Peripheral neuropathy is one most common, limiting and invalidating neurological symptom in subjects with hepatitis C virus and mixed cryoglobulinemia. Notably, the medical therapy proposed to eradicate HCV, can frequently exacerbate the painful neuropathy. Therefore, neuropathy therapies are insufficient and inadequate, and comprise immunosuppressive drugs, such as steroid or cyclosporine, intravenous immunoglobulin or plasma exchange. These have shown variable success in case reports, with a presumably temporary effect, but with major side effects.We assessed the effects of oxcarbazepine treatment in 67 cases of cryoglobulinemia related neuropathy, who did not respond to either steroid or Gabapentin, or Pregabalin. Oxcarbazepine was chosen based on the promising preliminary results.Patients treated with Oxcarbazepine showed a rapid, discrete and persistent relief of polyneuropathic signs, without consistent side effects, and with a limited interaction with concomitant drugs.These data favor the use of oxcarbazepine as a useful tool in the management of neuropathic pain associated with Hepatitis–C cryoglobulin neuropathy. Cryoglobulins are cold-precipitating immunoglobulins , which fCryoglobulins can be divided into three types, following the Brouet classification , essentiDespite varying from country to country, the prevalence of peripheral neuropathies in HCV-associated cryoglobulinemia substantially varies in the Mediterranean , 3, 8. Ovasa nervorum [Pathological findings suggest a direct damage of the small vessels around nerve, the so-called nervorum , 11, 12,nervorum , 13, 14.nervorum –17.Peripheral neuropathy is the most common reported symptom in patients with HCV-associated mixed cryoglobulinemia –20, whervasa nervosum microcirculation and vasculitis-induced ischemia, as well, despite seldom reported, by an immunological mediated demyelination. Electrophysiological studies and teased nerve fiber studies allowed neuropathies to be classified as predominantly sensory axonopathies [At biopsy, axonal degeneration is shown, possibly triggered by the deposit of cryoglobulins at the level of opathies , 22, eveopathies , 21–24.There is no conventional treatment for HCV cryoglobulin neuropathy. It is accepted nowadays that prolonged antiviral therapy led to a reduction of HCV-RNA levels, associated with a reduction of cryoglobulinemia . The redAfter the promising results of a previous work , we presSixty-seven HCV-positive patients  were not used, since at the time of the recruitment they were not available. All of the 67 patients reported progressive painful paresthesias, shock pain episodes, boot-glove dysesthesia sensations. All the patients showed signs of cryoglobulinemia . Cryocrit levels were measured as the percentage of packed cryoglobulins after cold centrifugation of the serum, and cryoglobulin composition was determined by immunodiffusion on Ouchterlony plates against specific antisera. Fifty-eight had polyneuropathy and 9 had mononeuropathy multiplex. All subjects had an electroneurographic confirmation of peripheral neuropathy, 57 presented the axonal profile and 10 showed the axonal-demyelinating signs of damage Table . Thirty-Reduced complement C4 activity has been found in 39 patients; positive search for antinuclear antibodies has been found in 13 patients, anti-mitochondrial in 19 patients and C-reactive protein has been found in 32 patients.As shown in Fig. p-values are provided where appropriate.Statistical analyses were performed using SAS® software . Within-group changes from baseline were tested using the Wilcoxon Signed Ranks test. Between-group comparisons of changes from baseline were tested using the Marginal Homogeneity Test. Spearman correlation test has been employed for each significant variable. This was done for each efficacy variable. Results are presented as mean changes from baseline with standard deviations, and As in Fig. One month after the steroid washout, gabapentin. It was prescribed (1887 ± 205 mg/day) followed by a moderate improvement in the painful sensation . After one month of follow-up, due to daytime sleepiness, nausea, dizziness and gait alteration the drug was stopped. The average duration of the treatment was 1.4 ± 1.2 months.In 23 strongly motivated patients, pregabalin  was prescribed; 14 patients showed cholestatic and liver damage, 2 presented overt jaundice and 7 patients a prolongation of the prothrombin time. All side effects subsided after the medication was stopped. No amelioration of pain symptoms was observed.p < 0.001) after one month. The average SF-MPQ at 6-month was 12.5 ± 3.7 . At the 6th month of follow-up, the dose of Oxcarbazepine was reduced to 600 mg/day; 33 patients were pain free and maintained the dose for two additional months while 34 increased to 900 mg/day. All the 67 patients, who have been prescribed Oxcarbazepine, completed the 12 months follow-up: 46 patient arte asymptomatic and do not take any anti-epileptic drug. All patients referred sleepiness and drowsiness at the beginning of the therapy that rapidly disappeared; no other side effects were observed.At the end of this period of treatment (average time of 5.6 months), all the 67 patients reported side effects and persistence of pain. After two weeks of washout of any other pain-relief drug(s), oxcarbazepine was given at a dose of 300 mg/day for a week, increased to 600 mg/day the following week, and then further increased to 900 mg/day. The dosage was increased to 1200 mg/day in 11 patients for 10.2 ± 2.3 days, due to persistence of pain, to be then readjusted to 900 mg/day. Each patients was follow-up monthly for 12 months, and each check-up, the Short form McGill Pain Assessment Questionnaire (SF-MPQ)  was admiHepatitis C is a serious health concern, affecting millions of people worldwide. The majority of the subject positive for HCV antibody are asymptomatic. More recently, central (CNS) and peripheral nervous system (PNS) have been studied as focal collateral damage regions, tightly involved in HCV.The treatment of HCV-cryoglobulins -associated PNS is actually based IFN plus ribavirin therapy, eventually associated with steroids , 35–37. Painful neuropathy is a dramatic and persistent condition, which affects many patients, and is an invalidating condition. The several options available for pain control are confusing and daunting. The best solution seems to be an escalating regime matching the intensity and nature of the sensory components of the pain state. Moreover, in chronic conditions, such as HCV- related hepatitis, where many different clinical details should be considered, pain relief therapies should not interfere with the underline disease and the concomitant antiviral treatment. Therefore, pain-treatment should be efficacious, should not interfere with their general and hepatic condition, should not create side effects as, in particular, disequilibrium, gait imbalance, drowsiness and reduced vigilance.more common, but rapidly and spontaneously solving side effects (1:100): Blurred vision, disequilibirum, mental depression, emotional incontinence, cough and sore throat sensation. Less common (less than 1:1000): Agitation, awkwardness, mental confusion, persistent disequilibrium associated with orthostatic hypotension, fast or irregular heartbeat, thirst, muscle cramps, headache, skin rash, weakness. Usually they spontaneously disappeared, and they do not need a suspension of therapy. Rare (less than 1: 3500): Anxiety, burning feeling in the chest or stomach, hives or itching, irritability, restlessness, muscle pain or weakness, purple spots on the skin and rectal bleeding; these needs a careful medical examination, and the consequent decision to stop it.Oxcarbazepine is a safe drug, without significant side effects, and the rarely described hepato-toxicity seems to be related to a hypersensitivity or to a immune –mediated response to some metabolites of the drug, rapidly and totally reversible . OxcarbaOxcarbazapine possess intrinsic pain-relief properties , either In this work, patients not responsive to steroids, gabapentin at high dosage and to pregabalin, benefit from oxcarbazepine. The limited side effects, associated to the favourable and rapid response, the reduced interaction with concomitant drugs support the use of oxcarbazepine as an effective and safe treatment of the of HCV-cryoglobulins related neuropathy.


