P < .001), which persisted 12 months after the endoscopy. All evaluated dimensions of the EQ-5D-5L questionnaire indicated a significant improvement in the assessed quality of life (P < .001). The study showed that percutaneous endoscopic lumbar discectomy is an effective pain-treating intervention that can improve the quality of life. There was no observed difference in the percentage of complications or re-herniations when comparing the transforaminal and interlaminar, approaches.Herniated lumbar discs are a common cause of low back pain, which can negatively impact the quality of life of working-age individuals. This study aimed to evaluate changes in the quality of life in patients with sciatica who underwent endoscopic discectomy, a minimally invasive surgical procedure. The study  included 470 patients who underwent transforaminal, interlaminar, or translaminar endoscopic discectomy. Quality of life and pain perception were evaluated by comparing statistically weighted values of EQ-5D-5L, EQ-VAS, Oswestry disability index, and numerical pain scales for lower limb and back pain before and 12 months after the endoscopic procedure. After the procedure, there was a significant improvement in the reduction of back and lower limb pain, as well as in all monitored questionnaires ( Low back pain with sciatica caused by lumbar disc herniation (LDH) affects nearly 60% of patients and is increasingly common as the global population ages. This condition is particularly prevalent in the working-age population, with 70% of disability caused by LDH occurring in people aged 20 to 65 years. The diagnosis of LHD is confirmed by magnetic resonance imaging, and the major symptoms include low back pain and sciatica. However, there is no clear evidence regarding the best treatment approach.–4 The health-conditioned quality of life in patients with LHD is a result of both subjective perception of the disease and objective conditions.–7 Therefore, various questionnaires are used to evaluate the health-related quality of life (HRQoL) of patients undergoing treatment.,9Recently, percutaneous endoscopic lumbar discectomy (PELD) has been used as an alternative to open discectomy. PELD is a minimally invasive technique that reduces the use of general anesthesia and results in less damage to surrounding soft tissues and paravertebral musculature, faster wound healing time, reduced spine instability, and shorter hospitalization.This study aimed to assess changes in the quality of life in patients with sciatica who underwent endoscopic discectomy using the EuroQol 5-dimension questionnaire. The study also evaluated the Oswestry disability index (ODI), the numerical scale of quality of life, and numerical scales of leg pain and back pain. The statistical weight values for the studied countries were determined. The results showed significant improvements in all monitored parameters, including a reduction in back and lower limb pain, as well as improvements in HRQoL that persisted 12 months after the endoscopic procedure. PELD was found to be an effective intervention for treating pain, and no significant differences were observed in complications or re-herniations when comparing the different approaches.Between January 2016 and June 2021, we enrolled 470 patients who underwent ELD. These patients were between the ages of 18 to 80 years old and were classified according to their physical status using the American Society of Anesthesiology grading system  .Exclusion criteria were: bleeding diathesis, urination or defecation problems, presence of infection or neoplasm, possible pregnancy, and patient disapproval. The procedure was performed by either a spine surgeon or an interventional pain management specialist, and each patient received a unique clinical trial ID number.The primary outcomes of the study were the intensity of pain radiating to the back and legs, measured using the numerical rating scale (NRS) (ranging from 0 to 10), and the evaluation of the ODI, which assesses the extent of low back pain-related disability on a scale of 0 to 100%. Scores between 0 and 20% indicate minimal disability, while scores between 81 and 100% indicate bedridden patients or those with exaggerated symptoms. We also assessed the EuroQol survey using the EQ-5D-5L questionnaire. The descriptive system consists of five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression, with scores ranging from 1 to 5 (representing the best to worst state). The EuroQol survey also includes the EQ-VAS vertical visual analog scale, which utilizes a grading scale from 0 to 100 to evaluate the quality of life. A score of 0 indicates “The worst health you can imagine,” while a score of 100 indicates “The best health you can imagine.”No significant changes were made to the methods after the study commenced. Prior to the operation, the NRS for back and leg pain, EQ-VAS, and ODI were assessed in one of the pain clinics participating in the study. The second assessment was conducted 12 months after the procedure, either during an appointment in one of the included centers or via a phone call follow-up, to assess pain severity by NRS and neurological state.This technique uses a natural entrance into the spinal canal (neuroforamen). The working channel for the endoscope is inserted through the paravertebral musculature latero-medially. During TFED, it is not necessary to disrupt the dorsal border of the spinal canal . The risk of postoperative fibrosis formation is, therefore, minimal.With more central protrusions that are harder to reach or more voluminous sequesters, especially at the L5/S1 level, the interlaminar approach was used. The working channel with the endoscope was introduced in the midline, very similar to a microdiscectomy. To enter the spinal canal, only a small part of the ligamentum flavum needs to be removed. The dural sac is then moved medially with a special maneuver to enable working in the central part of the channel.In cases, where entry into the spinal canal slightly above or below the interlaminar windows was desirable, translaminar endoscopic discectomy was used. The working channel for the affected disc level was inserted at the lateral inferior part of the lamina. Part of the lamina and ligamentum flavum are removed. This approach is very similar to ILED.The perioperative management of patients in our study involved several components. Prior to the operation, patients were premedicated with midazolam in a peroral dose ranging from 4 to 7.5 mg. During the procedure, standard monitoring was conducted, including electrocardiography, monitoring of oxygen saturation, and noninvasive blood pressure measurements.During the procedures, the patients were positioned in the prone position. We employed the propofol-remifentanil target-controlled infusion sedation technique. Throughout the sedation process, the patients maintained consciousness and were responsive to our inquiries. They breathed spontaneously with the assistance of oxygen masks. The target-controlled infusion sedation technique was maintained by administering a continuous infusion of remifentanil at a rate ranging from 0.05 to 2 µg/kg/min. Additionally, propofol was administered with dosages varying from 0.5 to 4.0 μg/ml, depending on the specific needs of the surgical procedure.During the operation, the surgical operator infiltrated the wound and operating canal with a mixture of local anesthetics. This combination consisted of 0.5% levobupivacaine and 1% trimecaine, with a total volume of up to 20 ml.After the operation, patients were transferred to the recovery room where they were observed for up to 3 hours. During this time, standard monitoring was performed based on the patient’s clinical situation. This included continuous monitoring of vital signs such as heart rate, blood pressure, respiratory rate, and oxygen saturation. Additionally, any specific postoperative complications or concerns were addressed and managed accordingly.To manage postoperative pain, patients received intravenous paracetamol at a dose of 1 g. For at-home medication, patients were prescribed tramadol at a dosage of 100 mg every 12 hours, diclofenac at a dosage of 75 mg per day, and paracetamol at a dosage of 500 mg every 8 hours.These medications and interventions were part of our standardized protocol for perioperative management in our study. They were designed to ensure adequate pain control and patient comfort during the postoperative period. Zhou, and Rapčan et al.Statistical analysis of the EQ-5D-5L questionnaire scores (in each of the 5 dimensions considered) was conducted using Wilcoxon rank-sum test and, alternatively, the estimated reliability parameter . The Wilcoxon rank-sum test is a standard statistical, nonparametric test that checks whether 2 independent samples come from continuous probability distributions (populations) with the same medians. Although the original version of the test was designed to compare continuous distributions, a simple generalization is possible for applications with discrete distributions . Secondly, as an alternative, we have used the estimated reliability parameter t test was used to assess the statistical significance of changes within each treatment group. P values of <0.05 were considered significant. Analyses were performed using MATLAB (R2021a) with Statistics and Machine Learning Toolbox version 12.1  and the statistical software package SPSS version 11.0  .Descriptive statistical methods were also used to evaluate the results . Examination of the distributional form for score and time data was determined by box plots. Each box plot indicated minimal value, lower quartile (lowest 25% of data), median, upper quartile (highest 25% of data), and maximal value. Normality of data distribution was assessed by the Shapiro–Wilk test. Homogeneity of variances was estimated using the Levene test. Differences between continuous variables were analyzed by a nonparametric Kruskal–Wallis 1-way test. A paired Student Four hundred seventy patients were included in the statistical processing. Three hundred nineteen patients underwent TFED and 86 patients ILED with a 1-year follow-up  questionnaire responses using a carefully determined weighting. In particular, for each subject the combined value P values of the Wilcoxon rank-sum test and the estimated values of the reliability parameter R with the associated 2-sided 95% CI. These results are presented for all hypotheses about the equality of the probability distributions of the questionnaire responses in the patient groups considered for each of the 5 dimensions of the EQ-5D-5L questionnaire, that is mobility, self-care, everyday activities, pain/discomfort, anxiety/depression, and the combined weighted questionnaire score. The Wilcoxon rank-sum test convincingly rejected all considered null hypotheses of equality of the medians of the distributions of the questionnaire responses before and after treatment against the stated 1-sided alternative, which states that the respective dimension of the EQ-5D-5L questionnaire response is better after treatment