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Kathrin Jobski,1 Michael Dörks,1 Carsten Bantel,2 Falk Hoffmann1 1Department of Health Services Research, Carl von Ossietzky University Oldenburg, Oldenburg, Germany; 2University Department of Anesthesiology, Critical Care, Emergency and Pain Medicine, Klinikum Oldenburg, Oldenburg, GermanyCorrespondence: Kathrin Jobski Department of Health Services ResearchCarl von Ossietzky University Oldenburg, Ammerländer Heerstr 114-118, Oldenburg 26129, GermanyTel +49 441 - 798 2330Fax +49 441 - 798 5824Email kathrin.jobski@uni-oldenburg.deBackground: Regional variations of opioid use have been reported from many countries. The objective of this study was to examine opioid prescribing patterns in Germany including low- and high-potency opioids (LPO and HPO) focusing on regional differences.Methods: Data source was the “Information system for health care data” comprising statutory health insurance funds data for about 70 million Germans of all ages. For 2010, we received aggregated data (by age, sex, federal state and district) of Germans (18+) who had been prescribed at least one opioid including the number of prescribed packages. For each stratum, we further received the number of insured persons. We calculated LPO and HPO prevalences and the mean number of prescribed packages.Results: Among 57 million adult Germans (mean age: 50.2 years, 53.8% female), opioid prevalences were 38.7 per 1000 persons for LPOs and 12.8 for HPOs. Prevalences rose with increasing age and were higher in women than in men. On average, LPO users were prescribed fewer packages than HPO users (3.5 vs 7.0). LPO use was highest in the eastern states ranging from 32.9 per 1000 persons (Hamburg) to 47.2 (Saxony-Anhalt). HPOs were most often prescribed in the North and in the East with prevalences varying between 10.6 per 1000 persons (Baden-Württemberg) and 16.9 (Mecklenburg-Western Pomerania). On the district level, prevalences varied by the factors 2.6 and 3.2 for LPOs and HPOs, respectively.Conclusion: We found large regional variations in opioid prescribing which probably cannot only be attributed to differences in patient characteristics.Keywords: opioids, prescribing patterns, prevalence, regional variations, Germany

C Bantel,1,2 F Hoffmann,3 K Jobski3 1Department of Anesthesiology, Critical Care, Emergency and Pain Medicine, Universität Oldenburg, Klinikum Oldenburg, Oldenburg, Germany; 2Department of Surgery & Cancer, Anaesthetics Section, Imperial College London, London, UK; 3Department of Health Services Research, Carl Von Ossietzky University Oldenburg, Oldenburg, GermanyCorrespondence: C BantelUniversitätsklinik für Anästhesiologie, Intensiv-, Notfallmedizin und Schmerztherapie, Universität Oldenburg, Klinikum Oldenburg Campus, Rahel-Straus-Strasse 10, Oldenburg 26133, GermanyTel +49 441 403 77173Fax +49 441 403 2774Email carsten.bantel@uni-oldenburg.deBackground: Gabapentinoids (gabapentin and pregabalin) are psychoactive medications that are increasingly used for different conditions. Since there is evidence that psychotropic drugs, in general, are often inappropriately prescribed in elderly patients, we aimed to determine frequency and indications of gabapentinoid prescribing for nursing home residents.Methods: We analyzed data from a large German statutory health insurance database. Included were records from people ≥65 years-of-age, who were admitted to a nursing home between January 2010 and December 2014. We determined the number and proportion of common indications for on- and off-label prescriptions, the most frequent co-medications, and the characteristics of patients and prescribers.Results: Of 127,277 residents, 9539 (7.5%) received gabapentinoids and 4852 initiated treatment (4.0%; with 66.3% pregabalin). Median age of gabapentinoid initiators was 84 years (78.5% females). In these users, on-label prescribing was found in 57.4%, predominantly for neuropathic pain. Other painful conditions were also chief causes (84.7%) for off-label prescribing. Gabapentinoids were mainly started by general practitioners (64.5%) while pain specialists contributed