Misdiagnosis of symptomatic lumbar lateral stenosis (LS) may result in an unfavourable prognosis after surgical treatment. This study investigated the diagnostic accuracy of a standardised qualitative sensory test (SQST) in the detection of symptomatic LS in patients who had degenerative spinal disorders involving the L5 spinal nerve. We prospectively identified 75 patients, of which 60 met the inclusion criteria. Lateral recess stenosis at the L5 level or foraminal stenosis at the L5/S1 level on MRI was identified and graded by a neurosurgeon blinded to any clinical information. The reference criteria for the diagnosis of symptomatic LS were grade III LS on MRI and relevant clinical symptoms. Cutaneous sensory functions of the L5 dermatome on the symptomatic side were evaluated using the SQST. Each item of the SQST showed a satisfactory performance in the diagnosis of LS . A stepwise selection model identified low-strength von-Frey, high-strength von-Frey, and vibration as the most accurate predictors of symptomatic LS with an area under the receiver operating characteristic curve of 0.9563 . In combination with MRI, the SQST is a promising diagnostic tool for detecting symptomatic LS involving L5 nerve roots. On the basis of anatomy, degenerative LSS can be classified as central stenosis (CS) and lateral stenosis (LS)4. Lumbar LS can easily be overlooked, especially when there is coexisting lumbar CS, and misdiagnosis of symptomatic LS may result in an unfavourable prognosis after surgical treatment6. Because patients with LS and CS usually have similar clinical presentations8, differentiating LS from CS on the basis of only clinical symptoms or signs is difficult. A prospective randomised study conducted in 1995 showed no differences in symptoms, neurological findings, or signs between LS and CS8. Since then, few studies have examined differences in clinical presentations between LS and CS. Only in 2014 did a comparative study report that leg pain at rest was more severe in LS than in CS7.Degenerative lumbar spinal stenosis (LSS), the most common cause for lumbar spinal surgery in patients older than 65 years13. Neuropathic pain is redefined as “pain arising as a direct consequence of a lesion or disease affecting the somatosensory system”; this redefinition was suggested by the International Association for the Study of Pain Special Interest Group on Neuropathic Pain in 2008. A substantial proportion of patients with chronic low back pain experienced a neuropathic pain component16, and the most frequently reported symptoms included hypoesthesia, allodynia, and radiating pain17. Standardised qualitative sensory tests (SQSTs) described in the Standardised Evaluation of Pain (StEP)18 were validated to detect the neuropathic component of low back pain19.In contrast to CS, LS involves the dorsal root ganglia and spinal nerves, which are more vulnerable to compression and produce more severe neuropathic painOn the basis of the findings of the aforementioned studies, we hypothesised that patients with symptomatic LS have a higher incidence of abnormal SQST results than do those without symptomatic LS, and an SQST combined with magnetic resonance imaging (MRI) can help physicians in the diagnosis of symptomatic LS. This study investigated the diagnostic accuracy of an SQST in the detection of symptomatic LS in patients who had degenerative spinal disorders at the L4/5 or L5/S1 level with disabling back and leg pain.This was a cross-sectional diagnostic study. All data were prospectively collected at our hospital from April 2016 to February 2017. This study was approved by the Taipei Medical University Joint Institutional Review Board (N201602059). All procedures in this study were performed in accordance with relevant guidelines and regulations, and informed consent was obtained from all participants or their legal guardians.We identified patients older than 18 years who had disabling back pain with or without leg pain and were admitted to our hospital for lumbar spinal surgeries under the care of a single surgeon. Patients who met the following criteria were included: (1) back pain with or without leg pain lasting for more than 3 months after conservative treatment and (2) a corresponding lesion on MRI, such as (a) central spinal stenosis at the L4/5 level due to spondylolisthesis or disc herniation, (b) lateral recess stenosis at the L5 level, (c) foraminal stenosis at the L5/S1 level, or (d) segmental instability requiring surgical treatment at the L4/5 level. We excluded patients who had received a diagnosis of a spinal tumour or infection, presented with cauda equina syndrome, refused to undergo the SQST, had a visual analogue scale (VAS) score of less than 2 for leg pain or soreness, or had simultaneous involvement of L5 nerve roots on both sides. The SQST was designed to examine differences between the symptomatic and contralateral sides; thus, patients with bilateral L5 nerve root involvement may have normal SQST results. To particularly focus on the L5 nerve, we excluded patients who had only L4/5 foraminal stenosis or L5/S1 CS and those with a pathology not involving the L4/5 or L5/S1 level.18, except that we used 10 °C for the cold test. In our preliminary study, patients felt a clear cold sensation on their dorsal feet only until the temperature of water was less than 10 °C in a closed room with a temperature of 24–27 °C, and at 10 °C, they could clearly report a difference between the two sides if there was a sensory disturbance. When the temperature of water was 15–20 °C, they felt moderately cold and could hardly identify the difference in cold sensation between the two sides, even when other sensory tests strongly suggested a sensory disturbance. All tests were performed in a quiet room with the temperature maintained at 24–27 °C, and the patients were asked to sit on a chair with their naked feet comfortably situated on a leg rest. The skin of their medial dorsal foot was regarded as the L5 dermatome and the test area. This area was suggested as the L5 dermatome by a study combining clinical symptoms, electromyography, and imaging and surgical findings20. A complete SQST comprised eight sensory tests. For each sensory test, an abnormal finding was defined as decreased sensation or hyperalgesia on the symptomatic side compared with the contralateral side, whereas a normal finding was defined as the same sensation between both sides. An investigator  interviewed all patients and performed the SQST. Before this study, two investigators  evaluated the interrater and intrarater agreements of 18 patients. The interrater agreement of each item of the SQST and SLRT was 0.6–1, and the intrarater agreement was 0.7692–1  with a traditional cervical–thoracic–lumbar spine coil  at the study hospital. The patients were placed in a supine position with a cushion under both knees, and T2-weighted fast spin-echo axial and sagittal images were obtained .22. CS was regarded to be present if the grade was B, C, or D according to Schizas’s classification  and corresponding grade III lateral recess stenosis or grade III foramina stenosis on MRI. In this study, the foraminal stenosis or lateral recess stenosis of patients with symptomatic LS was surgically confirmed, and their leg pain improved immediately after the surgery.The reference criteria for the diagnosis of symptomatic LS were a grade III LS on MRI and clinical symptoms . A neurosurgeon (the first author) graded the LS and CS of each patient and then classified each patient as having LS or CS or no stenosis based on MRI findings. This observer was unaware of the patient’s medical history or the results of SQSTs. The observer had 8 years of postresidency experience in reading spinal MRIs. CS was defined as central spinal stenosis at the L4/5 level caused by spondylolisthesis or disc herniation and was graded according to Schizas’s and Lee’s classificationion Fig. . LS was  23 Fig. . Lateral26, the Japanese Orthopedic Association (JOA) score for low back pain27, the Oswestry disability index 28, and VAS scores for leg pain or soreness, or back pain or soreness . We regarded soreness as a discomfort in patients with symptomatic LS.We prospectively collected the data of all patients, including age, sex, diagnosis, results of the preoperative Short Form-36 t test, one-way analysis of variance (ANOVA), and the Mann–Whitney U test. Comparisons between categorical variables  were performed using the chi-square test. The Holm–Sidak correction method was used for multiple comparisons. Logistic regression models were used to evaluate the receiver operating characteristic (ROC) curve for various sensory and test assessments to identify LS. The areas under the curves (AUCs) indicated the highest possible sensitivity and specificity. A stepwise model selection method was used to confirm logistic regression as the best method to build a predictive model. Statistical analyses were performed using Prism 7 for Mac  and SAS software, version 9.4 .Data are presented as the mean ± standard deviation. Comparisons between continuous variables  were performed using the Student The datasets generated and/or analysed during the current study are available from the corresponding author on reasonable request.p < 0.0001; 73% vs. 3% for high-strength von-Frey, p < 0.0001; 55% vs. 0% for pinprick, p < 0.0001; 45% vs. 0% for brush, p < 0.0001; 59% vs. 3% for blunt, p < 0.0001; 59% vs. 8% for vibration, p < 0.0001; 68% vs. 3% for warmth, p < 0.0001; and 73% vs. 16% for cold, p < 0.0001; Supplement Table Between April 2016 and February 2017, 75 patients were assessed for eligibility Fig. . In the Table The results of this study demonstrated that among patients with a pathology at the L4/5 or L5/S1 level involving the L5 spinal nerve root, those with symptomatic LS had a higher incidence of abnormal SQST results, and low-strength von-Frey, high-strength von-Frey, and vibration were identified to be the most accurate predictors of symptomatic LS.7. In agreement with this finding, we found a trend of leg pain being more severe in patients with LS, but the difference was not statistically significant. However, a prospective randomised trial showed that sensory disturbances did not differ between patients with LS and those with CS8. In contrast to this finding, our study results revealed that patients with symptomatic LS had a significantly higher incidence of abnormal SQST results. We believe that the standardised protocol of the SQST in the StEP improved the sensitivity and specificity of the diagnosis of symptomatic LS in our study. Furthermore, symptomatic LS is easily overlooked, particularly when there is coexisting CS. In our study, 10 patients had both CS and LS, and all of them exhibited sensory disturbances in at least one item of the SQST in their affected limb. Patients with both CS and LS had more LS-like clinical presentations. Compared with patients with only CS, more patients with both CS and LS had abnormal findings in SQSTs .Demonstration of the relevant lesion or disease by at least one confirmatory test.In our study, patients with symptomatic LS had a higher incidence of abnormal findings in the SQST, which are indicators of neuropathic pain. Neuropathic pain refers to pain arising as a direct consequence of a lesion or disease affecting the somatosensory systemThe grading of certainty for the presence of neuropathic pain is considered “defined” if all criteria are met, “probable” if both criteria 1 and 2 plus either 3 or 4 are met, and “possible” if only 1 and 2 are met without confirmatory evidence from 3 or 4.Leg pain below the knee along or not along the L5 dermatome.A history of low back pain or leg pain.Abnormal findings in the SQST.Stenosis showing the involvement of the L5 dorsal nerve root or dorsal root ganglion on MRI.In this study, on the basis of the grading system of neuropathic pain, we modified these four criteria for grading neuropathic pain in lumbar radiculopathy specifically involving the L5 spinal nerve:13. In summary, the relatively narrow anatomical structures and the nerve structures comprising the lumbar lateral canal may underpin the mechanism that explains why patients with symptomatic LS have more abnormal sensory test results and neuropathic pain.Leg pain in patients with stenosis, particularly LS, and abnormal findings in the SQST were classified as definied neuropathic pain . Leg pain in those with stenosis but with normal findings in the SQST was defined as probable neuropathic pain. Leg pain in those without either stenosis or abnormal findings in the SQST was defined as possible neuropathic pain. Accordingly, leg pain in 100% of patients with symptomatic LS and 18% of patients with CS was definite neuropathic pain. Leg pain in 82% of patients with CS was probable neuropathic pain and that in four patients without LS or CS was possible neuropathic pain. The risk of nerve root injury is higher in LS than in CS because of the anatomic structures. In contrast to the central canal, the lateral canal has a much narrower space; thus, nerve root injury can easily occur in LS. In addition, nerve structures involved in LS and CS are different. In LS, the dorsal root ganglia and their spinal nerves are involved, and injuring these structures caused much severer pain responses in an animal model compared with injury of dorsal roots in the central canal24. In our study, 25% (4/16) of patients with grade II LS and 95.5% (21/22) of patients with grade III LS exhibited abnormal SQST results. Although four patients with grade II LS had abnormal SQST results, their leg pain was not more severe than their back pain, was not in a radiating or shooting manner, and did not extend below the knees. On the basis of their clinical presentations, a diagnosis of symptomatic LS was not established. Accordingly, grade III was defined as the presence of LS, not including grade II. The VAS scores for leg pain of patients with grade 0–1 LS, grade 2 LS, and grade 3 LS were 4.86 ± 3.73, 5.19 ± 3.66, and 7.23 ± 2.68, respectively . The VAS score for leg pain increased with the grade of LS. Accordingly, the results of the current study showed that grade 3 LS in either the lateral recess or foramen is more likely to result in abnormal sensory test results or leg symptoms.We defined grade 3 as the presence of LS in both the lateral recess and foramen. The grade at which LS causes symptoms remains controversial. Grades II and III were defined as the presence of stenosis in a previous study24. In other words, the sensitivity of MRI in the detection of lateral recess stenosis related to disc protrusion is not known. Another study reported that the sensitivity, specificity, and accuracy of MRI in the detection of a lumbar disc protrusion is 92%, 91%, and 92%, respectively, which was confirmed by surgical findings37. Thus, we believe that MRI can more accurately detect lateral recess stenosis related to disc protrusion compared with that related to degenerative bony changes. In this study, 67% of grade III lateral recess stenosis was related to disc protrusion, and 33% was related to degenerative facet joint hypertrophy or pars interarticularis hypertrophy. Grade III lateral recess stenosis shown on preoperative MRI of all patients was surgically confirmed in our study. In patients with grade 0–II lateral recess stenosis, a disc protrusion or very severe stenosis related to the bony structure was not found at the lateral recess during the operation, but it was very difficult to grade lateral recess stenosis intraoperatively. Thereafter, a bias may have occurred due to our underestimation of the incidence of grade II or III LS related to degenerative bony changes in patients in the LS(−) group. However, for lateral recess stenosis related to disc protrusion, the bias was very limited.LS consisted of lateral recess stenosis and foraminal stenosis. A study reported 72% sensitivity of MRI in the detection of Grade II–III lateral recess stenosis related to the degenerative bony changes of the surrounding structure, but it excluded stenosis related to disc protrusion20. However, the medial dorsal foot may not be the L5 dermatome in a few patients. The results of this study should be interpreted with caution. Finally, because MRI has only 72% sensitivity in the detection of grade II–III lateral recess stenosis related to the degenerative bony structure, a bias may have occurred in this study due to the underestimation of the incidence of such stenosis. However, for lateral recess stenosis related to disc protrusion and foraminal stenosis, underestimation was limited.This study has some limitations. Although the number of participants was small, and confidence intervals around the estimates of sensitivity, specificity, and positive and negative predictive values were therefore slightly wide, the power was still satisfactory (87.29%) when we considered the cold sensory test with the smallest ROC curve (0.73). This study included only patients who experienced disabling pain for more than 3 months; thus, the results of the SQST in patients with acute pain would not necessarily be the same. The focus of this study was to identify symptomatic LS. For asymptomatic LS, the SQST was not validated in this study. All patients were recruited from a single hospital, and local factors influencing the incidence of lumbar LS cannot be excluded. Therefore, the generalisability of our results may be limited. The SQST is used to detect differences in sensation between two sides. Thus, it may be not able to detect differences in a patient who has sensory disturbance on both sides. The SQST is a qualitative test, and it cannot reflect how different patients feel between sides. The accuracy of the SQST is based on patients’ responses, and it heavily depends on patients’ understanding and cooperation. This study excluded patients who could not respond correctly to the SQST. In addition, the L5 dermatome may vary among patients. The skin site tested in this study was the medial dorsal foot, which was regarded as the L5 dermatome in a comprehensive study combining clinical symptoms, electromyography, and imaging and surgical findingsThe incidence of abnormal sensory test results was higher in patients with symptomatic LS than in those with CS. The results of this study indicated that in combination with MRI, the SQST can serve as a diagnostic tool in the identification of symptomatic LS in patients with symptomatic lumbar stenosis involving the L5 spinal nerve.supplementary tables


Previous research has identified preoperative determinants that predict health related quality of life (HRQoL), functioning and pain after total knee or hip arthroplasty (TKA/THA), but these differed between studies and had opposite directions. This may be due to lack of power and not adjusting for confounders. The present study aims to identify the preoperative determinants that influence health related quality of life (HRQoL), functioning and pain after total knee or hip arthroplasty (TKA/THA).n = 1783 TKA and n = 2400 THA) in the Netherlands. We examined the influence of age, gender, BMI and preoperative values of HRQoL, functioning and pain on postoperative status and total improvement. Linear mixed models were used to estimate the effect of each preoperative variable on a particular outcome for each cohort separately. These effects were pooled across cohorts using a random effects model.We pooled individual patient from 20 cohorts with OA patients data . Similarly, each point increase in preoperative functioning, resulted in a higher postoperative functioning of 0.31 (TKA) and 0.21 (THA) points . For pain this was 0.18 (TKA) and 0.15 (THA) points higher  (higher means less pain). Even though patients with better preoperative values achieved better postoperative outcomes, their improvement was smaller. Women and patients with a higher BMI had more pain after a TKA and THA. Higher age and higher BMI was associated with lower postoperative HRQoL and functioning and more pain after a THA.Patients with a better preoperative health status have better outcomes, but less improvement. Even though the independent effects may seem small, combined results of preoperative variables may result in larger effects on postoperative outcomes. Total knee or hip arthroplasty (TKA/THA) is an effective treatment for most individuals who suffer from pain and loss of function due to end stage symptomatic osteoarthritis of the hip and knee (OA). In 2010, 109 and 153 patients per 100,000 persons received a TKA or THA respectively in Europe .TKA and THA should not be performed too early since revision rates are higher in younger patients and the length of life of a prosthesis is limited . On the Previous research has identified preoperative determinants that influence outcomes, but these differed between studies and had opposite directions . This maThe present study aims to examine the independent effect of several preoperative determinants for outcomes after TKA or THA by pooling individual patient data from available prospective cohorts in the Netherlands.The ARGON-OPTIMA (Outcome Predictors for TIMing of ArthropLasty) study is part of the ARGON program (Arthritis Research Group Orthopaedics in The Netherlands). Within this study, we pooled individual patient data from all available prospective TKA/THA cohorts in the Netherlands. All orthopaedic clinics in The Netherlands were invited to participate and submit data. We included prospective cohorts among patients with primary OA who underwent TKA or THA, with at least one preoperative and one postoperative measurement on functional or clinical outcomes and a follow-up of at least one year. Cohorts regarding metal-on-metal (MoM) prostheses were excluded, since these are not recommended in current guidelines in The Netherlands.Twenty hospitals submitted data and 20 cohorts from 11 hospitals were included. Nine hospitals were excluded because they did not meet the inclusion criteria. Of the included cohorts, 8 cohorts included 1783 knee OA patients undergoing primary TKA and 12 cohorts included 2400 hip OA patients undergoing primary THA. Table The assessed preoperative determinants were age, gender and BMIs. Furthermore, we examined the influence of preoperative health related quality of life (HRQoL), functioning and pain.We studied the effect on the absolute level of the postoperative outcome, but also on the extent of improvement to assess which patients would benefit most from change in health related quality of life (HRQoL), functioning and pain.Since different cohorts used different questionnaires, these were standardized to compare the same domains across different questionnaires. Furthermore, multiple questionnaires were sometimes used to measure the same domain within a cohort. As each patient should be included only once for each domain, we ordered questionnaires in their ability to measure each outcome reliably. This was done during an ARGON consortium meeting. A group of experts within the ARGON consortium discussed about