This cross-sectional study uses data from the IBM MarketScan Commercial Database to examine the association between increases in wholesale list prices of branded medications and amounts paid by patients and insurers for the same drugs. How are increases in wholesale list prices for medications distributed among increases in patient out-of-pocket costs, insurer payments, and changes in rebates and discounts?In this cross-sectional analysis of 14.4 million pharmacy claims made by 1.8 million patients for the top 5 patent-protected specialty and 9 traditional brand-name medications with the highest total drug expenditures by commercial insurers in 2014, the median drug wholesale list price  increased by 129% from 2010-2016, while median patient out-of-pocket costs increased by 53% and median insurance payments after rebates and discounts increased by 64%.This study’s findings suggest that, after adjusting for inflation, increases in drug list prices are associated with increased patient out-of-pocket costs, which may have implications for cost-related nonadherence, and insurer payments. High out-of-pocket drug costs can cause patients to skip treatment and worsen outcomes, and high insurer drug payments could increase premiums. Drug wholesale list prices have doubled in recent years. However, because of manufacturer discounts and rebates, the extent to which increases in wholesale list prices are associated with amounts paid by patients and insurers is poorly characterized.To determine whether increases in wholesale list prices are associated with increases in amounts paid by patients and insurers for branded medications.Cross-sectional retrospective study analyzing pharmacy claims for patients younger than 65 years in the IBM MarketScan Commercial Database and pricing data from SSR Health, LLC, between January 1, 2010, and December 31, 2016. Pharmacy claims analyzed represent claims of employees and dependents participating in employer health benefit programs belonging to large employers. Rebate data were estimated from sales data from publicly traded companies. Analysis focused on the top 5 patent-protected specialty and 9 traditional brand-name medications with the highest total drug expenditures by commercial insurers nationwide in 2014. Data were analyzed from July 2017 to July 2020.Calendar year.Changes in inflation-adjusted amounts paid by patients and insurers for branded medications.In this analysis of 14.4 million pharmacy claims made by 1.8 million patients from 2010-2016, median drug wholesale list price increased by 129% , while median insurance payments increased by 64%  and out-of-pocket costs increased by 53% . The mean percentage of wholesale list price accounted for by discounts increased from 17% in 2010 to 21% in 2016, and the mean percentage of wholesale list price accounted for by rebates increased from 22% in 2010 to 24% in 2016. For specialty medications, median patient out-of-pocket costs increased by 85%  from 2010 to 2016 after adjustment for inflation and 42%  for nonspecialty medications. During that same period, insurer payments increased by 116% for specialty medications  and 28% for nonspecialty medications .This study’s findings suggest that drug list prices more than doubled over a 7-year study period. Despite rising manufacturer discounts and rebates, these price increases were associated with large increases in patient out-of-pocket costs and insurer payments. However, after accounting for these price reductions, total payments manufacturers received rose faster than general inflation. What remains unknown, however, is how this mix of increases in list prices with rising discounts and rebates affects patients’ out-of-pocket costs. If discounts and rebates are large enough and targeted to patients, patient out-of-pocket costs may not rise as list prices increase. However, this hypothesis cannot be evaluated without evaluating discounts, rebates, and amounts paid by payers and by patients out of pocket in a single analysis. This issue is particularly relevant to clinical practice in which news about list price changes must be translated into discussions about drug costs with patients.Hernandez et al18 We analyzed changes over time in wholesale list prices and amounts paid by patients and insurers after accounting for discounts and rebates to understand how rising list prices are associated with patients’ out-of-pocket costs and the net cost of these drugs to insurers.To address these issues, we studied a national sample of employer and commercial insurer pharmaceutical claims and sales data from 2010 to 2016 for drugs previously identified as contributing the most to total drug expenditures for commercial insurers.19 The most widely used specialty drugs include treatments for rheumatoid arthritis, Crohn disease, psoriasis, cancer, and HIV, among other conditions.20 Specialty medications commonly have high prices and have been implicated in driving rising national drug expenditures.21We focused our analyses on the top 5 patent-protected specialty and 9 traditional brand-name medications with the highest total drug expenditures by commercial insurers nationwide in 2014.insurers. Claims for patients aged 65 years and older were excluded because of likely confounding differences in benefit design secondary to dual coverage with Medicare. We excluded claims in which reported prescribed dose exceeded the maximum clinical dose. This study was determined to be exempt from review by the institutional review board at the University of California, San Francisco because the patient claims data were deidentified. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for cross-sectional studies.We used Health Insurance Portability and Accountability Act–compliant, deidentified, patient-level outpatient pharmacy claims data from the IBM MarketScan Commercial Database. This database represents the claims of 67.4 million employees and dependents participating in employer health benefit programs belonging to large employers between January 1, 2010, and December 31, 2016. The plans represented include a variety of fee-for-service, preferred provider organization, and capitated health plans. For clarity, we refer to these collectively as Each pharmacy claim reports the Average Wholesale Price (AWP) for the drug prescribed, actual payment to the pharmacy , and the patient’s out-of-pocket cost for the medication. Because drug manufacturers report substantial discounts and rebates, for this analysis we use the AWP, equivalent to the manufacturer’s suggested retail price, as the starting wholesale list price. Another price available on claims is the Wholesale Acquisition Cost, but manufacturers would argue that this price already includes a discount they offer, so we start with the higher AWP as the wholesale list price. We calculated the manufacturer’s discount for each claim as AWP minus actual payment to the pharmacy.We converted all costs for each claim into unit price , to ensure that variation in prices was not due to differences in dosing. Mean AWP, patient out-of-pocket costs, and discounted price were calculated by totaling all claims for a drug and dividing by the number of claims. Discounts were calculated as the difference between AWP and the discounted price. Mean AWP per unit and discounts were calculated for each drug per quarter, whereas mean patient costs were calculated annually to account for patient deductibles.17 we obtained rebate data from SSR Health, LLC, a health care–focused investment research firm, and Symphony Health. SSR Health compiles data from pharmaceutical company investor reports to determine total revenue after all price reductions (including discounts and rebates) have been factored in. This is divided by the total number of prescriptions, estimated by Symphony Health, to calculate the net payment for drugs, accounting for discounts and rebates.Like Hernandez et al,SSR Health estimated discounts to Medicaid payers by using the sum of the Medicaid statutory rebate (23.1% of average manufacturer price) and the pricing penalty for price increases exceeding the Consumer Price Index increase. These are discounts offered to state Medicaid programs as part of “best price” regulations to make drug spending more affordable for Medicaid. The number of units of each medication sold to Medicaid was obtained by SSR Health from the Centers for Medicare & Medicaid Services’ drug utilization files. SSR Health then estimated total revenue from Medicaid by multiplying the discounted Medicaid price by the number of units sold to Medicaid. SSR Health calculated revenue from non-Medicaid sales for each drug by subtracting Medicaid revenue from total revenue. Similarly, the number of non-Medicaid units sold for each medication was estimated by subtracting Medicaid units sold from total units sold. SSR Health then divided non-Medicaid revenue by the number of non-Medicaid units sold to estimate the net price for non-Medicaid insurers. To allow for comparison with the pharmacy claims data (which does not include Medicaid payers), we used only the non-Medicaid sales data from this data set.We then calculated the mean rebate for non-Medicaid payers as the difference between the mean discounted price paid on claims and the non-Medicaid net price from SSR Health. With these figures, we could assess how the AWP for each drug could be broken down into discounts shown on the claim, rebates passed on to insurers, patient out-of-pocket costs, and insurer payments net of discounts and rebates such thatOur primary independent variable was percentage of change in AWP from 2010 to 2016 for medications maintaining patent protection during this period. Our secondary independent variables were percentage of change in AWP from 2010 to 2014 and from 2010 to 2015 for medications maintaining patent protection during these respective periods. Our primary dependent variables were the percentage of change in patient out-of-pocket costs and insurer payments after rebates. Secondary dependent variables included the mean percentage of change in discounts and rebates over the study period. In addition, differences in the changes in AWP, net payments (sum of insurer payments and patient out-of-pocket costs), insurer payments, and patient out-of-pocket costs between specialty medications and nonspecialty medications were evaluated. The proportion of change in AWP accounted for by changes in discounts, rebates passed on to insurers, insurer payments, and patient out-of-pocket costs was computed for all medications.We assessed differences in price trends between specialty and nonspecialty medications by comparing the proportion of increase in AWP from 2010 to 2016 accounted for by changes in rebates, discounts, insurer payments, and patient out-of-pocket costs between these 2 groups of drugs. Median values were used as a measure of central tendency to reduce the impact of outlier claims or benefits designs. All prices and payments shown were adjusted to 2016 dollars using the Consumer Price Index for All Urban Consumers. Analyses were performed with Excel 2013, version 15.0.4535.1507 (Microsoft Corp). Data were analyzed from July 2017 to July 2020.Some information about Medicaid discounts and rebates, such as best price discounts or rebates required by individual states, was not available to SSR Health. However, we could calculate a range of possible Medicaid