than before treatment (After ˂ Before). Furthermore, the estimated values of the reliability parameters and the corresponding 95% CIs show that the calculated values for all considered EQ-5D-5L dimensions are higher than 0.5, which clearly confirms the results of the statistical tests.Table This study aimed to evaluate clinical parameters, including pain intensity, ODI, and EQ-5D-5L scores, in patients with acute sciatica pain before and after endoscopic discectomy in the Slovak and Czech Republic. The study aimed to test the comprehensibility and face validity of EQ-5D-5L scores compared to other health measurement tools such as the ODI and NRSs for pain.,15For all patients with LHD in the clinical trial, conservative therapy was initiated after the onset of clinical symptoms for 6 to 8 weeks. This included a combination of steroids, nonsteroidal anti-inflammatory drugs, physical therapy, epidural steroid injections, and rest. If the clinical state did not improve or worsened over time, the treatment strategy was changed to an endoscopic surgical approach. Although there are no proven differences in outcome between conservative and surgical treatment, timely neurosurgical treatment can lead to good long-term results. Nerve decompression performed at the right time is a good prognostic factor for neuronal recovery and can help prevent further irreversible neuronal damage and pain chronification.,16 Minimally invasive surgical approaches offer several advantages over open surgery, including the preservation of paraspinal structures and a reduction in postoperative pain, which often leads to earlier discharge. Additionally, these procedures can be performed under local anesthesia.Among the monitored patients, the majority had a single-level herniated intervertebral disc in the intervertebral spaces L5/S1 (108 patients) and L4/L5 (169 patients). We observed a persistent improvement in the perception of back pain and pain radiating to the lower limbs, with a significant improvement in quality of life 1 year after the follow-up as measured by the EQ-VAS visual scale and the Oswestry disability questionnaire. These findings are consistent with the results of other clinical trials using various surgical approaches for lumbar herniated discs. A systematic review and meta-analysis of 99 articles focused on various spinal conditions found that spine surgery was associated with improved HRQoL for all groups in which postoperative scores were measured. The analysis included 22,312 cases for EQ-5D utilities, 2312 cases for SF-6D utilities, and 11,927 cases for SF-36 PCS scores with a median follow-up time of 12 months. Clinical trials monitoring the treatment of lumbar herniated discs with open surgical approaches, such as hemilaminectomy and microdiscectomy, have also shown the benefit of the procedures and improved patient quality of life after surgery. However, open surgery is associated with disadvantages such as extensive retraction and dissection of paraspinal muscles, longer operating time, larger wounds, and bone resection.A meta-analysis was conducted to compare the effectiveness of open lumbar surgery with lumbar endoscopic discectomy. The analysis included 9 randomized controlled trials with 1092 patients. The results showed that endoscopic surgery had slightly better clinical outcomes than open surgery based on the Macnab criteria, but this difference was not clinically significant. However, patients who underwent endoscopic surgery reported significantly higher satisfaction rates, lower intraoperative blood loss volume, and shorter hospital stays.P = .021). There were no significant differences in quality of life and ODI before and after the procedure between the interventions. The study’s limitation was the relatively low number of clinical trials included. Nevertheless, published results concerning open-operative techniques are also associated with a good prognosis.Similarly, a meta-analysis compared the efficacy of PELD with other surgeries for LDH and demonstrated better outcomes of PELD in 14 clinical trials involving a total of 2528 patients. PELD had a shorter duration of surgery, lower blood loss, and similar complications compared to other surgeries for LDH. However, PELD operations resulted in a higher recurrence rate . We also calculated the statistically weighted questionnaire values for each dimension of the EQ-5D-5L questionnaire in the Slovak and Czech region, which also indicate a significant improvement in social quality of life (P < .001).To evaluate the quality of life, we chose the EQ-5D-5L questionnaire as it offers a comprehensive assessment of a patient’s health status. This questionnaire measures 5 dimensions of perceived problems, each with 5 levels of severity, which improves sensitivity and reduces the ceiling effect. The EQ-VAS scale, which is easier to complete and score, was also used. The “Usual activities” dimension evaluates a patient’s performance in work, studying, housework, family, or leisure activities, as well as other dimensions like mobility, self-care, everyday activities, and anxiety/depression. Our analysis shows a significant improvement in the quality of life lasting >1 year after endoscopic surgery  may have influenced the results. Additionally, a loss to follow-up of 39 patients resulted in missing data for statistical analysis, potentially impacting the robustness and generalizability of our findings. Future studies should minimize loss to follow-up and ensure comprehensive data collection. Recognizing these limitations is crucial for interpreting our findings accurately and planning future research in acute sciatica treatment.Endoscopic discectomy is a highly effective minimally invasive surgical method for treating LHD, with a significant impact on the patient’s clinical state. Clinical assessments of the quality of life using different types of measurement instruments are useful in demonstrating the efficacy of pain-treating interventions.Conceptualization: Ladislav Kočan, Juraj Mláka, Róbert Tirpák.Data curation: Róbert Rapčan, Ladislav Kočan, Viktor Witkovsky.Formal analysis: Róbert Rapčan, Ladislav Kočan, Viktor Witkovsky, Miroslav Gajdoš.Funding acquisition: Ladislav Kočan, Simona Rapčanová, Juraj Mláka.Investigation: Ladislav Kočan, Viktor Witkovsky, Simona Rapčanová, Juraj Mláka, Róbert Tirpák, Hana Kočanová.Methodology: Ladislav Kočan, Hana Kočanová.Project administration: Ladislav Kočan, Janka Vašková.Resources: Ladislav Kočan, Miroslav Burianek, Janka Vašková.Software: Róbert Rapčan.Supervision: Róbert Rapčan, Ladislav Kočan, Juraj Mláka.Validation: Róbert Rapčan, Ladislav Kočan, Miroslav Burianek.Visualization: Miroslav Burianek.Writing – original draft: Ladislav Kočan, Simona Rapčanová, Róbert Tirpák, Hana Kočanová.Writing – review & editing: Ladislav Kočan, Simona Rapčanová, Hana Kočanová.


Treatment strategies of patients suffering from pyogenic spondylodiscitis are a controverse topic. Percutaneous dorsal instrumentation followed by surgical debridement and fusion of the infectious vertebral disc spaces is a common approach for surgical treatment. Technical advances enable spinal navigation for dorsal and lateral instrumentation. This report investigates combined navigated dorsal and lateral instrumentation in a single surgery and positioning for lumbar spondylodiscitis in a pilot series.Patients diagnosed with 1- or 2-level discitis were prospectively enrolled. To enable posterior navigated pedicle screw placement and lateral interbody fusion (LLIF) patients were positioned semi-prone in 45-degree fashion. For spinal referencing, a registration array was attached to the pelvic or spinal process. 3D scans were acquired intraoperatively for registration and implant control.2 were included. Mean duration of surgery was 146 ± 49 min. Mean blood loss was 367 ± 307 ml. A median of 4 (4–8) pedicle screws were placed for dorsal percutaneous instrumentation with an intraoperative revision rate of 4.0%. LLIF was performed on 31 levels with an intraoperative cage revision rate of 9.7%.27 patients suffering from 1- or 2-level spondylodiscitis with a median ASA of 3 (1–4) and a mean BMI of 27.9 ± 4.9 kg/mNavigated lumbar dorsal and lateral instrumentation in a single operation and positioning is feasible and safe. It enables rapid 360-degree instrumentation in these critically ill patients and potentially reduces overall intraoperative radiation exposure for patient and staff. Compared to purely dorsal approaches it allows for optimal discectomy and fusion while overall incisions and wound size are minimized. Compared to prone LLIF procedures, semi-prone in 45-degree positioning allows for a steep learning curve due to minor changes of familiar anatomy. InciTreatment strategies regarding PS vary widely. The primary indications for surgery include progressive neurological impairment, epidural abscess, pain caused by spinal instability, progressive deformity, or failure to respond to conservative treatment –10. Howevia dorsal instrumentation by percutaneous pedicle screw placement and debridement of the disc space and cage placement via lateral lumbar interbody fusion (LLIF) in a second surgery. A surgical approach to perform dorsal and lateral instrumentation in one single positioning surgery under fluoroscopic control was reported by Drazin et al. in 2015 in cohort of patients with degenerative spinal disease . We performed the study in accordance with the Declaration of Helsinki and in accordance to the STROBE statement.2.3.Patients diagnosed with single- or two-level PS of the lumbar spine who were surgically treated by a combined navigated lumbar 360-degree instrumentation in a single positioning at our institution. between June 2021 and October 2022 were prospectively enrolled. Subsequently, patients undergoing conservative treatment or instrumentation in a staged approached were excluded. Perioperative complications as well as the clinical and radiographic outcome were further analyzed.2.4.All patients underwent preoperative MRI and CT-imaging to diagnose PS. Indication for surgery was an infectious alteration of the intervertebral discs and anterior longitudinal ligament combined with a bony destruction of the adjacent vertebral body endplates. Patients suffering from low-back pain, sciatica or neurological deficits were scheduled for surgical treatment.2.5.For spinal navigation, a mobile navigation system  or operating room-installed ceiling-mounted navigation system  was used in all cases. For the registration of the spinal navigation system, an intraoperative 3D-imaging scan using a mobile cone-beam computed tomography scanner (CT)  or operating room-installed CT  covering all planned vertebral bodies was performed accordingly. For referencing during surgery, a registration array equipped with reflective sphere markers was attached to a pelvic or spinal process.2.6.The patient was positioned semi-prone in a 45-degree right-sided positioning on the operation table during the whole procedure . For ref2.7.For radiographic analysis, intraoperative 3D-imaging and