the ordering of questionnaires until consensus was reach. The following main points were taken into concern: is it a general or disease specific questionnaire, how many items are used to calculate the composite score, and is it a common used questionnaire in the Netherlands.Physical component summary scale of the 36-item short form health survey (SF-36/RAND-36) (36 items)Physical component summary scale of the 12-item short form health survey (SF-12) (12 items)EuroQoL 5 Dimensions (EQ-5D) (5 items)Health related quality of life:Hip/knee disability and Osteoarthritis Outcome Score (HOOS/ KOOS) subscale Activities of Daily Living (ADL) (17 items)Western Ontario & McMaster Universities Osteoarthritis Index (WOMAC) subscale Physical Function (PF) (17 items)HOOS-Short form (PS)/KOOS-Short form (PS) (5 items)Oxford Hip Score (OHS) subscale function (6 items)/ Oxford Knee Score (OKS) subscale function (5 items) according to Harris et al. , 16Functioning:HOOS/ KOOS subscale Pain (10 items)WOMAC subscale Pain (5 items)OHS subscale Pain (6 items)/ OKS subscale Pain (7 items) according to Harris et al. , 16Visual Analogue Scale (VAS) pain scalePain:Only the highest rated questionnaire in each dataset was included. The following ordering was used:For each patient we calculated the standardized score at each time point using the following formula (functioning as example):Some questionnaires differed in the direction of the scale e.g. on the VAS pain scale, lower scores mean less pain whereas lower scores mean more pain on the HOOS/KOOS subscale pain. The direction of all scales were recoded so that higher scores referred to better values).Data of TKA and THA were analyzed separately. As a first step, linear mixed models (LMM) were used to estimate the influence of each preoperative variable on each major outcome for each cohort separately, adjusted for the other variables. As determinants were included in the fixed part of the LMM: the standardized preoperative score , age, sex, BMI and follow-up time. Interaction terms were fitted between the determinants and follow-up time. In the LMM the patients were specified as the subjects, with an unstructured covariance matrix. This was done for each standardized postoperative outcome. In the second step, the regression coefficients from all cohorts were pooled using a random effects model to obtain one pooled estimate for each preoperative variable and outcome. Given the pooled estimates of the impact of preoperative status on postoperative status, we can also determine the total improvement (postoperative minus the preoperative status). If patients would have the same amount of improvement, 1 point higher in preoperative status would result in a postoperative status of 1 point higher. So if the increase in postoperative status is < 1 (e.g. 0.4), this means that the improvement is 0.6 points smaller for every point increase in preoperative status.Given that preoperative scores were standardized, the pooled regression coefficient should be interpreted as the number of standard deviations that an outcome will change, per point increase in the preoperative variable. For example looking at the effect of age on postoperative functioning with a standardized regression coefficient of 0.2 and the preoperative SD of functioning is 7, this means that one year increase in age is estimated to increase the postoperative functioning by: 0.2*7. To facilitate interpretation of the pooled standardized regression coefficients of age, BMI and gender, we transformed standardized regression coefficients back to a 0–100 scale , using the preoperative standard deviation (SD) of the study with the highest weight in the random effects model. In addition, we will illustrate the potential size of the effects by describing scenarios.p-value of 0.05 was considered significant in all analyses.SPSS 20 was used to perform the LLM and Stata 11.1 for the random effects model. A 2 statistic was used to quantify heterogeneity between cohorts. This can be interpreted as the percentage of total variability in a set of effect sizes due to between-studies variability. We considered results as heterogeneous when I2 was 50% or greater [The I greater .The Medical Ethical Committee of the Leiden University Medical Center (CME P15.043/SH/sh) confirmed on February 13 2015 that ethical approval for this type of study is not required under the Dutch Medical Research (Human Subjects) Act. The hospitals that supplied anonymous data obtained written informed consent from the study participants.Table Four cohorts examined the effect of preoperative HRQoL on postoperative HRQoL in 760 patients after TKA Fig. . Eight cSix cohorts examined the effect of preoperative functioning on postoperative functioning in 1021 patients with a TKA Fig.  and 10 cSix cohorts examined the effect of preoperative pain on postoperative pain in 1102 TKA patients Fig.  and 12 cEven though the independent effect of one variable may be small, the combined effect of different determinants may result in clinically relevant differences. Table The present pooled analysis of 1783 knee and 2400 hip OA patients shows that patients with a higher preoperative quality of life or functioning and less pain also have better postoperative outcomes but that they improve less. Furthermore, women and patients with a higher BMI had more postoperative pain and less improvement after both TKA and THA. Higher age and higher BMI was associated with lower postoperative HRQoL and functioning and more pain after a THA. However, preoperative quality of life, functioning and pain seem to be most consistently associated with outcomes after both TKA and THA.Our results regarding the effect of preoperative status on outcomes are consistent with other studies that also found that patients with worse preoperative functioning had greater improvements –21, but The effect of different preoperative determinants on the postoperative outcomes after TKA and THA may seem to be small on itself, but if taken together they may add up to a clinically relevant effect. However, the scenarios should be interpreted with care, because these are hypothetical examples based on observational data and cannot be interpreted causally. The overall effects of the virtual scenarios which were calculated as examples vary between 1.2 and 6.5 points better postoperative outcomes and between 1.6 and 9 points worse postoperative outcomes. These scenarios provide more insights how small differences may add up or cancel each other out. This probably explains why most effects do not reach a clinically significant difference. Usually a 10% difference  is consIt is important to realize that the effects found in our study are not only the effect of the surgery, but also the effect of regression to the mean (RTM). RTM occurs because values are observed with random error, such as random fluctuations in a subject . This meThe information regarding the combined effects of preoperative determinants on postoperative outcomes will support orthopaedic surgeons to estimate differences in outcome after a joint replacement for specific patient groups, i.e. poorer outcomes for patients with a worse preoperative status, but with greater postoperative improvement compared to patients with higher preoperative scores. In addition, preoperative status may decline during a long surgical delay period and thereby lead to worse postoperative outcomes if no other non-surgical treatments are started. On the other hand, it may sometimes be better to first optimize the patient’s preoperative condition or to reduce for example their BMI. The present study may support orthopaedic surgeons in their decision making by giving an estimate of the magnitude of the effect for different scenarios. Future studies should combine the results of our study with observational cohort studies among OA patients who did not have surgery yet, specific survival data from medical literature and the effects on survival of the artificial joint to assess optimal timing of surgery. This is needed to assess the long-term impact for the patient of the decision to perform surgery at a certain preoperative state of specific patient groups.


One of the most effective means of preventing the transduction and transmission of acute and perioperative pain is through the use of local anaesthetics. However, local anaesthetics currently available have a relatively short duration of action. Although there are several tools available to treat perioperative pain in companion animals, overall, there is an unmet need for products that can be administered in the clinic, and provide pain relief for the crucial first few days following surgery in the home environment. Specifically, in relation to local anaesthetics, there is a clear unmet need for a long‐acting local anaesthetic that can be added to the multimodal analgesic protocol to provide pain relief to patients in the home environment or during extended hospitalization. Bupivacaine liposomal injectable suspension recently became available for use in humans, and has proven efficacious and safe. This paper will review the use of local anaesthetics, particularly bupivacaine, in dogs and cats, and introduce a new formulation of prolonged release bupivacaine that is in development for dogs and cats. All surgical procedures result in some degree of tissue trauma and associated pain. Over the last two decades in veterinary medicine, there has been a dramatic shift in the approach to perioperative pain, with an increased recognition of pain and increased use of analgesics to control perioperative pain  provide pre‐emptive analgesia, (ii) utilize multimodal pain management, (iii) deliver overlapping/ continuous analgesia and (iv) match the analgesic plan to the degree of surgery. The pain transmission system is complex, with a lot of redundancy, and therefore in order to minimize postoperative pain and any long‐term sequelae of unrelieved pain, an effective multimodal approach should be employed that interrupts the pain transmission and detection system at multiple levels Fig. . Veterinet al. ™, Elanco) have been approved for post‐surgical analgesia in dogs, and injectable buprenorphine  and the cyclooxygenase inhibiting NSAID robenicoxib  in cats. Meloxicam  is approved for use in cats preoperatively, but only for a single dose. Beyond these options, there are unapproved fentanyl patches manufactured for human use, which have been suggested to be efficacious . This paper will review the use of local anaesthetics, particularly bupivacaine, in dogs and cats, introduce a new formulation of prolonged release bupivacaine and review the published literature on this product.Overall, there is a clear unmet need for effective analgesic products that can be given in the clinic and continued in the home environment, or products that can be administered in the clinic and provide pain relief for the crucial first few days following surgery in the home environment. Specifically, in relation to local anaesthetics, there is a clear unmet need for a long‐acting local anaesthetic that can be added to the multimodal analgesic protocol to provide pain relief to patients in the home environment or during extended hospitalization. Bupivacaine liposomal injectable suspension is currently being developed for dogs and cats, with a target indication of 72 h of local analgesic efficacy following intra‐operative tissue infiltration  reported the average dose and arterial plasma concentration at seizure onset for several local