Malte Baldewig,1 Olaf Goldbaum,2 Christiane Richter-Landsberg,2 Andreas Weyland,1 Carsten Bantel1 1Department of Anesthesiology, Klinikum Oldenburg, Oldenburg, Germany; 2Molecular Neurobiology, Department of Neuroscience, University of Oldenburg, Oldenburg, Germany Purpose: Gabapentinoids are currently the mainstay of pharmacological treatments for patients with neuropathic pain. Little is known about the effects of this therapy on the integrity of neuronal networks, especially in patients with an already-damaged nervous system. Since gabapentinoids can worsen cognitive functions and recent studies have shown alterations in the brains of patients with neuropathic pain, it may be possible that these drugs have neurotoxic effects.Methods: Rat clonal PC12 pheochromocytoma (autonomic) and primary sensory dorsal-root ganglion (DRG) neurons from newborn Wistar rats were employed for this study. To mimic neuronal damage, cells were exposed to cytotoxins using either hydrogen peroxide (H2O2) or vincristine.Results: No direct cytotoxic effects were observed after incubating PC12 cells for 24 hours with increasing concentrations of gabapentin or pregabalin using MTT cytotoxicity assays. Even a 7-day incubation did not cause cellular damage. Furthermore, in preinjured PC12 and DRG neurons, neither gabapentin nor pregabalin prevented or enhanced the cytotoxic effects of H2O2 or vincristine after incubation for 24 hours and 7 days, respectively. Cell morphology and integrity of the cytoskeleton assessed by employing immunostaining of cytoskeletal proteins (α-tubulin, neurofilament L) remained intact and were not altered by gabapentinoids.Conclusion: Based on these results, gabapentinoids are unlikely to be neurotoxic in cultured autonomic (PC12) and sensory DRG cells, even when cells are preinjured. These results are of high clinical relevance, as it seems unlikely that the morphological changes recently observed in the brains of neuropathic pain patients are caused or worsened by gabapentinoids. Keywords: gabapentin, pregabalin, cytotoxicity, cytoskeleton, neuropathic pain

Ana Mimic,1 Carsten Bantel,2,3 Jelena Jovicic,1 Branko Mimic,4 Darija Kisic-Tepavcevic,5 Otas Durutovic,6,7 Nebojsa Ladjevic1,7 1Department of Anaesthesia, Urology Clinic, Clinical Centre of Serbia, Belgrade, Serbia; 2Department of Anaesthetics, Klinikum Oldenburg AöR, Oldenburg, Germany; 3Section of Anaesthetics, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, UK; 4East Midlands Congenital Heart Centre, University Hospital Leicester, Leicester, UK; 5Institute of Epidemiology, School of Medicine, University of Belgrade, Belgrade, Serbia; 6Department of Urology, Urology Clinic, Clinical Centre of Serbia, Belgrade, Serbia; 7Department of Surgery and Anaesthesiology, School of Medicine, University of Belgrade, Belgrade, Serbia Purpose: There is an increasing interest in the identification of predictors for individual responses to analgesics and surgical pain. In this study, we aimed to determine psychological factors that might contribute to this response. We hence investigated patients undergoing a standardized surgical intervention (open nephrectomy). Patients and methods: Between May 2014 and April 2015, we conducted a prospective observational cohort study. The following psychological tests were administered preoperatively: Mini-Mental State Examination, Amsterdam Preoperative Anxiety and Information Scale (APAIS), Hamilton Anxiety Rating Scale, Hamilton Depression Rating Scale, and Pain Catastrophizing Scale. The primary outcome, postoperative pain intensity (11-point numerical rating scale, [NRS]), was assessed in the “immediate early” (first 8 hours), “early” (12 and 24 hours), and “late early” periods (48 and 72 hours).Results: A total of 196 patients were assessed, and 150 were finally included in the study. NRS scores improved from 4.9 (95% confidence interval [CI]: 4.7–5.1) in the “immediate early” to 3.1 (95% CI: 2.9–3.3) in the “early” and 2.3 (95% CI: 2.1–2.5) in the “late early” postoperative period. Most (87%) patients received intravenous opioids, while 13% received analgesics epidurally. Repeated measures analysis of variance indicated better pain management with epidural analgesia in the first two postoperative periods (F=15.01, p

Stephen Ward,1 Charlotte Guest,2 Ian Goodall,2 Carsten Bantel3,4 1Pain Service, Barts Health, St Bartholomew’s Hospital, London, UK; 2Pain Medicine, Chelsea and Westminster Hospital NHS Foundation Trust, London, UK; 3Section of Anaesthetics, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, UK; 4Department of Anesthesiology, Intensive Care Medicine, Emergency Medicine and Pain Management, Universität Oldenburg, Oldenburg, Germany Background: Perioperative pain carries a considerable risk of becoming persistent; hence aggressive preventive approaches are advocated. Persistently high prevalence of postoperative pain, however, suggests anesthesiologists underuse these strategies. A prospective cross-sectional study of patients in the postanesthetic care unit (PACU) and a survey of anesthesiologists were thus conducted to evaluate practice and uncover bias in intraoperative pain management. Methods: Notes of PACU patients were reviewed and information regarding surgical context, comorbidities, and analgesic administration was retrieved. Variables were analyzed for their predictive properties on pain and intraoperative analgesic management. Furthermore, clinical dose–effect estimates for intraoperative morphine were determined. Finally, anesthesiologists completed a questionnaire comprising statements regarding pain relating to surgical context and morphine administration. Results: Data of 200 patients and 55 anesthesiologists were analyzed. Prevalence of pain in PACU was 28% and was predicted by local anesthetic (LA) and low-dose morphine administration. Additionally, when LA was used, little coanalgesics were employed. These results suggest a restrained approach by anesthesiologists toward intraoperative pain management. It is supported by their reluctance to administer more than 10 mg morphine, despite these individuals regarding this practice as insufficient. The hesitancy toward morphine also transpired in the dose–effect estimates with the average applied dose operating on an ED63 instead of an ED95 level. Conclusion: This study confirmed a high prevalence of pain in PACU. It also indicated conservative intraoperative analgesic administration by anesthesiologists. The modest morphine usage and overreliance on LA application, which are not supported by published evidence, additionally suggest bias in current intraoperative pain management. Keywords: intraoperative morphine, multimodal analgesia, local anesthetic infiltration, clinical decision making, effective-dose, postoperative pain

