is in linkage disequilibrium with a VNTR polymorphism in intron 2 of the IL1RN gene IL1A T/IL1RN A genotype have overall enhanced levels of IL1 relative to IL1Ra, resulting in an increased activation of IL1 receptors and a more pronounced inflammatory response.The IL1A together with MMP3 gene variation has previously been associated with Modic changes MMP1 has also been suggested to contribute to low back pain and sciatica Analyses of intervertebral disc samples from patients suggest that a high IL1 to IL1Ra ratio may be associated with degenerative disc disease IL1A T/IL1RN A genotype.IL1, along with IL6 and TNF, secreted by a herniated disc may sensitize peripheral nociceptors. For example, IL1α increases the production of PGE2 in human disc cells in a dose dependent manner IL1B T/C SNP, it has been suggested that a shift from T to C results in a disruption of the TATA box resulting in a less active promoter. The T allele confers higher expression of the IL1β gene compared to the C allele IL1B polymorphisms have previously been associated with symptomatic lumbar disc herniation IL1RN polymorphism associated with low back pain in the general population IL1B T/IL1RN A genotype.Regarding the In addition to genetic influences, other risk factors such as physical work factors, psychosocial aspects and smoking may contribute to development of persistent back pain and disability IL1A rs1800587 T allele and IL1RN rs2234677 A allele may increase the risk of a chronic outcome and persistent pain following lumbar disc herniation. However, the combination of IL1B rs1143627 T allele and IL1RN rs2234677 A allele was not associated with increased pain in these patients.In summary, our findings suggest that the development of chronic lumbar radicular pain may be associated with a high IL1 activity relative to IL1Ra. The combination of


Purpose. To compare pain scores between first-eye and second-eye cataract surgery and to determine the affecting factors. Methods. 106 first-eye and 53 second-eye cataract surgery patients  were enrolled. The patients completed simplified State-Trait Anxiety Inventory and visual analog scale (VAS) for anxiety questionnaires before surgery, and VAS for pain and Wong-Baker Faces Pain Rating Scale questionnaires after surgery. Blood pressure (BP) and heart rate (HR) were recorded perioperatively. Results. A greater proportion of patients who underwent second-eye surgery reported intraoperative pain compared with first-eye surgery patients . The pain scores were higher in second-eye surgery, while the VAS anxiety score was lower in second-eye surgery. Moreover, 31 patients reported greater pain during second-eye surgery than their first one, with higher pain scores than other 22 patients . The VAS pain score of these 31 patients was positively correlated with the differences between the intraoperative and postoperative diastolic BP, mean arterial pressure, and HR. Conclusions. Cataract patients were likely to have more pain during second-eye surgery, which may be related to lower preoperative anxiety. Monitoring perioperative BP and HR may help to identify patients with intraoperative pain. Uncomplicated cataract extraction is usually conducted under topical anesthesia. Perioperative pain management not only reduces the patient's anxiety before and after cataract surgery, but also improves the patient's intraoperative cooperation. Therefore, pain management is particularly important when performing cataract surgery.Currently, phacoemulsification plus implantation of an intraocular lens under topical anesthesia is the main surgical approach to treat cataract. Topical anesthesia significantly reduces the perceived pain at the time of making the clear corneal incision and small incision, as compared with historical techniques .Previous studies, including our clinical practice, have revealed that patients experience more painful sensations during second-eye surgery. Although an earlier study found no significant difference in the mean pain scores between patients undergoing second cataract extraction compared with patients undergoing first cataract extraction , in 2011Several studies have examined the possible causes of the increased pain during second-eye surgery. For example, Ang et al. found that nearly 20% of patients reported frightening intraoperative visual experiences that were associated with previous cataract extraction . HoweverTherefore, we used subjective and objective measures in the perioperative period, with the following aims: (1) to compare the anxiety and pain scores between first-eye and second-eye cataract surgery, (2) to identify factors correlated with the severity of pain during cataract surgery, and (3) to help surgeons evaluate and manage perceived pain during cataract surgery.The Ethics Committee of the Eye and Ear, Nose, and Throat Hospital, Fudan University, approved our study. Patients with bilateral age-related cataract were considered eligible for this study. Exclusion criteria included baseline eye pain, deafness, poor compliance to cataract surgery under tropical anesthesia, involuntary movement, history of allergy to topical anesthetics, posterior capsule organization, or other complicated cataracts. Patients were enrolled between April 2013 and July 2013. Written informed consent was obtained from all patients after they were informed of the nature and possible consequences of the study. The consent procedure was approved by the hospital's ethics committee.http://dx.doi.org/10.1155/2015/383456.Preoperative anxiety was evaluated using the validated simplified State-Trait Anxiety Inventory  , and a vPostoperative pain was evaluated using a VAS for pain, which was presented as a numbered line ranging from 0 (no pain) to 10 (unbearable pain)  and the The preoperative anxiety assessments were completed while the patient was in the waiting room before surgery. The assessments were orally administered by a trained investigator. The postoperative pain assessments were completed when the patient was transferred to the recovery room. The questionnaires were administered by the same investigator. Patients who were unable to read the VAS for pain by themselves were asked to verbally report the perceived pain using the same scale.Systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate were measured using an electric sphygmomanometer  by an experienced nurse at the following times: before surgery, during phacoemulsification, and in the recovery room. Mean arterial pressure (MAP) was calculated using the following formula: MAP = SBP × 1/3 + DBP × 2/3.The preoperative examination and surgery were strictly performed according to established outpatient surgical procedures in all patients. The same operating room was used for all procedures with the same surgical equipment and instruments. Tropicamide was administered 30 min before surgery to fully dilate the pupil. The conjunctival sac was rinsed with povidone iodine (0.02%) 5 min before surgery. Topical anesthesia consisted of 3 applications of 2% lidocaine before surgery, 1-2 drops per time, with the first application 5 min before surgery, the second application at 1 min before surgery, and the final application after placing the eyelid retractor. Oral and intravenous sedatives or analgesics were not permitted. All procedures were performed by the same right-handed surgeon (Yi Lu).After topical anesthesia, a 2.6 mm temporal clear corneal incision was created, followed by viscoelastic  injection and 5.5 mm continuous curvilinear capsulorhexis. Hydrodissection, chopping, nucleus rotation, and phacoemulsification were then performed. A foldable intraocular lens  was implanted using a dedicated injector. After aspiration of residual viscoelastic, the incision was hydrated with balanced salt solution and checked for water tightness.χ2 test was used to compare categorical variables. Comparisons of continuous variables between two groups were made using two-tailed Wilcoxon's rank-sum test for nonparametric variables and Student's t-test for parametric variables. The changes in blood pressure and heart rate over time were analyzed by one-way analysis of variance (ANOVA) followed by the least significant difference test to compare means between group. Spearman's correlation analysis was used to analyze the correlations between selected variables. A P value of <0.05 was considered statistically significant in all analyses.All statistical analyses were performed using SPSS version 13.0 . Quantitative data are presented as the mean ± standard deviation. The Between 1 April 2013 and 30 July 2013, 167 ARC patients undergoing cataract surgery were enrolled in this study. These 167 patients were administered the questionnaires, of which 159 provided valid responses and were analyzed in this study. The valid patients were divided into two groups, as follows: 106 patients underwent first-eye surgery and 53 underwent second-eye surgery. There were no significant differences between the two groups in terms of age and proportions of males/females .