We performed a nested study in the ENIGMA-II trial and compared postoperative neurocognitive recovery of patients randomly receiving N2O (70%) or Air (70%) in 30% O2 during anesthesia. We included adults having non cardiac surgery. We compared recovery scores for episodic memory, decision making/processing speed and executive functions measured with the computerised Cambridge Neuropsychological Test Automated Battery (CANTAB). Assessments were performed at baseline, seven and ninety days. At first interim analysis, following recruitment of 140 participants, the trial was suspended. We found that the mean (95%CI) changes of scores for episodic memory were in the Pocock futility boundaries. Decision making/processing speed did not differ either between groups (P > 0.182). But for executive functions at seven days, the mean number (95% CI) of problems successfully solved and the number of correct box choices made was higher in the N2O group, P = 0.029. N2O with the limitations of an interim analysis appears to have no harmful effect on cognitive functions (memory/processing speed). It may improve the early recovery process of executive functions. This preliminary finding warrants further investigations.There is a large controversy as to whether nitrous oxide (N Nitrous oxide (N2O) is used in a significant number of procedures. In the USA, for example, around 35% of all general anesthesia include nitrous oxide2. N2O is also increasingly administered with oxygen (50%) for pain and stress management in obstetrics during delivery, in pediatrics and ambulatory medicine for peripheral minor surgery. For general anesthesia, because of its weak anesthetic properties, it is used as an adjuvant that enables dose reduction of other anesthetic drugs and limits their side-effects. Considered for decades as innocuous, there is emerging evidence that N2O carries a number of potential side effects3. It enlarges natural air spaces . It can cause transitory leucopenia4, postoperative nausea and vomiting5. N2O also increases plasma homocysteine for up to a week after surgery7. Elevation of plasma homocysteine causes endothelial dysfunction and mismatches between cerebral metabolism and blood flow9. As a result N2O may also lead to cerebrovascular dysfunction resulting in delirium, delayed neurocognitive recovery or persisting neuro cognitive disorders10. Existing evidence on the true impact of N2O on postoperative cognitive performance and recovery is however controversial. Whilst some reports  attribute postoperative learning difficulties, loss of memory, disorientation13 and reduced psychomotor performance to N2O15, others including randomized trials, fail to identify any detrimental effect of N2O on cognitive performance20. Some authors even find in animal studies a neuroprotective effect of N2O21.The number of surgical procedures performed worldwide is estimated at 312 million2O in the development of delayed neurocognitive recovery remains to be determined. As part of the ENIGMA-II randomized multicenter trial initially designed to assess cardiovascular complications in patients undergoing major non-cardiac surgery, we performed a nested study assessing postoperative neurocognitive recovery. Using three computerized neuropsychological tests (thirteen outcome scores) of the Cambridge Neuropsychological Test Automated Battery (CANTAB), we compared postoperative neurocognitive recovery of patients receiving N2O in the anesthetic gas mixture administered during surgery with patients receiving N2O free anesthesia.Thus, the role of N2O on postoperative neurocognitive recovery. It was a study nested in the original ENIGMA-II trial in two participating centers (Hong-Kong and Geneva), both University affiliated Hospitals. Adults aged at least 45 years, at risk of cardiovascular complications and having general anesthesia for non-cardiac surgery exceeding 2 h were eligible. We excluded patients with untreated deficit in Vitamin B6, B12 and folic acid, those with marked impairment of gas-exchange requiring inspiratory oxygen concentration > 0.5, those with specific circumstances where N2O is contraindicated . In addition, we also excluded patients with mini mental state examination (MMSE) test score ≤ 24 and advanced Parkinson’s disease, those suffering from alcohol dependency or taking tricyclic antidepressants or neuroleptics. Patients with a handicap  likely to hinder the correct performance of the CANTAB computerized neuropsychological tests were also excluded. The study protocol was approved by the Central Ethics Committee of the Geneva University Hospitals CER: 08–075 (NAC 08–021) and Joint Chinese University of Hong Kong – New Territories East Cluster Clinical Research Ethics Committee (CRE-2012.197-T). It also received approval by the Swiss Agency for Therapeutic Products (Swiss Medics). The research project was performed in accordance with institutional standards and regulations. The study is registered with ClinicalTrials.gov, number NCT00430989 (reg.02.02.2007) and NCT02489097 (reg. 02.07.2015).The International ENIGMA-II study on Postoperative Cognitive Disorders (ISEP) trial was a randomized, controlled, multicenter parallel-group study performed to assess the effect of N22 but was extended beyond the end of the original trial until May 2016. Following written informed consent from all study participants, they were randomized to receive a general anesthetic with a mixture of either N2O (70%) or Air (70%) in 30% O2. We used computer generated randomization in permuted blocks of 10 patients and stratified randomization by site. Group allocation could be accessed via an automated telephone voice-recognition service or in case of malfunction, it was sent directly by email to research staff. Patients, surgical team members, research staff including postoperative interviewers and cognitive testing assistants were blinded to group allocation. Only the anesthesiologist in charge was aware of the gas mixture provided during anesthesia.The study was nested in the ENIGMA-II trial23. For the study, we initially selected five tests to be performed at 7 and 90 days: screening tests MOT (Motor Screening Task), visual memory tests PAL(Paired Associates Learning), episodic memory tests PRM (Pattern Recognition Memory), decision making and processing speed tests RTI (Reaction time) and executive function tests OTS (One Touch Stocking of Cambridge). All these tests, except the MOT test, were chosen because they are assessing cognitive domains most likely to be influenced by anesthesia24. The MOT test is a standard screening test that is systematically performed before all other CANTAB tests in order to train participants to the use of the computer and touch screen technology24. It was therefore not selected as a main study outcome. The PAL test proved to be particularly challenging for patients in addition to all the other tests (average duration of testing sessions without PAL test: 45 min) and it was finally removed from the testing battery. Thus only the PRM test was used to assess memory, a choice which was approved by the neuropsychologists of our research team. Details of the CANTAB tests are provided in “Supplementary On the day before surgery, after an initial screening for pre-existing cognitive disorders (MMSE test ≤ 24), Parkinson’s disease, visual or auditive impairment and other study exclusion criteria, a specially trained research assistant and a certified neuropsychologist performed the initial battery of cognitive tests CANTAB. The overall computerized battery includes 7 different categories of tests assessing the different domains of cognitive function . These tests are designed to detect subtle changes in cognition. The CANTAB testing battery was preferred over other type of cognitive tests, since it is language-independent, culturally neutral and has been validated for the diagnosis of a wide range of cognitive disorders and syndromes2O or N2O-free anesthesia. Group allocation prepared by study coordinators on each study site was provided in opaque sealed envelopes to the anesthesia team in charge. All patients received standard anesthetic and perioperative care. Choice of anesthetic agents, muscle relaxants, perioperative analgesia and prophylactic antibiotics was left to the discretion of the anesthesiologist in charge and only N2O administration and concentration was defined according to group random allocation. Additional neuraxial and other regional anesthetic techniques were accepted. Anesthesiologists were expected to maintain oxygenation, heart rate and blood pressure within the patient’s usual range at all times perioperatively and were advised to avoid intraoperative hypothermia (Temperature < 36 °C).Supplemental O2 could be administered at any time if required by impaired gas exchanges.On the day of surgery, patients were randomly allocated (1:1) to NOn the day of surgery, patients were assessed by a neuropsychologist in recovery for the presence of acute postoperative delirium according to the DSM-IV criteria .On day 7 following surgery, cognitive test administrators used the same computerized battery of tests (CANTAB) as in the preoperative period. To minimize learning effect and testing administrator bias, a parallel 1 version of PRM tests was used and the same administrator performed the testing process. On day 90 following surgery, the same computerized battery of tests (CANTAB) was used in a parallel 2 version of PRM test.http://www.euroqol.org/. When adverse events or unexpected outcomes were detected, further testing and clinical review were also organized.The CANTAB tests were administered either at the hospital or at home, if patients had been discharged. Quality of life was also measured using the EuroQol test , the verbal pain score (VRS) and recorded all benzodiazepine use, cortisone, alcohol consumption opiates, antidiabetic drugs, non-tricyclic antidepressant drugs, antihypertensive drugs, natremia before each cognitive testing session. We also recorded preoperative blood glucose, hemoglobin level, blood pressure, heart rate and body temperature.The primary outcome was postoperative neurocognitive recovery at 7 days and testing repeated at 90 days. It was defined as the within subject change between preoperative (baseline) and postoperative scores for each of the outcome measures selected within the following CANTAB tests: 1) PRM (Pattern recognition memory) test; 2) RTI (reaction time) test; 3) OTS (One Touch Stocking of Cambridge) test. Details of the tests are provided in “Supplementary 25. We also measured all adverse events occurring after surgery in both groups. Study data collected were stored locally in a locked database before being all securely transferred to the Geneva Study Centre. After all queries from the database manager were answered, individual center data were cleaned, aggregated and finally transferred to the statistical unit of the Center for Clinical Research.The secondary outcomes were postoperative delirium, the number of unplanned intensive care unit (ICU) admissions, duration of hospital stay and quality of life using the EQ-5D questionnaire16. To detect a 11.8% difference in cognitive impairment at 7 days with an increase from 15.7% to 27.5% between patients receiving or not N2O during anesthesia, we calculated a need for 190 patients per group, with 80% power and a significance level of 5%. To account for two planned interim analysis and the loss of follow-up (assumed to be limited) we targeted an overall recruitment of 420 patients. A constant likelihood group sequential method with formal futility boundaries was used with a two-sided Pocock stopping rule. There was no contingency for early termination for efficacy. An acceptance region plot (or a futility region plot) was generated using Spotfire SeqTrial for S+, TIBCO Spotfire S+ Version 8.2.0 for Windows, TIBCO Software Inc, Palo Alto, CA, USA https://edelivery.tibco.com/storefront/eval/tibco-spotfire-s-/prod10222.html. The