Carsten Bantel,1 Shiva S Tripathi,2 David Molony,3 Tony Heffernan,3 Susmita Oomman,4 Vivek Mehta,5 Sara Dickerson6 1Chelsea and Westminster Hospital NHS Foundation Trust, London, 2Royal Preston Hospital, Preston, UK; 3Mallow Primary Healthcare Centre, Mallow, Ireland; 4Withybush General Hospital, Haverfordwest, 5Pain & Anaesthesia Research Centre, Barts Health NHS Trust, London, 6Mundipharma International Limited, Cambridge, UK Background: Opioids are an effective treatment for moderate-to-severe pain. However, they are associated with a number of gastrointestinal side effects, most commonly constipation. Laxatives do not target the underlying mechanism of opioid-induced constipation (OIC), so many patients do not have their symptoms resolved. Fixed-dose prolonged-release (PR) oxycodone/naloxone (OXN) tablets contain the opioid agonist oxycodone and the opioid antagonist naloxone. Naloxone blocks the action of oxycodone in the gut without compromising its analgesic effects.Aim: To evaluate the effectiveness of PR OXN in patients with severe pain who had laxative-refractory OIC with their previous opioid.Methods: The study was carried out in 13 centers across the UK and Ireland, using a bespoke online tool to capture patients’ data. Patients were reviewed according to normal clinical practice of each center and rated any changes in their constipation and quality of life (QoL) since starting PR OXN. Any change in patients’ laxative use was also recorded.Results: One hundred and seven patients were entered into the database, and 81 went on to attend at least one review. Of these, 54 (66.7%) reported an improvement in constipation and 50 (61.7%) reported an improvement in QoL since starting PR OXN. Fifty-seven patients (70.4%) said they had reduced laxative intake; 48 (59.3%) only needed laxatives as required.Conclusion: PR OXN reduced symptoms of constipation, improved QoL and reduced laxative intake in patients with OIC. It has a potential place early in any treatment strategy for severe pain in patients using opioids, particularly in patients who may be predisposed to constipation. Keywords: laxatives, opioid, opioid-induced constipation, oxycodone/naloxone, PR OXN, real-world data, severe pain

Charlotte Guest,1 Fabian Sobotka,2 Athina Karavasopoulou,3 Stephen Ward,3 Carsten Bantel4,5 1Pain Medicine, Chelsea and Westminster Hospital NHS Foundation Trust, London, UK; 2Division of Epidemiology and Biometry, Department of Health Services Research, Faculty 6, Medicine and Health Sciences, Carl von Ossietzky Universität Oldenburg, Oldenburg, Germany; 3Pain Service, Barts Health, St Bartholomew’s Hospital, London, UK; 4Department of Anaesthesiology, Intensive Care, Emergency Medicine and Pain Therapy, Oldenburg University, Klinikum Oldenburg Campus, Oldenburg, Germany; 5Department of Surgery and Cancer, Anaesthetics Section, Imperial College London, Chelsea and Westminster Hospital Campus, London, UK Objective: Pain remains insufficiently treated in hospitals. Increasing evidence suggests human factors contribute to this, due to nurses failing to administer opioids. This behavior might be the consequence of nurses’ mental models about opioids. As personal experience and conceptions shape these models, the aim of this prospective survey was to identify model-influencing factors. Material and methods: A questionnaire was developed comprising of 14 statements concerning ideations about opioids and seven questions concerning demographics, indicators of adult learning, and strength of religious beliefs. Latent variables that may underlie nurses’ mental models were identified using undirected graphical dependence models. Representative items of latent variables were employed for ordinal regression analysis. Questionnaires were distributed to 1,379 nurses in two London, UK, hospitals (n=580) and one German (n=799) hospital between September 2014 and February 2015. Results: A total of 511 (37.1%) questionnaires were returned. Mean (standard deviation) age of participants were 37 (11) years; 83.5% participants were female; 45.2% worked in critical care; and 51.5% had more than 10 years experience. Of the nurses, 84% were not scared of opioids, 87% did not regard opioids as drugs to help patients die, and 72% did not view them as drugs of abuse. More English (41%) than German (28%) nurses were afraid of criminal investigations and were constantly aware of side effects (UK, 94%; Germany, 38%) when using opioids. Four latent variables were identified which likely influence nurses’ mental models: “conscious decision-making”; “medication-related fears”; “practice-based observations”; and “risk assessment”. They were predicted by strength of religious beliefs and indicators of informal learning such as experience but not by indicators of formal learning such as conference attendance. Conclusion: Nurses in both countries employ analytical and affective mental models when administering the opioids and seem to learn from experience rather than from formal teaching. Additionally, some attitudes and emotions towards opioids are likely the result of nurses’ cultural background. Keywords: nurses, opioids, mental models, decision-making