χ2 test, P < 0.001; A significantly greater proportion of patients who underwent second-eye surgery  reported pain during cataract surgery compared with patients who underwent first-eye surgery   and in patients undergoing second-eye surgery . The change in heart rate during surgery was not significantly different between the two groups of patients.Regarding the objective measures, there were no significant differences between the two groups in terms of the type of cataract, mean operating room time, or phacoemulsification time. Furthermore, there were no significant differences in perioperative blood pressure or heart rate between the two groups of patients . HoweverWe next analyzed the correlations between the perioperative changes in objective measures (blood pressure and heart rate) and the subjective measures (preoperative anxiety and postoperative pain).ρ = −0.300, P = 0.029).The preoperative VAS anxiety score was significantly and negatively correlated with the postoperative WBS pain score .Among patients who underwent first-eye surgery, the STAI and VAS anxiety scores were significantly and positively correlated with preoperative heart rate , DBP , and MAP . The STAI score was significantly and negatively correlated with the difference between intraoperative and preoperative MAP .Among patients who underwent second-eye surgery, the VAS anxiety score was significantly and positively correlated with preoperative SBP (Spearman's n = 53) were divided into two subgroups according to their responses to the additional question regarding the difference in pain between the first and second surgeries  and the STAI anxiety score was significantly and negatively correlated with the differences between the intraoperative and preoperative values for DBP , MAP , and heart rate .In the subgroup of patients who reported that second-eye surgery was more painful than first-eye surgery, the VAS anxiety score was significantly and positively correlated with preoperative SBP , MAP , and heart rate .In the subgroup of patients who reported that second-eye surgery was more painful than first-eye surgery, the VAS pain score was significantly and positively correlated with differences between intraoperative and preoperative values for DBP  and objective (blood pressure and heart rate) measures in this study indicate that cataract patients were more sensitive to pain during second-eye surgery than during first-eye surgery. There was a subtle increase in the severity of pain in second-eye cataract surgery relative to first-eye surgery. This increase in pain appears to be associated with decreased preoperative anxiety scores. Preoperative blood pressure and heart rate could reflect the patient's anxiety level, while perioperative MAP and changes in heart rate could reflect the patient's perceived pain level. Therefore, despite considering subjective factors, such as preoperative anxiety monitoring, our findings indicate that perioperative MAP and changes in heart rate may be significant markers for preoperative anxiety and could predict the severity of perceived pain during cataract surgery.A questionnaire on anxiety and pain evaluation we designed, which combined the validated simplified State-Trait Anxiety Inventory, a visual analog scale for anxiety, a visual analog scale for pain and the Wong-Baker FACES Pain Rating Scale, is provided below with both English and Chinese versions.


Supplemental Digital Content is available in the text Chronic postsurgical pain (CPSP) is 1 important aspect of surgical recovery. To improve perioperative care and postoperative recovery knowledge on predictors of impaired recovery is essential. The aim of this study is to assess predictors and epidemiological data of CPSP, physical functioning , and global surgical recovery  3 and 12 months after hysterectomy for benign indication.A prospective multicenter cohort study was performed. Sociodemographic, somatic, and psychosocial data were assessed in the week before surgery, postoperatively up to day 4, and at 3- and 12-month follow-up. Generalized linear model (CPSP) and linear-mixed model analyses  were used. Baseline data of 468 patients were collected, 412 (88%) patients provided data for 3-month evaluation and 376 (80%) patients for 12-month evaluation.After 3 and 12 months, prevalence of CPSP  was 10.2% and 9.0%, respectively, SF-36PF means (SD) were 83.5 (20.0) and 85.9 (20.2), global surgical recovery index 88.1% (15.6) and 93.3% (13.4). Neuropathic pain was reported by 20 (5.0%) patients at 3 months and 14 (3.9%) patients at 12 months. Preoperative pain, surgery-related worries, acute postsurgical pain on day 4, and surgery-related infection were significant predictors of CPSP. Baseline level, participating center, general psychological robustness, indication, acute postsurgical pain, and surgery-related infection were significant predictors of SF-36PF. Predictors of global surgical recovery were baseline expectations, surgery-related worries, American Society of Anesthesiologists classification, type of anesthesia, acute postsurgical pain, and surgery-related infection.Several predictors were identified for CPSP, physical functioning, and global surgical recovery. Some of the identified factors are modifiable and optimization of patients’ preoperative pain status and psychological condition as well as reduction of acute postsurgical pain and surgery-related infection may lead to improvement of outcome. But nonetheless, impaired recovery after hysterectomy may have huge social and economic impact.–6 Therefore, further knowledge on incidence and risk factors of CPSP after hysterectomy is needed.In 2010, 11,697 hysterectomies were performed in women between 20 and 65 years old in the Netherlands. A study among hysterectomy patients, reflecting on their own recovery, revealed 4 domains: physical symptoms, emotional well-being, activity levels, and decision making. Other researchers described 5 domains of recovery, based on a concept analysis and interview studies among surgery patients and healthcare workers: physical symptoms, physical functions, psychological, social, and activity.–12 This article will be based on a framework presented in 2013, proposing core predictor and outcome domains for CPSP in epidemiological studies, according to the IMMPACT recommendations.,14 Four outcome domains are suggested: pain, physical functioning, psychological functioning, and global ratings of outcome. Within each domain outcome measures are suggested.CPSP is just 1 aspect of postoperative recovery. Several other aspects may be important for a patient's experience of the success of an operation. Despite many publications on the concept and domains of postoperative recovery, there is no consensus yet about a generally accepted and validated assessment package for the evaluation of postoperative recovery. and other areas of postoperative recovery.,17 One of the existing studies on this subject that assessed a subset of the whole range of potential predictors was performed in 2007 at the Maastricht University Medical Center+ (Maastricht UMC+). Predictors of CPSP, functional limitations, global surgical recovery, and quality of life 6 months after various types of surgery were assessed. The most important somatic predictors of suboptimal recovery were a long duration of the operation and high levels of acute postoperative pain. Psychological variables associated with suboptimal long-term outcome were a high level of preoperative fear of surgery and low optimism. However, despite the fact that studies like this can be very indicative, heterogeneity in types of surgery implies the need for further studies to be performed in homogeneous populations. Even in the case of 1 type of surgery under study, heterogeneity in study design may impair the strength of conclusions. To further refine our previous findings in a more homogeneous surgical population, and according to the call for studies on hysterectomy with detailed baseline and follow-up assessments, the present prospective multicenter study was performed.To improve perioperative care and postoperative recovery, knowledge on risk factors of impaired recovery is essential. Currently, many studies have provided insight into predictors and processes involved in chronic pain,15,18–21 Important candidate predictors were acute postoperative pain, preoperative pain, and several psychosocial variables. For pre- and postoperative pain, besides the intensity, also location, duration, onset, interference, and the neuropathic character were assessed. The psychosocial variables included both vulnerability and resilience factors. Previous studies have shown that anxiety and pain catastrophizing are among the most important vulnerability factors for CPSP. Other variables that have previously been associated with higher prevalence of CPSP are depression,24 and negative outcome expectancies.,26 We also included a measure of childhood abuse as this has been related to the prevalence of chronic pain in general and more specifically to gynecological pain. One of the most prominent resilience factors for CPSP appears to be optimism.