two-sided futility boundary (for the differences in proportions between the N2O and the Air/Oxygen group) at planned interim analysis T1 (N = 140) was from -0.0244 to + 0.0244 and at analysis T2 (N = 280) from -0.0696 to 0.0696  following non-cardiac surgery26.The trial data and safety monitoring committee monitored compliance and the analysis of study results. Because repeated cognitive testing following anesthetic care can generate significant anxiety in patients, two interim analyses assessing episodic memory (PRM test) were scheduled. One after enrolment of 140 and another after 280 patients. The interim analysis was adjusted according to the Pocock Type I error function. The futility boundaries were ± 0.0244 at the first and ± 0.0696 at the second analysis for the between trial groups difference at seven days in the primary outcome (proportion of successful results for immediate and delayed PRM tests)2 test or Student t test or Mann–Whitney test as appropriate. A modification of the intervention effect between days 7 and 90 was investigated by using mixed effect linear regression models with a random intercept considering only timing (day 90 or day 7) and study group (N2O vs Air/O2) as independent variables with fixed effects and an interaction term. For co-variates analysis we used multivariate linear regressions and an interaction between timing and study group was tested in a linear model with mixed effects27. Group allocation, duration of surgery and average concentration of sevoflurane used were introduced into the model.Categorical variables were summarized as frequencies and percentages and continuous variables as means with standard deviation (SD). For primary and secondary outcomes, changes from baseline were compared between groups using the χPossible collinearity was tested and could be formally excluded. The final results are expressed as adjusted 95% CI and P values. A P-value of < 0.05 was considered statistically significant. We used the Statistical Package for Social Sciences-SPSS  and R .At interim analysis 1, investigators submitted data to the Data Safety and Monitoring Committee. For the primary outcome used for sample size calculation (episodic memory[PRM test] :proportion of correct answers immediate and delayed) the between group difference observed at 7 days was < 0.0244 and within the stopping boundaries for futility at T1. Study recruitment proved also to be particularly difficult and resources falling short. Based on both arguments, the committee decided to stop the trial.2 study arm and 72 in the N2O/O2 group. By day 90, seven patients were lost to follow up (5 in the group Nitrous Oxide and 2 on group Air/Oxygen). The whole cognitive testing process  could be achieved in 114 patients. In the remaining group of 28 patients, only preoperative, day 7 or day 90 testing could be performed. The study flow chart is provided in Fig. During the study period, 609 patients were found eligible for the study of which 140 consented to be randomized; 68 patients were in the Air/OAll randomized patients were included in the statistical analysis and analyzed as complete cases. Both intention-to-treat and as-treated analyses for outcome measures of the CANTAB test were performed. Results are provided in “Supplementary 2 group and 69.4 years in the N2O group. About two-thirds of patients were men. Alcohol consumption, benzodiazepine or antidepressant drugs use was similar in both groups. The mean inspired oxygen concentration did not differ between groups .Baseline characteristics such as age, education level, MMSE and HAD tests scores were similar between groups Table . Study p2 group [1.2% vs. 0.7% ] (Table There was no between group difference in procedure related data except a longer duration of surgery (35 min on average) and a higher concentration of sevoflurane consumption (expired concentration) in the Air/OFor outcome measures of the PRM test (episodic memory), the mean (95% CI) between group difference for the change in the proportion of correct answers  was -1.5% (-7.1 to 4.0), P = 0.583. At Day 90, it was -0.9% (-6.8 to 4.9), P = 0.744. For delayed recall at Day 7, the mean (95% CI) difference was 2.9% (-4.1 to 10.0), P = 0.406. At Day 90, it was 4.4% (-2.1 to 11.0), P = 0.182 (Table For outcome measures of the RTI test (decision making and processing speed) there was no between group difference at day 7 or day 90. At 7 days, the mean (± SD) reaction time change from baseline (single stimulus mode) was 19.4 (85.5) msec in the Air/O2 group and 43.3 (164.7) msec in the N2O group. The mean (95% CI) between group difference was -23.9 (-75.2 to 27.4), P = 0.356 (Table 2 group and 1.2 (2.1) in the N2O group. The mean (95% CI) between group difference was -1.3 (-2.7 to -0.1), P = 0.048 in favor of N2O. The mean (± SD) change from baseline for the number of box choices made to correctly solve the problem was 0.01 (0.1) in the Air/O2 group and -0.1 (0.1) in the N2O group. Mean (95% CI) between group difference was 0.11 (0.01 to 0.20), P = 0.029 in favor of N2O. At Day 90, the between group differences disappeared showing marginal differences with preoperative values, particularly for the RTI test, suggesting a full recovery of preoperative function at 3 months.For outcome measures of the OTS test (executive functions) we found a significant between group differences at 7 days Table . The mea27. Following multivariate adjustment for duration of surgery and the concentration of sevoflurane (higher in the Air/O2) group, we found a persisting difference for the OTS test (P = 0.042 and P = 0.026). Results are provided in Table To adjust for confounding factors we selected covariates that were imbalanced between treatment and control groups and likely to be significantly related to the outcome (cognitive function)2 group than in the N2O group, 12 (17.6%) vs 5 (6.9%). This just not reach statistical significance (P = 0.05).In the analysis of secondary outcomes, we found that the number of unplanned ICU admissions was higher in the Air/OThe duration of hospital stay, the number of patients with acute postoperative delirium, utility and pain scores for EuroQoL 5D were similar between both groups. The number of adverse events did not differ between both groups either, P = 0.66. Table .Table 7G2O or N2O-free anesthesia. For all outcome measures of the CANTAB tests used for episodic memory and decision making/processing speed assessment, there were no between group differences at 7 and 90 days following surgery, suggesting harmlessness of N2O. Surprisingly, outcome measures of executive function tests significantly differed at 7 days. Patients receiving N2O had improved postoperative neurocognitive recovery compared with patients receiving Air/Oxygen. This finding cannot be explained by preexisting differences in the level of preoperative anxiety and depression (HAD), age, cognitive reserve or education level29 since all were equal between groups. For secondary outcomes  no difference was found between the two groups.The study purpose was to compare postoperative neurocognitive recovery in patients receiving N2O. A detrimental effect of nitrous oxide on brain function is advocated in these studies to explain these findings32. However, in these animal studies, subjects were submitted to long durations of exposure to N2O (between 4 to 8 h) and to the combined administration of several different anesthetic drugs and gases such as isoflurane. As a result the specific contribution of N2O to cognitive changes following anesthesia is difficult to demonstrate33. In studies on humans, only a limited number of studies  seem to support the evidence of the noxious effect of N2O on brain function35. These studies find modified psychomotor performance after surgery, particularly reduced reaction time and short term memory in patients having received N2O during their anesthesia. In one case report, severe lesions of the brain with nerve demyelination following the administration of N2O is even described36. However, large observational studies and randomized trials do not seem to confirm these findings, including in the long term (i.e. 3 months)37. Likewise in our trial, we did not find evidence of a detrimental effect of N2O on memory or reaction time, including at 90 days. In contrast, we found that patients receiving N2O compared with patients receiving Air/O2 had an improved recovery process of executive functions at seven days after surgery.Our study findings significantly differ from those from animal studies which describe impaired memory and learning as well as neuro behavioral disturbances following anesthesia with N2O21 and Leung JM et al19, found in a randomized trial involving 228 elderly patients a higher  incidence of postoperative cognitive disorder in the Air/ O2 group compared with the N2O group (18.6% vs 14.8%). This finding similar to the one in our study requires further discussion. The association between an improved recovery process of executive functions following surgery and the use of N2O for anesthesia is quite unexpected.Some other authors in animal studies describe a neuroprotective effect of N2O when used in combination with other anesthetic agents such as isoflurane or sevoflurane. It allows the use of lower concentrations of volatile anesthetics and consequently decreases the risk of detrimental cognitive side effects often observed when high doses of isoflurane or sevoflurane are used39. However, this cannot explain our study findings. Following multivariate adjustment for volatile anesthetic concentration and duration of surgery, a significant difference could still be observed for the OTS test. This suggests an independent effect of N2O on the recovery of executive functions after anesthesia. Another possible explanation is a regression to the mean phenomenon. Patients in the N2O group started with lower preoperative scores for the OTS test compared with patients receiving Air/O2. Their postoperative improvement could be simply explained by a natural variation following repeated testing. Another explanation could be the selective blockage of N-methyl-D-aspartate (NMDA) receptors and a possible neuroprotective effect of N2O. The NMDA channel allows the influx of Ca2+ into specific brain cells. This mechanism is considered as critical for synaptic plasticity and it can affect both circuit and brain function41. When extra synaptic NMDA receptors are over-activated by high glutamate secretion  an excessive influx of Ca2+occurs, leading to excitotoxicity and progressive cellular death42. Blocking NMDA receptors could therefore protect ischemic neurons from cellular death and promote functional recovery44.Several hypotheses can be formulated to explain this finding. One is the sparing effect of N2O may have protected this cerebral area from the effect of intraoperative stress or hypoxemia. Subgroup analyses of the IHAST Trial45 show that patients in the N2O group could be discharged home earlier and had improved recovery46. However further studies are needed to confirm this hypothesis. Another interesting finding of our study, although just not statistically significant, is the lower number of ICU admissions in patients receiving N2O. While this may be due to chance, it could also be the result of a lower number of postoperative complications in patients receiving N2O47. The mechanism to explain this finding is however unclear.Since a high number of NMDA receptors are located in the prefrontal cortex involved in executive functions, their selective blockade by N2O group not only recovered better but even significantly improved their OTS score following surgery. This may seem counterintuitive and lead to the conclusion of an incorrect finding. This cannot be excluded. However a meta-analysis of patients having Coronary By Pass Graft (CABG) surgery48 confirms that cognitive performance can improve following surgery. This may be due