Savan Shah,1,2 Alexandra C Ho,1,2 Bianca M Kuehler,1 Susan R Childs,1 Glyn Towlerton,1 Ian D Goodall,1 Carsten Bantel1,2 1Pain Medicine, Chelsea and Westminster Hospital, NHS Foundation Trust, 2Section of Anaesthetics, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, UK Background: Chronic pain clinics aim to improve challenging conditions, and although numerous studies have evaluated specific aspects of therapies and outcomes in this context, data concerning service impact on outcome measures in a general pain population are sparse. In addition, current trends in commissioning increasingly warrant services to provide evidence for their effectiveness. While a plethora of outcome measures, such as pain-intensity or improvement scores, exist for this purpose, it remains surprisingly unclear which one to use. It also remains uncertain what variables predict treatment success. Objectives: This cross-sectional study was conducted to evaluate clinic performance employing different tools (pain scores, pain categories, responder analysis, subjective improvement, satisfaction), and to determine predictors of outcome measures. Patients and methods: Patients attending scheduled clinic follow-up appointments were approached. They were asked to complete the modified short-form Brief Pain Inventory (BPI-SF) that also included assessments for satisfaction and subjective improvement. Comparisons were made with BPI-SF responses that were completed by each patient on admission. Nonparametric tests were employed to evaluate service impact and to determine predictors for outcome. Results: Data of 118 patients were analyzed. There was considerable variation in impact of pain clinics depending on the outcome measure employed. While median pain scores did not differ between admission and follow-up, scores improved individually in 30% of cases, such that more patients had mild pain on follow-up than on admission (relative risk 2.7). Furthermore, while only 41% reported at least moderate subjective improvement after admission to the service, the majority (83%) were satisfied with the service. Positive treatment responses were predicted by “number of painful regions” and “changes in mood”, whereas subjective improvement was predicted by “helpfulness of treatments”. Conclusion: Depending on the outcome measure employed, pain clinics showed varying degrees of impact on patients’ pain experiences. This calls into question the current practice of using nonstandardized outcome reporting for evaluation of service performances. Keywords: Brief Pain Inventory, chronic pain clinics, pain-intensity scores, patient satisfaction, responder analysis, subjective improvement

Susan R Childs,1,* Emma M Casely,2,* Bianca M Kuehler,1 Stephen Ward,1 Charlotte L Halmshaw,1 Sarah E Thomas,1 Ian D Goodall,1 Carsten Bantel1,3 1Pain Medicine, Chelsea and Westminster Hospital NHS Foundation Trust, London, 2Anaesthetic Department, Hillingdon Hospital, Uxbridge, 3Section of Anaesthetics, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital Campus, London, UK *These authors contributed equally to this manuscript Abstract: Recent research has confirmed that between 25% and 33% of all hospitalized patients experience unacceptable levels of pain. Studies further indicate that this reduces patient satisfaction levels, lengthens hospital stays, and increases cost. Hospitals are aiming to discharge patients earlier, and this can interfere with adequate pain management. Therefore, the pain service at Chelsea and Westminster Hospital has adapted to this changing model of care. An increasing body of evidence demonstrates that psychological factors are key components of patients’ pain experiences in both acute and chronic pain. Therefore, it is reasonable to suggest a clinical psychologist should be involved in inpatient pain management. This small study discusses three cases that highlight how patient care could be improved by including a clinical psychologist as part of the inpatient pain team. Two cases particularly highlight the active role of the psychologist in the diagnosis and management of common conditions such as fear and anxiety, along with other psychiatric comorbidities. The management therefore employed an eclectic approach adapted from chronic pain and comprising of behavioral, cognitive behavioral, and dialectical behavioral therapeutic techniques blended with brief counseling. The third case exemplifies the importance of nurse-patient interactions and the quality of nurse-patient relationships on patient outcomes. Here, the psychologist helped to optimize communication and to resolve a difficult and potentially risk-laden situation. This small case series discusses the benefits derived from the involvement of a clinical psychologist in the management of inpatient pain, and therefore illustrates the need for novel initiatives for inpatient pain services. However, future research is warranted to validate this approach. Keywords: acute pain, aggression, anxiety, borderline personality disorder, psychology