–31 In addition, social support and more general measures of wellbeing,33 have been proposed as protective factors. Thus, a comprehensive set of demographic, medical, and psychosocial variables was obtained and assessed for its association with long-term surgical outcome.To obtain a broad view of the patients’ preoperative status, a comprehensive set of demographic, medical, and psychosocial predictor variables was assessed. Of the outcome domains previously mentioned, that is, pain, physical functioning, global surgical recovery, and psychological recovery, this publication will focus on predictors for the first 3 domains. The selection of predictor variables was based on findings from previous studies on CPSP and supplemented with some general background characteristics of patients and routinely obtained medical variables.The primary aim of this study was to establish somatic and psychosocial risk factors for pain after 3 and 12 months, in Dutch patients undergoing elective hysterectomy. Secondary aims were to establish somatic and psychosocial risk factors for poor physical functioning and global surgical recovery, to assess the prevalence, incidence, and characteristics of chronic pain, and to assess epidemiological data regarding the secondary outcome variables and predictors. Epidemiological data on predictors and outcomes on the 3 domains of recovery will be described for the total population, and those concerning the predictors also separately for patients with and without CPSP. Also, patient-reported complications during follow-up will be described. To provide better insight in the course of recovery, outcome assessment was performed at multiple relevant time points: postoperative day 1 to 4, and at 3 and 12 months following surgery.2http://www.trialregister.nl/trialreg/index.asp). This article was written in accordance with the STROBE guidelines.For this study, approval of the local Medical Ethical Committee's was obtained and all participants gave informed consent. This study was registered at the Dutch Trial Register under number NTR2702  Eindhoven, the Máxima Medical Center (MMC) Veldhoven, and from May 2012, the Orbis Medical Center (OMC) Sittard-Geleen. Surgery was performed between September 2010 and January 2014. Patients were admitted to the gynecology or the short stay ward. Data collection took place in the week before surgery, postoperatively up to day 4, and at 3- and 12-month follow-up. Preoperative and follow-up assessments were performed at home by postal questionnaires. Pain was recorded in a pain diary, provided by the study coordinator, until 4 days after the operation. In case of earlier discharge, the diary was continued at home. Pain medication was recorded during the hospital stay only and stopped with discharge. Data on surgery and anesthesia were collected during surgery by the attending anesthesiologist, gynecologist, or study coordinator.Participants underwent hysterectomy for a benign indication in 1 of the hospitals involved in the study. Patients were selected for inclusion during the preoperative screening visit. Inclusion criteria were informed consent, age between 18 and 65 years, good command of the Dutch language, elective surgery, and total or subtotal hysterectomy with or without oophorectomy. All types and combinations of surgical approach were allowed: vaginal, abdominal, or laparoscopic. Exclusion criteria were history of cancer, illiteracy, and cognitive impairment, as indicated in the medical record or assessed during the informed consent procedure. Patients with a history of malignancy or an oncological indication for surgery were excluded because of potential differences in prognosis as well as perioperative treatment like chemotherapy or radiotherapy that might bias preoperative baseline and predictor data as well as postoperative outcome.2.1Confounding was addressed in several ways. A homogeneous population was selected, that is, females between 18 and 65 years, only hysterectomy as type of surgery, and absence of malignancy. Data were collected prospectively, missing perioperative data were extracted afterward from the medical file, when available. If the pain diary or follow-up questionnaire was not returned, patients received 1 reminder by post. Missing values on multi-item psychosocial questionnaires, physical functioning, and pain interference scale, if <20%, were imputed by the participants’ mean score on that scale. Single-item sociodemographic, surgical, and outcome variables were not imputed. Use was made of validated questionnaires. All questionnaire packages were designed in collaboration with MEMIC Maastricht, center for data and information management. Completed questionnaires were scanned by MEMIC Maastricht and provided directly in SPSS format. Statistically, using multivariate analyses, the collected control and process variables allowed for correction of bias caused by baseline status of outcome and sociodemographic or surgical factors. Finally, all patients who underwent other surgery or reported a malignancy during follow-up were excluded from follow-up analysis.2.2 American Society of Anesthesiologists (ASA) physical status classification was recorded. Physical functioning was measured with the physical functioning subscale of the RAND health survey short-form 36 (SF-36). This subscale consists of 10 items assessing perceived difficulties in physical activities, range from 0, indicating severely restricted physical activity, to 100 indicating unrestricted physical activity.,37Baseline data consisted of the sociodemographic variables such as age, education level, employment status, marital status, number of children, and gynecological history, including whether women were sexually active or not. Health behavior , general health status, and comorbidity were assessed using the screening list developed by Statistics Netherlands. The scale was slightly adapted to assess intensity of both hysterectomy-related  and nonhysterectomy-related pain over the last week instead of the last 24 h. We added 1 item to assess “any pain” at the moment of completion of the questionnaire, using the numeric rating scale (NRS) 0 to 10. In order to further characterize the pain, the Douleur neuropathique 4 (DN4) was administered. The DN4 is a 10-item screening instrument to assess the neuropathic character of the pain. Because examination at home by study team members was not possible, only the 7 self-reported items on neuropathic pain (NPP) could be applied, the DN4-interview. When using this 7-item variant of the instrument, a score ≥ 3 indicates presence of NPP, with a sensitivity of 78% and specificity of 81%. In case of missing data on the DN4-interview scale, NPP was considered present if at least 3 positive scores were completed on the DN4-interview scale, or absent in the case of at least 5 negative scores.Pre-existing pain was assessed by the Brief Pain Inventory—Short Form (BPI-SF), including location, duration, intensity, intermittence, and pain therapy. The BPI-SF is a 12-item self-administered questionnaire which references pain during the past 24 h. It consists of 2 subscales: pain severity (4 items) and pain interference (7 items). Questionnaire items are scaled from 0 (meaning no pain/no interference) to 10 (meaning worst pain/complete interference).Collected surgery-related data were type of incision , total or subtotal hysterectomy with or without oophorectomy, indication for the operation, type of anesthesia , postoperative analgesics, duration of operation, blood loss, complications, conversion of incision type, hospital where the operation took place, and experience of the attending gynecologist expressed as years of training including fellowship. Acute postsurgical pain was assessed until day 4. Every evening patients reported pain at rest and at movement, highest and average pain over the last 24 h (NRS 0–10), use of pain medication yes/no, and at day 4 also NPP. expected level of surgical recovery 3 months after hysterectomy assessed with the global surgical recovery index, and expected time until full return to work/normal activities. The first 2 items were chosen so as to match the corresponding outcome domains assessed in this study. As previously noted, expectancy measures whose domain of behavior matches that of the outcome will have the highest predictive value.,42 In addition, expectations about the effect of hysterectomy on feelings of femininity and whether hysterectomy would mean a relief or a loss,44 were assessed on the basis of 2 tailored items. Surgical fear was measured by using the 8-item Surgical Fear Questionnaire (SFQ), whose validation was recently described. Pain catastrophizing was measured with the Dutch version of the Pain Catastrophizing Scale (PCS). The PCS consists of 13 items assessing an exaggerated negative interpretation of the meaning of pain. It has good reliability and validity.The psychological predictors included were outcome expectancy, surgical fear, pain catastrophizing, optimism, social support, depression, well-being, and