anaesthetics  strongly recommends the routine use of local anaesthetic .Local anaesthetics are also frequently used for regional nerve blocks and these techniques have demonstrated significant enhancement of postoperative analgesia in dogs and cats  for use as a single‐dose infiltration into the surgical site to effect post‐surgical analgesia in human surgical patients. The prolonged‐release technology used in this product consists of multi‐vesicular liposomes encapsulating aqueous bupivacaine. The liposomes are microscopic structures made of non‐concentric lipid bilayers designed such that bupivacaine is gradually released from vesicles over 96 h as the lipid bilayers break down. The lipids making up the bilayer structures consist of phospholipids, cholesterol and triglycerides, and importantly do not contain lecithin which has been associated with tissue necrosis and toxicity. The technique for instilling bupivacaine liposomal injectable suspension into a wound differs slightly from using traditional bupivacaine formulation because the liposomes do not readily diffuse into tissues. This is due to the size of the liposomes – each liposome is approximately 10–30 μm in diameter . A moving needle technique is used to inject the solution into all tissue layers within the surgical field . The 30% reduction in pain compared to placebo over the 72 h was considered clinically meaningful. Furthermore, bupivacaine liposome injectable suspension‐treated patients required significantly less opioid medication (P < 0.0008) during the first 72 h and had significantly greater overall satisfaction with postoperative analgesia (P = 0.0007)  in favour of bupivacaine liposome injectable suspension, and there were significantly more treatment successes (reduction in pain scores) in the bupivacaine liposome injectable suspension group compared to placebo over each 24‐h period  up to 72 h postoperatively. No significant adverse events were seen (unpublished data). Recently, the top‐line results from the subsequently performed larger pivotal study were announced, with similar efficacy seen. Pilot studies using this product are also in progress in cats.Bupivacaine liposome injectable suspension is currently being investigated for use in dogs and cats. At the time of writing, a multi‐centre, placebo‐controlled pilot trial in dogs undergoing orthopaedic surgery has been completed and the results presented. In dogs undergoing lateral retinacular suture stabilization of cruciate deficient stifles, 46 dogs were enrolled in a blinded, placebo‐controlled study and evaluated postoperatively using subjective assessments. Bupivacaine liposome injectable suspension was injected intra‐incisionally at the time of closure of the wound to provide postoperative analgesia. There was a significant overall treatment effect of pain reduction (Local anaesthetics are potentially the most effective analgesic class available to veterinarians for use in the perioperative period because they have the potential to completely block nociceptive signals from reaching the CNS. However, their clinical effectiveness is limited by the relatively short duration of action. The recent development and approval for use in humans of a prolonged duration of action liposome formulation of bupivacaine appears to be having a dramatic and positive impact in human postoperative pain control. The development of this product for the veterinary market shows promise to be an effective tool for practitioners, and would help address a significant unmet need – the ability to provide prolonged postoperative analgesia using the most effective class of perioperative analgesic available.NoneThe authors are both paid consultants of Aratana Therapeutics.KKS and BDXL both planned, drafted and finalized the manuscript


The aim of this study was to compare the effectiveness of spinal anesthesia with subdiaphragmatic lidocaine at the beginning of surgery versus spinal anesthesia in pain reduction for gynecological laparoscopic surgery. This was a clinical trial conducted in Arash Hospital, Tehran, Iran. Eighty-four patients were randomized to either spinal anesthesia with subdiaphragmatic lidocaine, spinal anesthesia, or general anesthesia (GA). The primary outcome was patients' pain perception during surgery, 2, 4, 6, and 12 hours after surgery, and prior to discharge and was assessed by visual analogue scale (VAS).F = 0.37, P = 0.82). The severity of pain experienced by patients at all-time interval after surgery was similar between groups . The results showed that there are no significant changes in pain perception over time in none of the three groups (IRCT2016022226698N1. The use of subdiaphragmatic lidocaine at the beginning of surgery combined with spinal anesthesia was not associated with a statistically significant difference in patients' postoperative VAS scores compared to spinal anesthesia and GA during and after gynecological surgical procedures. The study was registered in Iranian Registry of Clinical Trial by the number of  Laparoscopic surgery for women traditionally is done under general anesthesia, but nowadays spinal anesthesia is appropriate alternative with few complications in the surgery . Spinal http://www.IRCT.ir) by the number of IRCT2016022226698N1.This study was designed as a single-center, randomized, parallel-group, controlled trial in accordance with Consolidated Standards of Reporting Trials (CONSORT) guidelines. The study was approved by Institutional Review Board of the Tehran University of Medical Sciences. Women attending the Department of Obstetrics and Gynecology, Tehran University of Medical Sciences, at Ruin Tan Arash Hospital for infertility treatment were recruited when the following criteria were met: (a) American Society of Anesthesiologists (ASA) physical status I-II, (b) age of 15–45 years, and (c) a signed informed consent form. Exclusion criteria included (a) severe coagulopathies, (b) severe cardiovascular diseases, (c) allergy to local anesthetics, (d) pathologies connected with abdominopelvic pain that could confuse the perception of pain directly related to the procedure , (e) chronic pain syndromes, (f) BMI > 35, (g) a history of abdominal surgery, (h) a history of psychological diseases, (i) being unable to comprehend visual analog scale, and (j) patients in disagreement with the study protocol. The written informed consent was obtained from the patients before conducting any study-related tests. The study was registered in Iranian Registry of clinical trial . The pain VAS is a continuous measurement instrument that is operationally comprised of a horizontal line, anchored at each end by verbal descriptors, such as “no pain” and “the worst pain imaginable.” Visual analog scale (VAS) is a robust and reliable instrument which has been regularly used in similar trials by multiple investigators for different procedures.Following our standard practice, all patients were premedicated with oral midazolam 0.05 mg/kg. Standard monitoring, including electrocardiography, noninvasive blood-pressure measurements, and pulsoximetry, was undergone throughout the operation.−1 Ringer's lactate solution was administered before the spinal block commences. Afterwards, the subarachnoid space was entered from the L3-4 or L4-5 interspace using a 25-G Quincke spinal needle in the sitting position. Once the cerebral spinal fluid (CSF) flow had been observed, 4 mL of hyperbaric bupivacaine 0.5% was injected into the subarachnoid space at a rate of 0.1 ml/s. The patient was then positioned supine, with a right hip pad to minimize aortocaval compression. The level of sensory block was tested using the gentle pinprick method and recorded.In the operating room, an IV cannula was inserted; then a 10 mL kgPatients in Group B received subdiaphragmatic injections of 10 mL of 1% lidocaine at the port sites at the beginning of the procedure.μg/kg) (Aburaihan Co. Iran) and for endotracheal intubation we used succinylcholine (1.5 mg/kg b.w.). For maintenance of anesthesia, propofol 100–150 μg/kg  was administered. During the operation, atracurium 10 mg and fentanyl 50 μ were given every 30 minutes.For the induction of anesthesia, we used midazolam (0.02 mg/kg) , propofol (1% 1–2.5 mg/kg) Liporo 1% , and fentanyl  with a 0-degree view was inserted, insufflating approximately 2 L of COThe calculation of the sample size was based on the primary end point (VAS score). The study was designed to have 80% power to detect a 35% difference in pain scores on visual analog scale, with two-sided alpha levels of 0.05. Using sample size calculation for independent proportions, the minimum number of participants in each group should be 28 .All data analyses were conducted using SPSS version 21.0 for Windows . Descriptive statistics for continuous variables were presented as mean ± standard deviation (SD) and for categorical variables as numbers (percentage). The baseline characteristics of the three groups were compared using analysis of variance test (ANOVA) for continuous variables and the Chi-square test for categorical variables. The endpoint mean VAS score was analyzed using repeated measures analysis of variance. The model included treatment as fixed factor and age and parity as covariates. All statistical tests were two-sided and the level of statistical significance was set at 0.05. All analyses were performed on an intent-to-treat basis. The conduct and analysis of the trial adhered to the 2010 CONSORT guidelines.Between April 2016 and July 2016, 194 patients were enrolled in the study. Of the 84 eligible patients, 28 patients were allocated to each of the treatment groups. The analysis was done by intention-to-treat and included all patients who were randomly assigned. F = 0.54, P = 0.58].The severity of pain experienced by patients at all-time interval after surgery was presented in F = 0.37, P = 0.82).Although the mean of pain increased for all groups during the study, repeated measures ANOVA revealed that there are no significant within-subject effects, indicating no significant change over time in none of the three groups  and vomiting (P = 0.94).There were no statistically significant differences between the three groups with regard to narcotic analgesic usage  and Modified McGill Pain intensity scores also were used in other studies –26. WithGiven that the time of these studies is different and from 1980 until now no search has been conducted, the effect of the development of surgical techniques and anesthesia may be the reason for heterogeneity of results of studies .Although the majority of studies that were retrieved in the literature indicated the effectiveness of local anesthesia on pain after surgery, in three RCTs, similar to our study, there was no effect of local anesthesia on pain. All of three RCTs were conducted after a systematic review by Marks et al. in 2012. In a study conducted in 2016 by Collins et al., 55 patients who underwent laparoscopic and robotic gynecologic procedures were women and were assigned to two groups of intraperitoneal ropivacaine and placebo. Pain intensity was measured 2, 4, 8, and 12 hours after surgery. However, the mean pain score in the placebo group was more than the treatment group, but this difference was not statistical significant . In a stThe use of intraperitoneal lidocaine combined with spinal anesthesia was not associated with a statistically significant difference in patients' postoperative VAS scores compared to spinal anesthesia and GA during and after gynecological surgical procedures.