to the beneficial effect of surgery on overall inflammatory status (once diseased organs have been removed) or to a learning effect of the cognitive tests administered29. This is particularly true when using tests sensitive to changes in the speed of psychomotor function. The OTS test used in our study is very sensitive to such changes. It assesses a fine set of cognitive abilities such as planning, decision making and impulse control. These functions involve for a large portion brain cells that are located in the pre-frontal cortex and that can easily be altered by perioperative stress, inflammation or transitory hypoxemia50. Significant improvement may be observed, particularly in patients receiving N2O. A third limitation of the trial is the confounding effect of the learning phenomenon when the same tests are performed several times. Participants’ performance automatically improves by learning. Score differences in cognitive testing may therefore reflect a learning effect rather than a true difference in cognitive function. But since we used, whenever possible, parallel versions of the CANTAB cognitive tests, a learning phenomenon is quite unlikely to explain our study results. The fourth limitation is the “ceiling effect”. It is observed in tests based on relatively easy tasks to perform. Patients can easily achieve a high score during the initial phase of the testing (for example preoperatively in our study) and a slight change in further testing may consequently not be detected since initial scores are already quite high. This increases the risk of type 2 errors in studies. In our trial, preoperative results of the reaction time test (RTI) were relatively high with a simple accuracy score of respectively 10.8 (3.3) and 11.2 (3.5) in the Air/O2 and N2O groups. This is however quite unlikely to have had an impact on our study results since we used several different outcome measures to compare each group. Many of these outcome measures are unlikely to be affected by a “ceiling effect” since they include no predefined upper limits . A ceiling effect cannot occur since no maximum score can be reached.A limitation of our study is the premature discontinuation of patient recruitment at first interim analysis. The trial fell in the futility margins of the Pocock boundaries for outcome measures of the PRM test, with no difference identifiable in episodic memory change between the two groups compared. There was however a significant difference in cognitive function recovery, using the OTS test. Yet this outcome had not been used for sample size and interim analysis boundaries estimations. Thus this result may be due to chance following interim result analysis and a fully completed trial may possibly not confirm this finding. Furthermore, we found that patients in the N51.Another limitation is the relatively low level of education of participants (two thirds had lower secondary or elementary school level). This may be responsible of performance limitations at the lower ranges of the tests, making decline more difficult to detect, particularly for tests that are less sensitive such as the PRM test. To minimize this effect we chose to define cognitive change following administration of N2O as a within individuals and between groups difference of either 1 SD or at least 25% difference in 1 or 2 tests. We also compared group differences using t tests for statistical differences 2O had no impact on postoperative episodic memory and processing speed functions at 7 days and 3 months following surgery. Patients who received N2O appeared even to have improved recovery of executive function at seven days. Due to the limitations of this interim study analysis finding, further studies are however needed to confirm a possible neuroprotective effect of N2O administered during anesthesia.Despite these limitations we found that N2O on executive memory and processing speed function this study opens interesting clinical and research perspectives on a possible use of N2O for high risk surgery, for patients with brain trauma or those having prolonged sedation in ICU care units and requiring neuroprotection.In conclusion, while confirming the harmlessness of NSupplementary Information 1.Supplementary Information 2.Supplementary Information 3.


Knee osteoarthritis is a common disease in the elderly. Patients suffer from long-term chronic pain and reduced life quality. Acupuncture has been proven to be an effective treatment for KOA. However, the neural mechanism of acupuncture is unclear, so far. Periaqueductal gray (PAG) and raphe nuclei (RPN) are essential structures associated with chronic pain in human brains. This study aims to investigate functional connectivity (FC) changes of PAG and RPN in KOA to interpret the neural mechanism of acupuncture.In 15 patients with KOA and 15 healthy controls (HC), we acquired Visual Analog Scale (VAS) scores and resting-state fMRI images of each participant before and after acupuncture stimulation on EX-LE5 acupoint. Then, PAG and RPN were selected as seeds to perform FC analysis based on resting-state fMRI images. Finally, we compared FC patterns of PAG and RPN between patients with KOA and HC, then between pre-acupuncture and post-acupuncture. Correlations between FC values and VAS scores were calculated as well.p <0.001, uncorrected). For dorsal RPN, FC of patients with KOA was significantly higher in right putamen at post-acupuncture compared with HC , and FC changes were significant between pre-acupuncture and post-acupuncture in patients with KOA. Post-acupuncture FC values between dorsal RPN and right putamen were correlated with VAS scores. For medial RPN, FC of patients with KOA was lower in the right cerebellum at post-acupuncture compared with HC , but no significant FC changes were found between pre-acupuncture and post-acupuncture in patients with KOA. FC values between medial RPN and right cerebellum were not correlated with VAS scores at pre-acupuncture and post-acupuncture.For PAG, FC of patients with KOA was lower in the right lingual gyrus at post-acupuncture compared with HC (Our study demonstrated that acupuncture enhanced FC between dorsal RPN and the right putamen in patients with KOA, which was associated with chronic pain intensity. This result suggests that acupuncture stimulation can enhance FC between dorsal raphe and striatum, illustrating a neural mechanism that acupuncture can drive the patients' brain, with KOA, to perceive pain. Knee osteoarthritis is a common type of arthritis and prevalently affects the quality of life among the elderly . ChronicPeriaqueductal gray and raphe nuclei, located in the brainstem, play a well-established pain responses because these structures have optimal anatomical positioning to integrate relevant contextual information, driving the central neural system to release pain-related neurotransmitters , 12. RecAcupuncture, one of the traditional Chinese treatment modalities, has a good therapeutic effect on chronic pain , that inTo test this hypothesis, we respectively calculated FC for patients with KOA and healthy controls (HC) at pre-acupuncture and post-acupuncture stimulation. The group differences between KOA and HC, and between pre-acupuncture and post-acupuncture, were evaluated, as well as the correlations between altered FC and the related clinical symptom were further calculated to assess how the FC changes through acupuncture stimulation have modulated chronic KOA pain.Fifteen patients with chronic KOA pain , whose pain lasts at least 4 months, were recruited from the First Affiliated Hospital of Anhui University of Chinese Medicine (AUCM), while 15 HC  were recruited from the local community. The patients who presented with neurological or psychiatric diseases, poorly controlled hypertension, head injury, or any other conditions that might affect the study were excluded. All the participants had signed an informed consent before the study, which was approved by the Ethics Committee of the First Affiliated Hospital of AUCM (No. 2021AH-29).The diagnostic criteria of KOA were determined according to the Chinese Guideline for Diagnosis and Treatment of Osteoarthritis (2021 edition) formulated by the Joint Surgery Branch of the Chinese Orthopedic Association . PatientPain intensity was evaluated by the Visual Analog Scale (VAS), a tool widely used to measure pain . The patde-qi sensation   , task-stMRI data were acquired using a 3.0-Tesla MRI scanner , with an eight-channel high-resolution radio-frequency head coil. Sagittal 3D T1-weighted images were acquired using T1-3D BRAVO sequence with repetition time (TR)/echo time (TE): 8.16 ms/3.18 ms, flip angle (FA): 12°, matrix: 256 × 256, field of view (FOV): 256 × 256 mm, slice thickness: 1 mm, with 170 axial slices with no gap. Resting-state and task-state fMRI data were acquired using a gradient-echo single-shot echo planar imaging sequence with TR/TE: 2,000/30 ms, FOV: 220 × 220 mm, matrix: 64 × 64, FA: 90?, slice thickness: 3 mm, with 205 volumes. All the participants were instructed to lie down with their eyes closed, keep their minds relaxed, and not fall asleep during the scanning.3 resolution; (5) images were spatially smoothed with a 6-mm full width at half-maximum (FWHM) Gaussian kernel; (6) the data were linearly detrended, and the residual signals were band-pass temporal filtered at.01–0.1 Hz; and (7) nuisance variable regression was performed to regress out the six head motion parameters, as well as the signals of white matter (WM) and cerebrospinal fluid (CSF).For each participant, resting-state fMRI images were preprocessed using a combination of analysis packages, including FSL and AFNI. Functional images were preprocessed using the following steps: (1) the first 10 functional images were discarded to eliminate transients and account for T1 relaxation effects, followed by slice timing to compensate for acquisition delays across slices; (2) motion correction was performed by realigning all functional images to the middle image, and the data with head motion over 2 mm or 2° were excluded; (3) functional images were co-registered to the high-resolution anatomical images, and then normalized to Montreal Neurological Institute standard brain; (4) voxels were re-sampled to 2 × 2 × 2 mmhttps://www.nitrc.org/projects/atag/), in which the nonlinear elderly atlas of PAG was selected for FC analysis. RPN was divided into dorsal and medial sub-regions, defined based on a previous study  of p < 0.001.A paired two-sampled We explored the relationships between FC values and the VAS scores in the patient group to identify how acupuncture affects chronic pain through mediating brain function. For all correlation analyses, we used partial correlations to factor out age and sex.p < 0.001, uncorrected).No FC changes of PAG were observed between pre-acupuncture and post-acupuncture in both patients with KOA and groups with HC. No FC differences of PAG were found between the two groups at pre-acupuncture. Lower FC of PAG in patients with KOA was found in right lingual gyrus at post-acupuncture compared with HC . The FC difference of right putamen was significant between pre-acupuncture and post-acupuncture in patients with KOA . FC difference of right cerebellum was not significant between pre-acupuncture and post-acupuncture in patients with KOA  plays a central role in the descending modulation of pain . DysfuncPrevious studies have interpreted the neural mechanism of dorsal RPN in the regulation and the perception of pain from electrophysiology and neuroimaging, based on the fact that FC between dorsal RPN and cortical/subcortical regions was increased in patients with chronic pain after treatment , 16. TheThere were also several limitations in this study. The sample size of the participants was relatively small so that individual variation may affect the accuracy of the results. Moreover, considering the comfort and cooperation of the patients, short-term acupuncture stimulation was conducted in this research rather than typical acupuncture therapy, because the participants were lying in the bore of MRI equipment through the whole experiment. Our study pursued the instantaneous effect of how the brain perceives the pain right after the acupuncture stimulation; not the neural mechanism of the acupunctural therapeutic effect. For further research, more participants will be recruited, and we will simultaneously study the effects of both the short-term acupuncture stimulation and long-term acupuncture therapy.In conclusion, our results have demonstrated that acupuncture stimulation can enhance FC between dorsal raphe and striatum, illustrating a neural mechanism that acupuncture can drive the patients' brain, with KOA, to perceive pain.