childhood abuse. Outcome expectancies were measured on the basis of 3 items: expected pain intensity at postoperative day 4, Social support was measured with the Dutch version of the Medical Outcomes Study—social support survey (MOS-SSS). This is a 19-item self-report questionnaire with 4 support subscales: emotional/informational, tangible, positive interaction, and affectionate. We present the overall support index and the number of close friends/relatives available for support. Depression was measured with the Center for Epidemiological Studies—Depression (CES-D) questionnaire. This self-report instrument is developed for the assessment of depressive symptoms in the general population. Psychological well-being was assessed with the 12-Item Well-Being Questionnaire (W-BQ12). The W-BQ12 provides a brief measure of positive well-being, energy and negative well-being. The W-BQ12 avoids the use of somatic items, and is therefore particularly suitable for use in patient populations. The negative well-being subscale of W-BQ12 was omitted to avoid overlap with the CES-D. Childhood physical or sexual abuse was assessed using a validated 2-item screening questionnaire.Optimism/pessimism was assessed by the revised Life Orientation Test (LOT-R). The LOT-R has 10 items, 3 of which measure a positive outlook on the future and 3 items measure a negative outlook. After reversal of the negative items, a single-optimism score can be obtained.2.3,53 The second outcome measure used for predictor analysis was SF-36 physical functioning, range 0 to 100. The third outcome measure in predictor analysis was self-perceived recovery, assessed with the global surgical recovery index. The global surgical recovery index is a generic 1-item scale on which patients score to what extent they feel recovered from surgery. The patients themselves decide which aspects of recovery are most relevant and thus mirrored in their recovery score. The scale ranges from 0%, meaning not recovered at all, to 100%, meaning full recovery. It has been used in previous surgical studies and the correlation with another, more extensive, recovery scale was 0.72.,40Predictors were assessed for 3 outcomes of postoperative recovery at 3- and 12-month follow-up. For the primary outcome, CPSP, the BPI-SF was used. Patients first had to answer a question about whether they had pain related to the surgical procedure or not. If so, the BPI-SF had to be completed. In the case of absence of hysterectomy-related pain, they could continue with the next section of the questionnaire and the pain scores were replaced by 0. Predictor analysis was performed with 1 of the 4 pain severity items, the highest hysterectomy-related pain score during the last week, NRS 0 to 10. In accordance with clinical practice and previous CPSP studies, the NRS score was dichotomized into the no-CPSP group, NRS 0 to 3 indicating no or slight pain, and the CPSP group, NRS 4 to 10 indicating moderate to severe pain. Also, 1 question assessed the number of days after which the patient was capable of performing all activities of daily living again. Finally, the incidence of surgery-related infections, healthcare visits as a result of a complication during follow-up, and the incidence of significant health events, such as an accident, were explored by 3 questions. Data on sexuality, baseline genetics, and psychological recovery were also collected, but to avoid overload of data these results will be published separately at a later stage.In line with the secondary aim, epidemiological data on outcome measures and predictors are presented. For numbers of prevalence and incidence, the scores were dichotomized if applicable. The primary outcome measure pain was dichotomized into the no-CPSP group, NRS from 0 to 3, and the CPSP group, NRS 4 to 10, based on NRS highest hysterectomy-related pain score. In addition to the primary outcome, the neuropathic characters of the pain (DN4-interview), location, onset, and intermittence of the hysterectomy-related pain were assessed. Intensity and location of nonhysterectomy-related pain was also assessed. Patients were asked to report on pain interference, analgesic use, and other forms of pain treatment. Furthermore, health behavior was assessed using the overall physical activity question from the screening list developed by Statistics Netherlands: “How many days per week do you have physical exercise during at least 30 min?”2.4We planned to include 500 patients. With an expected loss of 40% , 300 patients were expected to be available for the follow-up analyses. With a regression analysis with 7 prior covariates (control variables) explaining 20% of variance, alpha set at 0.05 and a power of 90%, this would enable the detection of an R-square increase of 0.027 (R = 0.16). Eventually 517 participants were included, 412 were available for the analyses at 3-month follow-up and 376 at 12-month follow-up.U test because of non-normal distribution. Other continuous data were tested by Student t test and presented as mean and standard deviation (SD). Categorical data are presented as number (%) and analyzed using Chi-squared or Fischer exact test. Baseline and follow-up results are shown for the total study sample. Baseline data and self-reported complications are also shown for the groups CPSP and no CPSP separately, for both 3- and 12-month outcomes, available as Supplementary File .Data were visually assessed for normality by creating histograms and by Shaphiro–Wilk test. Pain intensity and interference scores are presented as median and interquartile range  and analyzed using Mann–Whitney Predictor analysis of the primary outcome pain at 3- and 12-month follow-up was performed on the highest hysterectomy-related pain score during the last week, the no-CPSP group versus the CPSP group. Because of the dichotomized outcome CPSP, generalized linear model analysis was performed using binary logistic regression and furthermore a time variable defining 3- and 12-month follow-up. The results are presented as beta (SD). See Supplementary Table 5B “Final multivariate models: additional legend concerning data reduction and analysis” for detailed information on the statistical analysis. Predictor analyses for the SF-36 physical functioning and global surgical recovery index scores were performed on continuous scores. No clinically accepted cut-off point is available for global surgical recovery index, while the SF-36 physical functioning score can only be interpreted in light of the presurgical SF-36 score. For these outcomes, linear-mixed model analysis with random intercept and a time variable defining 3- and 12-month follow-up was used. Results are presented as estimate (SD), which reflect the change in outcome for each unit of change in the predictor. Goodness-of-fit model is reflected by Akaike Information Criterion (AIC), the lower the better the fit.P < 0.10 level in bivariate analysis. Furthermore, to maintain a certain uniformity across multivariate analyses of the 3 outcome measures and to further reduce the number of variables, for predictors with a high level of similarity or overlap an a priori choice was made regarding which 1 to retain. This selection was based on congruency between predictor and outcome measures, general applicability or frequent clinical use, or contribution to model fit. See Supplementary Table 5B “Final multivariate models: additional legend concerning data reduction and analysis” for detailed information on the process of data reduction. In the multivariate analyses, type of incision was dichotomized as laparotomy versus vaginal/LH/LAVH. Type of anesthesia was dichotomized as GA versus other, including combination of types. Finally, to reduce the number of psychological predictors a factor analysis with oblimin rotation was performed on the SFQ, PCS, LOT-R, CES-D, and W-BQ12. Principal component analysis revealed 2 factors. The first factor consisted of the SFQ and PCS and was named surgery-related worries. Thus, this factor represents high fear of surgery and high-pain catastrophizing. The second factor consisted of LOT-R, CES-D, and W-BQ12 and was named general psychological robustness. This factor represents a high level of optimism and psychological well-being and a low level of depressive symptoms. Aggregate scores were calculated by summing the weighted scores on the respective questionnaires belonging to the 2 new variables. The MOS-SSS was analyzed separately because, in contrast to the selected 5 psychological variables that reflect intraindividual differences, the MOS-SSS reflects interindividual differences, namely the availability of social support. Also, childhood physical or sexual abuse and outcome expectancies were entered as separate predictors. The outcome expectancy variable corresponding with the particular outcome was used in the multivariate analysis. For the outcome CPSP this was expected pain intensity, and for outcome global surgical recovery this was expected global surgical recovery. For outcome physical functioning, no corresponding baseline