prices. Because total discount and rebate amounts given by drug manufacturers are split between Medicaid and non-Medicaid purchasers, assuming higher Medicaid discounts and rebates would result in an estimation of lower non-Medicaid discounts and rebates.For our main analysis, the estimates made by SSR Health about Medicaid statutory rebates and pricing penalties led to the highest possible estimates of discounts and rebates to the commercial insurers being studied to maximally reflect manufacturer claims about high discount and rebate rates. As a sensitivity analysis and to estimate a range of patient out-of-pocket costs and insurer payments, we also calculated those outcomes with the assumption of every Medicaid unit in the SSR Health data set being rebated at 100% of average manufacturer price. Because this would be the maximum possible discount paid to Medicaid, it would consequently result in the lowest possible discounts and rebates to commercial insurers.For 2010-2016, the MarketScan database included data for 67.4 million enrollees who filled at least 1 prescription, with 1.8 million enrollees having 14.4 million pharmacy claims for the drugs of interest  and 64% , respectively. During this time, manufacturer discounts and rebates passed on to insurers rose by a median of 163%  and 103% . As a result, the mean percentage of wholesale list price accounted for by discounts increased from 17% in 2010 to 21% in 2016, and the mean percentage of wholesale list price accounted for by rebates increased from 22% in 2010 to 24% in 2016  . PatientAmong all study drugs retaining patent protection from 2010 to 2016, every $1 increase in AWP was associated with a median increase in patient out-of-pocket costs of $0.04 . Patient out-of-pocket costs increased $0.05  for nonspecialty drugs and $0.03  for specialty drugs. Insurer payments for this period increased $0.57  for all eligible study drugs during this period. Insurer payments increased $0.13  for nonspecialty drugs and $0.74  for specialty drugs for every $1 increase in AWP during this period.In total, median patient out-of-pocket costs for specialty medications increased by 85%  after adjustment for inflation as compared with 42%  for nonspecialty medications from 2010 to 2016, while insurer payments for specialty medications increased by 116%  compared with 28%  for nonspecialty medications .In our sensitivity analysis in which we assessed the range of possible discounts and rebates to commercial insurers, patient out-of-pocket costs were unchanged. Median insurer payment increases were slightly lower than those in our primary analysis, although still far above the rate of increase in the Consumer Price Index. With these assumptions, median insurer payments for drugs retaining patent protection through 2016 increased by 61%  after adjustment for inflation.In a large, national sample of patients with commercial insurance, we found that increases in drug wholesale list prices were accompanied by increases in out-of-pocket payments by patients and by insurers. Increases in payments for specialty medications from 2010 to 2016 were greater than those for nonspecialty medications in our analysis over the study period.15 Our analysis corroborates that rebates and discounts are large, and the proportion of AWP attributed to discounts and rebates did increase from 2010 to 2016 (eFigure 3 in the Pharmaceutical manufacturers have argued that increases in drug wholesale list prices are accompanied by corresponding large increases in discounts and rebates, reducing the impact of list price changes on patients and insurers.22 so these out-of-pockets costs have increased relative to income. Because we used claims to determine out-of-pocket costs, this finding persists despite coupons and patient assistance programs aimed at lowering patient spending. This observed rise in patient out-of-pocket costs with increasing drug list prices is of particular concern to clinicians because high drug costs can lead to poor drug regimen adherence, increased use of utilization management systems such as prior authorizations and step therapy, and adverse health outcomes.20 Although patients paid a smaller percentage of the wholesale list price over time, the absolute amount that they paid for the drugs we studied continued to increase at rates higher than general inflation or the growth of income, which may have important implications for the ever larger population of patients with chronic diseases.24 This study highlights that increases in prices for drugs that have been on the market for several years increase the cost of treatment for patients.Although patient out-of-pocket costs for drugs vary greatly, patients paid a median of 53% more for these drugs in 2016 than they did in 2010, after adjusting for general inflation. During the same period, median household income rose 8.6%,26 Our results indicate that discounts and rebates for these drugs are lower relative to list prices than discounts and rebates for nonspecialty medications. Insurer payments for Nexium and Humalog did not outpace inflation in our analysis, presumably because they face more competition from similar drugs in their classes. Manufacturers of single-source specialty medications may offer fewer price concessions because most face little market competition.27 Consequently, insurer payments for specialty drugs are also rising at a much higher rate than payments for nonspecialty medications, also increasing coinsurance costs. Although patient out-of-pocket costs are a smaller proportion of the total price of specialty medications than nonspecialty medications, specialty drugs are still more costly to patients. As use of these drugs increases, the high costs may affect patients through higher out-of-pocket spending per prescription and rising premiums, as well as both government programs and commercial insurers.28Spending for specialty drugs has increased significantly over the past decade and is projected to contribute to rapidly increasing health care costs.Our study has several limitations. Given differences in pricing of generic medications with regard to discounts and rebates, we opted not to include medications that did not have patent protection during our study period. The findings of our study reflect the pricing breakdown of the 14 medications accounting for the greatest portion of insurer medication expenditures and may not be generalizable to other medications. In addition, several of the analyzed medications lost patent protection shortly after the study period. Further study is needed to characterize how impending patent protection expiration affects list prices, discounts, rebates, and amounts paid for medications.We were also unable to control for changes in cost sharing during this period, which may also contribute to changes in amounts paid for medications. Furthermore, contracting and pricing are different for Medicare, Medicaid, the 340B program, and the Department of Veterans Affairs, so it is not clear how generalizable our findings are to those markets.In addition, we could not obtain precise estimates of all Medicaid discounts and rebates, resulting in some uncertainty about the total discounts and rebates offered to the commercial insurers we studied. Therefore, our sensitivity analyses provide only a range of possible insurer payments rather than exact figures. However, under any set of assumptions, we found that increases in list prices resulted in increases in insurer payments. This limitation has no effect on our estimates of patient out-of-pocket costs, since these were identified directly from claims data.29 We are not aware of data that allow description of how rebates are shared among these relevant parties, but they are not shared with patients.Our study also does not characterize who receives manufacturers’ rebates in detail. Rather, we report what can be directly measured: the amount that is passed on to insurers. Insurers may then pass some of these savings on to employers, but rebates are also frequently paid—at least in part—to pharmaceutical benefits managers.Finally, we were not able to measure other mechanisms by which rising drug prices may increase patient out-of-pocket costs, such as increasing insurance premiums. Additional study of the association between rising insurer payments and these other patient out-of-pocket costs is needed to further clarify the total effect of these pricing changes on patients.In this cross-sectional study, we found that increases in drug wholesale list prices are associated with increases in net patient out-of-pocket costs and insurer payments. This finding suggests that, although discounts and rebates significantly reduce the amount paid for drugs and have increased over the past several years, they have not prevented an inflation-adjusted rise in patients’ and insurers’ costs. This could have both important clinical implications for patient outcomes and an impact on total health care expenditures.


QOL scores significantly increased by 3 months , a benefit which was retained at 12 months. Linear regression analyses identified statistically significant predictors in preoperative ASI-3, SF-36 MCS and STAI-S for postoperative QOL and ODI scores. There is a benefit for patients in terms of quality of life and function after undergoing surgery for degenerative cervical spine disease. With the ASI-3, SF-36 MCS and STAI-S there exist some predictors for postoperative QOL and ODI scores.We aimed to identify independent psychological predictors of quality of life (QOL) and functional outcome after anterior cervical discectomy and fusion (ACDF) for degenerative cervical spine disease. We prospectively included patients undergoing ACDF for degenerative cervical disc herniation and stenosis. Patients completed a structured psychological assessment including the Center for Epidemiological Studies Depression Scale (ADS-K), Post-Traumatic Stress Scale-10 (PTSS-10), State Trait Anxiety Inventory-State Anxiety and - Trait Anxiety (STAI-S and STAI-T) and Anxiety Sensitivity Index-3 (ASI-3) before surgery, after 3 and 12 months. Outcome measures included EuroQol-5D (EQ), Short Form-36 (SF-36) and Oswestry Disability Index (ODI) scores. Of 104 included patients who underwent ACDF between March 2013 and November 2017, 92 completed follow-up after 3 and 12 months. The mean Visual Analogue Scale (VAS) scores for neck pain (− 1.4;  Despite several testaments to the benefit of the procedure, there are patients who may benefit to a lesser extent than desired, at times requiring the operating surgeon to consider altering their treatment strategy accordingly. Various research groups have investigated somatic predictors of impaired QOL after ACDF10. However, while evidence demonstrating the significant influence of a psychological predisposition of patients on QOL and the functional outcome after surgery for degenerative diseases in the thoracolumbar region continues to emerge, to the best of our knowledge, only a few studies have addressed these aspects after ACDF prospectively15.Degenerative diseases of the cervical spine are known to encompass a variety of pathologies producing pain, disability and impaired health-related quality of life (QOL). Surgical treatment of these pathologies via an anterior cervical discectomy and fusion (ACDF) procedure has been documented with favourable results in an abundant number of case