To evaluate the influence of pain on quality of life in breast cancer patients.A cross-sectional study of 400 patients, including 118 without metastasis, 160 with loco-regional metastasis and 122 with distant metastasis. The instruments used were the European Organization for Research and Treatment for Cancer Quality of Life Questionnaire-Core 30 and the Breast Cancer-specific 23 and short McGill Pain Questionnaire.p=0.001). Subjects with loco-regional metastasis had score of 59.1 (SD=21.3) when in pain, and those without pain had a significantly higher score of 72.4 (SD=18.6) (p<0.001). Patients from the distant metastasis group showed similar results with a mean score of 48.6 (SD=23.1) for those in pain and 67.6 (SD=20.4) for those without pain (p=0.002). Regarding the association of pain intensity and quality of life, patients with distant metastasis and intense pain had the worst scores for quality of life with a functional scale mean of 49.9 (SD=17.3) (p<0.009), a Symptom Scale score of 50.0 (SD=20.1) (p<0.001) and a Global Health Scale score of 39.7 (SD=24.7) (p<0.006).In total, 71.7% of patients reported pain. The most frequent sensory descriptor used by patients was ‘jumping.’ In the evaluative dimension, the main descriptor chosen was troublesome. The Global Health self-assessment showed pain to be inversely correlated with quality of life: the group without metastasis had a mean score of 55.3 (SD=24.8) for those in pain, which rose to 69.7 (SD=19.2) for those without pain (Pain compromises the quality of life of patients with breast cancer, particularly those with advanced stages of the disease. Breast cancer (BC) is often associated with long-term psychological distress, chronic pain, fatigue and impaired quality of life (QoL) Pain is one of the most frequently reported adverse effects that occurs as part of the disease process or as a side-effect of treatment. It is a problem for a majority of BC patients and has an unfavorable effect on QoL More recent epidemiological data obtained from a meta-analysis suggest that pain is prevalent in 39.3% of cases after curative treatment, 55.0% during cancer treatment, and in 66.4% in advanced or terminal stages of the disease The frequency of pain increases as the disease progresses, causing physical, emotional, spiritual and functional discomfort. This impedes performance of daily activities and disturbs sleeping and eating habits. As a result, cognitive function is impaired and affective, sexual and family relationships are strained, and work and leisure activities are difficult. This leads to greatly decreased QoL for these women Pain is understood as a complex multidimensional experience that must be evaluated in its affective and cognitive dimension. Emotional and cognitive factors have a strong influence on pain perception Pain is a stressful, individual and subjective human experience and has been associated with feelings of social isolation The purpose of this study was to evaluate the influence of pain on the QoL of women with BC. A detailed evaluation of pain enables caretakers to create a strategy to reduce pain and prevent any secondary symptoms, which improves patient QoL.This prospective study was conducted with 400 women diagnosed with BC undergoing chemotherapy, radiotherapy, surgery, hormone therapy, or exclusively in palliative care. The study occurred in the oncology center at a referral hospital in a medium-sized city in the northeast of Brazil from July 2014 to April 2015. Patients were selected through non-probability sampling, and patient interviews were conducted during appointments or in the chemotherapy infusion room.A patient was considered eligible for the study if they were diagnosed with BC, undergoing treatment for the disease or exclusively in palliative care, and were over 18. Women without cognitive ability and/or verbalization, patients who had not started treatment, and those who had been previously diagnosed with depression were excluded.Three study groups were created within the sample: 1-118 patients without metastasis (MTX), 2- 160 patients with loco-regional MTX and 3- 122 patients with distant MTX.Ethical issues were considered, and the Local Research Ethics Committee approved the present study (n°. CAAE 17956113.9.0000.5293) in compliance with the Declaration of Helsinki and Resolution 466/12 of the Brazilian National Health Council, which addresses research on human beings. Before starting the interview, the study objectives were explained, and the patients participating in the study were asked to sign a free and informed consent form. This ensured that participation was voluntary and that answers would be kept anonymous and confidential.Pain was evaluated using the Short-Form McGill Pain Questionnaire (SF-MPQ) proposed by Melzack These descriptors were classified as “present” or “absent.” In addition to these descriptors, the instrument also integrates a Numeric Pain Rating Scale. The level of pain intensity was classified as mild, moderate and severe. These levels were based on the intensity with which each patient classified their pain on the Numerical Scale. Thus, 1 to 3 represents mild pain, whereas 4 to 6 represents moderate pain and 7 to 10 intense pain. The questionnaire also includes a Body Diagram to determine the location of the pain referred to by the subjects.To assess QoL, the European Organization device for Research and Treatment for Cancer Questionnaire-Core 30 (EORTC QLQ-C30) was used. This questionnaire is a valid and reliable evaluation of cancer patient QoL and has been considered useful in many clinical trials and studies. The EORTC QLQ-C30 (version 3.0) is composed of 30 items, embedded in three scales, corresponding to the patient’s condition in the past week. The first scale, the Functional Scale, consists of five domains: physical, emotional, social, cognitive, and role functioning. The second scale, the Scale of Symptoms, consists of three sub-scales  and six single items  and finally, the Global health scale.Questions 1-28 are answered on a four-point scale, with each item classified from none  to very much . Questions 29 and 30 are answered on a seven-point scale going from bad  to good . All items were then linearly transposed onto a scale from 0 to 100. For the five functional scales and global health scale, a higher score indicates a higher level of functioning or overall QoL. Conversely, for the symptom scale and single items, a higher score implies a higher level of symptoms or problems A second questionnaire associated with the EORTC QLQ-C30, also translated and validated for use in Portuguese, was used to evaluate QoL. This instrument, EORTC BR23, is specifically used for BC patients and consists of 23 questions answered on a 4-point scale (from 1 to 4). It is composed of two scales: the Functional Scale composed of 4 sub-items  and the Symptom Scale consisting of 4 sub-items  A descriptive analysis of the qualitative variables was performed through the absolute and relative frequency distribution. The T-test for independent samples was used to compare the mean total scores of the EORTC QLQ-C30 and BR23 variables for pain in the three groups of cancer patients. An analysis of variance (ANOVA) was performed to identify any existing correlations between all collected variables. Then, the Tukey test was applied to evaluate the magnitude of the latter. A significance level of 5% was used, and all calculations were performed using SPSS.V.13.Evaluating the sociodemographic profile of the 400 women, we see that most women were between 51 to 60 years of age (28.8%) or 41 to 50 (28%), and 60% were from the countryside. Other sociodemographic characteristics show that more than half, or 54.8%, had only received an elementary school education, 51% were married, only 39.3% were on sick leave, and Catholicism predominated in 63.3% of the patients. Concerning clinical variables, 87% of the women had a tumor with the histological appearance of invasive ductal carcinoma, 40% had loco-regional MTX, 76.5% had undergone some prior treatment , and 99% were undergoing some type of treatment  at the time of the interview.p<0.001). The mean Global Health score for patients with pain was 55.3 (SD=24.8), whereas it was 69.7 (SD=19.2) for those without pain (p=0.001). For the loco-regional MTX group, the mean symptom score for patients with pain was 29.0 (SD=15.3), whereas those without pain had an average score of 13.4 (SD=10.8) (p<0.001). On the Global Health Scale, patients in pain scored 59.1 (SD=21.3), and those without pain scored 72.4 (SD=18.6) (p<0.001). For the group with distant MTX, the mean symptom scores for patients with pain and without pain were 39.6 (SD=19.5) and 17.5 (SD=10.0), respectively (p<0.001). On the Global Health Scale, the mean score for those reporting pain was 48.6 (SD=23.1), whereas the mean score for those without pain was 67.6 (SD=20.4) (p=0.002). It is important to highlight that the higher the score on the symptom scale, the more symptoms were listed by the patient, thus compromising their QoL.p=0.016). Patients without pain had a better score on self-image evaluation, thus demonstrating how pain can influence self-esteem and how the limbic system influences pain. On the Symptom Scale, the same group of patients obtained a mean of 26.9 (SD=14.2) for those who were in pain and an average of 16.5 (SD=13.8) for those without pain (p=0.006).p<0.009), a mean symptom score of 50.0 (SD=20.1) (p<0.001) and a Global Health Scale mean of 39.7 (SD=24.7) (p<0.006). Functional capacity assessed by the KPS also showed a significant correlation between increased pain intensity and decreased QoL. The latter was observed in all three groups of patients. Women with distant MTX who reported intense pain obtained a mean KPS of 69.0 (SD=13.9) whereas mild pain reports reached a mean KPS of 78.9 (SD=8.7) (p<0.040).p=0.012). This same association was also observed in the sub-item related to “symptoms of the arm” with a mean of 40.7 (SD=29.4) (p=0.001).Pain intensity was also evaluated by EORTC BR23, as shown in Pain is one of the most common and distressing symptoms experienced by cancer patients. Cancer pain involves physical, social, psychological and spiritual components, all of which belong to the term “total pain”, which is used to refer to the multidimensional nature of pain (Cicely Saunders). The contribution of each component varies based on both individual factors and circumstances faced by the patient. Therefore, the perception of pain is affected by several variables such as fatigue, insomnia, fear, anxiety, anger, sadness, depression, social isolation, altered perception of self-image and impairment of functional capacity The occurrence of pain may be due to the disease process itself or as treatment aftermath, such as post-mastectomy pain, chemotherapy-induced neuropathy or brachial plexus neuropathy from radiation therapy Despite cancer pain having been very prevalent in this study , even in the non-metastatic group (56.8), the heterogeneity of sociodemographic and clinical characteristics of the subjects did not allow a specific statistical additional comparison between groups. This result was similar to that found by Tamai et al. The use of descriptors in the evaluation of pain has been increasingly considered pertinent to research and everyday clinical practice. These words help professionals determine type of pain and appropriate therapy to provide patients with the most pain relief and QoL possible p=0.002).When analyzing the association between the presence of pain and the EORTC domains, it was determined that pain negatively influenced QoL. This was true for the patients with and without MTX. The Global Health scale showed that women in pain considered themselves less healthy overall compared to those without pain (The effect of pain on QoL is not only related to