postoperative imaging was analyzed. Pedicle screw positioning was evaluated on intraoperative 3D-scans according to the Gertzbein and Robbins scale (GRS) . Cage pl2.8.p < 0.05 were performed. Figures were created using Prism .Statistical analyses were performed using Prism . Descriptive statistics including mean, median, minimum, maximum, and standard deviation were calculated for patient characteristics as well as radiographic measurements. For statistical testing between groups, Mann–Whitney U tests for unpaired samples as well as Fisher's exact tests with a level of significance set at 3.3.1.A consecutive series of 27 patients  with 32 levels of spondylodiscitis of the lumbar spine was analyzed . All pat3.2.Duration of surgery was 146 ± 49 min (69–233) minutes . EstimatRegarding dorsal instrumentation, 124 screws were implanted in total. In 20 patients, single segment instrumentation was performed, while in five (18.5%) patients two segments and in two (7.4%) patients three segments were instrumented . OverallRegarding lateral instrumentation, 30 cages including one expandable cage due to severe end plate osteolysis  were implanted. Intraoperative cage revision was performed in three cases, and in two cases the cage was further inserted in the intervertebral disc space after the control scan. In one case no cage was implanted as reduced height of the intervertebral disc space did not allow for cage placement.3.3.Pedicle screw placement was reviewed on initial intraoperative imaging instrumentation according to GRS. Screw positioning rated GRS A and B was achieved in 111 screws (89.5%) .Regarding cage placement in sagittal plane—cages showed contact to the anterior border of the upper and lower endplates of the adjacent vertebral bodies in nine (30.0%) cases with the cage exceeding the endplates in two cases (6.7%), and contact to the posterior border in two (6.7%) cases .3.4.All patients were treated with intravenous antibiotics for a minimum of 14 d, followed by 10 weeks of oral antibiosis. Treatment schemes were individually adapted and discussed during interdisciplinary ward rounds lead by the department of microbiology. Three patients (11.1%) required ICU treatment, with a mean ICU stay of 13.3 (3–28) days. Mean hospital stay was 18.5 ± 12.2 (4–64) days, and 11 patients were referred to a secondary care hospital for further intravenous antibiosis and rehabilitation.Regarding surgery-related neurological deficits persisting at the time of discharge one patient showed postoperative deterioration of motor function related to an intraoperative nerve-root injury. Atrophic wound healing disorders requiring local surgical wound revision occurred in five cases (18.5%) with one patient aged under 65 years (14.2%) and four patients (20%) over 65 years.Follow-up examinations were available on 25 patients on 129 ± 111 (22–484) d postoperatively. One patient had to undergo a second surgery due to ongoing bony destruction of the vertebral body leading to cage subsidence requiring a complete vertebral body replacement using an expandable cage. Two multimorbid patients died due to cardiac complications induced by the systemic infection. Another patient suffered a severe acute respiratory syndrome coronavirus 2-infection four weeks postoperatively and was subsequently treated with best supportive care due to multiple comorbidities and advanced age. Two patients had to be re-hospitalized due to persistent infection parameters in blood testing. Further diagnostics ruled out persistent spondylodiscitis—both patients were effectively treated by a prolongated scheme of intravenous antibiotics followed by oral antibiosis. All six patients younger than 65 years with follow-up data available showed regular healing.4.4.1.via posterior discectomy or LLIF including cage implantation has been proven to show most favorable outcomes, especially regarding long-term fusion rates  were reported with pedicle screw revision in this study, resulting in a total screw revision rate of 4.0%, which is comparable to previous studies in patient positioning in prone position , 36.4.5.via percutaneous pedicle screw placement.This study was performed as a pilot study to confirm the feasibility and safety of this surgical approach. Therefore, no control group was included. In this study, patients with single or two-level PS of the lumbar spine were treated. In more extensive cases of PS including patients requiring multi-level instrumentation or instrumentation of the middle and upper thoracic spine a staged approach should be favored. When applying a modified patient positioning, the potential time benefit should be weighed against potential limitations and impairments regarding the surgical field and safety. In all cases in this study, dorsal instrumentation was performed 5.Navigated lumbar dorsal and lateral instrumentation in a single operation and 45-degree positioning is feasible and safe. It enables rapid 360-degree instrumentation in these critically ill patients and potentially reduces overall intraoperative radiation exposure for patient and staff. Compared to purely dorsal approaches it allows for optimal discectomy and fusion while overall incisions and wound size are minimized. Compared to prone LLIF procedures, semi-prone in 45-degree positioning allows for a steep learning curve due to minor changes of familiar anatomy.


Some patients with neuralgia of cranial nerves with otherwise therapy-refractory pain respond to invasive therapy with local anesthetics. Unfortunately, pain regularly relapses despite multimodal pain management. Transcranial direct current stimulation (tDCS) may prolong pain response due to neuro-modulatory effects.This controlled clinical pilot trial randomized patients to receive anodal, cathodal or sham-tDCS stimulation prior to local anesthetic infiltration. Pain attenuation, quality-of-life and side effects were assessed and compared with historic controls to estimate effects of tDCS stimulation setting.p = 0.726). Compared with a historic control group, a lower rate of responders with 50% reduction of pain intensity indicates probable placebo effects . 76.9% (n = 10) of tDCS patients reported mild side-effects. Of all initially included 17 patients, 23.5% (n = 4) withdrew their study participation with highest proportion in the cathodal group (n = 3). A sample size calculation for a confirmatory trial revealed 120 patients using conservative estimations.Altogether, 17 patients were randomized into three groups with different stimulation protocols. Relative reduction of pain intensity in per protocol treated patients were median 73%, 50% and 69% in anodal, cathodal and sham group, respectively (This pilot trial does not support series of anodal tDCS as neuro-modulatory treatment to enhance pain alleviation of local anesthetic infiltration series. Notably, results may indicate placebo effects of tDCS settings. Feasibility of studies in this population was limited due to relevant drop-out rates. Anodal tDCS warrants further confirmation as neuro-modulatory pain treatment option. Chronic< 0.001) . Further< 0.001) –12.Recent fMRI studies support the use of infiltration series, since they change resting state functional activity in domains relevant for pain. Single infiltrations seem to facilitate small network changes  which main vitro and in vivo studies suggest long term central changes of repetitive transcranial direct current stimulation (tDCS) mediated by metaplasticity rather than long-term potentiation or depression as discussed earlier in the literature . T. Tin vitterature , oro-facterature . Treatmeterature  and moduterature , 26. A rterature . A diffeterature .tDCS has been used in studies in a variety of conditions focussing on pain, neurological and psychiatric diseases . A higheDepending on polarity, tDCS either enhances  or reduces  motor cortical excitability measured in motor-evoked potentials (MEP) , 30. ThoNot only the direction of the current but also the electrode montage is critical in tDCS . In painSince it appears to be safe, the use of tDCS additional to other treatment is common . For insTherefore, this pilot study was performed to investigate trial feasibility, individual course of pain and pain relief, associated symptoms and side effects of tDCS and subsequent local infiltration series in patients with refractory cranial neuropathic pain syndromes.13. Painful lesions of the cranial nerves and other facial pain, e.g., trigeminal-neuralgia, post-herpetic trigeminal neuralgia, persistent idiopathic facial pain (PIFP)] was mandatory . Patients fulfilling inclusion criteria were offered to participate in the study to receive additional tDCS application before each local infiltration. Eligible patients were asked for written informed consent. All infiltration series were performed as part of a multi-modal therapy concept following current recommendations , 43. ThiPatients were planned to receive 10 consecutive sessions of the infiltration and stimulation series with 48–72 h between each session following recommendations for long-lasting after-effects , 46–48. The primary outcome parameter was relative pain intensity reduction after completion of therapy series  measured in NRS score as a numeric value between 0 and 10. The secondary outcome parameter include absolute and relative pain reduction measured in NRS score after completion of tDCS stimulation vs. initial NRS score measured before stimulation and time until patients need additional regional-anaesthesiological interventions. The number of required regional-anaesthesiological interventions to achieve sufficient pain reduction and the analysis of adverse reaction  were other secondary outcome parameter.post-hoc sample size calculation was conducted.We further evaluated patients' conditions, the used blockade technique, the response rate and the effect of sole tDCS stimulation. In addition to that, analyses of side-effects, drop-outs, self-assessment and a For pain assessment, two assessment tools were used: the pain assessment protocol for infiltration series and the German Pain Questionnaire . The as® with saline soaked, square sponge electrodes (surface 25cm2) similar to Nitsche and Paulus et al. .In the active groups , stimulation started with an initialization phase with increasing current over 30 s. Afterwards, tDCS with 2 mA was applied for 20 min, following a phase with decreasing current over another 30 s. In the sham group, patients received increasing and immediately decreasing current at the beginning and similar application at the end of the stimulation for the purpose of blinding.