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the Ethics Committee of the First Affiliated Hospital of Anhui University of Chinese Medicine. The patients/participants provided their written informed consent to participate in this study.NG and HS wrote the first draft of the article, edited, and revised the article. BZ, AY, JS, and YF analyzed imaging data. JB, HX, and JC contributed to data acquisition. SH, XW, CL, BQ, and JY designed the study. All the authors contributed to and have approved the final version of the article.This work was supported by the National Natural Science Foundation of China (No. 81873370), Ministry of Science and Technology of the People's Republic of China (No. 2018YFC170460-4), the Support Project of Natural Science Foundation for Distinguished Young Scholars of Anhui Province (No. gxyq2020016), and the Key Project of Natural Science Foundation of Anhui Province (No. KJ2020A0394).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The perioperative period provides a critical window to address opioid use, particularly in patients with a history of chronic pain and presurgical opioid use. The Toronto General Hospital Transitional Pain Service (TPS) was developed to address the issues of pain and opioid use after surgery.To provide program evaluation results from the TPS at the Toronto General Hospital highlighting opioid weaning rates and pain management of opioid-naïve and opioid-experienced surgical patients.Two hundred fifty-one high-risk TPS patients were dichotomized preoperatively as opioid naïve or opioid experienced. Outcomes included pain, opioid consumption, weaning rates, and psychosocial/medical comorbidities.Six months postoperatively, pain and function were significantly improved. Opioid-naïve and opioid-experienced patients reduced consumption by 69% and 44%, respectively. Forty-six percent and 26% weaned completely. Consumption at hospital discharge predicted weaning in opioid-naïve patients. Pain catastrophizing, neuropathy, and recreational drug use predicted weaning in opioid-experienced patients.The TPS enabled almost half of opioid-naïve patients and one in four opioid-experienced patients to wean. The TPS successfully targets perioperative opioid use in complex pain patients. The risk factors associated with the development of CPSP have been previously elucidated and are described in 2In the province of Ontario, Canada, 49.2% of major surgery patients who were not using an opioid before surgery are discharged from hospital with an opioid prescription, and 3.1% continue to use opioids 90 days after surgery.6 However, concerns about the current opioid crisis and the risk of persistent opioid use after surgery have highlighted the need for improved perioperative and postdischarge care.7 Several authors have called for more refined interventions to reduce opioid use and the escalation of opioid doses after surgery, including the implementation of a Transitional Pain Service (TPS) as a practical model to address the multiple factors associated with the transition from hospital to community for complex postsurgical pain patients.12Opioids continue to be the most effective option for the management of acute pain both in posttraumatic and postsurgical settings.13 The potential cost savings to the institution and the health care system as a whole has been described previously.14 The structure and associated protocols of the TPS, including descriptions of recruitment, risk factors, and interventional approaches, are discussed in previous publications in detail.14Launched in 2014, the TPS at Toronto General Hospital (TGH) is, to our knowledge, the first perioperative pain service to comprehensively address the specific problems of CPSP and opioid use at three perioperative stages: (1) preoperatively, (2) postoperatively in hospital, and (3) postoperatively in an outpatient setting for up to 6 months after surgery. This pain service aims to bridge the gap in suboptimal pain management for complex patients and in unsafe prescribing practices. Toronto General Hospital performs 6000 surgeries per year; 4000 are considered major surgery , making it an ideal institution within which to pilot and implement a service such as the TPS.12 This population is not only at higher risk for misusing opioids but are slower to taper and require additional care when weaning.13 One critical aspect to the pain management approach at the TPS involves obtaining the patients’ commitment to wean from their opioid-based medication with the aid of nonpharmacologic and nonopioid medication strategies, making an interdisciplinary team with multimodal interventions necessary.Participation by the patients described in this article continued for an average of 6 months after surgery. Patients who were at high risk for developing pain and problematic opioid use were targeted in order to safely and efficiently wean them from opioids and optimally manage their pain.13 Nurse practitioners and physicians specializing in anesthesia, pain management, and addiction are responsible for determining and managing each patient’s care plan and applying pharmacological approaches to pain, prioritizing alternatives to opioids whenever possible.15 The clinical psychologists make up a large proportion of the team, providing behavioral interventions for pain and addiction as part of their multimodal approach.16 Physiotherapists and other allied health professionals offer other services based on patient need.Briefly, the interdisciplinary team charged with treating patients at the TPS includes nurse practitioners, physicians, psychologists, and other allied health professionals.Broadly, the goals of the TPS are to effectively manage long-term pain, maintain function, reduce opioid consumption, and monitor the efficacy of these interventions. The purpose of this article is to report the preliminary results of the TPS focusing on quantifying opioid consumption at the time of discharge following major surgery in opioid-naïve and opioid-experienced patients. This article will also describe the relationship between opioid consumption and psychometric parameters related to pain to evaluate the psychosocial variables that should be targeted as predictors of opioid weaning.This study was approved by the research ethics board of TGH  and by the Human Participants Review Sub-Committee York University . All data included in this article were anonymized from patients who gave written informed consent and were free to withdraw their consent at any time.13 Our team has developed risk factors for developing chronic pain postsurgically, which were used as a guide for physicians at TGH .Patients followed by the Acute Pain Service (APS) for more than 3 days postoperatively for poorly controlled postoperative pain  or complex pain patients requiring multiple pain consultations prior to hospital discharge after the APS had signed off.Patients consuming more than 90 mg/day of oral morphine equivalents (MEQ) on postoperative day 1, patients being discharged on long-acting opioids, patients on buprenorphine or methadone without community follow-up, or those requiring specialized postsurgical interventional procedures.Patients with psychological risk factors for persistent opioid use or drug addiction such as a past or present history of anxiety, depression, and high pain catastrophizing scores, identified by the APS or TPS.n = 51, 20%); (2) admitted patients seen by the acute pain service ; and (3) patients seen postsurgically at the TPS clinic after hospital discharge . Surgery types included thoracic (27%), general (16%), otolaryngology (12%), transplant (11.2%), cardiac (10%), vascular (8%), obstetrics and gynecology (4.4%), plastics (4.4%), urology (4.4%), neurosurgery (1.2%), orthopedics (0.4), and other (0.8%).In total, 411 patients were seen by the TPS between May 2014 and July 2017. Consent for participation was obtained from 304 surgical patients. Of those who agreed to participate, 53 were missing information on opioid consumption, leaving 251 patients  for analysis. Patients were assessed through three referral routes at different time points: (1) patients arriving to hospital for surgery ; after hospital discharge ; and at a mean of 6 months following surgery. Patient information on physical and psychological functioning was collected during TPS visits by self-report and medical history with prespecified forms and entered into the database.Exclusion criteria were limited to those based on publication of data: (1) Patient refusal to have their data used for publication purposes or (2) no signed consent form.18 Posthospital discharge visits occurred twice a month for the first 2 months after surgery typically followed by monthly visits thereafter or tailored to the specific needs of the patient.Broadly, the TPS interventions fall under three main categories in the context of an interdisciplinary framework: nonpharmacological and pharmacological pain management, opioid weaning, and psychosocial/psychological interventions. An overview including the development and structure of the TPS has been previously described.Pharmacological interventions to manage pain included opioid and nonopioid analgesics. Nonopioid medications included acetaminophen, nonsteroidal anti-inflammatory drugs, and anticonvulsants . Patients are engaged early and involved in the decision-making process when determining the most suitable weaning strategies, including nonpharmacological pain management techniques and psychological intervention where appropriate. Methadone and buprenorphine/naloxone protocols are applied for patients for whom typical opioids no longer meet their analgesic needs. Because of their analgesic properties in addition to their use as opioid replacement and addiction therapy, a rotation to buprenorphine/naloxone was used to balance analgesia with improved functioning and quality of life after years of chronic pain.18Psychological treatment to help with opioid weaning and pain management and/or to address concomitant mental health problems is provided by a registered clinical psychologist and/or several supervised clinical psychology graduate student trainees or registered clinical psychology postdoctoral fellows under supervised practice. The most used psychological intervention at the TPS is acceptance and commitment therapy (ACT), a form of cognitive–behavioral therapy tailored to chronic pain. The ACT intervention targets the management of inner experiences  and the nurturing of adaptive psychosocial behaviors by employing mindfulness-based approaches and a visual aide known as the ACT Matrix.The variables collected include (1) patient demographics, (2) intraoperative and postoperative parameters, and (3) psychometrics for pain management, opioid consumption, and psychosocial indices as follows.Patient demographics and medical information variables include age, gender, ethnicity, previous medical history, family history, chronic pain history, current problem list, and surgical procedure. Preoperative medication included opioids, anticonvulsants, nonsteroidal anti-inflammatories, acetaminophen, acetylsalicylic acid (ASA), angiotensin-converting