series18. One such investigation drew these conclusions from retrospective data, with a limited follow-up time of 7 months in the control group being the primary limitation16. Elsamadicy et al. retrospectively compared patients diagnosed with depression and treated with antidepressants at least 6 months prior to surgery with a non-depressive control group, concluding that the pretreatment resulted in similar outcomes between the groups after ACDF18.The available evidence concerning outcome for the cervical spine suggests somewhat conflicting results, without an unambiguous solution for a routinely feasible and reliable psychological assessment of patients. To assume that the psychological profile directly modulates a patient’s perception of pain and disability seems plausible, but a concise psychological assessment for preoperative preparation in clinical practice has not yet been established. In principle, the identification of independent psychological scores that predict the degree of clinical benefit after ACDF may facilitate the implementation of a preemptive psychosocial intervention in the future, thereby possibly optimizing the surgical outcome. Most studies with a retrospective design have reported an inverse correlation between preoperative depression scores and the postoperative QOL improvementIn our study, standardized assessments of psychological scores and various dimensions of QOL were conducted before surgery and during follow-up. The psychological profile of patients gathered from the individual scores represented a surrogate index of the patients’ depression and anxiety in light of undergoing surgery of the cervical spine. With this set-up, we hypothesized that our psychological test battery of depression, anxiety and PTSD scores may be used for prediction of QOL increases after ACDF surgery. Our primary outcome was thus represented by the relationship between the preoperative psychological baseline scores and QOL after 12 months, as examined by multiple regression analyses.20. Our preoperative assessment encompassed various scales of depression and anxiety disorders, which we sought to identify via the following commonly employed psychological instruments: the Center for Epidemiological Studies Depression Scale22 , Post-Traumatic Stress Scale–1023 (PTSS), State Trait Anxiety Inventory–State Anxiety (STAI-S), State Trait Anxiety Inventory–Trait Anxiety24 (STAI-T) and Anxiety Sensitivity Index-326 (ASI). The scores of the aforementioned instruments were correlated with the scores for the EuroQol27 (EQ), Short Form 3628 (SF-36) and Oswestry Disability Index30 (ODI).We applied a similar methodology as studies concerning this topic previously published by our study group by prospectively screening patients scheduled for elective ACDF at our institutionThis is a monocentric prospective cohort study conducted between March 2013 and November 2017 at the Department of Neurosurgery, Technical University Munich. We recruited a cohort of patients scheduled for an elective ACDF procedure involving one to three consecutive segments that were affected by a degenerative spondylotic deformity defined as stenosis by spondylophytes in the central or lateral compartments, disc herniation and degeneration, or a combination of the aforementioned conditions. The analysis included patients aged over 18 years exhibiting symptoms consistent with pathomorphologic changes found in imaging results for a minimum duration of 6 weeks. No financial compensation was provided for participating patients. Conventionally, two distinct clinical syndromes are associated with these pathomorphologic changes: most predominantly, patients with cervical spondylosis presented with neck pain, pain radiating to the upper extremities or both types of pain. In the presence of clinically manifested cervical spondylotic myelopathy (CSM), decompression was indicated and offered irrespective of the symptom duration. CSM was diagnosed by a board-certified attending neurosurgeon at our institution by an examination for gait ataxia, coordinative disorders, latent weakness of the hands, pronounced tendon reflexes of the lower extremities and clonus. In contrast, cervical radiculopathy (CR) manifested as radiating pain and possible sensory dysfunction at the dermatome of the affected nerve root. In cases of acute neurological deterioration due to CR or CSM, defined as severe neurological motor deficits with a grade of 3 or lower according to the Medical Research Council scale or vegetative symptoms, patients were not eligible for study participation after screening. The standard preoperative diagnostic work-up of the cervical spine beyond the thorough clinical examination comprised magnetic resonance imaging (MRI) scans and additional computed tomography (CT), dynamic radiography or bone densitometry assessments, as needed on a case-by-case basis.35. For more information on the psychological scales, see Table 40. There is conclusive evidence that depression, anxiety and posttraumatic symptoms influence surgical outcomes after neurosurgical procedures44. The neuropsychologists of our study group hence designed an assortment of psychological instruments for a comprehensive account of the patients’ psychological profile. While 4 out of the 8 sections of the SF-36 assessment focus on physical health and are summarized through the SF-36 PCS, the other 4 function as markers of emotional health and are aggregated into the SF-36 MCS.An assortment of psychological instruments, including the German versions of the ADS, PTSS, STAI-S, STAI-T and ASI, constituted the prime focus of this study. All of these instruments have been used extensively and validated in a multitude of explorative studies, which provided instructions and tested cut-off valuesEuroQol 5D (EQ) and Short Form 36 (SF-36), which was further classified into the Physical and Mental Component Scores (PCS and MCS). The Oswestry Disability Index (ODI) provided an evaluation of the self-perceived functional capacity of the patients. Furthermore, we acquired the history of prior psychiatric consultations, intake of psychiatric medication and in-patient psychiatric treatment during the recent 12 months.The preoperative screening and all psychological assessments used in the follow-up sessions at 3 and 12 months after surgery were conducted by a trained neuropsychologist. The postoperative developments in health-related QOL were assessed by the The intensity of pain was evaluated both by the Visual Analogue Scale (VAS), which depicts intensity on a continuous, linear scale from the least to the most intense level of pain, and the SF-36 Bodily Pain subscale. The assessments of pain according to these scales pertain to the given patient’s predominantly affected site, i.e., arm pain for an individual with CR.A Likert-scaled “Patient Satisfaction” item spanning from 1, corresponding to “no improvement”, to 10, corresponding to “full resolution of complaints”, allowed patients to subjectively rate their individual surgical success.ACDF surgery was conducted according to well-established and documented standards; a ventral left paramedian transversal incision at approximately the level of the pathology was made for complete discectomy as well as reduction of spondylophytes at the uncinate processes and neuroforamen bilaterally. The cartilaginous end-plates were fully ablated to allow for subsequent bony fusion. Supplemental ventral plate osteosynthesis was conducted in the presence of apparent instability in the imaging results or risk factors for non-fusion, including smoking or recent long-term steroid use.For the primary outcome, we performed multiple linear regression analyses with stepwise forward selection to predict the QOL scores after 12 months as dependent variables and preoperative psychological assessments as independent variables. For every dependent variable, a Q-Q plot was generated, and a normal distribution of the residuals, a prerequisite for the regression analysis, was demonstrated by these plots. Similarly, the linear relationships between each of the dependent variables and independent variables were assessed by scatter plots. The Durbin-Watson test (d) was used to detect and exclude first-order autocorrelation in each of the regression models. The composite scores of the QOL scales, the ODI and the Patient Satisfaction scale were fitted as continuous dependent variables in separate regression models, while the preoperative psychological scores were included as independent variables.A variable was only included if the significance level of its F value was less than 0.05. The estimated unstandardized coefficient statistics, t-values and corresponding p-values were used for reporting the results.The secondary analyses involved the developments in QOL, disability and pain scores over follow-up times and their correlation with the independent variables and demographics, which were addressed with three-level repeated measures analysis of variance (rANOVA), one-way ANOVA for multiple pairwise comparisons, Student’s t-test and the Chi-square test. The Bonferroni method was used to correct for multiple comparisons. Further, the proportions of patients with pathological depression and anxiety scores were compared over time via the Cochran Q test followed by posthoc pairwise testing with the McNemar test.α = 0.05.We used the 25th version of IBM SPSS for the statistical analyses, and the level of significance was defined a priori as All procedures were indicated and conducted in compliance with our department’s standards and the Declaration of Helsinki. The operating surgeons and ward personnel were blinded to study participation. The local ethics committee approved the study , and informed consent was obtained from all participants before study inclusion.All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The study group acquired approval by the local ethics committee .Every participant of this study provided written informed consent.Between March 2013 and November 2017, 159 eligible patients with degenerative symptomatic cervical spine disease scheduled for elective ACDF were screened, and 104 (65.4%) opted for study participation. Of these patients, 92 (89.5%) completed follow-up examinations 12 months after surgery. Table Most patients presented with signs and symptoms of cervical myelopathy exclusively , 19 (20.7%) had radiculopathy only and 9 (9.8%) presented with a mixture of these signs and symptoms.There were no revision surgeries due to immediate complications and no mortality during the follow-up period.p = 0.060; Fig. p = 0.156; Fig. A total 20.7% of the patients stated at baseline that they received psychiatric treatment according to the above definition within the previous 12 months. The proportion of patients with pathological STAI scores reached 58% at baseline and declined to 43% after 12 months  = 35.216; p < 0.001; η2 = 0.345) as well as the STAI-S  = 6.536; p = 0.004; η2 = 0.088) decreased significantly for both scales  = 3.038; p = 0.056; η2 = 0.043), although reaching a significant difference of means between baseline and 3 months  = 5.266; p = 0.025; η2 = 0.072; Fig. F = 1.984; p = 0.153; η2 = 0.028) nor STAI-T  = 0.726; p = 0.473; η2 = 0.011) had significant differences in the repeated measures ANOVA.Between baseline and 12 months, the mean scores of the PTSS (SD = 2.1) for neck pain and 5.6 (SD = 2.5) for arm pain, as