®. A block-randomization was used with blocks of six to ensure comparable group sizes in case of early stop of the study. Randomization was performed using a computer-generated random list for patient allocation with four blocks with size of six provided by study statistician. After inclusion, patients were treated following the randomization list. For allocation concealment, block sizes and study randomization list were prepared blinded to study physicians.This study was performed in a triple-blinded setting. The patient, the tDCS applying physician and the person performing statistics were blinded to group allocation. Blinding of tDCS was performed using the study mode of the NeuroConn DC StimulatorTo explore the intrinsic effect of the stimulation setting, we compared tDCS patients with patients without tDCS obtained in a historic cohort  with thvia telephone calls using the German Pain Questionnaire  and infiltrations at the N. occ. major [n = 1 (7.7%)] were seldom reported as main infiltration site. For SPG blockade local anesthetics (2–3 ml bupivacaine 0.25%) was applied via infra-zygomatic injection. For GLOA infiltration, lipophilic opioids and local anesthetics (5 ml 0.5% bupivacaine and 0.03 mg buprenorphine) were injected close to paravertebral cervical ganglions. In patients with mononeuropathic pain patterns, nerve blocks with local anesthetic  were used. Included patients received 2–10 infiltrations and stimulations in a series with median 9 infiltrations and stimulations (IQR 6–10). All 13 per-protocol treated patients received 20 min of tDCS before each infiltration in the series.Most patients received a blockade at the sphenopalatine ganglion (SPG) p = 0.249). Throughout series, there was a significant overall decrease of NRS scores in treated patients (before median 7 (IQR 5.00–9.50), at the end of series median 3 (IQR 1.00–4.00), p < 0.001; see The NRS score before infiltration and stimulation series for per-protocol patients were at median 7 (IQR5.00–9.50). There was no significant difference between dropouts and non-dropouts (p = 0.181). NRS scores decreased in all three study groups throughout series. The anodal stimulation group started with lowest NRS scores before series 5.50  and achieved lowest NRS scores after series 1.00 , resulting in the highest relative NRS reduction throughout series of 73.33% . The cathodal stimulation group had higher NRS scores before series 9.00  and after series 4.00  and, thus, lowest relative NRS reduction 50.00% . The NRS scores in the sham group before series were 7.50 , after series 2.50  and a consequent relative NRS reduction of 68.75% . The relative NRS reduction throughout series did not differ significantly between the study groups . Odds ratio in the anodal group for 50% NRS reduction was 1.667 (CI 0.074–37.728) and in the cathodal group 0.667 (CI 0.025–18.059) compared with sham group.76.9% of patients had a 50% NRS reduction throughout series. Response of 50% NRS reduction was highest in anodal group (83.3%), followed by sham group (75.0%) and cathodal group (66.7%). Differences in response rate were non-significant (p = 0.644).The time to the event of 50% NRS reduction was at Median 3 sessions (IQR 2–3). The time to event was shortest in the cathodal group , followed by sham  and anodal group . Differences in time to event were not significant between stimulation groups . Nevertheless, no difference between anodal, cathodal or sham stimulation was noted (p = 0.482).Overall, there was a significant immediate effect of tDCS before performance of local anesthesia on pain intensity: NRS scores were reduced in median 1 point  reported some kind of side-effects due to tDCS. A prickling  or burning sensation  was the most common side-effect. Mild local pain  and skin redness  was reported seldom. No patient reported increased headache due to stimulation. There was no severe side-effect or reported drop-out due to side-effects.Of included per-protocol treated patients, 76.9% (n = 3) group followed by the sham group (n = 1). No patient dropped out of the anodal group.Four patients dropped out of the study. One reported psycho-social distress not related to the study as the reason for dropout. One patient reported non-sufficient effect of the infiltration and two did not report a reason. Notably, most patients dropped out of the cathodal  and stimulation group  were not significant (p = 0.054). A higher proportion of responders with 50% NRS reduction was noted in group with stimulation setting  than in non-stimulation group , three-month follow-up time point (p = 0.626) and 6 month follow-up time point (p = 0.835). There was as well no statistically significant difference in tDCS study groups regarding average pain measured in NRS at 1 month follow-up time point (p = 0.404), 3 month follow-up time point (p = 0.618) and 6 month follow-up time point (p = 0.632).There was no statistically significant difference in tDCS study groups regarding maximum pain measured in NRS at 1 month follow-up time point ; sham median 1 (IQR 0.25–1.75), cathodal median 5 (IQR 2–5); p = 0.231] and endurance of pain  cathodal stimulation apparently showed worse scores. At both, 3 and 6 months follow-up, we observed no statistical differences in impairment in daily activities, mental distress and endurance of pain.At 1 month follow-up, there was a significant difference in mental distress between subgroups with cathodal stimulation group having the highest rating in impairment [anodal median 3 (IQR 0–8); sham median 0 (IQR 0–0); cathodal median 8 (IQR 5–8); n = 1, sham n = 1 and cathodal n = 1) and the time to the series  did not differ between subgroups (p = 0.368).In total, three patients received additional local infiltration series outside the study after completion of stimulation and infiltration series. The patients with additional series were equally distributed among the study groups .To determine patient blinding, patients were asked in a self-assessment to which group they belong. Group assignment and self-assessment to active or sham stimulation did not show any statistical association   . This st= 0.008) .Effects of tDCS on pain could be partly attributed to changes in endogenous inhibitory pathways . In a poA reduction of 50% pain intensity is common as a description for successful treatment and used in this study , 16, 66.It has been reported that invasive procedures might have more powerful placebo effects than less invasive procedures. Expectancy is one of the most powerful causes of placebo effects. Infiltration and stimulation with tDCS enhances expectations regarding pain relief . FurtherAlthough providing insights into tDCS for chronic neuropathic pain patients, this pilot study has some limitations. Especially the small sample size in pilot studies limit generalizability of results. Furthermore, individual pain perception differs between patients and other outcome measurements like change in medication would be an interesting variable to include in future protocols . In addi®. There was no connection noted between the self-assessment of patients and the actual study group. Thus, our results support the use of an increasing and decreasing current at the beginning and end of a sham stimulation to imitate effects of tDCS. This goes with the results of the study by Gandiga et al. who described this sham procedure. In their pooled data analysis including several studies over 3 years with 170 stimulation sessions, there was no difference in the incidence of side-effects between tDCS and sham groups . The patients provided their written informed consent to participate in this study.JDW: acquisition of data, analysis and interpretation of data, creating of all figures and tables, drafting the article, revising the article critically for important intellectual content, and final approval of the version to be published. JK: acquisition of data, revising the article critically for important intellectual content, and final approval of the version to be published. TF: conception of study, revising the article for important intellectual content, and final approval of the version to be published. CD: revising the article for important intellectual content and final approval of the version to be published. MS: giving advice to conception and design of study, revising the article critically for important intellectual content, and final approval of the version to be published. ST: conception and design of study, analysis and interpretation of data, revising the article critically for important intellectual content, and final approval of the version to be published. All authors contributed to the article and approved the submitted version.


Chronobiology is the science of how physiological processes in the body follow a pattern of time. Pain has been shown to follow a circadian rhythm, with different types of pain having variable expression along this rhythm.This article reviews the nature of diurnal variations in pain along with a discussion of the mechanisms of circadian rhythm of pain.We conducted a literature search on the PubMed and Google Scholar electronic databases, through April 2022. Publications were screened for English language, full‐text availability, and human subjects. Randomized controlled trials and observational trials were included. Data were extracted from studies on patients with acute or chronic pain phenotypes, which provide pain severity data and corresponding diurnal time points.The literature search led to the inclusion of 39 studies. A circadian pattern of pain was found to be present in nociceptive, neuropathic, central, and mixed pain states. Postoperative pain, fibromyalgia, trigeminal neuralgia, and migraines were associated with higher pain scores in the morning. Temporomandibular joint pain, neuropathic pain, labor pain, biliary colic, and cluster headaches increased throughout the day to reach a peak in the evening or night. Arthritis and cancer pain were not associated with any circadian rhythmicity. Furthermore, the circadian rhythm of pain was not found to be altered in patients on analgesics.The results of this review suggest that an understanding of diurnal variation may help improve therapeutic strategies in pain management, for instance through analgesic titration. Chronobiology is the science that studies how physiological processes in the body follow a pattern of time. The suprachiasmatic nucleus (SCN) in the brain is considered to be the principal clock driving the human body.The circadian pattern of pain has been demonstrated in both animal and human studies.Clinically, the chronobiology of pain has been poorly studied, especially in states of acute pain. This review aims to provide an updated compilation of circadian rhythms of pain described clinically in both acute and chronic pain conditions, as well as touch on known contributory mechanisms, in humans and rodents alike. A better understanding of the chronobiology of pain would enable using knowledge of this phenomenon to aid in the development of therapeutic strategies.We conducted a comprehensive bibliographic search on the PubMed and Google Scholar electronic databases, through April 2022. Additional records were identified and assessed from recently published reviews. Data extraction was focused on chronobiology in both acute and chronic pain conditions. The search was conducted using the following strategy: (pain) AND ((chrono‐) OR (circadian) OR ). Publications were screened for English language, full‐text availability, and human subjects.Authors