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Pain is a common and distressing symptom experienced by intensive care patients. Assessing pain in this environment is challenging, and published guidelines have been inconsistently implemented. The Pain Assessment in INTensive care (PAINT) study aimed to evaluate the frequency and type of physician pain assessments with respect to published guidelines. This observational service evaluation considered all pain and analgesia-related entries in patients' records over a 24-h period, in 45 adult intensive care units (ICUs) in London and the South-East of England. Data were collected from 750 patients, reflecting the practice of 362 physicians. Nearly two-thirds of patients (n = 475, 64.5%, 95%CI 60.9-67.8%) received no physician-documented pain assessment during the 24-h study period. Just under one-third (n = 215, 28.6%, 95%CI 25.5-32.0%) received no nursing-documented pain assessment, and over one-fifth (n = 159, 21.2%, 95%CI 19.2-23.4)% received neither a doctor nor a nursing pain assessment. Two of the 45 ICUs used validated behavioural pain assessment tools. The likelihood of receiving a physician pain assessment was affected by the following factors: the number of nursing assessments performed; whether the patient was admitted as a surgical patient; the presence of tracheal tube or tracheostomy; and the length of stay in ICU. Physician-documented pain assessments in the majority of participating ICUs were infrequent and did not utilise recommended behavioural pain assessment tools. Further research to identify factors influencing physician pain assessment behaviour in ICU, such as human factors or cultural attitudes, is urgently needed. [ABSTRACT FROM AUTHOR]

Background: Ischemic preconditioning is an important intrinsic mechanism for neuroprotection. Preconditioning can also be achieved by exposure of neurons to K+ channel-opening drugs that act on adenosine triphosphate-sensitive K+ (K(ATP)) channels. However, these agents do not readily cross the blood-brain barrier. Inhalational anesthetics which easily partition into brain have been shown to precondition various tissues. Here, the authors explore the neuronal preconditioning effect of modern inhalational anesthetics and investigate their effects on K(ATP) channels.Methods: Neuronal-glial cocultures were exposed to inhalational anesthetics in a preconditioning paradigm, followed by oxygen-glucose deprivation. Increased cell survival due to preconditioning was quantified with the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide reduction test. Recombinant plasmalemmal K(ATP) channels of the main neuronal type (Kir6.2/SUR1) were expressed in HEK293 cells, and the effects of anesthetics were evaluated in whole cell patch clamp recordings.Results: Both sevoflurane and the noble gas xenon preconditioned neurons at clinically used concentrations. The effect of sevoflurane was independent of K(ATP) channel activation, whereas the effect of xenon required the opening of plasmalemmal K(ATP) channels. Recombinant K(ATP) channels were activated by xenon but inhibited by halogenated volatiles. Modulation of mitochondrial K-ATP channels did not affect the activity of K(ATP) channels, thus ruling out an indirect effect of volatiles via mitochondrial channels.Conclusions: The preconditioning properties of halogenated volatiles cannot be explained by their effect on K(ATP) channels, whereas xenon preconditioning clearly involves the activation of these channels. Therefore, xenon might mimic the intrinsic mechanism of ischemic preconditioning most closely. This, together with its good safety profile, might suggest xenon as a viable neuroprotective agent in the clinical setting. [ABSTRACT FROM AUTHOR]

Background: Decision support systems (DSSs) for suggesting optimal treatments for individual patients with low back pain (LBP) are currently insufficiently accurate for clinical application. Most of the input provided to train these systems is based on patient-reported outcome measures. However, with the appearance of electronic health records (EHRs), additional qualitative data on reasons for referrals and patients' goals become available for DSSs. Currently, no decision support tools cover a wide range of biopsychosocial factors, including referral letter information to help clinicians triage patients to the optimal LBP treatment., Objective: The objective of this study was to investigate the added value of including qualitative data from EHRs and referral letters to the accuracy of a quantitative DSS for patients with LBP., Methods: A retrospective study was conducted in a clinical cohort of Dutch patients with LBP. Patients filled out a baseline questionnaire about demographics, pain, disability, work status, quality of life, medication, psychosocial functioning, comorbidity, history, and duration of pain. Referral reasons and patient requests for help (patient goals) were extracted via natural language processing (NLP) and enriched in the data set. For decision support, these data were considered independent factors for triage to neurosurgery, anesthesiology, rehabilitation, or minimal intervention. Support vector machine, k-nearest neighbor, and multilayer perceptron models were trained for 2 conditions: with and without consideration of the referral letter content. The models' accuracies were evaluated via F1-scores, and confusion matrices were used to predict the treatment path (out of 4 paths) with and without additional referral parameters., Results: Data from 1608 patients were evaluated. The evaluation indicated that 2 referral reasons from the referral letters (for anesthesiology and rehabilitation intervention) increased the F1-score accuracy by up to 19.5% for triaging. The confusion matrices confirmed the results., Conclusions: This study indicates that data enriching by adding NLP-based extraction of the content of referral letters increases the model accuracy of DSSs in suggesting optimal treatments for individual patients with LBP. Overall model accuracies were considered low and insufficient for clinical application., (©Sebastian Fudickar, Carsten Bantel, Jannik Spieker, Heinrich Töpfer, Patrick Stegeman, Henrica R Schiphorst Preuper, Michiel F Reneman, André P Wolff, Remko Soer. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 30.01.2024.)