measured by a VAS from 0 to 10 across the entire cohort. Similarly, the mean Bodily Pain item scores on the SF-36 were 32.8 (SD = 23.5) for neck pain and 34.8 (SD = 23.3) for arm pain. For neck pain, both the SF-36 Bodily Pain subscale (t(90) = − 2.663; p < 0.001) and VAS (t(90) = -5.463; p < 0.001) parameters improved significantly by 12 months (Table t(90) = − 1.893; p = 0.044) and VAS (t(90) = − 2.017; p = 0.031) after 12 months.Mean pain intensity at baseline amounted to a score of 6.0  = 15.348; p < 0.001; η2 = 0.231), SF-36 MCS  = 5.360; p = 0.044; η2 = 0.092) and EQ VAS  = 12.629; p < 0.001; η2 = 0.179) all exhibited significant improvements over time, while the disability scale ODI did not  = 3.129; p = 0.060; η2 = 0.207; Fig. In the rmANOVA, the QOL scales SF-36 PCS , at baseline and 12 months (t(90) = − 5.029; p < 0.001), but not between 3 and 12 months (t(90) = − 0.009; p = 0.993). For the mean SF-36 MCS scores, a significant difference was found between baseline and 3 months (t(90) = − 2.315; p = 0.025), but not between baseline and 12 months (t(90) = − 0.907; p = 0.234) or between 3 and 12 months (t(90) = 0.835; p = 0.407). For EQ VAS, significant differences were found between baseline and 3 months (t(90) = − 4.330; p < 0.001) as well as between baseline and 12 months (t(90) = − 3.523; p = 0.001), but not between both follow-ups (t(90) = 1.447; p = 0.153).Posthoc pairwise t-tests with Bonferroni corrections for multiple comparisons revealed significant differences between the mean SF-36 PCS at baseline and 3 months (t(90) = − 4.651; p = 0.127); however, a failure to improve was rated significantly less frequently by the CR subgroup (15.8%) than by the CSM subgroup .A satisfactory improvement of preoperative complaints after 12 months, defined as an 8 to 10 on the ten-point Patient Satisfaction scale, was noted by 48.3% of the patients. Conversely, minor to no improvement at all was noted by 21.3% of the cohort and predefined as a 1 to 3 on the same scale. When the patients were stratified by subgroups, 44.3% of the patients presenting with CSM and 42.1% of those with CR subjectively improved without a significant difference between the subgroups  and SF-36 PCS increase  predicted the dependent variables fairly well, respectively, although with a low R2 for EQ VAS. The models for the ODI  and Patient Satisfaction scale changes  proved to be insufficiently fit for the data, however  and ASI-3  added significantly to the prediction model. For the increase in SF-36 PCS, the preoperative SF-36 MCS , ASI-3  and STAI-S  added significantly to the predictive model. For the decrease in ODI scores, both the preoperative SF-36 MCS  and STAI-S . There was no significant correlation between the ODI decrease and pain relief . The correlation between the baseline pain intensity and pain level by 12 months was negative and significant , with patients suffering from a high baseline pain intensity experiencing significantly more pain relief after 12 months.Additionally, a univariate correlation analysis revealed a significant, positive, and moderate correlation between pain relief after 12 months and improvement in the QOL scales  scores after ACDF suggested that high levels of anxiety and low EQ scores negatively impact these postoperative scores. The authors posited that the low baseline EQ scores rather than the preoperative pain level predicted greater pain relief after surgery. Another study suggested a similar conclusion, but no direct regression analysis between the somatic outcome and preoperative depression scores was provideddepressed and non-depressed patients after ACDF, even though the authors found substantially decreased QOL in depressed patients prior to the surgery. Their findings, however, hinge solely on the EQ-5D sub-scale of emotional assessment, since the authors did not use any psychometric instruments for depression or anxiety39.Likewise, Poorman et al. reported analogous results for 59. This concept is tied to the intricate interaction between somatic symptoms and psychological distress for degenerative spine disease, that is purported in some investigations62. While it is difficult to definitively specify whether somatic symptoms caused psychological distress or a manifest psychiatric disease produced somatization for each individual case, we maintain that this question remains subordinate in view of parallelly improving psychological and QOL scores.The aforementioned results imply that patients should be consistently screened preoperatively for abnormalities in their psychological profile, identifying predictors of impaired outcome after surgery; however, we see one particular fallacy with this approach. It must be emphasized that the psychological distress that accompanies somatic stressors such as pain and disability in the presence of a surgically curable condition is not sufficient evidence to disqualify a surgical candidate—on the contrary, these distressed patients may even benefit distinctly in both somatic and psychological aspects, which can provide even more incentive to proceed with the surgery. Consequently, a routine preoperative assessment may be warranted, but must be interpreted as a means to delineate variations of postoperative benefits, which are generally favourable after ACDF surgery for degenerative cervical disease, as has been described before63. The nature of the preoperative intervention varied considerably from a months long structured education and prehabilitation to handing out of an instruction booklet on the day of surgery. Despite no impact on postoperative QOL, return to work or postoperative complications, limited evidence demonstrated a positive influence on postoperative pain and disability scores. In an exemplary interventional study by Adogwa et al., the effect of pretreating a manifested anxiety disorder prior to ACDF surgery was examined. Of 27 patients, 11 patients received psychotherapy and pharmacotherapy 6 months prior to the procedure until the last follow-up, resulting in drastically and significantly increased pain relief compared to that in the control group after 6 months and thereafter. No other patient-reported outcome that reflected QOL had significantly changed, albeit the results may have been influenced by the small sample size and non-randomized nature of the study12. In summary, several investigations examined similar aspects of postoperative QOL after surgery for cervical spine disease, although the chosen psychological test instruments were invariably fewer in number and more selective in comparison to our rather broad assessment. Still, the identification of the SF-36 MCS as a reliable predictor in particular is in accordance to our own results. Moreso, we are able to present one of the largest comprehensively examined patient cohorts in literature.Based on these propositions and the low-risk practicability of such an assessment, an argument may be made to routinely conduct screenings of the psychological profile of patients, aiding clinicians in their perioperative consultation and management. An extrapolation of this approach sees patients undergo pretreatment by educatory measures or psychotherapy before proceeding with the surgery. In a review by Burgess et al., 11 studies with a preoperative intervention were examined, although only one was considered of high methodological quality66.Notably, this study succeeded in identifying predictors of QOL improvements after ACDF surgery, but failed to delineate one explicit cut-off to identify the patients at risk for failure to improve. The SF-36 MCS predictor has been prominently featured in several other publications assessing the psychological profile in the setting of cervical and lumbar spine surgery, while the ASI-3 and STAI-S have not been identified before67.The study was conducted to identify independent variables of the psychological profiles of patients that significantly influence the postoperative outcome, but no control group or additional assessments were included. Thus, observation bias may exist, as the psychological assessment itself may have induced abnormal psychological scores. Confirming the existence of this bias is a matter of debate in many works of literature and may exceed the scope of this study. In addition, the results must be interpreted in light of the high correlation between the EQ and SF-36 instrumentsThese limitations are magnified by the overall low number of cases in relation to the high number of statistical comparisons we employed. To address this, statistical analyses for the primary outcome were focused on the psychological parameters as tested by our assortment of instruments preoperatively, in turn neglecting independent surgical variables such as age, medication and the number of fused segments. These shortcomings would be compensated by a higher case number in a multicentric investigation.In summary, our results merely offer correlative evidence between self-reported psychological determinants and surgical outcome.There is a benefit after ACDF for degenerative cervical spine disease in terms of quality of life. The preoperative assessment of SF-36 MCS, ASI-3 and STAI-S scores serves to predict postoperative QOL increases.


Neck and low back pain represent dynamic conditions that change over time, often with an initial improvement after the onset of a new episode, followed by flare-ups or variations in intensity. Pain trajectories were previously defined based on longitudinal studies of temporal patterns and pain intensity of individuals with low back pain. In this study, we aimed to 1) investigate if the defined patterns and subgroups for low back pain were applicable to neck pain patients in chiropractic practice, 2) explore the robustness of the defined patterns, and 3) investigate if patients within the various patterns differ concerning characteristics and clinical findings.Prospective cohort study including 1208 neck pain patients from chiropractic practice. Patients responded to weekly SMS-questions about pain intensity and frequency over 43 weeks. We categorized individual responses into four main patterns based on number of days with pain and variations in pain intensity, and subdivided each into four subgroups based on pain intensity, resulting in 16 trajectory subgroups. We compared baseline characteristics and clinical findings between patterns and between Persistent fluctuating and Episodic subgroups.All but two patients could be classified into one of the 16 subgroups, with 94% in the Persistent fluctuating or Episodic patterns. In the largest subgroup, “Mild Persistent fluctuating” (25%), mean (SD) pain intensity was 3.4 (0.6) and mean days with pain 130. Patients grouped as “Moderate Episodic” (24%) reported a mean pain intensity of 2.7 (0.6) and 39 days with pain. Eight of the 16 subgroups each contained less than 1% of the cohort. Patients in the Persistent fluctuating pattern scored higher than the other patterns in terms of reduced function and psychosocial factors.The same subgroups seem to fit neck and low back pain patients, with pain that typically persists and varies in intensity or is episodic. Patients in a Persistent fluctuating pattern are more bothered by their pain than those in other patterns. The low back pain definitions can be used on patients with neck pain, but with the majority of patients classified into 8 subgroups, there seems to be a