A.N., I.P., A.P., and B.B.R. independently reviewed the titles, abstracts, and full texts according to the inclusion criteria. Consensus between authors was sought in case of discrepancies for the inclusion or exclusion of studies. Data from the resulting 39 publications were synthesized and presented in this review organized by type of pain.We included both randomized controlled trials and observational trials, including prospective and retrospective analyses of cohort, cross‐sectional and crossover study designs. Case reports and review articles were not included. Studies must include human patients with acute or chronic pain phenotypes. Our primary outcome was pain severity data and corresponding diurnal time point(s). The data extracted also included the study design and number of participants. The literature search and screening results are described in Figure Authors A.N. and I.P. independently assessed the risk of bias using the Agency for Healthcare Research and Quality checklist.A visual representation of the chronobiology of acute pain phenotypes discussed is seen in Figure p < 0.0001).Women with labor pain were found to experience more pain in the morning than in the evening. A cohort study with 222 first‐time pregnant women carrying singleton vertex pregnancy, spontaneous onset labor, cervical dilatation (3–5 cm), ruptured membranes, and normal fetal heart rate tracings were grouped into four different time periods and asked to rate their pain on a visual analogue scale (VAS) at the time of referral to anesthetist for epidural anesthesia. A circadian rhythm was observed with pain in the morning being less than in the afternoon and evening. Women who experienced labor pain in the morning from 07:00 to 13:00 had an average VAS of 75.6 when compared to 87.6 for women in evening , the intensity of pain in the early stage of labor  before receiving PCEA was significantly higher at night. It was also observed that the latency period was longer during the night and the duration of the pharmacologic effect was longer during the day. When pharmacological effects and analgesic consumption during labor pain were assessed via VAS, labor pain was significantly greater during the night than daytime. Additionally, longer latency periods of labor as well as shorter duration of pharmacological effect of analgesics at night were reported.p < 0.001) levels of labor pain before epidural analgesia in evenings (6.95 ± 2.4) and nights (7.38 ± 2.2) than mornings (6.67 ± 2.5) and afternoons (6.49 ± 2.7).p < 0.01).A very large cohort study including 1657 pregnant women showed significantly greater  with the peak pain at 00:25. Only 40% of study subjects reported that the pain was related to a meal, thus it is not exclusively related to the effect of the evening meal causing a late‐night peak in the biliary colic.Fifty patients who underwent emergency or elective cholecystectomies for symptomatic biliary tract stones were interviewed in their first postoperative week for variables such as time of pain onset, location, duration, and number of pain episodes. Variables were collected to describe pain episodes both pre‐ and post‐surgery. The pain was found to follow a circadian periodicity . A similar analysis for morphine requirements was significant for increase in morphine consumption on postoperative day two at 08:00 and 12:00 when compared to that at 16:00 and 20:00 (p < 0.05). However, no significant variation in morphine requirement was found on postoperative day one.There has also been a considerable interest in the variation of analgesic requirements in postoperative pain. A temporal variation in postoperative pain was described among women who underwent hysterectomies, in a low risk of bias RCT including 103 patients. Different types of pain were studied including rest pain, pain evoked by sitting, pain by forced expiration, and pain by coughing. On postoperative day 1, all types of pain were at a maximal intensity at 08:00 when compared to the pain experienced at 12:00, 16:00 and 20:00  required a higher dose of anesthetic drugs than evening operations (18:00–22:00). Additionally, evening surgeries were associated with more sleep disruptions, which may increase postoperative pain perception.A prospective, randomized clinical trial was conducted to compare postoperative outcomes in 44 patients who underwent either morning surgery, characterized by high cortisol levels, or afternoon surgery, characterized by low cortisol levels. The results of the study showed no significant difference between groups in terms of pain scores at any time point. Compared to morning surgery, however, afternoon surgery allowed for a more rapid recovery of cortisol levels to baseline, and lower IL‐6 and Il‐8 levels in the first two postoperative days.In summary, postoperative pain appears to be highest in the morning and lowest in the evening.A visual representation of the chronobiology of chronic pain phenotypes discussed is seen in Figure In a study conducted among 133 patients with temporomandibular disorders in a 2‐week period, patients recorded pain on a VAS. For most patients (79%), pain intensity was found to be highest late in the day (before dinner or bedtime). For the rest of the patients (21%), pain was found to be highest early in the day.2 per second. The patient was asked to report the moment when the sensation at the examination site changed from that of pressure to that of pain. The reported dolorimetry score is the mean of the sites examined.2 for men.2.In fibromyalgia (FM), pain was found to be most severe in the morning compared to the afternoon. In a study of 21 female patients with FM, subjects were asked to document their pain on a VAS at 6 specified time points for 10 consecutive days. Data were analyzed for 24‐h and 7‐day time effects, and for diurnal and weekly rhythms using the cosinor technique.p = 0.001) in aMT6s levels over the 24‐h period confirming a disruption in circadian rhythmic secretion of aMT6s. During daytime hours (06:00–18:00), FM subjects secreted 41.54% of their daily aMT6s secretion load while the healthy control group only secreted 20.73%. Higher secretion levels during night periods (24:00–6:00) correlated to overall lower depressive symptoms. Higher secretion during the hours of 6:00–18:00 correlated to more trigger points and a lower quality of sleep. A multivariate linear regression model was created using pain pressure threshold measurements as the dependent variable. Using the Bonferroni test, a negative correlation between pain pressure threshold and aMT6s levels was observed between 6:00 and 18:00. During the same time interval, a positive correlation between the number of trigger points and aMT6s levels was found.In a 2019 study, aMT6s (a melatonin indicator found in urine) secretion levels in 18 patients with FM were compared to healthy patients using the pain pressure threshold as the primary outcome.ρ: 0.49, p = 0.03; ρ: 0.67, p = 0.001).Fibromyalgia and major depression disorder (MDD) have common symptoms and markers in the hypothalamic–pituitary–adrenal axis and autonomic dysregulation systems (both help regulate stress).In summary, fibromylagia pain appears to be highest in the morning.p < 0.05).p = 0.013). Pain was found to have a bathyphase value of at least 16:10.The circadian rhythm of pain was found to be different in rheumatoid arthritis (RA) when compared to osteoarthritis (OA). RA patients had a peak onset of their pain in the morning, whereas the pain from OA got worse as the day progressed.p < 0.005) and late morning . Furthermore, patients showed lower levels of pain intensity in the late afternoon than the late morning (p = 0.22).In a large and low risk of bias clinical trial, Zhang et al. studied circadian rhythm of knee pain in 241 patients with knee OA in different testing sessions including 8:00–10:00, 10:00–12:00, 13:00–15:00 and 15:00–17:00. Based on VAS, patients in this study showed lower levels of pain intensity in the early afternoon (13:00–15:00) compared to the early morning , between 2 and 8 p.m. (n = 19), or between 8 p.m. and 8 a.m. (n = 8). In 23 patients, a bimodal circadian profile was seen, with both a morning and an evening peak. In 4 of the 66 patients, self‐rated pain intensity varied little throughout the day.Levi et al performed a double‐blind, crossover trial on 66 patients with hip or knee osteoarthritis. About half of the patients, a unimodal circadian profile was noted, with a single peak between 8 a.m. and 2 p.m.  that causes joint damage and inflammatory pain.Rheumatoid arthritis usually results in worse symptoms in the morningn = 10) used an actigraph and sleep diary at home for 1 week, followed by a 24 h stay at the clinical research facility. Non‐circadian conditions were set for standardized neutral light, entertainment, nutrition, and prescribed inactivity. PBML, saliva, and serum were collected at 06:00 and 18:00.A 2019 study by Poolman et al.To summarize, arthritis pain does not show a clear association with a circadian pattern. It is frequently bimodal, and one or more peaks may occur throughout the daytime.p < 0.0001). The pain scores were again analyzed when patients were on analgesics, and it was noticed that the diurnal variation of pain was maintained even when patients were treated with analgesics (p < 0.0001). In patients undergoing treatment, two‐way measures by analysis of variance (ANOVA) revealed a significant time of day (p < 0.001) and a significant effect of treatment (p = 0.004), but there was no interaction between the two (p = 0.38).Neuropathic pain such as diabetic neuropathy (DN) and postherpetic neuralgia (PHN) was also shown to exhibit a diurnal variation of pain. In a double‐dummy , 4‐period, crossover comparison study, 85 patients were randomized and then assigned to one of the predetermined sequences which included treatment with a placebo, gabapentin, morphine, and morphine‐gabapentin combination. Each treatment period was 5 weeks long including 3 weeks of dose titration, 1 week at maximum tolerated dose and 1 week of tapering and washout. Patients were asked to rate their pain on a numerical rating scale (NRS) at 08:00, 16:00, and 20:00, from 7 days before the study until the end of the study. The circadian nature of the pain was analyzed from the baseline data which patients recorded 7 days prior to beginning the study. Thirty‐four out of 55 patients having DN and 26 out of 30 having PHN showed a temporal relationship, with pain worsening throughout the day from 08:00 to 20:00  were randomized to receive treatment with gabapentin, nortriptyline and a gabapentin‐nortriptyline combination in a predetermined sequence. Patients recorded their pain on a numerical scale at 08:00, 16:00 and 20:00, 7 days before starting the study and continued the same until the end of study. The treatment data came from 47 patients. It was found that the pain score increased throughout the day, during the pretrial baseline and also during the treatment with the drugs.Tomson et al. performed a cohort study including seven patients with idiopathic trigeminal