Opioid dosage for general anaesthesia and sedation relies on surrogate parameters such as heartrate and blood pressure. This implies the risk of both under- and overdosing. A promising tool to provide target-oriented opioid dosing is measuring the nociceptive flexion reflex threshold (NFRT). The aim of this study was to investigate the individual trajectories and to determine this methods' clinical practicability in the perioperative setting of cardiac surgery. NFRT was measured preoperatively (twice as baseline), immediately after surgery and later in the general ward (primary outcomes). No intraoperative measurements were performed since neuromuscular blockade hinders NFRT assessment. Administered analgesics and pain scores were also recorded (secondary outcomes). Data were collected from August 2019 to March 2020. 264 patients scheduled for cardiac surgery were screened for eligibility. 55 patients were included, 30 rendered datasets for analysis. Thresholds after conclusion of surgery [T ICU : median (IQR), 31.1 mA (21.5-50.0 mA)] were significantly higher than preoperatively [T pre : 9.2 mA (5.4-13.4 mA); P < 0.001]. In 11 patients (36.7%), no immediate postoperative reflex response was elicited. Later, all reflexes returned, but thresholds remained significantly higher than preoperatively [T post : 11.9 mA (9.2-16.6 mA); P = 0.043]. NFRT values after surgery were higher compared to baseline measurements. Subsequently they decreased but did not reach their baseline levels. There was no corresponding dose-dependency, suggesting multimodal effects on the nociceptive system. Unless measurements are not prevented by technical issues NFRT-assessment appears to be a future tool to target analgesics in patients not able to self-report pain. Trial registration Study registration: DRKS00021617. https://www.drks.de/drks&#95;web/navigate.do?navigationId=trial.HTML&TRIAL&#95;ID=DRKS00021617 (registered retrospectively)., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Spontaneous reporting is based on the experience of all healthcare professionals (HCPs) but also consumers/non-HCPs and therefore reveals a broad picture of a drug's adverse reactions. Recent studies found substantial differences between reports from these varying sources including the reports' completeness. Using the example of opioid-associated abuse, dependence, or withdrawal, this study analyzed the completeness and characteristics of spontaneous reports from Germany focusing on the reporter. Based on EudraVigilance data, we included all cases of abuse, dependence, or withdrawal associated with opioids indicated for pain therapy and filed from Germany until 2018. Completeness and characteristics were analyzed by a reporter (physician, pharmacist, other HCPs, consumers/non-HCPs) and also by time period to account for other influencing factors. In total, 1721 cases were included, mainly filed by physicians (38.5%) and pharmacists (30.7%). Completeness of demographics varied from 74.5% (other HCPs) to 42.7% (consumers/non-HCPs). Consumers/non-HCPs most often provided any indication/comorbidity (75.2%), whereas this was the case for only 20.2% of pharmacists. Large differences between the reporters were found for almost all characteristics. Other HCPs far more often coded a history of drug abuse, dependence, or withdrawal than other reporters (46.9% vs. 11.6%-24.2%, respectively), and fatal outcomes were also mainly filed by other HCPs (68.1% vs. 14.8%-20.4% by all other reporters). Differences in completeness and characteristics were also observed over time. Studies analyzing spontaneous data should consider potential differences between the various reporting groups in terms of completeness and characteristics. Further, the impact of other influencing factors has to be assessed., (© 2023 The Authors. Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)