redundancy in the original model. Neck pain (NP) and low back pain (LBP) are costly, common, and among the health conditions with the highest impact on disability across the world . EvidencIn a review paper, a collaborative group of LBP researchers concluded that trajectory studies on LBP are numerous and have identified similar trajectory patterns . From a Kongsted and coworkers defined 16 subgroups based on two of the suggested constructs: pain variability and pain intensity, by outlining 4 standardized definitions of variation patterns  . These 4The definitions have so far only been applied to LBP patients. There are only two clinical course studies on NP for comparison , 10. ThiThe objectives of this study were to 1) investigate if the defined patterns and subgroups for LBP are applicable to NP patients in chiropractic practice, 2) explore the robustness of the defined subgroups, and 3) investigate if the patients in the defined patterns or subgroups differ with respect to baseline characteristics and clinical findings.This study was part of a prospective, observational study on patients with NP in chiropractic care setting. Members of the Norwegian Chiropractic Association were invited to participate in the recruitment of patients. We asked seventy-two chiropractors geographically spread in Norway to invite all consecutive patients with NP from September 2015 until June 2016 to participate in the study. The chiropractors gave interested patients written and verbal information about the study. Patients that accepted to participate signed a written consent. The study was approved by The Norwegian Regional Committees for Medical and Health Research Ethics (2015/89).We invited patients aged 18 years or more presenting with, or already in a treatment course for, a bothersome neck as a primary or secondary complaint with or without radiating arm pain to participate. They were eligible for inclusion regardless of pain duration and time since last chiropractic treatment. Patients had to possess and be able to operate a mobile phone and have basic Norwegian reading and writing skills. They were not included if serious pathology was suspected . All patients received standard chiropractic care at the discretion of the chiropractor, unaffected by inclusion in the study.Patients completed a self-administered questionnaire at baseline, 4, 12, and at 52 weeks, either on paper or digitally. The present study used questionnaire data from baseline. Additional descriptions of recruitment of the cohort, the procedures and the questionnaires have been published previously , 19. A rBaseline questionnaire  or maximum (Episodic and Single episode patterns) pain intensity across the 43 weeks: Severe (pain intensity ≥6), Moderate (4 ≤ pain intensity < 6), Mild (2 ≤ pain intensity < 4), and Minor (pain intensity < 2). As Ongoing and Persistent fluctuating patterns are characterized by few or no pain-free weeks, we divided them into intensity subgroups based on deviation from mean pain intensity, with Persistent fluctuating displaying larger variation. In contrast, Episodic and Single episode patterns are characterized by pain episode(s) between pain-free periods, where the highest maximum pain of the episode(s) would better describe the severity of the episode(s) reported during the study period. This resulted in 16 different subgroups in total, and we classified the patients into one of these. The “Minor Ongoing/recovered” subgroup also contained patients that scored zero on pain intensity every week. In addition, we repeated the procedure and classified only the patients recruited at first-time consultation into the same subgroups. We did the latter to assess if these patients distributed differently into the subgroups compared to the whole cohort.To describe how the pain differed between the subgroups we also calculated mean pain intensity and mean paindays across only the weeks when pain was present, as well as the total number of days and weeks with pain in each subgroup. In addition, we calculated and described the frequency and size of the absolute deviation from the mean pain and the duration and frequency of pain-free periods for the Persistent fluctuating and Episodic patterns.p < 0.05 was considered statistically significant (two-sided).Descriptive analyses are presented as means with standard deviations (SD) and medians with interquartile range (IQR) or range, for normal and not normal distributed continuous variables, respectively. Categorical data are presented with frequencies and percentages. In addition to the description of the characteristics of the patients in the four main patterns, we made a further distinction between the patients in the eight Persistent fluctuating and Episodic subgroups. We used Chi-square test and Fisher exact test to compare baseline data between patters and subgroups for categorical data. Furthermore, we used Dunn’s post-hoc pairwise comparison test  and BonfWe also made a separate analysis for the patients recruited at first-time consultation to examine if they distributed differently from the cohort, and to assess if our inclusion criteria influenced possible differences in distribution. We did similarly with the inclusion criteria, where we changed the criteria from a minimum of 20 to 10 answers out of 43 SMS. In addition, we repeated the t-test analyses comparing the characteristics of Persistent fluctuating and Episodic subgroups after reducing the Episodic definition of pain-free duration between NP episodes from 4-weeks to 2-weeks, as the subgroups differed only on duration of pain-free periods. We considered the patterns to be robust if the distribution did not change appreciably with inclusion of only the first-time consultation patients.All analyses were carried out using STATA 16 .A total of 1478 patients consented to participate. One patient withdrew the consent, one was excluded due to being diagnosed with severe pathology after seven weeks of participation, and seven patients did not receive any SMS for unknown reasons. Two-hundred and sixty-one (18%) patients responded to less than 20 SMS follow-ups, and we excluded them from the analyses (the excluded cohort)  age of 44  years anThe patients in the excluded cohort were younger and slightly more severely affected in terms of disability (NDI) and scored higher on psychosocial screening (Örebro). They did not differ substantially on other parameters Table .n = 663) completed all SMS-answers. Eleven percent (n = 135) had no pain-free weeks throughout the study period, and 25% (n = 301) had no pain-free period lasting more than one week.There was an overall high response rate (81–84%), and 55% , patients with pain duration above one month, and less first-time consultation patients. Patients in the Persistent fluctuating pattern scored significantly lower on general health (VAS 66/100), and higher on all other sociodemographic (apart from age and sick leave) and clinical factors than the other three patterns (p ≤ 0.006) , apart from the Minor subgroups on HSCL-10 (p = 0.29). The proportion of patients above the HSCL-10 cut-off ranged from 55.1% (CI 41.2–69.0) in the Severe Persistent fluctuating subgroup to 23.3% (CI 10.1–35.9) in the Minor Persistent fluctuating subgroup , a slightly lower percentage of patients were classified into the Persistent fluctuating pattern (41.4%) compared to the whole study cohort (48.3%) .Pain intensity and health characteristics followed a similar decrease in severity gradient throughout both Persistent fluctuating and Episodic subgroups. Patients in the Persistent fluctuating subgroups were significantly more distressed and negatively affected in terms of pain, disability and psychological distress than those in the Episodic subgroups, with the exception of the Minor subgroups.Minor subgroups contained few patients and interpretation of results with regards to those subgroups should be interpreted with caution. While many of the differences are small, the differences in NDI are all above the clinical significance of 30% , 36. TheWhether there are different underlying pain mechanisms for these types of patterns is uncertain , 43. TheTo our knowledge, this is the first study that collected data on treatment-seeking NP patients weekly over 43 weeks, providing evidence on clinical NP development over time. The cohort was large and had a wide geographical distribution. Thus, our data expectably represents NP patients treated by Norwegian chiropractors well. The response rate of SMS was high; between 81 and 84% throughout the study period. Norwegian and Danish populations appear to be rather similar, strengthening the similarities between the two cohorts for comparison purposes.The chiropractors were asked to invite consecutive patients with NP to limit bias, but we were unable to get usable data for patients who were not invited or declined participation. Selection bias can therefore not be ruled out. We excluded 261 (18%) patients who responded to less than 20 of the 43 SMS to ensure clear-cut subgrouping without imputing data. However, the excluded group did not differ significantly from the analyzed sample suggesting that this did not have substantial influence on the results.Frequent measures over a long period is time consuming, expensive, and impractical for use in clinical practice. The knowledge of self-reported versus data-driven trajectories is emerging for the LBP population , 51, andWe excluded data from the first nine weeks as they did in the Danish LBP study, to ensure the comparison of results . It seemOur study was the first to use defined, standardized definitions of subgroups based on LBP patients in a cohort with NP. We found that the definitions were readily applicable to NP patients. Both NP and LBP patients report mostly low pain intensity, and are characterized by persistent pain with variations in intensity or episodic conditions with pain-free periods. Steady, persistent pain was almost non-existing in this cohort. Persistent fluctuating pain indicate a condition that scores higher than the other patterns in terms of reduced function and psychosocial factors irrespective of severity of pain intensity. Thus, neck pain and low back pain appear to share the same trajectories, with similar baseline characteristics being associated with the various trajectories for both conditions. Our results underscore the importance of using both temporal variation and pain intensity when subgrouping patients.Additional file 1. English translation weekly SMS questions.Additional file 2. English translation baseline questionnaire.Additional file 3: Supplementary Table 1. Distribution patterns. Distribution of NP patients into pattern and subgroups with 1) original definition criteria, 2) definition of episode duration of two weeks between pain episodes as part of analyses of robustness of pattern and subgroup definitions, 3) patients recruited at first-time consultation for their neck pain only.Additional file 4: Supplementary Table 2. Intensity of symptoms after pain-free period. NP intensity and weekly days with pain in the first week following a pain-free period of 1 to > 20 weeks for analysis of robustness of pattern and subgroup definitions.Additional file 5: Supplementary Table 3. Distribution NP and LBP cohort comparison. Distribution of NP cohort in the defined patterns subgroups and Danish LBP cohort from Kongsted et al. [d et al. .