enzyme inhibitors, calcium channel blockers, fluids, statins, beta blockers, steroids, and antidepressants.Intraoperative and postoperative variables include date of surgery, type of surgery, surgeon, anesthesiologist, type of postoperative analgesia, analgesic medication, duration of analgesia, and pain scores via visual analogue scale/numeric rating scale (NRS). Physiotherapy outcomes include activity and sleep.Psychometric variables were those for monitoring psychosocial functioning, subjective pain experience, and those specific for TPS psychologists: The Brief Pain Inventory–Short Form (BPI-SF), the Hospital Anxiety and Depression Scale (HADS), the Pain Catastrophizing Scale (PCS), and the McGill Pain Questionnaire–Short Form 2 (SF-MPQ-2).Psychosocial measures were assessed at various timepoints, depending on the patient’s clinical progress, to evaluate the patient’s initial and ongoing level of psychosocial functioning, to develop a clinical plan for psychological treatments, and to monitor ongoing progress. Psychosocial assessments were completed as deemed necessary by the clinical psychologists involved in the TPS.19 is one of the most widely used scales for measuring pain and pain interference in patients with a variety of chronic pain problems. The BPI-SF is a 16-item, self-report questionnaire that consists of a body diagram patients use to mark the location of their pain, a question about pain treatments and medications, and one concerning the percentage of relief obtained. The BPI-SF uses an 11-point NRS (0–10) with end points labeled no pain and pain as bad as you can imagine to measure the intensity/severity of the “worst,” “least,” “average,” and “now” (present) pain. Another 0–10 NRS (with end points labeled does not interfere” and completely interferes) is used to measure the impact of pain on functioning (interference) in seven daily activities, including general activity, mood, walking ability, work, relations with other people, sleep, and enjoyment of life. The BPI has been used extensively in a variety of pain conditions and has been shown to have excellent psychometric properties, including validity and reliability in patients with chronic nonmalignant pain.20The BPI-SF21 consists of 13 items describing thoughts and feelings that individuals may experience when they are in pain. Each item is rated on a 5-point scale ranging from not at all (0) to all the time (4). The PCS yields a total score and three subscale scores assessing (1) rumination, (2) magnification, and (3) helplessness. The PCS has good to excellent psychometric properties.21The PCS22 is the most widely used scale for measuring symptoms of anxiety and depression among medical inpatients, outpatients and the general population and consists of seven anxiety and seven depression-related items. The psychometric properties  of the HADS are excellent.22The HADS23 is a 22-item, expanded and revised version of the SF-MPQ designed to measure the qualities of neuropathic and nonneuropathic pain. Exploratory and confirmatory factor analyses revealed the presence of the following four factors or subscales: (1) continuous pain, (2) intermittent pain, (3) neuropathic pain, and (4) affective pain descriptor. Preliminary analyses indicate that the SF-MPQ-2 has very good to excellent psychometric properties.23The SF-MPQ-2Duration of opioid therapy posthospital discharge.Rates of opioid weaning for opioid-naïve (% and MEQ postoperative [discharge] and 6 months) and opioid-experienced patients .Pain and pain interference .Predictors of opioid weaning and pain measures.Psychosocial function for opioid-naïve and opioid-experienced patients (% between first and last TPS visit).Patients were dichotomized into two groups based on their presurgical opioid consumption. Opioid-experienced patients were those consuming >0 MEQ/day. All other patients with 0 MEQ/day presurgically were classified as opioid naïve. Although medical histories were reviewed to supplement our quantification of past opioid consumption, data on this variable were limited to self-report. Opioid replacement therapies  were not included in the calculation of daily MEQ dose. Outliers in opioid consumption who differed by a standardized residual change score of greater than four were removed from the sample for analysis.t tests and nominal or categorical variables were compared with chi-squared tests. Analysis of covariance (ANCOVA) was computed to compare opioid consumption and weaning rates between and within groups using baseline opioid consumption as a covariate. Pain and function were also analyzed with ANCOVAs within and between groups with baseline NRS pain and pain interference scores as covariates. Pearson correlation coefficients were computed between opioid dose, pain outcomes, and psychometric scales of interest. All data analyses were conducted using SPSS version 23.Means and standard deviations were used to report continuous variables. Percentages and frequencies were used to describe nominal or categorical variables. Continuous demographic variables, nonopioid and recreational drug consumption, and medical comorbidities were compared between opioid-naïve and opioid-experienced groups using P = 0.003). The mean number of months since surgery for the whole study sample was 6 months and 5.24 (SD = 5.7) and 6.61 (SD = 6.59) for the opioid-naïve and opioid-experienced groups, respectively (not significant). The mean number of visits to the TPS was 5.67 (SD = 7.5) and 5.82 (SD = 6.8) for the opioid-naïve and opioid-experienced groups, respectively (not significant). Preoperatively, opioid-experienced patients had significantly higher rates of medical comorbidities, including diabetes (P = 0.001), peptic ulcer disease (P = 0.002), gastroesophageal reflux disease (P = 0.004), and chronic pain (P = 0.0004).n = 110) were taking a mean of 106.7 ± 80.6 MEQ at the time of hospital discharge. Daily opioid consumption was reduced to a mean of 37.3 ± 61.1 MEQ/day at the final TPS visit (65% decrease) an average of 6.6 months after surgery. Opioid-experienced patients (n = 137) were taking a mean of 78.8 ± 100.2 MEQ/day prior to surgery. At the time of hospital discharge, these patients were consuming an average of 140.5 ± 124.0 MEQ/day, which was reduced to 78.3 ± 113.9 MEQ/day by their last TPS visit (44.3% decrease) an average of 5.2 months after surgery. ANCOVA, using MEQ at the time of discharge as a covariate, revealed that the MEQ dose at the final TPS visit was significantly higher for the opioid-experienced versus opioid-naive group .Six months after surgery, 49 opioid-naïve patients (44.5%) had been successfully weaned to 0 MEQ/day, 39 (35.5%) had reduced their opioid use by ≥50% of their discharge dose, 11 (10%) had reduced their opioid use by <50%, and 11 (10%) had increased their opioid use since hospital discharge . Six monincreased their opioid consumption after discharge represents a population of interest who faced the most challenge weaning from opioids. When comparing this subgroup to the remainder of opioid-experienced patients who reduced opioid consumption, a greater proportion were male . This subgroup was also more likely to have been diagnosed with a mental health disorder  when compared to the opioid-experienced patients who had reduced their opioid consumption. Lastly, organ transplant patients were overrepresented in this group compared to the subgroup that decreased opioid consumption .The subgroup of opioid-experienced patients who r = 0.23, P = 0.02) among all patients (n = 251). These reductions were also predicted by baseline levels of pain , pain catastrophizing , and recreational drug consumption . However, when isolating groups, reduction in opioid consumption was predicted by MEQ at hospital discharge for opioid-naïve patients .MEQ at hospital discharge predicted percentage reduction in opioid consumption from discharge to the final TPS visit , lower levels of neuropathic pain as measured by the SF-MPQ , and a history of recreational drug use .Furthermore, the reduction in MEQ from discharge to the final TPS visit for opioid-experienced patients was predicted by less pain catastrophizing (n = 192 with complete questionnaire data). Opioid-naïve patients showed a decrease of 23.6%  and opioid-experienced patients showed a 13% decline  in NRS pain intensity. Using pain at discharge as the covariate, an ANCOVA revealed that mean NRS pain ratings at the final TPS visit differed significantly between the two groups .Average NRS pain intensity decreased by a mean of 17% for all patients (N = 166). ANCOVA, using hospital discharge pain interference scores as the covariate, showed that mean BPI pain interference scores at the final TPS visit were significantly lower (improved) in both opioid-naïve and opioid-experienced groups, with the opioid-naïve group reporting larger improvement than the opioid-experienced group . Change in pain interference from discharge to final TPS visit amounted to a 28% and 15% improvement, respectively, for the opioid-naïve (n = 76) and opioid-experienced (n = 90) patients who completed this self-report measure.Functional impairment from pain reported by BPI pain interference scores improved by 21% from hospital discharge to the final TPS visit for the total study sample of patients . Opioid-experienced patients decreased their anxiety scores by a mean of 8% (SD = 57%). HADS depression scores also did not show a statistically significant difference within and between groups. Percentage depression scores decreased in opioid-naïve patients by a mean of 17% (SD = 50%) and in opioid-experienced patients by a mean of 7% (SD = 62%).24 The results of the present study suggest that intensive follow-up immediately postdischarge, followed by two visits a month for 2 months and monthly for 3–6 months, has a positive impact on opioid consumption and pain outcomes. Because this is a preliminary report documenting the effect size of the TPS, it lacks a formal control group. We have received funding to conduct a multisite randomized controlled trial that includes a control group and will follow this analysis with a pragmatic controlled trial at five institutions to determine the efficacy of the TPS in reducing pain and pain interference as well as in weaning patients from opioids.This article introduces evaluative findings of the TPS focusing on describing opioid weaning rates , quantif26 We cannot say with certainty that this dose was the minimum necessary dose to adequately control each patient’s pain because many of these patients were discharged from hospital with prescriptions written by surgeons before they became involved with the TPS. A recent report from the province of Ontario, Canada, included statistics showing that 275,778 opioid-naïve patients were discharged from hospital following surgery with 21,297 (8%) on greater than 90 mg of morphine as their starting dose.27 Taken together, these data speak to the complexity of managing postsurgical pain and identify a high-risk group that receives high doses of opioids at hospital discharge. These results further highlight the importance of institutional and perioperative oversight and the need to develop multidisciplinary transitional pain services to help patients maximize pain relief and quality of life with the lowest possible dose of opioid.There are important highlights to our analysis that deserve further comment. Opioid-naïve patients received an average of 106.7 mg/day of oral morphine , well ov28 and total joint arthroplasty.29 In a small pilot study of five patients, an interdisciplinary preoperative weaning program resulted in a reduction in mean daily opioid use from 238 mg (SD = 226.9) before surgery to 139.1 mg (SD = 84.0) one month after surgery for spine surgery patients. Pain interference scores also decreased over time.28 A retrospective matched cohort study of patients scheduled for total joint arthroplasty reported that patients