the intensity of pain experienced by patients but also to how pain is perceived in its multidimensional aspect Pain seemed to impact QoL primarily in patients with distant MTX. These patients not only deal with acute pain but also have significant impairment of the Functional and Symptom Scales. They also suffer from poor body image and are emotionally scarred by the process of treatment and lack of functional capacity. The latter may be because the patient is often disfigured by the palliative treatments made necessary by advanced disease In addition, the perception of pain may contribute to a warped self-image due to the limbic system’s influence on the complexity of pain behavior. Corroborating our findings, a survey of 1965 women with BC conducted in Australia found sexual function to be reduced due to pain and negative body image Interestingly, among those without MTX, those with pain had lower means than those without for the Future Perspectives item. We believe that this reflects the fact that pain is one of the most feared symptoms, and its presence causes patients worry about its possible cause. This may lead to further worrying about the possibility of MTX and disease progression and consequently one’s mortality. The Relationship between QoL and pain seems to be inversely proportional because the higher the pain, the lower the QoL. In accordance with our results, the study by Nesvold et al. Despite these interesting findings, the present study should be interpreted with caution in light of its limitations. Pain was evaluated based on self-assessment and included estimates in relation to length of time, without the use of physical parameters. We recognize that some treatments by themselves can highly influence pain and QoL of these patients, and the correlation of these parameters with the results would be desirable; however, the heterogeneity of the used protocols made that impossible. Therefore, the results do not take into account the influence of confounding factors and the sample homogeneity. Further studies using different approaches with longitudinal design may provide better explanations of the complex manifestation of breast cancer.BC is the most frequent cancer in women worldwide, and pain is one of the most common symptoms, compromising QoL. In this study, pain was highly prevalent and was detected in 71% of the patients. These findings are significant and justify more attention in the management of these patients in daily practice to minimize this unpleasant symptom that damages functional capacity and haunts the patients emotionally.Costa WA was responsible for planning the research, collecting the quantitative data, discussing the results and writing the manuscript. Monteiro MN was responsible for analyzing the qualitative data and discussing the results. Queiroz JF was responsible for analyzing the qualitative data, discussing the results and writing the manuscript. Gonçalves AK was responsible for planning and supervising the research, analyzing the data, discussing the results, producing the final revisions and submitting the manuscript.


Postoperative pain is a persistent problem after surgery and can delay recovery and develop into chronic pain. Better patient education has been proposed to improve pain management of patients. Serious games have not been previously developed to help patients to learn how to manage their postoperative pain.The aim of this study was to describe the development of a computer-based game for surgical patients to learn about postoperative pain management and to evaluate the usability, user experience, and efficacy of the game.A computer game was developed by an interdisciplinary team following a structured approach. The usability, user experience, and efficacy of the game were evaluated using self-reported questionnaires , semi-structured interviews, and direct observation in one session with 20 participants recruited from the general public via Facebook . Adjusted Barriers Questionnaire II and 3 questions on health literacy were used to collect background information.P=.001).Theories of self-care and adult learning, evidence for the educational needs of patients about pain management, and principles of gamification were used to develop the computer game. Ease of use and usefulness received a median score between 2.00 (IQR 1.00) and 5.00 (IQR 2.00) , and ease of use was further confirmed by observation. Participants expressed satisfaction with this novel method of learning, despite some technological challenges. The attributes of the game, measured with AttrakDiff2, received a median score above 0 in all dimensions; highest for attraction  followed by pragmatic quality , hedonic quality interaction , and hedonic quality stimulation . Knowledge of pain medication and pain management strategies improved after playing the game (A computer game can be an efficient method of learning about pain management; it has the potential to improve knowledge and is appreciated by users. To assess the game’s usability and efficacy in the context of preparation for surgery, an evaluation with a larger sample, including surgical patients and older people, is required. Computer games as a medium for learning have been studied increasingly in recent years. Games have the potential to improve attention and motivation as players work on the challenges of the game . “SeriouSerious games can facilitate adult learning with features such as interesting aims, goal-oriented problem-solving, active participation, and use of previous experience, and they can provide continuous feedback, which can stimulate motivation . FurtherWithin health care, serious games have been developed for educating both patients and health care professionals. For example, serious games have been tested with the goals of (1) improving patients’ self-care for diabetes, asthma, cancer, and Warfarin use and (2) improving diet, pain, mobility, lifestyle, and health-related knowledge ,6-9. WitAlthough still inconclusive, many studies on serious games within health care have reported positive outcomes. An example is the game Re-Mission that is intended to help young cancer patients improve their self-care. Players win by destroying cancer cells and other enemies in the body with weapons such as chemotherapy. The game was found to have significant effects on cancer knowledge . AnotherGames have been used successfully as tools for managing pain, such as affecting the experience of pain and improving pain tolerance through distraction. Both commercial videogames  and gamePain management is an area that currently needs improvement, since the prevalence of postoperative pain remains high, occurring in more than 80% of patients ,17. PainToday, surgical patients are being discharged earlier than in previous years and same day–surgery accounts for nearly 70% of all surgery performed . This haThe knowledge expectations of surgical patients are high ,27 but aTo pursue optimal health outcomes, there is a need to develop more effective educational interventions, and serious games have shown promising effects in the context of health care and patient education ,11,12. IDuring the early development and evaluation phase of a serious game, usability and efficacy are primary concerns. Usability is the extent to which a product can be used to achieve specified goals with effectiveness, efficiency, and satisfaction, and part of usability is the user experience that refers to the perceptions and responses to the anticipated use or after using the product . User exThe aims of this study were, therefore, (1) to describe the development of a computer game for surgical patients about postoperative pain management and (2) to evaluate the usability, user experience, and efficacy of the game.This study has a pre- and posttest design and data were collected using multiple methods, including questionnaires, direct observation by a nonparticipant observer, and short semistructured interviews.In planning the development and evaluation of the game as an intervention we used the first 3 principles of the Intervention Mapping protocol  , and we The game was developed and evaluated in an Icelandic setting. The process took place from January 2015 to January 2016. An interdisciplinary team of computer scientists, game and graphic designers, nurse researchers, and clinical nurse specialists  collaborated in the design and development of the game. The nurse researchers defined the clinical problem and its context and developed the idea of how a serious game could be used in patient education. The computer scientists and designers, who had expertise in game design and computer programming, contributed by transforming those ideas into a usable game to educate patients about pain management.The development of the game involved 3 phases: preparation, defining learning goals, and game design and development .The preparation of the game design began by choosing and defining the clinical problem that the game was to address and searching the available literature for similar games.The game is intended to help adult patients learn about pain management, a common self-care activity after surgery. Adult learning theories and the middle-range theory of chronic illness  were theWe integrated data from our previous qualitative study on patients’ experiences and their perceptions about both traditional and novel methods to learn about postoperative pain management, including serious games . In thatThe learning goals of the game were based on scientific literature regarding pain management and on the expertise of the nurses in the research team. The main learning goal was to improve knowledge about common pain medications that are frequently prescribed after surgery, including how they work, their dosages, effects, and side effects . AdditioThe game was programmed in the C# programming language using the Unity game development environment  to be plBrainstorming sessions were used to ensure that the educational components of the game idea were accurately translated into the design of the game and to develop solutions for the interface, the continuous feedback system, and the after-action review. Such sessions were repeated, and the design of the game refined until a prototype was ready to be evaluated. To help pursue the identified learning goals, the adult learning principle that adults want to learn what is useful and relevant  was usedThe story of the game was designed to be a simulation of a relevant real-life situation, where the player’s character (avatar) has returned home from the hospital after having had surgery. By making different decisions about the character’s daily activities , players can observe how their decisions influence the character’s recovery.The setting (game environment) was designed to look and react like a typical (Icelandic) home, to improve its familiarity to the game’s intended audience. The game’s interactions were designed to simulate 2 types of activities that are highly relevant for recent surgery patients: (1) keeping up with the activities of everyday life, including household chores  and regular self-care  and (2) managing their postoperative pain through various methods . To simplify the user interface, every activity was designed to be accessible with only a few taps on the screen .Experiential learning  emphasizA computational model of pain and medication effects was designed for the game using both scientific data and professional expertise. The model controls how each activity affects the avatar’s pain level, as shown by the NRS at the left of As the avatar’s pain becomes more severe, the model causes their mobility to decrease, making it more difficult to perform the activities that require movement around the house. Furthermore, the model occasionally and randomly simulates a real-life situation in which the pain