expectation was assessed. Expectancies of hysterectomy as a relief or loss and expectancy regarding femininity were used for all outcomes.To reduce the large number of available predictor variables that could potentially be used in the regression analyses, first bivariate association with the 3 outcomes was assessed. Predictor variables were only entered in the multivariate model if significant at P < 0.10). A final significance level of P < 0.05 was used. For each outcome, 2 prediction models are presented. Model 1 reveals the results of multivariate prediction analyses using the control variables supplemented with the significant preoperative predictors. This allows establishing a preoperative risk profile. In model 2, the final model, the pre- and postoperative predictors are added. For all 3 outcome measures, multicollinearity was assessed using the variance inflation factor and tolerance, obtained by entering the predictors used in the multivariate models in a linear regression model. Criteria for absence of multicollinearity are variance inflation factor <10 and average variance inflation factor around 1, tolerance ≥ 0.2. Analyses were performed using IBM SPSS Statistics for Windows, Version 22.0 .The control variables, such as hospital, age, type of incision (dichotomized), type of anesthesia (dichotomized), and the time variable defining 3- and 12-month follow-up, were entered in the multivariate model using a forced entry method. All other predictors were entered using a backward deletion procedure  was indicated by 42 patients (the CPSP group), prevalence 10.2%, 9 of whom had no pain at baseline, incidence 2.2%. In 169 (82.8%) of the patients reporting preoperative hysterectomy-related pain, the pain had disappeared at 3-month follow-up. Median (IQR) pain intensity in the CPSP group was 6 (4.8–7.3) and in the no-CPSP group 0 (0–0) (hysterectomy-related NRS highest pain last week). Nonhysterectomy-related pain at 3 months  was indicated by 102 (25.0%) women. Any pain at 3-month follow-up  was indicated by 67 (17.0%) women. An indication of NPP (DN4-interview ≥ 3) was present in 16 patients (45.7%) of the CPSP group versus 4 patients (1.1%) of the no-CPSP group. Occurrence of NPP in relation to type of incision was median lower abdominal 0 (0%), Pfannenstiel 6 (14.0%), vaginal 6 (3.7%), LH 3 (3.7%), and LAVH 5 (5.7%) cases. NPP occurred in 19 patients (5.7%) with GA and in 1 (2.0%) with spinal analgesia. Three months after surgery, 61.9% of the patients in the CPSP group used pain medication as compared with 24.4% of the patients of the no-CPSP group. Pain interference in the CPSP group was 3.9 (2.9–5.6).At 12 months a minor decrease of CPSP was shown, with 34 women reporting an NRS ≥ 4, prevalence 9.1%. Pain intensity  in the CPSP group was 6 (5–7) and in the no-CPSP group 0 (0–0). Nonhysterectomy-related pain was reported by 121 patients (32.5%), an increase compared with the 3-month results. Any pain at 12-month follow-up (hysterectomy- and/or nonhysterectomy-related pain at the moment of completing the questionnaire) was indicated by 70 (19.7%) women. Hysterectomy-related NPP was reported by 10 women (38.5%) of the CPSP group and 4 women (1.2%) of the no-CPSP group. In the CPSP group, 19 women used analgesia (55.9%) versus 95 (28.4%) of the women in the no-CPSP group. Pain interference in the CPSP group was 3.1 (2.1–6.6).The mean scores on the SF-36 physical functioning subscale of 83.5 (SD 20.0) at 3-month follow-up appeared to be relatively stable when compared with the preoperative scores of 82.4 (19.3). At 12 months the mean score was 85.9 (20.2).P < 0.001). However, the expected level was achieved after 12 months of recovery with a mean score of 93.9 (SD 13.4). The time until patients were able to perform their normal daily activities, reported after 3 months, was 44 days. This was in line with their expectations. However, the same question asked at 12 months revealed a mean of 69 days. Data on CPSP, SF-36 physical activity, global surgical recovery, and other indicators of recovery are presented in Table Self-perceived recovery after 3 months was high with a mean global surgical recovery index score of 88.1 (15.6), but significantly lower than the expected global surgical recovery index of 93.2 (10.8)  including interaction with time, expectations about hysterectomy , expected pain on postoperative day 4, number of close friends/relatives (MOS-SSS), surgery-related worries, general psychological robustness, having undergone prolapse surgery, acute pain at the postanesthesia care unit (PACU), NPP on postoperative day 4, and surgery-related infection during 3- and 12-month follow-up including interaction with time were entered in the multivariate model.Of the control variables such as hospital, age, type of anesthesia, and type of incision, only hospital reached significance at 0.10 level in bivariate analysis: CzE beta −0.785, Model 1, based on the control variables including time and supplemented with the preoperative predictors, revealed significant differences in the risk of CPSP between the participating hospitals. Also time (12 months compared with 3 months), baseline hysterectomy-related and nonrelated highest pain, and surgery-related worries were predictors of CPSP. Finally, gravidity decreased the risk of CPSP at 12 months .P = 0.54 and −0.632, P = 0.06, respectively, the time by gravidity interaction was (P < 0.05). This is in line with the near-significant effect for the 12-month outcome .The results of model 2 are presented in Table 3.2.2P = 0.26, MMC 9.530, P = 0.03, OMC 7.191, P = 0.26, reference Maastricht UMC+. Type of anesthesia, GA with epidural 5.277, P = 0.56, spinal 0.407, P = 0.94, GA with spinal 58.048, P = 0.001, reference GA. Type of incision, median lower abdominal 9.200, P = 0.25, Pfannenstiel 13.493, P = 0.02, vaginal 9.582, P = 0.03, LAVH 0.760, P = 0.88, reference LH. Interaction with time not shown. In addition to baseline physical functioning, marital status, employment status (paid job yes/no), ASA classification, expectations about femininity, social support , the psychological aggregate scores of surgery-related worries and general psychological robustness, baseline hysterectomy-related and nonrelated pain, indication, acute pain at the PACU, NPP day 4, and surgery-related postoperative infection at 12-month follow-up were entered for multivariate analyses.For the outcome physical functioning in bivariate analysis, 3 of the control variables were significant at 0.10 level. Hospital, CzE estimate 4.667, Model 1, based on the control variables including time and the preoperative predictors, revealed that higher baseline levels of physical functioning and general psychological robustness, and the indication abdominal pain predicted higher postoperative levels of physical functioning. Baseline nonhysterectomy-related pain was a risk factor for lower scores. Concerning the level of physical functioning at 12 months, however, the positive effect of indication abdominal pain was attenuated by a time by indication interaction effect. Furthermore, a time by hospital interaction effect revealed that patients of 1 hospital were at increased risk for lower physical functioning scores at 12 months .P = 0.007, simple effect at 3-month follow-up 12.288, P = 0.21. Interaction effects of time by hospital (P = 0.004), time by indication abdominal pain (P = 0.02) or indication “other” (P = 0.04), and time by self-reported infection at 12 months (P = 0.03), indicated an attenuated effect of the corresponding reported simple effects on 12-month follow-up results .Model 2 is shown in Table 3.2.3P = 0.20, Pfannenstiel −11.427, P = 0.02, vaginal −2.344, P = 0.52, LAVH 2.187, P = 0.60, interaction with time not shown. Further added to the model were expected global surgical recovery, marital status, employment status, ASA, indication, expectations about hysterectomy, expectations about femininity, history of sexual abuse, the psychological aggregate scores surgery-related worries and general psychological robustness, baseline hysterectomy-related and nonrelated pain, total versus subtotal hysterectomy, experience of the attending gynecologist, NPP day 4, and surgery-related infection during 3- and 12-month follow-up.Only type of incision was a significant control variable at 0.10 level in bivariate analysis. Reference LH, median lower abdominal estimate −8.380, Model 1 of the multilevel analyses, based on the control variables including time and the preoperative predictors, revealed that higher global surgical recovery index scores were predicted by higher expected global surgical recovery and history of sexual abuse. Risk factors were type of incision (laparotomy) and increased baseline hysterectomy-related pain and surgery-related worries .P = 0.004, and simple effect with 3-month outcome 12.292, P = 0.27. Patients reporting an infection at 3 or 12 months showed poorer recovery at the corresponding time. The simple effect for the 3-month outcome was −13.203, P = 0.008, and the simple effect for the 12-month outcome was −39.706, P < 0.001 .Model 2 is presented in Table Multicollinearity did not play any role in the multivariate analyses of the 3 outcomes.3.3 Blood loss ≥ 1000 mL occurred in 20 patients (4.7%), genitourinary tract injury occurred in 11 patients (2.6%), and gastrointestinal injury was reported in 1 patient (<1%).Conversion of incision type during surgery occurred once in the CPSP group and 12 times in the no-CPSP group (CPSP at 3 months). The incidence of surgical complications such as bleeding, genitourinary tract injury, and gastrointestinal injury was relatively low and in line with recent findings.A surgery-related infection was reported by 50 (12.4%) patients at 3-month follow-up. Assessed in a different way, 59 (14.3%) patients reported a healthcare visit for reasons of infection or fever, not necessarily surgery-related. At 12 months, these numbers were 17 (4.6%) and 20 (5.3%), respectively. The numbers of patients who contacted their general practitioner, specialist, or the emergency department for different types of complications during follow-up are presented in Table 6 (Supplementary File). Hospitalization during 3-month follow-up was reported by 10 patients, for reasons of: pneumonia, sepsis, wound infection/abscess/hematoma (3); ileus; gastrointestinal complaints, and for flash-backs of incest induced by hysterectomy; urine retention/obstipation, ultimate diagnosis multiple sclerosis; pulmonary embolism; and stroke. At 12 months, reasons for hospitalization were gastroenteritis (2) and stroke.4The primary purpose of the present study was to examine predictors of CPSP, and secondarily of other indicators of recovery, that is, self-reported physical functioning and self-perceived global recovery. CPSP was predicted by the presence of moderate to severe hysterectomy-related and hysterectomy-unrelated pain before the operation and NPP 4 days after the operation. Other predictors were surgery-related worries and surgery-related infection. Interestingly, for the secondary outcome variables, partly different predictors were found. Preoperative pain was not significantly associated with poor physical functioning or global surgical recovery at follow-up. However, abdominal pain as the indication for hysterectomy predicted better physical functioning. Other predictors of physical functioning, besides preoperative physical functioning and indication, were participating center, general psychological robustness, NPP pain at day 4, and surgery-related infection. For global surgical recovery, we identified expected global surgical recovery, surgery-related worries, ASA classification, type of anesthesia, NPP at day 4, and surgery-related infection as predictors.,55 including hysterectomy.,3,56,57 We used the highest pain intensity score as predictor instead of the often used mean pain intensity score. Differences were small, but highest pain proved to be the most powerful predictor. Furthermore, there is extensive evidence that high levels of pain in the acute postoperative period are associated a high prevalence of CPSP.,55–57 In the present study, we found that especially pain with neuropathic characteristics was associated with CPSP, and additionally with physical functioning and global surgical recovery. The predictive value of surgery-related worries for CPSP is in agreement with previous studies in women undergoing hysterectomy.,56,57 Moreover, a systematic review and meta-analysis revealed that preoperative fear and anxiety as well as pain catastrophizing are associated with CPSP across many different interventions. Because of the overlap of these measures, for the current study we created an aggregate measure representing high surgical fear and high pain catastrophizing. Similarly an aggregate score was created for the 3 more global individual difference variables, that is, optimism, depression, and well-being. This aggregate did not prove predictive of CPSP, although 2 of its constituent parts, depression and well-being energy, were significant (P < 0.01) in bivariate analyses. In contrast to the findings of several other studies, optimism was not associated with CPSP in our bivariate analyses.–31,33 To check whether an aggregate of only depression and well-being would be retained in the multivariate model, we performed a post hoc analysis (data not shown). This truncated aggregate did not reach significance either, suggesting that psychological factors that are more specific for the operation have greater predictive power for CPSP than global psychological states and traits. However, physical functioning was predicted by general psychological robustness. For this outcome, besides depression and well-being energy, the positive well-being subscale was also significant at P = 0.01 level. Changes in physical functioning in the course of 1 year may be less directly related to the surgical intervention compared with the other outcomes in this study and additionally determined by the general psychological state of an individual.The prominent role of preoperative pain as predictor of CPSP in the present study is congruent with many other prediction studies across various surgical procedures,42,58 Here, we found expected global surgical recovery to predict actual global surgical recovery, but expected pain was not predictive of CPSP. Surgery-related infection was a risk factor for physical functioning, global surgical recovery, and also CPSP. Infection may delay healing and affect all aspects of recovery. However, it should be noted that according to the original definition of CPSP, other causes for pain should be excluded. Our data did not allow us to assess whether reported infection was still present at the moment of pain assessment. Therefore we addressed potential confounding effects of infection with regard to outcome CPSP by including infection in the multilevel analyses.Preoperative expectations have also been found predictive of outcome in previous studies. At 3-month follow-up, the overall rate of NPP was 5% in our study, and 46% of the patients reporting CPSP indicated that their pain had neuropathic characteristics. At day 4, 53% in the CPSP group reported NPP against 19% of patients in the no-CPSP group. Time to recovery of NPP depends on the type of nerve injury. Unfortunately, our data do not allow assessing whether the nerve injury in the no-CPSP group was less severe as compared with patients with CPSP. NPP was reported most after Pfannenstiel incision. Previously it was suggested that indeed Pfannenstiel incisions yield a higher risk of NPP compared with other types of incision.–64The only other predictor showing significance across all 3 outcomes was NPP. Because NPP at day 4 contributed most to statistical model improvement, it was selected as the index for acute postsurgical pain over NRS pain and analgesia use. The obvious role of NPP suggests that at least part of the problem is persistence of NPP that already starts in the early postoperative period.The present study provides several clues toward interventions that might reduce the incidence of CPSP after hysterectomy. We presented 2 different predictor models, with the first model including only those variables that can be obtained preoperatively. This may guide the selection of variables to be included in a future risk assessment tool. High-risk patients can be identified before surgery and offered intensified attention by the nursing staff or some form of counseling. A risk assessment tool might also guide treatment decisions regarding the surgical procedure and analgesic regime. The second model, including pre- and postoperative variables as well, gives an even more complete overview of risk factors for long-term outcome and points to the necessity of adequate postoperative pain management and infection prevention. Future studies should also establish the causality of these relations.,66 and a sample of Dutch females 80.4 (24.2). Some of the other study variables also indicated generally good recovery with the number of active days/week increasing significantly from baseline to follow-up with 0.5 days. The number of days until complete reuptake of full activities was within patients’ expectations, at least at 3 months, presumably in line with the prescribed 6 weeks recovery period. Overall, our results are in line with the findings of Linenberger, reporting that most patients described their physical condition 8 weeks after hysterectomy as “better than before.”The results of this study also show that in general patients recovered well from hysterectomy. The prevalence of moderate to severe hysterectomy-related pain  was significantly lower at 3- and 12-month follow-up (10.2% and 9.1%) than it was before the operation (50%). The scores of SF-36 physical functioning, between 82.4 and 85.9, are within the range as measured in female populations in the UK 86.7 (20.2), Australia 85.1 (18.7),,3,56,57 The high prevalence in the latter study may have resulted from the definition of CPSP, namely any pain at follow-up, whereas the other studies, including the present 1, used more stringent