who were successfully weaned before surgery by 50% of their preoperative opioid dose showed greater improvements in disease-specific and general health outcome measures than patients who did not wean preoperatively and outcomes comparable to those of patients who preoperatively were opioid naïve.29 A multidisciplinary program similar to the TPS reported that 54% and 32% of 200 patients were discharged from hospital after surgery on weak and strong opioids, respectively.30 At the end of the outpatient treatment component of the program lasting a median of 3 months, 20% and 6% of patients were reported to be taking weak and strong opioids, respectively. This represents a drop from 171 patients using opioids at hospital discharge to 50 (70.7% decrease) at the end of the outpatient clinic treatment; however, data on preoperative opioid use and daily doses were not reported, making it difficult to compare these data with the present results.30 With the TPS, 35 (26%) of our opioid-experienced patients who were taking long-term opioids prior to surgery were able to wean from opioid-based analgesics once engaged in our program. Long-term endpoints including relapse rates are an ongoing part of the development of the TPS and will be included in future program evaluations.Until recently, few places in the world have had transitional pain services  that aim to (1) prevent the transition of acute pain to chronic postsurgical pain and (2) help patients return to baseline levels of opioid medications or, if possible, wean to zero. It is clear that a proportion of patients cannot be weaned from long-term opioid therapy with traditional means because they have developed chronic postsurgical pain that is effectively managed by their opioid. Doing so with traditional means often involves uncontrolled pain, a return to problematic opioid consumption, and impaired psychosocial functioning. Comparable data on opioid weaning rates in surgical patients are sparse. However, two studies report success with preoperative opioid weaning programs in patients scheduled for spine surgery31 In the more challenging opioid-experienced patient cohort, we demonstrated a greater wean with the use of the behavioral ACT intervention provided by the TPS. A recent study demonstrated that patients referred to an ACT intervention demonstrated greater reductions in opioid use and pain interference and showed reductions in depressed mood by the end of treatment.16 Given the success of this subgroup of difficult patients, we are developing a model for postoperative weaning that integrates the ACT paradigm into a pragmatic randomized controlled trial.The present study demonstrates that, in our sample of opioid-naïve patients, greater efforts should be taken to maintain the lowest effective MEQ possible while in hospital because it is a strong predictor for the likelihood of weaning long term . To achi32 Another study looking at the Ontario population demonstrated that males were at higher risk of dying of an opioid overdose than females within the general population.33 Thus, special attention should be provided to younger males being discharged on higher doses of opioid medications postoperatively.Another notable finding is that 21 of the 26 opioid-experienced patients who increased opioid consumption after discharge were male . This su35 in order to transfer the needs of these complex patients back to the primary care setting. If this can be done efficiently and in a timely manner, we can circumvent a capacity bottle neck that prevents access to other patients who require transitional pain services, approximately 5%−15% of the surgical volume of any surgical institution.13One clear limitation is the need to develop a system for follow-up once patients are discharged from our TPS to determine whether patients continue to be opioid free. We are currently attempting to link patient data to our provincial health care databases to determine whether prescription outcomes change in the long term. Related to this is the limitation of data extending to only 6 months after surgery on average. Anecdotally, there remains a subpopulation within the TPS that extends well beyond our targets for discharge. Therefore, some of the conclusions drawn from this data are based on patients who have continued with the TPS beyond 6 months because they tend to have more severe psychosocial functioning limitations and may skew these outcomes. More community resource allocation is needed for chronic pain patientsLastly, the lack of randomization and a non-TPS control group limits our ability to draw clear conclusions with respect to our intervention when compared to no intervention, standard of care, or other opioid-weaning strategies. Given the success of our current program with respect to opioid weaning following major surgery—that is, 45% of opioid-naïve and 26% opioid-experienced completely weaned and 80% and 61% respectively weaned to less than half their baseline dose —we have 14 The development, staff, and overview of the TPS has been previously described.18 In addition, we believe that a TPS can function effectively with as few as three professionals . The time has come for perioperative physicians and institutions to face the potential negative consequences associated with life-saving surgery and create supports for the complex postsurgical pain patient. Further research will elucidate whether long-term investment into transitional pain clinics should be made a priority and whether the involvement of e-technology in this process might enhance the ability for widespread availability and uptake.In conclusion, close monitoring of patients in the acute postoperative setting and timely identification/intervention of the ~15% of surgical patients who are not recovering appropriately while in hospital and being discharged on high-dose opioids should become a priority within perioperative care over the coming years. We have previously published on the cost associated with the development of chronic postsurgical pain as a consequence of the top ten priority surgeries in Canada to be an estimated 1.8 billion dollars annually to the Canadian economy.


Subjects with ruptured aneurysms are less convinced about the influence of internal factors on pain control H (2) = 5.26; p < 0.05. The respondents’ conviction about the influence of doctors on pain control increased together with their age, rHO = 0.38, p < 0.05. Conclusion: Pain intensity after surgery did not significantly correlate with beliefs about pain control. Patients with ruptured AAA are less convinced about the influence of internal factors on pain control. With age, patients have more confidence in their doctors than in themselves to control their pain.Introduction: Pain-control beliefs significantly influence the perception of disease and, therefore, may influence the treatment outcomes of surgical patients. The sense of control is related to the sense of agency and the ability to influence one’s own life and environment. This construct may be external or internal. The belief that pain control depends on internal or external factors can depend on many variables. This may be influenced by socio-demographic and clinical characteristics, as well as the source and cause of pain. The aim of the study was the assessment of the relationship between the intensity of postoperative pain and beliefs about pain control in patients after AAA surgery and assessment of the relationship between socio-demographic and clinical variables and beliefs about pain control in patients after AAA surgery. Materials and Methods: The research material consisted of 42 patients aged 57 to 85, hospitalized at the Department of Cardiac Surgery and Vascular Surgery of the University Clinical Center in Gdańsk. The research was conducted from March to September 2020. The study uses a survey technique based on a standardized research tool: the Polish version of the BPCQ (The Beliefs about Pain Control Questionnaire), the NRS , and the author’s own questionnaire that allows for the collection of socio-demographic data. Results: The highest intensity of pain was observed in subjects with ruptured AAA H (2) = 6.19;  The International Association for the Study of Pain (IASP) updated the 1979 definition of pain, which now reads: “pain is an unpleasant sensory and emotional experience related or similar to, actual or potential tissue damage” .Abdominal aortic aneurysm (AAA) is a common, asymptomatic disease involving local expansion of the aorta by more than 50% of its normal diameter. Although some patients with AAA experience back or abdominal pain, most remain asymptomatic until rupture. Its severity can vary from mild to strong . The appThe main goal of treating an abdominal aortic aneurysm is to prevent the often fatal complication of aneurysm rupture. The only treatments for AAA are classic (open method) or endovascular surgery. The indication for surgery is an aneurysm larger than 55 mm and symptomatic or ruptured aneurysm. The classic method involves implanting a vascular prosthesis into the retroperitoneal space. The endovascular method is the placement of a stent graft within the lumen of the aneurysm through the peripheral vessel .Open abdominal aortic repair usually requires standard median laparotomy. This classic method of removing an abdominal aortic aneurysm is associated with a heavy burden on the patient. Long-term treatment leads to a significant cooling of the body. After surgery, the patient requires observation in the Intensive Care Unit. The extent of the procedure is conducive to the appearance of severe postoperative pain, and to reduce these ailments to a minimum, epidural analgesia is used ,10,11.The endovascular procedure involves small incisions in the groin. The patient requires increased observation and care for 24 h, with the difference that the epidural anesthesia used minimizes the risk of respiratory failure. In the following days, the analgesic treatment is limited to mild non-opioid analgesics used according to medical orders ,10.Various factors influence the size and extent of postoperative pain. Attention is paid to the influence of non-physical factors that are an important element of the perception of the pain phenomenon. Psychological factors include beliefs about pain control and the ability to use techniques that reduce pain perception . The senThe aim of the study was the assessment of the relationship between the intensity of postoperative pain and beliefs about pain control in patients after AAA surgery and the assessment of the relationship between socio-demographic and clinical variables and beliefs about pain control in patients after AAA surgery.This study had a descriptive and relevant research design using the prospective collection of data from the medical records of patients hospitalized in a hospital in northern Poland.Data collected from the medical records of hospitalized patients included age, sex, disease category, admission date, discharge date, hospitalization days, and pain level. Pain scores in this study were obtained from patients who self-rated their pain scores on a 0–10 point numerical scale. Pain-control beliefs were obtained from patients based on the BPCQ scale.This was a cross-sectional survey study. The STROBE checklist was used to ensure quality reporting during the study.The research was carried out at the Department of Cardiac Surgery and Vascular Surgery of the University Clinical Center in Gdańsk in 2020. The material consisted of 42 patients aged 57 to 85 years who underwent AAA (open surgery or endovascular aneurysm repair—(EVAR)). The inclusion criteria included informed consent form, a diagnosis of AAA, and age > 18 years. We excluded patients who did not consent or submitted incomplete questionnaires. The respondents were subjected to the study with two time assessments: on day 0 and the second day after surgery.Patients who did not meet anatomical