Previous studies of herpes zoster (HZ) have focused on acute patient manifestations and the most common sequela, postherpetic neuralgia (PHN), both serving to disrupt brain dynamics. Although the majority of such patients gradually recover, without lingering severe pain, little is known about life situations of those who recuperate or the brain dynamics. Our goal was to determine whether default mode network (DMN) dynamics of the recuperative population normalize to the level of healthy individuals.For this purpose, we conducted resting‐state functional magnetic resonance imaging (fMRI) studies in 30 patients recuperating from HZ (RHZ group) and 30 healthy controls (HC group). Independent component analysis (ICA) was initially undertaken in both groups to extract DMN components. DMN spatial maps and within‐DMN functional connectivity were then compared by group and then correlated with clinical variables.Relative to controls, DMN spatial maps of recuperating patients showed higher connectivity in middle frontal gyrus (MFG), right/left medial temporal regions of cortex (RMTC/LMTC), right parietal lobe, and parahippocampal gyrus. The RHZ (vs HC) group also demonstrated significant augmentation of within‐DMN connectivity, including that of LMTC‐MFG and LMTC‐posterior cingulate cortex (PCC). Furthermore, the intensity of LMTC‐MFG connectivity correlated significantly with scoring of pain‐induced emotions and life quality.Findings of this preliminary study indicate that a disrupted dissociative pattern of DMN persists in patients recuperating from HZ, relative to healthy controls. We have thus provisionally established the brain mechanisms accounting for major outcomes of HZ, offering heuristic cues for future research on HZ transition states. It is the first time to demonstrate that a disrupted dissociation pattern of DMN still exists in recuperative herpes zoster patients compared with healthy controls even the rash disappeared and pain was relieved. This study could provide heuristic cues for future research about herpes zoster transition mechanism. Typically, a unilateral erythematous rash develops in affected skin, accompanied by various pain sensations, such as burning, stabbing, soreness, bloating, or allodynia.However, after comparable episodes of acute shingles, the majority of patients gradually recover, and the pain attenuates. Lack of prescribed treatments or clinical follow‐up in this recuperative population has hampered investigations, creating a scarcity of data on their life situations and brain dynamics. Procuring such data is indispensable in deciphering HZ transition mechanism. The present preliminary study was conducted to ascertain whether brain dynamics in patients recuperating from HZ normalize to the level of healthy individuals.In previous efforts, widely distributed abnormalities of brain activity in acute and chronic pain have reflected multidimensional dysfunction of pain sensation, pain‐related emotion, and cognition.It is worth noting that acute HZ and PHN  similarly disrupt activity of DMN nodes .22.1All study procedures described herein were approved by the Ethics Committee of the Second Affiliated Hospital of Zhejiang University School of Medicine. Each enrollee granted written informed participatory consent. Overall, 30 right‐handed patients recuperating from HZ  and 30 age‐matched right‐handed healthy controls  were recruited for study. The PHN diagnostic criteria are often defined by the International Association for the Study of Pain (IASP).2.2All questionnaires were completed 1 hour prior to brain scans. Each participant completed the McGill pain questionnaire (MPQ) short form, the chief elements being 12 sensory and 4 affective descriptors. VAS, present pain intensity (PPI), and ID Pain scores for assessing neuropathic pain were also completed by each. Depression and anxiety states were assessed via Hamilton Depression (HAMD) and Hamilton Anxiety (HAMA) Scales. Participants also completed the two‐part Positive Affect Negative Affect Schedule (PANAS) and the Medical Outcomes Study (MOS) 36‐item short‐form survey (SF‐36) on health‐related life quality.2.32; flip angle = 11°; matrix size = 256 × 256; slice thickness = 1.2 mm; and 196 continuous sagittal slices. Resting‐state fMRI images were obtained using a gradient recalled echo (GRE)‐echo planar imaging (EPI) sequence: TR = 2000 ms, TE = 30 ms, flip angle = 77°, FOV = 240 × 240 mm2, matrix = 64 × 64, slice thickness = 4 mm, slice gap = 0 mm; and 38 interleaved axial slices.All MRI scans were performed using a 3.0‐Tesla MRI scanner  equipped with an 8‐channel head coil. During these procedures, each patient was positioned supine, the head firmly restrained by foam pads; and earplugs were provided to reduce noise during scanning. They were asked to remain still as long as possible, keeping eyes closed but staying awake. High‐resolution structural T1‐weighted images were acquired using a fast spoiled gradient recalled echo pulse sequence as follows: repetition time (TR) = 7.3 ms; echo time (TE) = 3.0 ms; field of view (FOV) = 260 × 260 mm2.4http://www.restfmri.net) and Statistical Parametric Mapping  were accessed, using MATLAB platform (MathWorks). The first 10 volumes of each functional time series were discarded to avoid transient signal changes before magnetic field steady states were reached, allowing subjects to acclimate in this scanning environment. We then corrected the other images for timing differences (slice 37 used as reference) and head motion, determining translation (mm) and rotation (degrees) by six parameters . There were no group‐wise exclusions due to head motion beyond 2 mm of displacement or 2° of rotation. Subsequently, we spatially normalized images to the Montreal Neurological Institute (MNI) space using EPI templates with resampling voxel sizes of 3 × 3 × 3 mm. All images generated were spatially smoothed using a Gaussian kernel of 6 × 6 × 6 mm, full width at half maximum (FWHM).In preprocessing of fMRI time series volume data, the Resting‐State fMRI Data Analysis Toolkit . Independent components (ICs) were estimated at 37 (RHZ group) and 41 (HC group) by minimum description length (MDL) criteria, identified via Infomax algorithm.Independent component analysis is a powerful tool based on data‐driven blind source separation that captures essential components of multivariate rs‐fMRI signals, extracting independent sources from mixed sources.2.6t test was invoked for DMN spatial maps to evaluate within‐group data integrity , powered by Statistical Parametric Mapping (SPM12). To further restrict DMN comparisons between groups, the DMN spatial maps of both groups were combined, creating a DMN mask. Two‐sample t test was engaged to determine between‐group differences in DMN spatial maps, with significance set at P < .05 (corrected by FDR and cluster size >43).One‐sample 2.7To examine the within‐DMN functional connectome, regions of interests (ROI) were extracted from significantly discrepant DMN spatial maps of RHZ and HC groups, based on two‐sample testing of above‐mentioned areas . We then identified one of these seven regions as ROI, performing voxel‐wise within‐DMN FC analysis by using the combined DMN spatial map as a mask. Correlation coefficients were ultimately converted (Fisher's z‐transformation) to a normal distribution. A total of seven voxel‐wise within‐DMN connectivity analyses were completed.2.8t test, applying chi‐squared or Fisher's exact test to categorical variables. All computations were driven by standard software , setting significance at P < .05.Demographic and clinical variables of RHZ and HC groups were assessed, expressing continuous variables as mean ± SD and testing for normality by Shapiro‐Wilk test. Intergroup differences in variables with no evidence against normality were subjected to independent two‐sample t test. To exclude possible confounding effects, age, sex, and education level were included as covariates in two‐sample testing.Intergroup FC differences were assessed by two‐sided unpaired P‐values <.05 considered statistically significant. Because some pain‐related clinical variables  were unavailable in the HC group, these were analyzed in the RHZ group only. All other clinical variables  were available for partial correlation analyses of the combined groups.When investigating correlations between abnormal within‐DMN FCs and clinical variables , partial analyses were conducted, eliminating effects of age and education (in years), 33.1P = .797) or age , although duration of education differed significantly . We also found that slight persistent pain existed in RHZ group members, as shown by VAS, MPQ (sensory/affective), PPI, and ID Pain scores, whereas pain‐related scores in the HC group were unavailable. Compared with the HC group, significantly higher HAMD (P = .006) and HAMA (P = .016) scores were observed in the RHZ group, while PANAS positive (P < .001) and life quality (SF‐36) scores (P < .001) were significantly lower. PANAS negative scores did not differ significantly by group (P = .689).A total of 60 participants  were selected for this study. As shown in Table 3.2t test) corrected by FDR (P < .05). Similarities in DMN patterns were thus demonstrated in two groups within the following structural areas: MFG, posterior cingulate cortex (PCC)/PCu, right/left MTC, parietal lobe, and hippocampus/parahippocampus   group, including MFG, right/left MTC, right parietal lobe, right/left parahippocampus, and IFC areas  Figure , Table 2Compared with the HC group, we found significant augmentation of LMTC‐MFG (including mPFC) connectivity Figure  and LMTC3.4Because certain pain‐related clinical variables  were unobtainable in healthy controls, a partial analysis was undertaken, limited in the RHZ group, examining relations between these parameters and abnormal levels of within‐DMN FC. None of these variables correlated significantly with LMTC‐MFG or LMTC‐PCC connectivity in RHZ patients.r = .2695; P = .0373) scores   scores  or HAMA  scores were evident, nor did the intensity of LMTC‐PCC FC correlate significantly with clinical scores.Other clinical variables  were available in both groups, so partial analyses proceeded in the combined groups. We subsequently discovered that levels of LMTC‐MFG FC correlated significantly with emotional alterations and life quality, showing a positive relation with HAMD  Figure  and SF‐3s Figure . No sign4In this preliminary study, the following were major findings: (a) consistent with our initial hypothesis, DMN pattern disruption shown in the RHZ group  indicated that patients recuperating from HZ deviate from the brain dynamics of healthy individuals, even after the pain of acute shingles resolves; (b) compared with healthy controls, levels of LMTC‐MFG and LMTC‐PCC connectivity are increased in the aftermath of zoster episodes; and (c) the intensity of aberrant LMTC‐MFG connectivity correlates with pain‐induced emotional alterations and life quality.It is important to note that our study of the DMN was prompted by the existing body of knowledge on its role in a wide range of sensory and cognitive processing functions, including pain‐related rumination, attention, and memory.The three aforementioned DMN regions  marked by abnormal connectivity are key nodes in pain regulation. Temporal cortex is one area of the brain involved in pain perception and modulation, as confirmed in human neuropathic states and in animal models.The mPFC is a key component of MFG, exerting dual and opposing roles in pain.A recent study has further shown that patients with chronic pain due to spondyloarthritis exhibit complex relations between pain, resilience, and mPFC seed‐based within‐DMN connectivity. Resilience is a positive psychological factor, enabling rebound in response to adverse events, like pain.As a pivotal subregion of the mPFC, ventral medial prefrontal cortex (vmPFC) is often considered a sensory‐visceromotor aggregator associated with mood regulation, motivation, and social behavior.Posterior cingulate cortex, another key node of DMN, is activated during attention regulation and is extensively connected to medial temporal lobe memory systems.Finally, recent studies have contended that anterior (mPFC) and posterior (PCC) DMN subnetworks achieve a dynamic balance vital for maintenance of cognitive function.The current preliminary study has limitations that may be remedied by future endeavors. Insufficient data acquisition in patients with acute HZ or PHN prevented analysis of DMN differences in acute, recuperative, and persistent (PHN) phases of HZ, an issue addressed by cross‐sectional and longitudinal imaging studies currently underway. Longitudinal imaging investigations are needed to identify the evolution of DMN alterations during episodes of HZ. Other large‐scale networks and their internal/external connectivity implications should also be considered and are presently being explored. Finally, we did not measure behavioral changes through cognitive or attention‐demanding tasks or questionnaires to prove a correlation between intensity of PCC‐related connectivity and cognitive performance.In conclusion, the present efforts are the first to characterize disruption of DMN patterns and within‐DMN connectivity in patients recuperating from HZ, despite resolution of major symptoms . We have also determined a relation between within‐DMN connectivity and pain‐induced negative emotional states, attributing residual pain rumination, emotional alterations, and resilience to DMN divergence. Our preliminary results may help clarify the brain dynamics during recovery that likely persist well beyond the acute period, providing heuristic cues for additional research on neuromechanisms of HZ transition.The authors declare no conflict of interest.