criteria.Despite overall good outcomes, some patients still reported pain after 3 and 12 months. The prevalence of CPSP in our sample was 10.2% to 9.1%, and 3-month incidence 2.2%. These numbers are well within the ranges of 5% to 32% for CPSP and 0% to 15% for acquired/increased pain at follow-up resulting from earlier reports. However, a recent investigation presented a prevalence of even 50% at 4 months after surgery.This study has several strengths. First, we conducted a large-scale multicenter study with a homogeneous population, that is, females undergoing hysterectomy for benign indications. A comprehensive dataset was assessed allowing for broad analyses of predictors and the course of recovery. For future studies, the results can help to select the most appropriate predictor and outcome measures. Furthermore, based on this extensive baseline and recovery data, preoperative counseling can be further tailored to future patients. Second, compliance was high with 88% and 80% of patients providing follow-up data. Third, we created psychological aggregate scores which might yield more stable outcomes. Many psychological factors are correlated and depending on the specific sample and study, 1 factor might prevail in the multivariate model in one study and another in the next study. But our study still has some limitations. First, to avoid bias patients who underwent resurgery were considered as drop-out. As a result, this study cannot provide insight into causes of resurgery and related complications. Second, NPP was assessed using the 7 self-report items instead of the total DN4. Although validated as DN4-interview, sensitivity and specificity are slightly lower as compared with the 10-item DN4. Third, all psychological assessments were performed by self-assessment. Given the fact that 29% of the patients indicated a history of psychological problems, a clinical diagnosis of current psychopathology would have strengthened our conclusions. Fourth, a large number of baseline data were explored for predictor analyses. As a result, type 1 errors cannot be excluded and inferences with regard to our study population should be made with caution. However, aiming at the development of suitable and comprehensive prediction models for the different outcomes, we notice that despite the risk of type 1 error, narrowing down from a broad scope of potential predictors, many of the established predictors confirmed the results of previous research.4.1 Additionally, there is growing evidence that besides reduction of acute pain, perioperative treatment with pregabalin or gabapentin might prevent CPSP. This effect is mainly contributed to the efficacy of pregabalin and gabapentin in the treatment of NPP.,69 Also other anesthesiological treatment options such as epidural analgesia or patient-controlled analgesia might need reconsideration. Because the length of hospital stay has now been shortened to 2.5 days on average, this might preclude certain patients in need for prolonged acute pain treatment from optimal postoperative care. Besides continued attention for postoperative pain, nurses should be taught to recognize the occurrence of NPP from the day of surgery. Finally, another hypothesis deserving further study is whether reduction of preoperative pain by prolonged, pro-active, preoperative pain treatment can reduce acute postoperative and, subsequently, chronic pain. The rationale is the scarcity of studies on pre-emptive pain treatment starting earlier than 24 h preoperative.Future interventional studies should aim at further reduction of perioperative pain by using interventions on modifiable psychological and physical factors. This is not only of great clinical relevance, but could provide evidence for the causal status of the proposed predictors. Studies on dedicated acute pain treatment programs would allow evaluating whether patients’ recovery would indeed improve in the case of further postoperative pain reduction. Special attention should be paid to the prevention of NPP. A debate about surgical technique should be initiated among gynecologists, aiming at further reduction of iatrogenic NPP.–73 In addition, prehabilitation programs based on nurse counseling or physical therapy, for example, have proven successful in improving physical or mental status in different populations.–76 For hysterectomy patients, interventions to improve their physical condition and expectations upon recovery should be assessed and selection criteria for patients who would benefit most should be established. Postoperative care after discharge can be optimized by web-based information provision to discharged women. Web-based survey requests for hysterectomy patients to enter their health status on a daily basis during the 1st week postoperatively might also improve postoperative (tele) monitoring despite early discharge. Concerning postoperative complications extra attention is needed for prevention of infection and urinary tract complaints.,78 Because of the large impact of infection on recovery, preoperative counseling should pay more attention to this aspect. Finally, consensus meetings should be initiated focusing on the definition of postoperative recovery, including which outcome measure(s) to use.Further gains in postoperative outcomes may be derived from targeting psychological risk factors pre- or immediately postoperatively. The present study again pointed to the important role of preoperative anxiety and catastrophizing, here combined in a single surgical worries variable. Brief preoperative psychological interventions, directed at diminishing anxiety and negative cognitions relating to surgery and its outcomes, may prove effective in reducing both acute postoperative pain as well as CPSP and related long-term outcomes.5Predictors of CPSP are moderate to high baseline levels of pain, acute postsurgical pain on day 4, and surgery-related infection. Of the preoperative psychological factors, surgery-related worries were predictive of CPSP. Overall, recovery after hysterectomy was good in terms of postoperative pain, physical functioning, and self-perceived recovery. However, 1 out of 10 patients suffered from CPSP, frequently characterized by an NPP component. Further improvements in perioperative care should aim at optimizing baseline condition and further reducing acute postsurgical pain and surgery-related infection.


Fibromyalgia (FMS) and high frequency episodic/chronic migraine (M) very frequently co-occur, suggesting common pathophysiological mechanisms; both conditions display generalized somatic hyperalgesia. In FMS-M comorbidity we assessed if: a different level of hyperalgesia is present compared to one condition only; hyperalgesia is a function of migraine frequency; migraine attacks trigger FMS symptoms.t-test for paired samples was used to compare pre and post-treatment values.Female patients with fibromyalgia (FMS)(n.40), high frequency episodic migraine (M1)(n.41), chronic migraine (M2)(n.40), FMS + M1 (n.42) and FMS + M2 (n.40) underwent recording of: −electrical pain thresholds in skin, subcutis and muscle and pressure pain thresholds in control sites, −pressure pain thresholds in tender points (TePs), −number of monthly migraine attacks and fibromyalgia flares (3-month diary). Migraine and FMS parameters were evaluated before and after migraine prophylaxis, or no prophylaxis, for 3 months with calcium-channel blockers, in two further FMS + H1 groups . 1-way ANOVA was applied to test trends among groups, Student’s p < 0.0001). FMS monthly flares were progressively higher in FMS, FMS + M1 and FMS + M2 (p < 0.0001); most flares (86–87 %) occurred within 12 h from a migraine attack in co-morbid patients (p < 0.0001). Effective migraine prophylaxis vs no prophylaxis also produced a significant improvement of FMS symptoms (0.0001 < p < 0.003).The lowest electrical and pressure thresholds at all sites and tissues were found in FMS + M2, followed by FMS + H1, FMS, M2 and M1 (trend: Co-morbidity between fibromyalgia and migraine involves heightened somatic hyperalgesia compared to one condition only. Increased migraine frequency – with shift towards chronicity – enhances both hyperalgesia and spontaneous FMS pain, which is reversed by effective migraine prophylaxis. These results suggest different levels of central sensitization in patients with migraine, fibromyalgia or both conditions and a role for migraine as a triggering factor for FMS. Fibromyalgia Syndrome (FMS) is a chronic pain condition whose prevalence in the general population ranges from 4 to 7 %, with a net female predominance , 2. AccoPreliminary results have already been published in abstract forms , 26.The study was subdivided into two phases. The first phase evaluated the impact of migraine co-morbidity on somatic pain sensitivity and fibromyalgia pain. The second phase explored, in co-morbid patients, the effects of migraine prophylaxis on fibromyalgia symptoms. All patients attended the Headache and Fibromyalgia Center of the “G D’Annunzio” University of Chieti. The protocol adhered