criteria for stent graft implantation were qualified for vascular prosthesis implantation, with cardiological and anesthesiological qualifications for general anesthesia,Patients who met anatomical criteria and were disqualified from general anesthesia were qualified for stent graft implantation.The qualification for surgical treatment of an abdominal aortic aneurysm was in line with the Polish Recommendations for the Endovascular Treatment of Peripheral Artery and Aortic Diseases 2009 :PatientsAn author’s questionnaire was used to collect socio-demographic data. The second research tool was the BPCQ (The Beliefs about Pain Control Questionnaire) scale by S. Skevington (1990) School of Social Sciences, University of Bath, with Polish adaptation by Z. Juczyński and a scale for assessing pain intensity (NRS) ,16.This refers to scales measuring the location of control, including health control. This scale assesses the strength of individual beliefs about pain control using internal factors, the influence of doctors (the strength of others), and random events. It is intended to examine adults, the sick, and those who complain of pain. It can also measure beliefs about pain control in people who do not currently complain of pain ,16.The respondents assessed the questionnaire’s statements, basing their opinion on the Likert scale ranging from 1 = no, completely disagree to 6 = yes, completely agree.The BPCQ developed by Skevington consists of 13 items assigned to 3 subscales measuring beliefs about internal  of pain (IS), beliefs that powerful others  can control pain (PD), and beliefs that pain is controlled by chance events (CH). Higher scores in these subscales indicated stronger endorsements of the respective belief. The range of points for the location of internal control is 5–30 points; for the remaining ones, the influence of doctors and chance events is the same and amounts to 4–24 points ,15. A hiThe NRS is a numerical scale with 11 pain levels ranging from 0 to 10, where 0 is no pain at all and 10 is the worst pain imaginable. The NRS score of up to 3 points means mild pain, 4–6 points is moderate pain, and the score 7–10 points is acute pain .The scale was used in each subject twice on the “zero” and “second” days after the surgery.While collecting the data, the ethical principles set out in the Helsinki Declaration were taken into account. The research was approved by the Independent Bioethical Committee at the Medical University of Gdańsk, number NKBBN/124/2020.p ≤ 0.05 was assumed as the level of significance.All statistical calculations were performed using the IBM SPSS 23 statistical suite and Excel 2016. Qualitative variables were presented using counts and percentages, and quantitative variables were characterized using an arithmetic mean and standard deviation. The significance of differences between more than two groups was checked with the Kruskal–Wallis test , and between two groups was checked with the Mann–Whitney U test. To find the relationship of strength and direction between the variables, a correlation analysis was used to calculate the Spearman correlation coefficients. In all calculations, n = 35), while women accounted for 16.7% (n = 7). The age of the respondents ranged from 57 to 85 years of age, M = 70.4. The most numerous group of patients was 64 years old and accounted for 21% (n = 9). Among the respondents, the largest number of people were married residents of cities—61.9% (n = 26). A total of 33.3% (n = 14) had vocational education, 35.7% (n = 15) had secondary education, and only 11.9% (n = 5) had higher education. A significant part of the respondents, 54.8% (n = 23), confirmed that their main source of income was retirement pension. A total of 57.1% (n = 24) of patients were diagnosed with asymptomatic abdominal aortic aneurysm, symptomatic AAA was present in 35.7% (n = 15), and ruptured AAA was present in 7.1% (n = 3). Most of the respondents reported the presence of comorbidities. The study group most often exhibited arterial hypertension , followed by nicotine addiction , heart disease , and diabetes mellitus . The average number of cigarettes smoked per day was M = 14.73, SD = 7.03. Patients after classic abdominal aortic aneurysm surgery (n = 28) were more numerous (n = 28), and the group of patients who underwent endovascular treatment of abdominal aortic aneurysm (EVAR) 33.3% (n = 14) was smaller.Men accounted for the more numerous group of respondents, 83.3% .The examined patients showed pain intensity on day zero after the surgery, on average 3.81 points, SD = 1.97. Pain on day zero was diversified in terms of intensity. The lowest pain intensity at the time of the examination was 0 points, and the highest pain intensity was 8 points on the NRS. The applied non-parametric U Mann–Whitney test showed that gender did not change the level of pain intensity on day zero after surgery Z = −0.47; p < 0.05.Statistical analysis conducted using the Kruskal–Wallis test showed a relationship between the type of aneurysm and the intensity of pain. Further analysis by means of multiple comparisons showed that the subjects with ruptured AAA had the highest level of pain intensity compared to those with asymptomatic and symptomatic aneurysm, at a level of statistical significance, H (2) = 6.19; p > 0.05 (non-parametric Mann–Whitney U test). There was no statistically significant correlation between BMI, rHO = 0.02, p > 0.05, and age, rHO = −0.28, p > 0.05, and the level of pain on the second day after surgery (Spearman’s correlation test). The subjects who underwent the classic procedure, Z = −2.95, had a statistically significantly higher level of pain on the second day after the procedure; p < 0.05 (non-parametric Mann–Whitney U test).The examined patients showed pain intensity on the second day after the surgery, on average 1.4 points, SD = 1.64. Gender did not change the level of pain intensity on the second day after surgery, Z = −0.31; p < 0.001.Student’s T-Test was applied. The analysis showed that the pain on day zero was statistically significantly stronger than on the second day after surgery t (41) = 14.09; The BPCQ results show that patients operated on for AAA believe that internal factors play the greatest role in pain control, with an average of 21.02 and a standard deviation of 4.96 .p > 0.05; physicians’ influence, rHO = 0.06, p > 0.05; and the influence of chance, rHO = −0.03, p > 0.05) and on the second day after surgery .No statistically significant correlation was found between the intensity of pain and the point values obtained for the individual parameters of pain control on day zero , age , BMI , and type of surgery  did not affect beliefs about pain control in relation to internal control (p < 0.05 (p < 0.05 (The gender of respondents (Z = 0.42;  control . Only thp < 0.05 . In subjp < 0.05 .p < 0.05. The other socio-demographic and clinical variables did not significantly affect beliefs about pain control (Statistical analysis showed that with increasing age, the respondents’ conviction about the influence of doctors on pain management increased, rHO = 0.38,  control .Pain control through the influence of chance in patients with nicotine addiction was significantly dependent on the number of cigarettes smoked. As the number of cigarettes smoked per day increased, so was the perception that chance could influence pain control. The other socio-demographic and clinical variables did not significantly affect beliefs about pain control. .Research on beliefs about pain control is most often conducted among cancer patients ,20,21,22In our study, the BPCQ results show that patients undergoing AAA surgery believe that internal factors play the greatest role in pain control, with an average of 21.02 and a standard deviation of 4.96. In the case of doctors’ influence, the mean score was 19.09, and the standard deviation was 3.90. In turn, the mean result for random events was 15.28, and the standard deviation was 3.69. The inner sense of control is positively correlated with the belief in a strong ability to control pain. Such an attitude may translate into a reduction in the feeling of hopelessness and depression, and it helps to better cope with pain. The belief that pain control depends on internal or external factors can depend on many variables. This may be influenced by socio-demographic and clinical characteristics, as well as the source and cause of pain.Studies have shown that patients with chronic back pain and multiple sclerosis show greater internal control. Women with breast or uterine cancer, patients with chronic pain, and patients with chronic ischemia of the lower limbs show that physicians have the greatest influence on pain control. In the group of 100 patients with peripheral arterial disease in the study by Kadłubowska et al. , the medAlthough beliefs about internal control are more strongly associated with better mental and physical health, belief in physician control may be stronger during illness .In our study, internal beliefs about pain control seem to be independent of age, gender, and the type of surgery received.In the group of patients operated on for AAA, we can see that patients with ruptured aneurysms are less confident about the impact of internal factors on pain control. This confirms the hypothesis that patients treated surgically reveal a stronger belief about the influence of doctors on pain experiences. Severe pain can undermine patients’ confidence in their personal ability to control pain. They may view themselves as being less in control of their pain, and they may view doctors as having more control of their pain. A similar situation is for patients operated on for AAA. Conviction about the role physicians have in controlling pain grows with the age of patients. Nurses and doctors should be aware that their duty is not only to treat the patient but also to provide reliable information about the disease and the causes of pain and to provide psychological support ,33.Pain intensity after surgery did not significantly correlate with beliefs about pain control. Patients with ruptured AAA are less convinced about the influence of internal factors on pain control. With age, patients have more confidence in their doctors than in themselves to control their pain. In patients with nicotine addiction, the belief about the influence of internal factors on pain control decreased, and the belief about the influence of chance significantly increased with the number of cigarettes smoked.A limitation of this study is the low representativeness of the results, which makes it difficult to generalize the obtained results and formulate broader conclusions. The subject of this study was limited to patients hospitalized in one medical center. In a subsequent study, the number of patients tested should be increased. In addition, there are many social, psychological, and clinical variables that can influence the assessment of pain severity and beliefs about pain control, the effects of which have not been taken into account. For example, the effect of pharmacological pain management and levels of anxiety and depression were not accounted for, which can strongly influence beliefs about pain control. We propose to extend the research with additional variables. In the future, further research is needed to further clarify the interactions between the biological and psychosocial processes that have an important impact on pain experience.Despite the methodological limitations of the study, the obtained results may be useful in understanding the influence of some psychological and clinical factors on pain reporting in patients after abdominal aortic aneurysm surgery. These aspects may prove to be crucial in improving control over the disease. Beliefs about internal pain control may prove to be a useful target for psychological interventions to improve personal pain control and to increase control over the disease and its course.