Purpose: Fentanyl, a highly potent synthetic opioid used in cancer and non-cancer pain, is approved for various routes of administration. In Europe, fentanyl consumption increased substantially in the last decades but information on abuse, dependence and withdrawal associated with fentanyl is scarce, especially with respect to its different formulations., Methods: We analysed case characteristics of spontaneous reports of suspected fentanyl-associated abuse, dependence or withdrawal from European countries recorded in the EudraVigilance database up to 2018 with respect to the (designated) routes of administration and potential indications., Results: A total of 985 reports were included (mainly from France and Germany) with 43% of cases referring to transdermal fentanyl. Median age was 45 years (48.8% female) and 21.6% had musculoskeletal disorders. Only 12.6% of those using transdermal fentanyl had a cancer diagnosis compared to 40.2% and 26.8% of those using intranasal and oral transmucosal fentanyl, respectively. Depression was common (10.7%) and highest in cases with musculoskeletal disorders (24.9%) as was the use of benzodiazepines. Overall, 39.5% of reports resulted in a prolonged hospital stay and for 23.2% a fatal outcome was recorded. The respective proportions were especially high in cases with musculoskeletal disorders (56.3% with prolonged hospitalisation) and in those using transdermal fentanyl (35.2% fatalities)., Conclusions: In suspected cases of abuse, dependence or withdrawal, fentanyl was mainly used for non-cancer pain indications and most often as transdermal formulations. Depression and prolonged hospitalisations were common, especially in patients with musculoskeletal disorders, indicating a vulnerable patient group and complex treatment situations., (© 2022. The Author(s).)

Background: Chronic inflammatory joint diseases (CIJD) have been linked to increased cardiovascular morbidity and mortality. A decisive reason could be a dysregulation of the autonomic nervous system, which is responsible for the control of cardiovascular function. So far, the cause of changes in autonomic nervous system functions remains elusive. In this study, we investigate the role of chronic pain and the insular cortex in autonomic control of cardiac functioning in patients with CIJD., Methods: We studied the autonomic nervous system through the assessment of heart rate and heart rate variability (HRV) at rest and under cognitive stimulation. Furthermore, we investigated insular cortex volume by performing surface-based brain morphometry with FreeSurfer. For this study, 47 participants were recruited, 22 individual age- and sex-matched pairs for the magnetic resonance imaging analyses and 14 for the HRV analyses. All available patients' data were used for analysis., Results: Pain duration was negatively correlated with the resting heart rate in patients with chronic inflammatory joint diseases (n = 20). In a multiple linear regression model including only CIJD patients with heart rate at rest as a dependent variable, we found a significant positive relationship between heart rate at rest and the volume of the left insular cortex and a significant negative relationship between heart rate at rest and the volume of the right insular cortex. However, we found no significant differences in HRV parameters or insular cortex volumes between both groups., Conclusions: In this study we provide evidence to suggest insular cortex involvement in the process of ANS changes due to chronic pain in CIJD patients. The study was preregistered with the German Clinical Trials Register ( https://www.drks.de ; DRKS00012791; date of registration: 28 July 2017)., (© 2022. The Author(s).)

Influenced by Virginia Woolf pain is traditionally believed to be a private object that defies language. However, our analysis of classical and contemporary works of British and American poets, in addition to our own clinical experiences, leads us to challenge this notion. In accordance with Wittgenstein we instead view pain as a concept and objective experience that should encourage interaction. Reasons why patients and healthcare providers often assume language to be insufficient to grasp the complexity of pain are manifold. Based on neuro-cognitive mechanisms we propose an important contributor might be that patients in pain speak a different language than their pain-free peers and doctors., Competing Interests: Conflict of interest: The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article., (© The British Pain Society 2021.)

Background: Transversus abdominis plane (TAP) blocks have been shown to successfully reduce pain and opioid consumption after general and gynaecological surgery., Objective: To evaluate whether TAP blocks alleviate pain and opioid consumption after urological procedures., Design: A systematic review and meta-analysis., Data Sources: MEDLINE, Embase and CENTRAL., Eligibility Criteria: Without language restriction, randomised controlled trials (RCTs) that compared the effects of TAP blocks with placebo or no treatment in urological surgery., Main Outcome Measures: Primary outcomes were pain intensities at rest and movement at 6, 12 and 24 h after surgery. Secondary outcomes were postoperative opioid consumption in the first 24 h after surgery and postoperative nausea and vomiting. We performed meta-analyses using random effects models. Effect sizes were expressed as mean differences for continuous variables. We used the Cochrane risk of bias tool (RoB 2.0) to assess risk of bias., Results: We analysed 20 RCTs comprising a total of 1239 patients. The risk of bias of the studies was relatively high. TAP blocks significantly reduced postoperative pain at all time points compared with placebo or no treatment. Mean differences on an 11-point pain intensity scale were between 0.55 (95% CI: -0.90, to -0.21; P = 0.002; I2 = 94%) to 1.13 (95% CI: -1.62 to -0.65; P < 0.001; I2 = 95%) less at rest and 0.74 (95% CI: -1.25 to -0.23; P = 0.005; I2 = 79%) to 1.32 (95% CI: -1.83 to -0.81; P < 0.001; I2 = 68%) less on movements. TAP blocks also reduced opioid consumption in the first 24 h after surgery significantly by 12.25 mg (95% CI: -17.99 to -6.52 mg; P < 0.001; I2 = 99%) morphine equivalents. Possibly, this had no influence on postoperative nausea and vomiting (risk ratio: 0.98; 95% CI: 0.66 to 1.45; P = 0.91; I2 = 30%)., Conclusion: TAP blocks seem to offer improved analgesia when used after urological surgery. However, due to the large heterogeneity between and the considerable risk of bias within the included studies results should be viewed with caution., Systemic Review Registration: PROSPERO CRD42018112737., (Copyright © 2021 European Society of Anaesthesiology and Intensive Care. Unauthorized reproduction of this article is prohibited.)