neuralgia, a form of neuropathic pain affecting the trigeminal nerve in the face. Of note, all patients included were receving carbamazepine treatment. The study found that the frequency of pain attacks was lowest during night hours (23:00–5:00) and highest during the morning (8:00–11:00).In summary, neuropathic pain appears to be highest in the evening, and lowest in the morning. Trigeminal neuralgia shows a different pattern, with the highest pain levels in the morning, and lowest at night.p < 0.05).p < 0.001).In a low risk of bias cohort study of 15 patients with migraines taking place over 20 weeks, a total of 211 migraines were documented. The incidence of migraine onset from 06:00 to 12:00 was 3.3 times greater than the incidence during other 6 h periods (p < 0.001) and the second peak in the early morning .A study on female patients, including 58 patients prospectively recorded migraine attacks for 12 consecutive months with a total of 2314 attacks. The pain was found to peak around 13:40 and the peak/low ratio was 25.6 (95% CI:8.3–78.6).A large cohort study on 786 migraine patients found that the frequency of migraine attacks is higher throughout the day, with peaks at 10:00 and 22:00. Attacks were less frequently noted at night (3:00).A more recent RCT on 61 migraine patients did not identify differences in mean pain levels between morning and afternoon.In summary, migraine pain and frequency appears to be highest in the morning, and lowest between between late evening and nighttime.p = 0.0005).Thirty‐one patients were assessed for tension headaches using a computerized ecological momentary assessment. It was found that the intensity of tension headaches was significantly lower in the morning and the peak was in the late afternoon .In a study with 1134 patients, 58% of patients had attacks between 19:00 and 07:00, with the majority of patients showing a peak between 24:00 and 03:00, and 41% of responders showing a peak at 02:00 , and the lowest rates were noted around late morning and early afternoon (10:00–14:00). A third of patients noted no rhythmicity.In summary, cluster headache pain and frequency appear to be highest at night, and lowest in early afternoon.p < 0.001). In cancer patients on chronic opioid therapy, a similar pattern was seen, with patients experiencing more breakthrough pain in the morning hours when compared to the evening. For further analysis, cancer patients were split into two subgroups, based on whether they had visceral or bony metastasis and the circadian nature of pain in both groups was characterized separately. In patients with bony metastases, the acrophase was found to be at 9:45 (p < 0.0001) and in patients with visceral metastasis the acrophase was at 10:30 (p < 0.001).A 2019 article found that chronobiology plays a prominent role in the circadian physiology of cancer, through genes that control potentially painful oscillation processes.p < 0.001). For patients with bone metastases, acrophase was 12:15 (p < 0.001) and patients with visceral metastases acrophase was 12:30. For patients with an Eastern Cooperative Oncology Group (ECOG) performance score of 3 or higher, acrophase was at 13:00 (p < 0.01). For patients with an ECOG score of less than 2, acrophase was at 12:15.In a more recent study, cosinor analysis showed a similar circadian rhythmic pattern of BTP episodes. Ninety‐two subjects with life expectancies of less than 120 days were analyzed . The acrophase of all patients was 12:30 (p < 0.001) and patients with delirium required more analgesia in the evening and at night (p = 0.02).Patterns of breakthrough pain in cancer patients with delirium were found to be different. In a retrospective analysis of data collected for prospective study, circadian rhythm of breakthrough analgesia was different in 104 patients with or without delirium. Patients without delirium needed more analgesia in the morning (p = 0.34).In a randomized, double‐blind, crossover, placebo‐controlled study of 42 patients with advanced cancer, the sustained release of a once‐daily morphine sulfate (MS) dose in the morning versus evening had been studied.A much earlier study from 1976 showed intractable pain due to cancer to linearly increase throughout the day with maximum pain experienced at 22:00. Forty‐one patients  reported their pain every 2 h from 8:00 to 22:00, on a VAS for 7 consecutive days.To summarize, cancer pain and breakthrough pain do not show a clear circadian rhythmicity based on current available evidence.The aim of this review was to synthesize circadian pain patterns of human pain conditions. As a result, postoperative pain, fibromyalgia, trigeminal neuralgia, and migraines showed higher pain scores and episode frequency in the morning. In the afternoon, tension headaches could be expected in higher frequency. Temporomandibular joint pain and neuropathic pain were typically worst in the evening. At night, labor pain, biliary colic pain, and cluster headaches exhibited higher pain scores and episodic frequency. Furthermore, the circadian rhythm of pain was not found to be altered in patients on analgesics. On the other hand, different forms of arthritis and cancer pain were not associated with any circadian rhythms.It must be noted that the studies included here are largely observational, many of them several decades old. The risk of bias assessment aims to qualify how studies address some intrinsic limitations of such studies, such as uniformity of the study population, and efforts to obtain natural measurements at all times of day. Nonetheless, the majority of included studies did not exhibit a significant risk of bias, and there was very little variability between the patterns identified in different studies, increasing confidence in the results of this review.Several recent reviews have been published concerning mechanisms of circadian variation of pain, such as the one by Bumgarner et al.In the following discussion, we touch on a few additional circadian mechanisms of pain that have been studied, mostly in animals. As expected, the trends in the studies below do follow the circadian trends in the rest of the review.p = 0.03) when compared to males, and the variation was also more prominent in DN when compared to PHN (p = 0.03).To evaluate clinical factors affecting the circadian variation of pain, data from two previous double‐dummy crossover clinical trials conducted in patients with neuropathic pain were pooled together. In both of the trials, which were described before, patients were asked to rate their pain three times daily at 08:00, 16:00 and 20:00 starting from 7 days before the trial until the end of the trial. The degree of diurnal variation was defined as a difference in pain intensity between 08:00 and 20:00 averaged over 7 days. The baseline data from the preclinical time period were subjected to bivariable analysis order to find out the effect of sex, age, etiology, severity of short‐form McGill pain questionnaire (SF‐MPQ) pain quality and allodynia with respect to degree of diurnal variation. Among the many clinical factors only sex and etiology were found to be significant enough to be included in a multivariable analysis. The diurnal variation of pain was more prominent in females  are most effective in managing postoperative pain, healing and recovery when drug administration is limited to the active phase of the circadian rhythm. Several genes involved in the circadian clock pathway are upregulated, such as Per2, Nr1d1 and Nr1d2 were upregulated in mice who received NSAIDs during the active phase, compared to the resting phase.p < 0.05).A study on opioid secretion in humans was conducted where blood was collected from seven male volunteers via a polyethylene tube inserted between lumbar vertebrae. Plasma was sampled for endogenous opioids, demonstrating a peak in the morning and nadir in the late evening . Circadian rhythm was shown to present by analysis of variance in plasma (p = 0.0002).A study conducted in six healthy adult volunteers showed a circadian pattern in the plasma levels of beta‐endorphin levels with a peak level at 08:00 (6.5 ± 0.5 fmol/ml) and the trough levels at 20:00 (3.7 ± 0.6 fmol/ml).In the case of dental pain, studies have been demonstrated the presence of peripheral clocks in the production of dental pulp, periodontal tissues, oral mucosa, enamel, dentin, and mandibular bone.One group demonstrated that there is a circadian variation in opiate receptor binding in the forebrain of rats. A peak of opioid receptor binding was found at 22:00 during the activity period and a trough at 02:00.One animal study used RNA sequencing profiles to investigate gene networks involved in the circadian rhythm in mice with chronic morphine exposure. The results show that circadian rhythm processes were enriched among the genes oveexpressed in mice with opioid‐induced hyperalgesia relative to control mice.period of circadian rhythms.The neurotransmitter substance P modulates sensitivity to pain by activating the neurokinin‐1 (NK‐1) receptor.For a recent, in‐depth review of mechanisms connecting sleep and the circadian rhythm to neuropathic and inflammatory pain, headaches, and analgesia, see Palada et al.In a study done to determine the cause of sleep disturbances in neuropathic pain, mRNA expression of melatonin receptors in the hypothalamus was found to be altered in mice with sciatic nerve ligation. The mRNA expression of the melatonin receptor was studied in sham‐operated mice and in mice which underwent sciatic nerve ligation by reverse transcription polymerase chain reaction. Sciatic nerve ligated mice which exhibited thermal hyperalgesia, increased wakefullness and decreased nonrapid eye movement (NREM) sleep at 02:00, when compared to sham operated mice.Administration of melatonin has been demonstrated to produce antinociceptive effects in acute neuropathic and inflammatory pain.Due to pragmatic and ethical limitations, at this stage, most human studies associating pain with circadian patterns remain observational, with restricted possibility of carrying out repeatable, genuine, scalable multivariate experimentation. While it remains almost impossible to connect all circadian rhythmicity to all mechanisms for pain behaviors, there is a compelling amount of correlation between human chronobiology and pain patterns. A circadian pattern of pain was found to be present in nociceptive, neuropathic, central and mixed pain states. Postoperative pain, fibromyalgia, trigeminal neuralgia, and migraines were associated with higher pain scores in the morning. Temporomandibular joint pain, neuropathic pain, labor pain, biliary colic, and cluster headaches increased throughout the day to reach a peak in the evening or night. Arthritis and cancer pain were not associated with any circadian rhythmicity. Furthermore, the circadian rhythm of pain was not found to be altered in patients on analgesics. The results of this review suggest that there may be benefits in further studying the potential benefits of staggered dosing.The authors have no conflicts of interest to declare.