The results showed that the denitrification rates were inhibited by sulfamethoxazole (SMX) treatments (1–100 μg L−1) and the anammox rates decreased as the SMX concentrations increased, which may be due to the inhibitory effect of this antibiotic on nitrate reducing microbes. 2-Ethylhexyl-4-methoxycinnamate (EHMC) impacted nitrogen transformation mainly though the inhibition of the anammox processes. SMX and EHMC showed a superposition effect on the denitrification processes. The expression levels of the denitrifying functional genes nirS and nosZ were decreased and N2O release was stimulated due to the presence of SMX and/or EHMC in the sediments. To the best of our knowledge, this study is the first to report the effects of EHMC and its mixtures on the dissimilatory nitrate reduction processes and N2O releases in river sediments. Our results indicated that the widespread occurrence of emerging pollutants in high-altitude rivers may disturb the nitrogen transformation processes and increase the pressure of global warming.The nitrogen pollution of rivers as a global environmental problem has received great attentions in recent years. The occurrence of emerging pollutants in high-altitude rivers will inevitably affect the dissimilatory nitrate reduction processes. In this study, sediment slurry experiments combined with  The release of N2O is recognized as a cause of climate warming [To satisfy the growing industrial and agricultural demand of human beings, much anthropogenic nitrogen is lost to the air, water and land, and this has drastically disrupted the global nitrogen cycle ,2. Exces2) . Howeverl levels . In addi warming ,9. Many scholars have studied nitrogen pollution in typical rivers, lakes and the marine environment ,11,12,13Tetrahymena thermophila P-glycoprotein, and thereby inhibit the multixenobiotic resistance activity in Tetrahymena thermophila [Pharmaceutical and personal care products (PPCPs), as a kind of emerging pollutant, are ubiquitous in freshwater ecosystems worldwide and can disrupt ecological processes and functions . Recentlrmophila . Howeverd). Due to the low Kd, sulphonamides has highly mobile in sediments which causes a great risk of water pollution [2O release, as well as the abundances of the denitrifying related genes (nirS and nosZ) in the Yarlung Zangbo River sediments. This study provides comprehensive information on the effects of PPCPs on nitrogen conversion in high-altitude rivers and provides a basis for assessing the ecological and environmental risks associated with PPCPs in aquatic ecosystems.Sulfamethoxazole (SMX) was a typical sulfonamide antibiotic. It was detected frequently in surface water, sewage and soil ,23,24. Tollution . 2-Ethylollution ,27. It hollution . AccordiThe CAS number of sulfamethoxazole (SMX) is 723-46-6. The CAS number of 2-ethylhexyl-4-methoxycinnamate (EHMC) is 5466-77-3. SMX and EHMC were supplied by ANPEL Laboratory Technologies Inc. , and their purity levels were 98%. HPLC-grade organic solvents  and analytical-grade drugs  were supplied by Nanjing SenBeiJia Biological Technology Co., Ltd. . The near-bottom water and the surface sediments were collected from the Linzhi Section of the Yarlung Zangbo River (latitude of 29.44° N and longitude of 94.54° E) in May 2019, at an altitude of 2910 m. May corresponds to the high flow season of the Yarlung Zangbo River in which there are abundant source of nitrogen. The water quality parameters and sediments physicochemical properties at the sampling point are presented in −1. The optimum concentration was determined by a preliminary experiment. These solutions were purged with argon for 15 min to remove dissolved gases from the solutions. The contaminant solutions were served in the gastight borosilicate vials (120 mL) and the vials were sealed to prevent leakage of the solutions and gases [2) was added to inhibit the activity of the microorganisms [g (10 min) to obtain the supernatants. One millilitre of the supernatant from each set of sample was withdrawn, then filtered with 0.45 μm glass fibre filters. In addition, the concentrations of the SMX and EHMC were detected using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS) in accordance with our previous work [−1 for SMX and EHMC, respectively. The mean recovery values of SMX were 107% and the EHMC was 84%.To understand the removal dynamics of SMX and EHMC during the slurry incubation, pollutant-added slurry incubation experiments were performed. SMX and EHMC were added to methanol to prepare the stock solutions, and the stock solutions were added to the deionized water to make individual solutions with concentration of 10 μg Lnd gases . These vnd gases . And therganisms . This grous work . These a2. Then, the concentration change in the abiotic group is determined by hydrolysis and the adsorption of sediment. In biotic group, the removal rate of SMX (or EHMC) was determined by the change in concentration before and after incubation. The difference of the concentration between the biological group and the abiotic group was caused by biodegradation. The removal rate and adsorption rate of SMX (or EHMC) are calculated using following formulas.i is the concentration change rate of SMX (or EHMC) in the three groups. Cinitial is the initial contaminant concentration in each group (10 μg L−1). Cfinal is the final contaminant concentration in each group after incubation. Rh is the hydrolysis rate. Ra is the adsorption rate. Rb is the biodegradation rate. Rr is the removal rate.In the control group, the change of SMX (or EHMC) concentration was generated by the hydrolysis of SMX (or EHMC). In the abiotic group, it is assumed that all microbial activities are inhibited by HgCl15NO3−  were injected into the slurry vials so that the concentration of 15N was 100 μmol L−1 in each vial. SMX and EHMC  were added to the vials so that the final concentration was 1 μg L−1. This concentration was chosen because it best reflects the nitrogen conversion characteristics in the sediments. The control group received slurries without pollutants. The slurries were poured into the vials, and the vials were sealed. The vials were shaken and incubated (15 °C) in the dark. At 0, 2, 4, 6, 8, 12, 24, 36 and 48 h of culture, three replicate samples were collected. The nitrogen gases (29N2 and 30N2) were measured using a membrane inlet mass spectrometer .The time series experiments were performed first to determine the optimal response time of the effects of SMX and EHMC to the nitrate reduction processes. Deionized water was purged with argon for 15 min. The pre-incubated sediments were mixed with deionized water (water to sediments 1:7) and then stirred to make sure slurries thoroughly mixed. The slurries were pre-cultured for 24 h to eliminate background nitrate. The experiment was conducted in the gas-tight borosilicate vials (12 mL). The −1, were selected to study their influences on the nitrate reduction processes. The 15N isotope pairing technique was used to determine the denitrification and anammox rates [2 solution (200 μL) was injected into the vials to inhibit microbiological activity. The 29N2 and 30N2 were measured. The respective rates of assimilatory nitrate reduction (denitrification and anammox) were calculated using the following equations [15N g−1 h−1) are the denitrification and anammox rates derived from the 15NO3− during the incubation, respectively. N30 and N29 (μmol 15N g−1 h−1) indicate the total 29N2 and 30N2 production during the incubation. In addition, Fn is the fraction of 15N in the total nitrate pool.According to the results of the above time series experiments, the test period of the nitrate reduction processes was determined to be 12 h. Five gradient concentrations of SMX and EHMC, namely, 0.01, 0.1, 1, 10 and 100 μg Lox rates . The sluquations ,30:(6)D 2O in incubation processes were determined by the headspace equilibrium technique. The slurries were handled in the same manner as the above samples, except 25 mL vials were used. The 15NO3− was injected into the vials and the vials were split evenly into two groups. One of which was the initial group which was added to the saturated HgCl2 solution (200 μL). Another vials without HgCl2 served as the termination group. Both sets of vials were incubated (12 h) under the temperature 15 °C without light. Next, the reactions of the termination group were injected the saturated HgCl2 solution (200 μL) in order to terminate reaction. The supernatants (5 mL) were obtained by the centrifugation from the slurries, and the supernatants were transferred to evacuated serum vials. The dissolved N2O concentration was determined by gas chromatography [2O were calculated using equation [−1 h−1) is the N2O release rate, Nt (nmol mL−1) is the total amounts of N2O dissolved in the termination slurry samples, and Ni (nmol mL−1) is the total amounts of N2O dissolved in the initial group, V (mL) is the volume of the vial, W (g) is the dry weight of the sediment, and T (h) represents the incubation time.The concentration variations of the dissolved Ntography . The relequation :(8)R = (nirS) and nitrous oxide reductase (nosZ) were detected in the slurry to explore the molecular mechanism under the influence of SMX and EHMC. In short, the incubated slurries, which were freeze-dried, were used to extract the total DNA by a Fast DNA Spin Kit for Soil . The nirS gene was amplified from the extracted DNA with primers cd3aF and R3cd [nosZ gene [nirS and nosZ. The standard curves for the two genes were established with a 10-fold dilution sequence of standard plasmid DNA (102–109 copies). All qRT-PCRs were repeated three times. The amplification efficiencies were 97.7% (R2 = 0.9997) for nirS and 98.3% (R2 = 0.9993) for nosZ. Nitrate reduction related genes encoding nitrite reductase (and R3cd . PrimersosZ gene . The expnirS and nosZ) and N2O release were analyzed using Pearson correlation analysis. The statistically significant were considered when values of p < 0.05. Regression analyses were also used.The statistical analyses used the Statistical Package for the Social Sciences . One-way analysis of variance (ANOVA) and Tukey’s test were used to evaluate the differences among treatments. Correlations between nitrate reduction rates (denitrification and anammox), the abundance of genes  and the highest concentration (100 μg L−1). The maximum inhibition rate was up to 90%. The denitrification rate had significant concentration differences in the EHMC group. At low concentrations (0.01 μg L−1), EHMC biodegradation consumed nutrients in water, thus inhibiting denitrification. While in the medium concentrations, the carbon and nitrogen source were supplemented by the degradation of EHMC. As the concentration continues to rise to 100 μg L−1, denitrification was suppressed again. The inhibition of EHMC on microbial gene expression could explain the decrease of denitrification rates [EHMC significantly decreased the anammox rates at all the test concentrations , and theon rates . The den2O, referred to as a greenhouse gas, is an intermediate of the denitrification processes. Compared to the control group, the production