to the principles expressed in the Declaration of Helsinki and received ethic approval by the Institutional Review Board - Department of Medicine and Science of Aging – of the same University. A written informed consent was obtained from all patients (see inclusion criteria below).Inclusion criteria for FMS were: female sex; age 18–65 years; a diagnosis of fibromyalgia performed by a specialist 2–5 years previously , with start of symptoms not before 6 years preceding their first visit to the Center, average intensity of diffuse musculoskeletal pain between 50 and 70 mm of VAS, under a stable dose of amitriptyline (10 mg/day) in the preceding 3 months ; exclusion of any concurrent pathology able to interfere with the sensory evaluation  [Patients affected with fibromyalgia and/or migraine were considered for the study, subdivided into five groups: a) fibromyalgia (FMS), b) high frequency episodic migraine (8–14 days/month)(M1); c) chronic migraine (≥15 days/month)(M2); d) fibromyalgia plus high frequency episodic migraine (FMS + M1); and e) fibromyalgia plus chronic migraine (FMS + M2). iabetes) , 30; excInclusion criteria for M1 and M2 were: female sex, age 18–65 years, a diagnosis of migraine according to ICHD criteria  [riteria) , 32 withInclusion criteria for FMS + M1 and FMS + M2 were: female sex; age 18–65 years; a diagnosis of fibromyalgia as for the FMS group and of migraine as for the M1 and M2 groups; exclusion of any other chronic pain condition except fibromyalgia and migraine; exclusion of any concurrent pathology able to interfere with the sensory evaluation ; a negative clinical history of any form of acute pain in the preceding 6 months; exclusion of major psychiatric disorders at specialistic psychiatric examination; informed, written consent to participate in the study.Out of a total of 325 examined patients, n. 203 meeting the inclusion criteria were selected: a) FMS ; b) M1 ; c) M2 ; d) FMS + M1 ; e) FMS + M2 . The five groups did not differ in mean age.In all groups: pain thresholds to electrical stimulation in skin, subcutis and muscle were measured in multiple, nonpainful, body sites (control sites); muscle pressure pain thresholds were evaluated in the same locations and in the 18 TePs. Recording was also performed of: number of monthly migraine attacks in all migraine patients ; number of monthly fibromyalgia peak pain episodes (“flares”) in all FMS patients ; temporal relationship of FMS flares with migraine attacks in co-morbid groups .with prophylaxis) and patients not to be subjected to prophylaxis (FMS + M1 without prophylaxis).Patients affected with fibromyalgia plus high frequency episodic migraine (8-14 days/month) were considered (FMS + M1), subdivided into two groups: patients to be subjected to migraine prophylaxis .with prophylaxis group, but not those of the without prophylaxis group, were prescribed additional migraine prophylaxis with flunarizine (5 mg/die) for 3 months. Symptomatic treatment of fibromyalgia flares with paracetamol 1 g continued to be allowed.Out of 145 examined patients, n. 86 were selected who met the inclusion criteria: 47 patients for the treatment group (38.2 ± 6.2 years) and 39 for the non-treatment group (39.1 ± 5.1 years). The two groups did not differ in mean age. In basal conditions all patients underwent the following recordings: monthly number of migraine attacks and fibromyalgic flares ; monthly analgesic consumption for the fibromyalgia flares ; pain thresholds to electrical stimulation in skin, subcutis and muscle and pressure pain thresholds in multiple, nonpainful, body sites (control sites); pain thresholds to pressure stimulation at the 18 tender points . Patients of both groups were maintained on their standard chronic therapy for fibromyalgia with amitriptyline 10 mg/day. Patients of the FMS + M1 All patients were requested to note, in ad-hoc diaries, the number of migraine attacks, fibromyalgia “flares” and rescue medications taken for fibromyalgia flares during the 3-month period of migraine prophylaxis, at the end of which pain thresholds were re-evaluated at both control areas and TeP level.A standard pressure dynamometer was used for the evaluation  . The 1-cA computerized constant current electrical stimulator  delivered 18-ms trains of 0.5-ms monophasic square wave pulses, frequency 310 Hz, automatically every 2 s, to the skin via surface electrodes and to the subcutaneous tissue and the muscle through needle electrodes. Skin electrodes consisted of a 10-mm diameter circular plate in Ag/AgCl (reference electrode) and a cylinder in Ag/AgCl with a 0.3 mm-diameter base (stimulating electrode), placed 1 cm apart on the skin surface with interposition of conductor paste. Subcutis/muscle electrodes were two monopolar needles, 0.3 mm in diameter (teflon isolation except for 2 mm at the tip), inserted vertically, 1.5 cm apart, just below the skin surface for subcutis measurement and deep under the fascia for muscle measurement . Evaluated sites were the: lateral aspect of the upper border of the trapezius , lower half of the deltoid and lowest third of the quadriceps (anterior aspect of the thigh). Measurement of thresholds in each tissue was performed by the method of the limits, to record typical pain sensations in each tissue  according to a procedure already described in detail in previous publications –41.Measurements were always performed at the same time of day (10:00– 12:00 a.m.), in the pain-free interval. During all measurements, patients lay comfortably on an adjustable examination bed in a quiet room. The experimenters evaluating thresholds were not aware of the group the patient belonged to.For each patient, the mean threshold was calculated of values recorded at the 18 TePs as the reference value for the specific FMS painful sites, and the mean threshold of the 6 values recorded in trapezius, deltoid and quadriceps as the reference value for the control sites. Means ± Standard Deviation (SD) were calculated of all parameters. Comparison among all groups for each parameter was performed via 1-way ANOVA.To assess the temporal relationship between the occurrence of migraine attacks and fibromyalgic flares, for each patient the percentage was calculated of flares occurring within 12 h after a migraine attack vs occurrence of flares in any other period. Means ± SD were calculated of these percentages for each fibromyalgia patient group. The comparison between percentages of flares occurring within 12 h after a migraine attack and those of flares occurring at other time points in each group was performed via Wilcoxon matched-pairs signed-ranks test.t-test for unpaired samples. The comparison of parameters before and after prophylaxis in the treated group, and at comparable time points in the non-treated group, was performed via Student’s t-test for paired samples.Means ± SD were calculated of all parameters. The comparison between treated and untreated groups was performed via Student’s p < 0.05.The level of significance was established at p < 0.0001)  .In co-morbid patients, the mean number of monthly migraine attacks was: 11.7 ± 2.1 in the FMS + H1 group and 19.4 ± 3.2 in the FMS + M2 group. The majority of FMS flares occurred within 12 h after a migraine attack, i.e., in 87 % of the cases in FMS + M1 and 86 % in FMS + M2. The difference with respect to flares occurring at a longer time distance from an attack was highly significant (p < 0.0001), while in patients not subjected to prophylaxis evaluated at comparable time points it did not vary significantly. In patients with prophylaxis but not in those without, also the mean monthly number of fibromyalgia flares and the number of rescue medications taken to treat them were significantly reduced (p < 0.0001)  Figs.  and 5.Fip < 0.003 for skin, p < 0.0001 for subcutis and muscle) and pressure pain thresholds also significantly increased in both control areas (p < 0.0008) and TePs (p < 0.0005). No significant threshold changes were recorded in non-treated patients  and evoked  FMS symptoms. Such a result, obtained with a drug class  not able to directly influence pain symptoms in fibromyalgia, with both patient groups under exactly the same stable dose of amitriptyline basal treatment, is probably due to the reduction of the central effect of nociceptive inputs from the cephalic area onto sensory neurons , 34. FutIn conclusion, co-morbidity between migraine and fibromyalgia involves a higher state of generalized somatic hypersensitivity towards painful stimuli with respect to one condition only. The increase in migraine frequency – with shift towards chronicity – promotes an enhancement of the hypersensitivity and of the spontaneous FMS pain.These results suggest different levels of central sensitization in patients with migraine, fibromyalgia or both conditions and a role for migraine as a triggering factor for FMS. Prevention of headache chronification in migraine patients would thus appear crucial also for preventing the development of fibromyalgia in predisposed individuals or its worsening in co-morbid patients.