Pain scores were comparable between EA and CWI plus PCA or CTPVI on POD1 and POD2. Pain scores were comparable between EA and ITM on POD1. The procedure-related complications and length of hospital stay were not significantly different according to the type of analgesia. Conclusions: EA provided lower pain scores compared with PCA on the first postoperative day after pancreatoduodenectomy; the length of hospital stay and procedure-related complications were similar between EA and PCA. CWI and CTPVI provided similar pain relief to EA.Background: This systematic review explored the efficacy of different analgesic modalities and the impact on perioperative outcome in patients undergoing pancreatoduodenectomy. Methods: A systematic literature search was performed on PubMed, Embase, Web of Science, Scopus, and Cochrane Library Database using the PRISMA framework. The primary outcome was pain scores on postoperative day one (POD1) and postoperative day two (POD2). The secondary outcomes included length of hospital stay (LOS) and specific procedure-related complications. Results: Five randomized controlled trials and ten retrospective cohort studies were included in the systematic review. Studies compared epidural analgesia (EA), patient-controlled analgesia (PCA), continuous wound infiltration (CWI), continuous bilateral thoracic paravertebral infusion (CTPVI), intrathecal morphine (ITM), and sublingual sufentanil. The pain scores on POD1 ( The postoperative pain after open pancreatoduodenectomy (PD) is significant owing to big incisions and extensive abdominal dissection associated in many cases with preoperative pain and opioid use prior to surgery ,2. InadeEpidural analgesia (EA) using either continuous epidural or patient-controlled administration and intravenous opioid analgesia ) are still the most popular techniques for analgesia following pancreatoduodenectomy. Thoracic EA provided better pain control with less perioperative opioid consumption ,7,8,9,10On the contrary, intravenous PCA, one of the most common strategies for pain relief following pancreatoduodenectomy, offers effective pain relief, but with higher opioid consumption. Furthermore, it does not promote hypotension; consequently, the need for vasopressors and fluids is lower than EA ,12,27,28Continuous infusion of local anesthetic par transabdominal wound catheter or wall catheter (transversus abdominis plane block) associated with PCA provides effective pain relief in major abdominal surgery, reduced opioid consumption, and the risk of complications such as hypotension and block failure compared with EA ,32. The Single-shot intrathecal morphine (ITM) is an effective strategy for postoperative analgesia following abdominal surgery, having a prolonged duration of action and higher potency . ITM redSublingual sufentanil tablets (SSTs) as an alternative to EA seem to be an attractive analgesic option for pain management in major abdominal surgery and pancreatic surgery ,46.The present systematic review and meta-analysis aimed to summarize and compare the efficacy and safety of different analgesic modalities in patients undergoing pancreatoduodenectomy.This systematic review and meta-analysis were reported in accordance with the recommendations from the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines . No prioThe inclusion criteria were randomized controlled trials (RCTs) or observational cohort studies published in English language that compare two or more analgesic techniques and reported at least one outcome of interest.Studies that included minimally invasive cases (laparoscopic or robotic) or those that included open pancreatic resection  were excluded unless subgroup analysis of pancreatoduodenectomy was available. Case reports, conference abstracts, previously reported systematic reviews, studies with no full text available, and studies with fewer than ten patients were excluded too.We performed a systematic search of the electronic databases PubMed, Embase, Web of Science, Scopus, and Cochrane Library Database from 1 January 1995 through 1 October 2022. The following search terms were used  AND . The complete literature search is provided in Two independent reviewers  screened the titles and abstracts of all articles for relevance. Eligible full-text articles were subsequently reviewed by two other independent reviewers . In case of any disagreement between the two reviewers, a third reviewer (L.M.) helped make the selection. Manual screening of the reference lists in relevant articles was conducted to identify any additional articles.Data were extracted by two independent reviewers directly from articles . The following study characteristics were collected: country, study type, recruitment dates, centers, type of pancreatic resection, and analgesic modalities.The primary outcome measures were pain scores on postoperative day 1 (POD1) and day 2 (POD2). Pain scores were rated on the numerical rating scale (NRS) from 0 to 10, where 0 indicated no pain and 10 correlated to the worst pain possible. In articles that used VAS, these were converted to the corresponding number on the NRS .The secondary outcome measures included length of hospital day (LOS) and specific complications: postoperative pancreatic fistula, bile leakage, delayed gastric emptying (DGE), postoperative ileus, and gastrointestinal bleeding.All studies included in the final analysis were assessed by two reviewers  The risk of bias was evaluated using the Cochrane Risk-of-Bias tool 2.0  for RCTsThe meta-analysis was performed using R environment for statistical computing and graphics , version 4.1.2 , and thep-value of <0.05 was considered significant. The possible publication bias risk was assessed by the Egger test.For qualitative outcomes, the number of events and the total number of subjects in both intervention groups were extracted. For quantitative outcomes, the mean and SD were extracted. Data presented in the graphs of articles were extracted by Web plot digitizer . SeveralThe literature search identified 1903 studies. After duplicate removal and screening of titles and abstracts, 1775 studies were excluded because of irrelevance for this study. Details of the screening process are illustrated in Finally, 10 studies were included in the meta-analysis ,27,40,43n = 9), New Zealand (n = 1), Netherlands (n = 3), Italy (n = 1), and other parts of Europe (n = 1) and were published between 2008 and 2022. The characteristics of the studies are detailed in Overall, 2556 patients were included who underwent pancreatoduodenectomy. Studies were conducted in the USA (Nine articles compared iv opioid (PCA) analgesia to epidural analgesia (EA) ,23,24,27The results of the risk of bias assessment are presented in Pain scores on postoperative days 1 and 2.Seven studies ,23,24,27n = 166, EA = 404), of which one study was an RCT [p < 0.001) (p = 0.091) and it was explored with a leave-one-out sensitivity analysis (p = 0.001), which was statistically significant. The randomized study observed higher differences compared with non-randomized designs.Pain score on POD1 was reported in five studies ,18,23,24s an RCT ,18,24. T< 0.001) a. There analysis . No mattn = 255, EDA: n = 492), and reported pain scores on POD2. The mean pain score was higher in the PCA group compared with the EA group, but not statistically significant  (p = 0.05). In the leave-one-out sensitivity analysis  b. The heanalysis , the resp = 0.30), but a higher pain score in the PCA group versus the EA group, on POD2 .One retrospective cohort study  reportedp = 0.08) and POD2 . In an RCT of 48 patients [p = 0.67) and POD2 (5 (0–10) versus 5 (2–8), p = 0.92).One RCT  comparedpatients , compariAn RCT  of 21 pap = 1) (p = 0.007) (A retrospective study of 180 patients  comparedp = 1) a. On POD= 0.007) b. ITM paBurchard et al.  comparedLength of stay (LOS) was reported in 1918 patients included in seven studies. Five studies ,17,24,27p = 0.55) (p < 0.001). The heterogeneity was explored with a leave-one-out sensitivity analysis  a. A signanalysis . The stup = 0.3) (p = 0.17).There was no significant difference between ITM and EA  b. A modep < 0.0001). There was no significant difference regarding LOS between EA and bilateral thoracic paravertebral continuous infusion [Another retrospective study  of 233 pinfusion .p = 0.82) (p = 0.13).The analysis of postoperative complications such as pancreatic fistula was reported in six retrospective studies ,20,22,24 = 0.82) a. The hep = 0.53; I2 0%)   (p = 0.75) (p = 0.23) was found in the gastrointestinal bleeding analysis. One RCT [The bile leakage was analyzed in one RCT  and four; I2 0%) b. Delaye, I2 0%) c. There ; I2 0%) d and gas = 0.75) e between One RCT  and two  One RCT ,20 and g One RCT ,17 analyp-values above the threshold of significance.The Egger test, for all analyses, had The present systematic review and meta-analysis of analgesic management in patients undergoing pancreatoduodenectomy demonstrated that intravenous opioid analgesia (PCA) provided higher pain scores on postoperative day 1 compared with epidural analgesia. However, when continuous wound infiltration was added to opioid systemic analgesia (PCA morphine) and compared to epidural analgesia, no significant differences in pain scores were demonstrated. Furthermore, there were no significant differences in pain scores when comparing intrathecal morphine followed by iv PCA to EA for the first postoperative day. Continuous bilateral paravertebral infusion (CTPVI) provided similar pain relief as epidural analgesia on POD1 and POD2. The surgical complications and length of hospital stay were not significantly different according to the type of analgesia. LOS was reduced when comparing ITM followed by iv opioid PCA to PCA opioid alone.In major abdominal surgery, and more relevant in upper gastrointestinal and hepato-pancreato-biliary surgery, where procedures can be disabling and most patients undergo oncologic resection, poorly controlled postoperative pain is associated with increased morbidity, delayed functional recovery, prolonged hospital stays, and reduced quality of life ,4,5.Thoracic epidural analgesia was considered for decades as a gold standard for pain relief following open major abdominal surgery, providing a reduction in rest pain, but the evidence regarding the impact on dynamic pain was not conclusive ,25,28. Ap < 0.001) between PCA and EA were observed in POD1 and can be considered to have some clinical relevance. On POD2, the mean differences in pain scores between PCA and EA were lower  and can be considered of limited clinical relevance.In our meta-analysis following pancreatoduodenectomy, when comparing intravenous opioid analgesia (PCA) to epidural analgesia (EA), we looked at the effectiveness and safety of analgesia for the first and second days after surgery. Accordingly, higher pain scores were reported in PCA on both days, but the clinical relevance of the superiority of EA analgesia was reduced. The largest mean differences in pain scores  on days 0–3 compared with intravenous opioid analgesia. A significant difference in pain score was reported on POD1 . In addition, another meta-analysis by Akter et al. [p = 0.04).Our results are similar to those presented by Groen et al.  in theirr et al.  regardinThe general benefits of epidural infusion in pancreatic surgery, regarding better postoperative pain scores than intravenous analgesia, are observed in the first two postoperative days in most of the studies ,23,24,27Despite improved analgesia, the clinical benefits of epidural analgesia in terms of reduced postoperative morbidity  and, in consequence, the length of hospital stay (LOS) showed conflicting evidence in different studies ,24,28,58In our study, we did not find any association between PCA or EA and gastrointestinal complications after pancreatoduodenectomy . Similar results regarding pancreatic fistula, ileus, bile leak, and delayed gastric emptying were reported by other meta-analyses ,57 in pap = 0.55), but LOS was slighter longer in PCA when the study of Pratt et al. [p < 0.001). The RCT of Klots et al. [p = 0.003) in 748 patients that underwent pancreatoduodenectomy. On a multivariate logistic regression analysis of the predictors for LOS, the authors [p < 0.001). Our results were comparable to those reported by Akter et al. [p = 0.38; I2 0%) were shown. However, a significantly shorter LOS after pancreatoduodenectomy, in EA compared with PCA , was reported by Groen et al. [Regarding LOS, our analysis did not find a significant difference between PCA and EA  with continuous infusion of local anesthetic as a part of a multimodal analgesic regimen. TAWCs, compared with epidural analgesia, provide a similar level of pain relief but with fewer complications ,32,34,37In the present review, one RCT  comparedA non-inferiority of continuous wound infusion plus opioid PCA versus epidural analgesia in terms of pain relief, length of hospital stays, and opioid consumption was reported by Spoto et al.  in an RCRegarding the efficacy and safety of ITM compared with EA in open hepato-pancreato-biliary surgery, a recent review  showed tSublingual sufentanil (SST) showed promising results as an analgesic option following pancreatoduodenectomy when compared with iv opioid PCA or patient-controlled epidural analgesia . In thisThere are some limitations of the present review and meta-analysis. Most of the included studies were small, retrospective, non-randomized, single-center trials; although we included five RCTs in the narrative review, only two could be included in our meta-analysis. Regarding the risk of bias, the randomized controlled trials had some concerns of bias, and one trial had a high risk of bias. The observational studies included in our meta-analysis had a moderate risk of bias, except three studies that had a serious risk of bias. The postoperative pain scores and the specific gastrointestinal complications were not assessed in all studies; thereby, a meta-analysis was possible for opioid PCA versus epidural analgesia. The pain scores with movement were not reported. In our study, for several outcomes, we found the between-study heterogeneity to range from moderate to high, being statistically significant in the pain scores on the POD2 comparison and the length of stay comparison. We explored this heterogeneity with posthoc leave-one-out sensitivity analyses and, in the case of pain on POD1, the results were robust. Because of the limited data available regarding the opioid-sparing strategy analgesia  and the intrathecal opioid analgesia in pancreatoduodenectomy, the meta-analysis of primary or secondary outcomes was not possible and was limited to a narrative review.For clinicians, the present review and meta-analysis summarized the available evidence regarding pain management following pancreatoduodenectomy. Most of the evidence is centered around the efficacy and safety of EA, PCA, and other opioid-sparing strategies such as continuous wound infusion or continuous bilateral continuous paravertebral. In addition, ITM, as a part of multimodal analgesia, has emerged as a promising alternative to epidural infusion in pancreatic surgery, offering similar analgesia with an enhanced safety profile.More large randomized controlled trials that pay close attention to limit their biases are needed to evaluate the real advantages and disadvantages of these analgesic techniques in pancreatoduodenectomy, not only on postoperative pain, but on postoperative outcomes in the settings of ERAS pathways.EA provided lower pain scores compared with PCA on the first postoperative day after pancreatoduodenectomy; the length of stay and procedure-related complications were similar between EA and PCA. Continuous wound infusion added to opioid PCA, and continuous bilateral thoracic paravertebral infusion provided similar pain relief compared with EA in the first two postoperative days after pancreatoduodenectomy.