The therapeutic effectiveness and safety of occipital nerve blockade (ONB) on occipital neuralgia- (ON-) like acute postcraniotomy headache (ON-APCH) was evaluated.  Persistent occipital neuralgia is a subclassification of chronic postcraniotomy headache and has been investigated sporadically in previous publications. The long-lasting neuralgic pain significantly impairs postoperative recovery and quality of life. However, little is known regarding ON-APCH and its management.  All data were retrospectively acquired from consultation records and electronic institutional medical documents. Forty-one patients, who developed drug-resistant ON-APCH after elective craniotomy and received ONB with lidocaine for diagnoses, were included in this study, all of whom were treated using dexamethasone and lidocaine. Pain intensity and ONB correlated complications and side effects were collected and analyzed at three different time points: before ONB, at 1 day after ONB, and at discharge.  Nineteen males and twenty-two females aged 49.6 ± 15.2 years were diagnosed with drug-resistant ON-APCH. The mean NRS was 8.0 ± 0.9 before ONB, which later significantly decreased to 2.1 ± 1.4 and 1.6 ± 0.6 at 1 day after ONB and on discharge, respectively. At 1 month after ONB, thirty patients (73%) obtained complete pain relief without medication. At 3 months after ONB, only two (5%) patients had to continue oral medications to maintain pain relief. No adverse effects or complications were observed immediately after, or within 3 months, of the nerve blockade.  For drug-resistant ON-APCH, early occipital nerve blockade with dexamethasone and lidocaine is an effective and safe technique, which provides adequate pain relief and may prevent further development of persistent presentation of refractory ON. Occipital neuralgia (ON) is a neuropathic condition that mainly affects the occipital and suboccipital region. The pain is characterized by unilateral or bilateral throbbing, shooting or lancinating episodic aches, presenting along the greater, lesser, and third occipital nerve distribution or, sometimes, in an occipital-temporal-frontal distribution. Hypoesthesia or dysesthesia in the area of occipital nerve innervation, tenderness on palpation, and positive Tinel's sign are some of the major findings of ON. Moreover, severe neuralgic pain often presents with ocular pain, tinnitus, nausea, and dizziness. The accompanying symptoms of ON occur due to the nervous connections of occipital nerve with vestibulocochlear nerve, glossopharyngeal nerve, vagus nerve, and cervical sympathicus , 2. BaseStudies suggest that, following craniotomy, patients are likely to develop persistent ON, which is an uncommon subclassification of chronic postcraniotomy headache (PCH). According to the Headache Classification Committee of the International Headache Society (IHS), the International Classification of Headache Disorders, 3rd edition, PCH is defined as acute or chronic headache attributed to craniotomy . PericraConservative treatments failed in most of the above cases. Most patients must undergo surgical management for persistent ON. It is assumed that early management of ON-like acute postcraniotomy headache (ON-APCH) after craniotomy might better relieve pain and help prevent the development of persistent ON. However, based on the current literature, little is known about ON-APCH and its management. In this study, medical data of 41 patients who developed drug-resistant acute PCH, similar in nature to occipital neuralgia, within 7 days after craniotomy, and received occipital nerve blockade (ONB) using dexamethasone and lidocaine, were retrospectively collected and analyzed. The therapeutic effectiveness and safety of ONB on ON-APCH was evaluated.Patients' medical documents and case records between January 2012 and December 2020 were reviewed. Patients who fulfilled the following criteria were included in this study: underwent elective craniotomy for intracranial disease, asked for a consultation with the institutional pain management center, diagnosed with ON-APCH following craniotomy within 1 week as described by the Headache Classification Committee of the IHS, the International Classification of Headache Disorders  , 16, 17,For patients who underwent elective craniotomy, routine postoperative analgesia through oral analgesics, and patient-controlled intravenous analgesia (PCIA), containing opiates and antiemetics, were given as recommended, on the first postoperative day . PCIA waPatients were asked to be seated with their head forward, positioning the ears in front of the body's vertical line. The injection point of greater occipital nerve was identified by palpation, and superior nuchal ridge was palpated to confirm occipital artery pulsation. Occipital nerve is located medial to the occipital artery, approximately 2 cm lateral and 2 cm inferior to occipital protuberance. After sterilization, a 5 ml syringe, with 25–27-gauge needle of approximately 1–1.5-inch, was orthogonally inserted to a depth of 3-4 mm until stopped by the periosteum. Once the needle was stopped, it was withdrawn 1 mm backward and then reoriented cephalad. A fanlike injection was performed after aspiration. For lesser occipital nerve blockade, the puncture site was localized approximately 3-4 cm lateral and 0.5–1 cm caudal to the former site. The optimal position was confirmed by palpation as well. Sterilization, aspiration, and injection procedure were identical to ONB. For diagnostic blockade, 1% lidocaine was administered at each puncture point. As to therapeutic blockade, the injection was formulated with 1% lidocaine and dexamethasone (4 mg), diluted with normal saline. The solution was injected into the affected nerves based on the evaluation of pain distribution and intensity , 20.Data were collected by two research assistants by reviewing consultation records, case records, and institutional electronic medical record system. Preoperative baseline demographics were obtained from the electronic medical record system, which included gender, age, preoperative comorbidities, or headache disorders. Perioperative data were collected from the operation and anesthesia records, including preoperative regional management, side of surgical incision (right or left), reason for surgery, surgical approach, and duration of operation. Data on time of onset of ON, symptoms of pain presentation, pain intensity, analgesics requirement (required or not required), time-to-treat , side effects, or complications attributed to ONB were collected from case records. Routine revision and follow-up were scheduled one day after consultation. During hospitalization, a pain specialist made regular follow-up visits, one day after consultation, and before discharge, in order to observe the effects of treatment. After discharge, routine follow-up through telephone interviews were scheduled at 1 and 3 month(s) after ONB. Pain intensity was determined using a Numerical Rating Scale (NRS) during hospitalization, in which 0 indicated no pain and 10 indicated the worst pain imaginable, and the Barrow Neurological Institute (BNI) pain inventory after discharge, which is shown in P < 0.05 was determined for statistical significance.All data were analyzed using SPSS version 25.0. Normality was examined using the Shapiro–Wilk test. Normally distributed continuous variables were presented with mean and standard deviation. Skewed data were presented with median (range). Categorical variables were recorded as frequency (percentage). NRS before and after ONB was compared using the one-way repeated-measures analysis of variance (ANOVA). To evaluate the influence of timing of ONB on therapeutic effectiveness, two subgroups were formed based on time-to-treat (≤7 or≥8 days) with two-way repeated-measures ANOVA. We retrospectively reviewed institutional medical records from January 2012 to December 2020. A total of 51 patients fulfilled the inclusion criteria; four were confirmed to have pre-existing ON, and one had received acupuncture in the suboccipital region before consultation. Incomplete data due to loss of follow-up was recorded in five patients. Ultimately, 41 patients were included in the present study. Baseline demographics and perioperative data of eligible patients are shown in After craniotomy, ipsilateral ON-APCH was found in 38 of the 41 patients. 3 patients developed bilateral ON-APCH postoperatively. The onset of symptoms was 3.5 ± 1.3 days after craniotomy. 22 patients complained of throbbing and/or stabbing pain. The other 19 patients described the pain to be indistinguishable. The median time-to-treat was 6 (2–11) days. Unilateral greater and lesser occipital nerve blockade was performed in 13 and 17 patients, respectively. Unilateral blockade for both greater and lesser was performed in 8 patients. 3 patients received bilateral greater occipital nerve blockade.F = 444.3, P < 0.001). NRS was 8.0 ± 0.9 before ONB, 2.1 ± 1.4 at one day after ONB, and 1.6 ± 0.6 at discharge  patients discontinued analgesics one day after ONB, while only 11 (27%) patients continued analgesics use after discharge.F = 1.984, P=0.152). NRS fell analogously at each time point, regardless of the timing of ONB administration after craniotomy.To determine the impact of ONB timing on therapeutic effectiveness, patients were divided into two groups based on time-to-treat (≤7 or≥8 days). Twenty-five patients received ONB within 7 days after ON onset, while the other sixteen underwent treatment beyond 8 days. NRS before ONB, at 1 day after ONB, and at discharge were compared between the two subgroups. Although longer time-to-treat was associated with a higher NRS at each time point, the difference between the groups were not statistically significant   with dexamethasone and lidocaine in 41 patients with drug-resistant ON-APCH, by reviewing consultation records and electronic medical data between January 2012 and December 2020. ON following craniotomy is deemed an uncommon subclassification of PCH. Ever since Schankin et al. first subclassified ON following craniotomy , persistIn line with the management of ON, treatment of ON-APCH includes conservative treatment and interventional procedures. Conservative treatments including physical therapies, rest, heat, massage, and nonsteroidal anti-inflammatory drugs (NSAIDs) remain the first-line therapy. For drug-resistant patients, interventional procedures are performed. In the current study, significant improvement was observed in all patients after therapeutic ONB procedure. Compared to the NRS before ONB, mean NRS decreased by 74% at 1 day after ONB and 93% at discharge. Approximately 40% of patients stopped oral analgesic medications at day 1 after ONB. The result is in line with a previous study on ONB treating drug-resistant ON . EvidentAlthough imaging guidance was not applied, ONB procedures were performed by skilled physicians, and injection sites were confirmed by anatomical location and physical examinations. Dexamethasone, as recommended and used in previous literatures , 23, wasAlthough the etiology of ON-APCH remains unclear, recent reports suggest perioperative trauma to be the cause of ON . The undThis study has some potential limitations. According to the IHS International Classification of Headache Disorders (3rd version) , headachFor drug-resistant ON-APCH cases, early ONB with dexamethasone and lidocaine is an effective and safe choice, which provides reliable pain relief and prevents further development of persistent presentation of refractory ON.