becomes unmanageable (NRS ≥8) and does not respond to pain medication. The help button  “inner monologue.” They appear both at random (for fun) and to provide information about the avatar’s pain status .Learning through debriefings, where a learner is encouraged to review and analyze his or her experience after the fact, provides a fundamental link between the experience of playing and learning . AccordiParticipants in the study were recruited from the public via a Facebook advertisement (n=11) and through a snowball method (n=9). Included were adults who use computers in daily life, but health care professionals, people with chronic pain, and people using pain medication regularly were excluded. Those were excluded because they had more knowledge and experience of pain management, including use of pain medication, than the target group of patients who are expecting to have surgery. We included people with and without prominent health problems (other than chronic pain) to reflect the targeted patient population. For ethical and practical reasons, patients were not included in this first evaluation of the game. The study was approved by the Bioethics Committee of Iceland (VSN-15-164) and conforms to the Helsinki Declaration . All parData were collected from December 2015 to January 2016 by the researchers BI and KB, who are clinical nurse specialists and experienced in both qualitative and quantitative research methods. The testing and the pre-post testing data collection were done individually in one session, which took place in a hospital office and lasted approximately 90 minutes. Baseline data was collected first, and then the participant received a tablet computer and a simple, oral explanation of how to play the game. The playing session was video-recorded and directly observed by the researcher, who also took notes during the observation (nonparticipatory observation).After playing, the participant filled out a questionnaire and was interviewed by the researcher. The semistructured and video-recorded interviews lasted from 8 to 15 minutes. They covered 2 main topics: Knowledge acquisition  And, usability (“What do you think about this method of learning about pain management?” “What was easy and not so easy while playing?” “How did you perceive the game character (the avatar)?” “How can the game be improved?”).Usability was assessed with 2 instruments: AttrakDiff2 and the Postoperative Pain Management Game Survey (POP-MGS). AttrakDiff2 is an instrument used to evaluate an interactive product . It consPOP-MGS is an adjusted version of a previously validated instrument based on variables identified in the technology acceptance model . The 12 Efficacy was measured using the Patient Knowledge About Postoperative Pain Management questionnaire (PAK-PPM), a 15-item instrument specially designed for the purpose of this study and reflecting the educational content of the game. The multiple-choice questions are based on a literature review and the clinical expertise of the authors. The scale has 5 components of postoperative pain management: pain after surgery (2 items), common pain medications and their dosages (7 items), pain management strategies (2 items), side effects of the treatment (2 items), and what to do if problems arise (2 items). Each item offers 6 alternatives to choose from; one of them is the correct answer, and the remaining 5 (including one which is “do not know” to the item’s question) are incorrect answers. Scores are graded according to the proportion of correct answers. The face validity of the PAK-PPM was established in advance by administering it to 5 individuals, not included in this study, resulting in minor adjustment and the addition of one response option (“do not know”). The internal consistency of the scale in this study (the Kuder-Richardson formula 20) was .68.Demographic and background data were collected with questions on age, sex, education, employment, chronic illnesses, the use of computer, smartphone and computer games in daily life, health literacy and attitude toward pain management. Health literacy was assessed with 3 screening items . AttitudThe whole battery of questionnaires was pilot-tested by 5 individuals, to verify that the adjusted instruments were easily understood. No changes were required after that.Descriptive statistics (median and interquartile range [IQR]), frequencies, and proportions (%) were used to describe the sample characteristics, as well as knowledge, barriers to pain management, and usability as appropriate for nonnormally distributed data. The Wilcoxon signed-rank test was used to compare knowledge scores for the PAK-PPM total scale before and after testing the game. IBM SPSS-23 statistics were used for this analysis (IBM Corp). The video recordings of the playing session were analyzed by measuring how long time it took the participants to play the game, counting how often they needed assistance and how often they ran into problems while playing.Qualitative data were collected from the observations (free text notes) and from the interviews (open-ended questions). Data were analyzed with a directed approach to content analysis to validate the results of the survey on usability and efficacy (knowledge acquisition). With this approach, codes are derived from theory or relevant research findings and defined before or during data analysis, thus supporting or extending the existing theory . The 2 cWe recruited 20 people in the study. Their median age was 45 (range 24-67), they all used computers (n=20) in daily life, and most used smartphones (n=18) and played games (n=14) on the computer. Seven people had chronic illness, and health literacy was high . The totThe game session  took 34 minutes on average. The attributes of the game measured with AttrakDiff2 received median scores above 0 in all dimensions; highest for attraction  followed by pragmatic quality , hedonic quality interaction , and hedonic quality stimulation . The items on ease of use and usefulness as measured with the POP-MGS received a median score of 3.00 (IQR 1.75) to 5.00 (IQR 2.00) (possible scores 0-5) for all items except “I did not have any technical problems using the game” . The obsIn the interviews, participants confirmed the ease of use, and while some found it easy enough to give to older people: “My mother is 83 but I think she could use this” , others found it unsuitable for the very old. All participants managed to finish the session with minimum assistance but the observation revealed that the people with good computer skills were quicker to grasp what to do and how. The observations noted participants’ engagement while playing, and both the survey and interviews confirmed that they enjoyed playing the game.The perceptions of participants about the game character (avatar) differed. Most male participants could identify with the “young male avatar.” Some of the female players however perceived the avatar as a young male they were taking care of while others identified with it and perceived it as an “it” and without a specific gender.The participants suggested additions and improvements to the game, both on the game mechanics, such as receiving more continuous feedback, but also on other pain management strategies, which will be considered in the next version of the game. For example, they suggested adding more nonpharmacologic methods to relieve pain and methods to prevent and treat the side effects of pain medication.P=.001). Of the 20 participants, 18 improved their scores, one decreased his score, and one kept the same score. In 11 out of 15 questions the number of correct answers increased after playing the game (From the questionnaire (PAK-PPM) we found that knowledge increased immediately after playing the game, from 54% correct answers before playing the game to 71% after  said that one of the most important lessons learned was the importance of taking medications regularly instead of waiting for the pain to become intolerable, as they sometimes did in reality: “I learned the attitude that it is okay to take medication regularly, not to wait until the pain has reached the limit one can tolerate” . They also learned about the effects and side effects of different medications and how to use multimodal pharmacologic and nonpharmacologic approaches .The participants also confirmed our theoretical assumption that they used previous knowledge from their own experience and life situations while learning with the help of the game: “I never chose the Ibuprofen because my doctor forbade me to use it when I had surgery” .This is, to our knowledge, the first paper describing the development and evaluation of a serious game that has the purpose of teaching surgical patients about postoperative pain management, including the use of pain medications and effective pain management strategies. The results of this evaluation indicate that a serious game may indeed be a useful and an attractive option for prospective surgical patients to learn about pain management.There was an increase in participants’ knowledge about pain management, especially about individual medication dosages and side effects, but also about pain management strategies such as regular medication intake and combining pharmacologic and nonpharmacologic approaches. Knowledge acquisition is the most common outcome measured in serious games in general  and studAlthough the game was able to improve the knowledge of the players, it remains uncertain if and how this type of learning can facilitate translation of knowledge into optimal behavior. Answering these questions would require a complex intervention study  with folThe participants in this study rated the usability of the game rather highly as confirmed both in the interviews and through the observations. They were engaged in the game the whole time and many enjoyed playing it. They also associated themselves with the avatar, either as themselves or as someone they sympathized with. It has been proposed that using avatars increases social presence, and allowing players to choose an avatar that they would like to represent them has resulted in greater satisfaction than when the only option is a standard male or female avatar ,55. TherThe idea of playing a game to learn about pain management after surgery was well received by the participants in this study. They had different views on how appropriate it would be for older patients and those without computer skills, but nonetheless found it suitable in the case of prospective surgery , and simple and easy enough to navigate for a wide range of users. Older adults are playing more games than in prior decades, for example, 26% of game players in the United States are 50+ years of age , and theThe participants in this study were recruited from the general public, but the results might be different if surgical patients tested the game. Several factors, such as anxiety and impaired cognition due to anesthesia and medications may affect their learning capabilities during the perioperative period . HoweverNo validated instrument was available to measure changes in participants’ knowledge. The questionnaire designed for this study was useful in detecting changes in knowledge and had acceptable internal consistency, but it needs to be developed and validated further as it lacks established content and construct validity. Finally, since the postgaming test was implemented immediately after playing the game, we could not assess knowledge retention over a longer time.A serious game can be an efficient method to learn about pain management; it can improve knowledge and is appreciated by users. To assess the game’s usability and efficacy in the context of surgery, further development followed by an evaluation with a larger sample is required, including surgical patients, older people, and people with diverse health literacy.