Background and Objectives: Chronic critical illness (CCI) is a syndrome characterized by persistent organ dysfunction that requires critical care therapy for ≥14 days. Sepsis and respiratory failure constitute the two primary causes of CCI. A better understanding of this patient population and their clinical course may help to risk-stratify them early during hospitalization. Our objective was to identify whether the source of sepsis  affected clinical trajectory and prognosis in patients developing CCI. Materials and Methods: We describe a cohort of patients having acute respiratory failure and sepsis and requiring critical care therapy in the medical (MICU) or surgical (SICU) critical care units for ≥14 days. Given the relative infrequency of CCI, we use a case series design to examine mortality, functional status, and place of residence (home versus non-home) at one year following their index hospitalization. Results: In medical patients developing CCI (n = 31), the severity of initial organ dysfunction, by SOFA score, was significantly associated with the development of CCI (p = 0.002). Surgical patients with CCI (n = 7) experienced significantly more ventilator-free days within the first 30 days following sepsis onset (p = 0.004), as well as less organ dysfunction at day 14 post-sepsis (p < 0.0001). However, one-year mortality, one-year functional status, and residency at home were not statistically different between cohorts. Moreover, 57% of surgical patients and 26% of medical patients who developed CCI were living at home for one year following their index hospitalization (p = 0.11). Conclusions: While surgical patients who develop sepsis-related CCI experience more favorable 30-day outcomes as compared with medical patients, long-term outcomes do not differ significantly between groups. This suggests that reversing established organ dysfunction and functional disability, regardless of etiology, is more challenging compared to preventing these complications at an earlier stage. Advances in the treatment of acute sepsis, such as early antibiotic therapy, infectious source control, and goal-directed fluid resuscitation, have reduced short-term mortality rates . NonetheIn 2009, the healthcare costs associated with CCI amounted to USD 26 billion, and over 60% of these patients had sepsis upon ICU admission . In factMedical and surgical patients who develop sepsis-related CCI have distinct risk factors and comorbidity profiles, and their clinical trajectory would, therefore, be expected to differ ,10. PatiTo gain a better understanding of the clinical trajectory of this patient population with high morbidity and healthcare burden, we conducted an analysis of long-term outcomes in patients with medical CCI following sepsis. We then compared these outcomes with those of patients who developed surgical CCI following sepsis. Given that mechanical ventilation and sepsis are the top two known causes of CCI , we focuAll septic, critically ill adult patients described in this case series were treated in the medical intensive care unit (MICU) or surgical intensive care unit (SICU) at a quaternary care academic medical center between May 2013 and August 2022. Surgical ICU patients were defined as patients who have undergone a prior surgical procedure and were receiving critical care therapy in the SICU at the time of enrollment, whereas medical ICU patients did not undergo a prior surgical procedure during their hospitalization and were receiving critical care therapy in the MICU. For the purposes of this case series, the following inclusion criteria were used: (1) age ≥ 18 years, (2) acute respiratory failure requiring mechanical intubation or bilevel positive airway pressure (BiPAP) at the time of recruitment, and (3) sepsis or septic shock by Sepsis-3 criteria at the time of recruitment .Chronic critical illness (CCI) was defined as an ICU length of stay ≥14 days with evidence of persistent organ dysfunction, determined by using the components of the Sequential Organ Failure Assessment (SOFA) score  . Early dDescriptive statistics were used to characterize the study population, with continuous variables reported as mean ± standard deviation and categorical variables reported as counts with proportions. Statistical tests were two-tailed with a level of significance set at α = 0.05. Inter-cohort differences were analyzed using Analysis of Variance or Student’s t-test for continuous variables and Chi-Square Test or Fisher’s exact test for categorical variables. Nonparametric, pair-wise comparisons were performed using Wilcoxon method. The survival curves were calculated using the Kaplan-Meier method with a 95% confidence interval and end point of 365 days after ICU admission. Analyses were performed using Stata 14.5 . p = 0.0017).Eighty-two patients met the criteria for medical sepsis, of which 31 (38%) developed CCI A. Seventp-value was not calculated due to sample size.We report both short-term  and longWithin the confines of our sample size, we performed multivariable regression analyses to correct for clinically relevant variables that may affect long-term survival, including age, APACHE II, Charlson comorbidity index, and presence of septic shock .Patients suffering from CCI experience prolonged disability and impose a disproportionately large burden on healthcare resources. While patients who eventually develop CCI represent only a minority among septic patients, the number of these patients is increasing ,9. To reThe primary objective of the present analysis was to describe the trajectory of the most gravely ill patients with sepsis-induced CCI and to examine whether clinical trajectories differed between sepsis of medical versus surgical origin. Given the infrequency of CCI, a descriptive case series was the most feasible way to accomplish this. Our investigation is the first, to our knowledge, to compare medical versus surgical sepsis-induced CCI in this manner. It demonstrated that short-term clinical outcomes were better in patients having surgical CCI, while one-year mortality and the proportion of patients living at home were similar in both groups.Septic surgical patients who develop CCI often exhibit a well-recognized phenotype known as persistent inflammation, immunosuppression, and catabolism syndrome (PICS) ,21,22. CThe term CCI is uncommonly encountered in the medical  literature, especially as it relates to sepsis. Studies that focus on medical patients do not have a universally accepted definition of CCI, most likely due to the heterogeneity of the patient population . HoweverBeing a case series description, our report has several limitations. First, cohort sizes are relatively small, which may limit the generalizability of the findings to a broader population. Generalizability to other critically ill patients may also be reduced by our description of the ‘sickest of the sick’ patients . While the number of patients in this cohort precluded our ability to perform robust statistical queries such as regression analyses, the disproportionate healthcare burden imposed by this small number of severely ill patients nonetheless mandates a better understanding of their clinical trajectory. Secondly, as a retrospective case series, there is a potential for selection bias, as cases were identified based on available medical records. Additionally, the absence of a control group  restricts our ability to establish causal relationships. Lastly, the study design inherently carries the risk of incomplete or missing data, and although efforts were made to minimize this through meticulous data collection, there is a possibility of data incompleteness or measurement error. These limitations should be considered when interpreting the results of this case series.In conclusion, septic patients with acute respiratory failure who develop CCI represent a minority of septic patients but a tremendous healthcare burden. While the infrequency of this condition makes randomized and controlled trials unfeasible, our study adds value to the body of literature about this condition and may assist patients and healthcare providers in better understanding the epidemiology and short- and long-term outcomes of this disease. Long-term outcomes in CCI patients following sepsis of medical versus surgical origin may not differ significantly despite the different clinical profiles of these two patient populations. Rather, the persistence of organ dysfunction for 14 days or more following sepsis onset appears to be the most significant prognostic predictor.