of N2O was significantly increased in all groups in the course of the incubation  were markedly decreased when compared with those produced by the other concentrations. In the combined pollutants groups, the releases of N2O increased with the increase in the exposure concentration, revealing concentration-dependent trends. The N2O release rates increased by 1.6 to 2.7 times that of the control, which were higher than that of SMX alone and close to that of EHMC alone. The release rates of N2O in the denitrification process are determined by a balance between nitrite reduction to N2O and N2O reduction to N2 [2O accumulation that was induced by SMX and EHMC  indicated that the two PPCPs may either inhibit N2O reduction to N2 or stimulate N2O production. It has been reported that some antibiotics  increased the release of N2O by promoting soil respiration or accumulation of nitrite [2O release due to inhibition of denitrifying enzyme activities [2O release. The continuous input of PPCPs in the high-altitude rivers could induce more N2O release, and this might increase the pressure of global warming.Ncubation . The N2O nitrite ,23,47, wtivities . In the nirS and nosZ in the treatments with SMX and EHMC  are shown in nirS and nosZ gene expression values corresponded to increases in the SMX and EHMC concentrations, with the exception of one or two of the lowest concentrations. The maximum inhibition rates were 75% for nirS and 78.0% for nosZ. In the SMX group, there was no significant difference in nirS abundance when the concentration was less than 1 μg L−1. The abundance of nirS remained stable when the SMX concentration was greater than or equal to 10 μg L−1. In the EHMC group, low concentration (0.01 μg L−1) and high concentration (100 μg L−1) showed stronger inhibition on abundance of nirS and nosZ. The Pearson correlation coefficient indicates that the release of N2O is significantly correlated with nirS and nosZ  treatments (1–100 μg L−1), which may be due to the inhibitory effect of this antibiotic on the nitrate reducing microbes. The inhibitory effect of 2-ethylhexyl-4-methoxycinnamate (EHMC) on the anammox process was even stronger than its effect on the denitrification process. SMX and EHMC in combination showed a superposition effect on the denitrification processes. In addition, SMX alone and EHMC alone and in combination will decrease the expression levels of the denitrifying functional genes and thus promote the release of N2O. Stimulating production of N2O from exposure to emerging pollutants may increase the contribution of high-altitude rivers to global warming. In summary, the results of this study provide data that demonstrates the effects of PPCPs on nitrogen transformation and highlights the environmental risks due to the presence of emerging pollutants in high-altitude rivers.This study demonstrates that the denitrification rates and associated N


P ˂ 0.05) the difference between mean dose of opioid consumption over 24 h between two groups was not significant (P = 0.785). Patient’s satisfaction score in lidocaine group was significantly higher than saline group (P = 0.034). Differences in incidence of postoperative nausea and vomiting between two groups were not significant (P = 1.0). Intraperitoneal instillation of 50 mL of 0.8% lidocaine with epinephrine is an effective and safe technique for postoperative pain management after TAH. But this technique cannot reduce opioid consumption over 24 h after TAH.Pain after total abdominal hysterectomy (TAH) is a major concern. Pain management is very important issue after TAH. This study aimed to assess the efficacy of intraperitoneal instillation of lidocaine for postoperative pain relief after TAH. A double-blinded randomized placebo-controlled trial was conducted on patients undergoing total abdominal hysterectomy in Al-zahra hospital from June 2007 to July 2008. Forty patients were randomly assigned with equal number in two lidicaine (N = 20) and normal saline (N = 20) groups. The lidocaine group received 50 mL of 0.8% lidocaine with epinephrine and placebo group received 50 ml of saline 0.9%. We used 10 cm visual analog scale (VAS) for assessing pain at 8, 12, and 24 h at rest and 48 h on movement. Opioid consumption, patient’ satisfaction with pain control, and incidence of postoperative nausea and vomiting were assessed. Means of pain score at different times in lidocaine group were significantly lower than placebo group ( Abdominal hysterectomy is a prevalent surgery in women and causes extensive tissue injury. Pain after total abdominal hysterectomy (TAH) is a major concern and induces physical and psychological complications that can increase the length of the hospitalization , 2. PainLocal anesthetics are recognized as a useful technique for postoperative pain management. They can reduce inflammatory response after surgery and produce analgesia by blocking neural transmission at the site of tissue injury . A suitaTrial design and settingA two-arm parallel double-blinded randomized placebo-controlled trial with equal randomization (1:1) was conducted on patients undergoing total abdominal hysterectomy in Al-zahra hospital from June 2007 to July 2008. This hospital is the only governmental maternity hospital in Rasht in Guilan province, north of in Iran.PatientsEligible patients were all women who were undergoing total abdominal hysterectomy. Patients were excluded if they had history of hepatic, cardiovascular diseases, asthma, seizure disorder, cancer, chronic pain, opioid addiction, hypersensitivity or allergy to local anesthetics, or require further surgeries.This study was approved by the Ethical Committee of Guilan University of Medical Sciences. All patients provided written informed consent before inclusion in the study.Randomization and InterventionsA co-worker assigned participants to lidocaine and placebo groups using a random sequence that was prepared by a statistician with no clinical involvement in the trial. The randomization list was generated using permuted block size of four. Sealed envelopes labeled A or B were provided. After assignment, one of them was delivered to operating room. We put in each envelope one Syringe containing lidocaine or normal saline. Syringe for the lidocaine group containing 50 mL of 0.8% lidocaine with epinephrine  and in the placebo group syringe containing 50 mL of normal saline 0.9%. All patients received a standardized general anesthesia were induced with intravenous injection of sodium thiopental 4 mg/kg, fentanyl 2 µg/kg and neuromuscular blockade by 0.5 mg/kg atracurium. Tracheal tube was inserted and anesthesia was maintained by isoflurane, nitrous oxide and oxygen. Atracurium was repeated as necessary. The hysterectomy was performed using standard technique; Surgery in all patients was performed via a standard Pfannenstiel incision after closureof vaginal cuff and visceral peritoneal, content of syringes was administered into the peritoneal cavity. At the end of surgery, neuromuscular blockade was reversed by administration of atropine 0.02 mg/kg and neostigmine 0.04 mg/kg and the patients were extubated. In this trail, patients, research personnel, outcome assessor, and ward nursing staff were blind of group allocation.Data collection and outcomesPrimary outcome of this trial was pain scores at 8, 12, and 24 h at rest and 48 h on movement (induced by sitting). We used 10 cm visual analog scale (VAS)  for assessing pain. Before surgery all participants were educated about use of VAS. Also we collected data about duration of surgery, Opioid consumption over 24 h after surgery, and incidence of postoperative nausea and vomiting. Also patients’ satisfaction with pain control was assessed by interviewing at 24 h after surgery using a scale of 1 = poor, 2 = moderate, and 3 = good. Preoperative data including age, body mass index (BMI), and history of abdominal surgery were obtained by nurses that were no clinically involved in the trial.Sample sizeTo detect a difference in 0.9 cm in pain score between two groups with an error probability of 5% and a power of 80%, assuming a standard deviation (SD) of 1 cm, a sample size of 20 patients per group was needed.Statistical analysist-test was used to compare mean dose of opioid consumption, duration of surgery, and age between two groups. Also Fisher’s exact tests were used to compare proportions between two groups. A P-value less than 0.05 has been considered as statistically significant.Data were analyzed in IBM SPSS Software Version 21. Descriptive and analytic statistics were used. Numeric data were shown as mean and SD and categorical variables data were shown as number and percentage. For statistical analysis, the non-parametric Mann Whitney U test was used to compare pain scores in different postoperative times and satisfaction scores between two groups. Two-tiled independent During the period of study 51 patients underwent total abdominal hysterectomy were assessed for eligibility. Forty patients were randomly assigned with equal number in two lidicaine (N = 20) and normal saline (N = 20) groups. All participants completed the trial . BaselinMean of duration of surgery in lidocaine group was 63 ± 13.41 min and in saline group was 66 ± 18.47 min that this difference was not significant (P = 0.560). Mean dose of pethidine consumption over 24 h after surgery in lidocaine group was 106.25 ± 29.10 mg and saline group was 108.75 ± 28.42 mg that this difference between two groups was not significant (P = 0.785). Means of pain score at different time in lidocaine group were significantly lower than normal saline group (P ˂ 0.05) . In lidoLidocaine is the most widely used local anesthetic. Lidocaine like other sodium channel blockers reduces pain by neural impulses blocking . To prol The results of this study demonstrate that administration of intraperitoneal lidocaine with epinephrine during TAH can significantly reduce postoperative pain at 8, 12, and 24 h at rest and 48 h on movement compared with normal saline. Also patients in lidocaine group were significantly more satisfied with pain control than normal saline group. But this technique cannot reduce pethidine consumption over 24 h after TAH. The incidence of nausea and vomiting in both groups was similar.Consistent with our findings in Williamson et al. study that examined intraperitoneal lignocaine instillation for pain control after TAH, pain score at 24 h at rest was lower in lignocaine group compared with saline significantly. Also there was no significant difference in morphine consumption between two groups. But in contrast with our finding there was no significant difference in pain score at 48 h on movement between two groups . DiffereIn conclusion, intraperitoneal instillation of 50 mL of 0.8% lidocaine with epinephrine is an effective and safe technique for postoperative pain relief over 24 h at rest and at 48 h on movement after TAH. But this technique cannot reduce opioid consumption over 24 h after TAH.Further studies that assess pain in shorter time after operation and narrow interval among pain assessment time and assess opioid consumption in each time is recommended.