To identify robust and reproducible methods of cerebellar morphometry that can be used in future large-scale structural MRI studies, we investigated the replicability, repeatability, and long-term reproducibility of three fully automated software tools: FreeSurfer, CEREbellum Segmentation (CERES), and automatic cerebellum anatomical parcellation using U-Net with locally constrained optimization (ACAPULCO). Replicability was defined as computational replicability, determined by comparing two analyses of the same high-resolution MRI data set performed with identical analysis software and computer hardware. Repeatability was determined by comparing the analyses of two MRI scans of the same participant taken during two independent MRI sessions on the same day for the Kirby-21 study. Long-term reproducibility was assessed by analyzing two MRI scans of the same participant in the longitudinal OASIS-2 study. We determined percent difference, the image intraclass correlation coefficient, the coefficient of variation, and the intraclass correlation coefficient between two analyses. Our results show that CERES and ACAPULCO use stochastic algorithms that result in surprisingly high differences between identical analyses for ACAPULCO and small differences for CERES. Changes between two consecutive scans from the Kirby-21 study were less than ± 5% in most cases for FreeSurfer and CERES (i.e., demonstrating high repeatability). As expected, long-term reproducibility was lower than repeatability for all software tools. In summary, CERES is an accurate, as demonstrated before, and reproducible tool for fully automated segmentation and parcellation of the cerebellum. We conclude with recommendations for the assessment of replicability, repeatability, and long-term reproducibility in future studies on cerebellar structure.

We report the discovery of a dead Magellanic penguin (Spheniscus magellanicus) found on Juquehy Beach (23°46'S 45°44'W), municipality of São Sebastião, Brazil, on September 9th 2020. Following necropsy, we noted the presence of an adult size PFF-2 protective mask within the stomach of the penguin which we inferred as the cause of death. As far as we are aware, this is the first recorded instance of marine animal mortality by protective face mask ingestion. Whilst concerns have been raised relating microplastic contamination in marine environments from Covid-19 related waste, there has been relatively less attention paid to the potential risk of macro-scale contaminants, such as protective face coverings. We suggest that Covid-19 related macro contaminants be considered in coastal marine risk assessments and urge further research on this topic., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Nurses are the main administrators of opioids in hospitals and enjoy some autonomy when using them to manage pain. Nevertheless evidence suggests they exercise this freedom restrictively with the reasons for this self-limitation remaining unclear. Nurses are influenced by personal and professional values and by patients' attributes. Intoxicated patients pose a particular challenge. This study therefore investigated whether cautious attitudes towards opioids were aggravated in intoxicated patients and influenced by personal values., Methods: A two-version questionnaire was developed. Each presented a case vignette describing a patient in acute pain who was either intoxicated or not intoxicated. Questionnaires contained identical case statements inquiring about concerns regarding opioids, preferred analgesics and statements about opioids and personal values. They were distributed prospectively in a cross-sectional, multi-centre design. Equal distribution of both questionnaires was achieved through randomization of wards. Regression analysis was employed to determine predictors for responses to the case statements., Results: In total, n = 374 (26%) nurses returned questionnaires, 85% were female, 39% worked in surgery and 64% had >10 years experience. A total of 78% were concerned using opioids in the intoxicated patient and 70% preferred non-opioids instead. Most nurses agreed familiarity with an opioid gives them more confidence and they were more concerned in patients with a history of drug abuse. They neither associated opioids with helping patients to die nor with drug abuse. The majority endorsed value statements representing 'universalism', 'hedonism' and 'benevolence' while disagreeing with 'power' and 'stimulation'. Nurses concerns were predicted by values indicating 'conformity' and 'achievement'., Conclusion: Nurses were concerned giving opioids to intoxicated patients and preferred non-opioids instead. These concerns were predicted by personal values representing 'Conservation' ('conformity') and 'Self-Enhancement' ('achievement'). Therefore, stigmatizing mental models likely contribute to nurses' reluctance to use opioids. Interestingly, personal ambition might protect nurses from discriminatory thoughts and practice., Competing Interests: Conflict of interest: The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article., (© The British Pain Society 2019.)