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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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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.)

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.)

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: 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.)

The non-opioid analgesic metamizole (dipyrone) is commonly used in Germany despite its narrow indications and market withdrawal from several countries. In this study we analyzed prescribing patterns of metamizole focusing on regional differences. The source of data was the "Information system for health care data" which includes data from the statutory health insurance funds for about 70 million Germans. We received aggregated data of individuals with at least one metamizole prescription in 2010 as well as the number of prescribed packages by age, sex, state and district along with the number of insured persons in each stratum. We calculated prescription prevalence stratified by age, sex, state and district. Among 68.4 million insured persons (mean age: 43.6 years; 53.0% female) 5.5 million received at least one metamizole prescription (8.1%, overall 12.2 million packages). Prevalence increased with age, and women received metamizole more often than men. In adults (total prevalence: 9.4%), levels varied between 7.0% (Saxony) and 11.1% (Schleswig-Holstein), whereas on a district level use ranged from 4.3% to 14.3%. In 2010, one of 12 individuals received metamizole at least once. Noticeable were the large regional variations which certainly cannot be explained by patient-related factors.

Almost half of patients treated on intensive care unit (ICU) experience moderate to severe pain. Managing pain in the critically ill patient is challenging, as their pain is complex with multiple causes. Pharmacological treatment often focuses on opioids, and over a prolonged admission this can represent high cumulative doses which risk opioid dependence at discharge. Despite analgesia the incidence of chronic pain after treatment on ICU is high ranging from 33-73%. Measures need to be taken to prevent the transition from acute to chronic pain, whilst avoiding opioid overuse. This narrative review discusses preventive measures for the development of chronic pain in ICU patients. It considers a number of strategies that can be employed including non-opioid analgesics, regional analgesia, and non-pharmacological methods. We reason that individualized pain management plans should become the cornerstone for critically ill patients to facilitate physical and psychological well being after discharge from critical care and hospital.

[This corrects the article DOI: 10.3389/fnbeh.2018.00165.].

Chronic pain (CP) is linked to changes in cognitive function. However, little is known about its influence on number sense, despite the fact that intact numerical-spatial processing is a prerequisite for valid scale-based pain assessments. This study aimed to elucidate whether number sense is changed in CP, to determine if changes have an impact on pain assessments using pain rating scales and what patient factors might contribute. N = 42 CP patients and n = 42 matched controls were analyzed (age range: 33-68 years). Numerical-spatial abilities were investigated by using number line tasks, where participants either estimated the position of a given number (position marking) or the value of a predefined mark (number naming). Pain intensity was assessed using numerical rating (NRS), verbal rating (VRS), and visual analog (VAS) scales. Additional measures included attention and working memory, verbal intelligence, medication and depression. Results revealed that in number naming, patients deviated more from expected (correct) responses than controls, and that VAS scores were significantly higher than both NRS and VRS and correlated with deviations in position making. Changes in number naming were predicted by pain intensity, sex and IQ but not by attention, memory or opioid medication. This article presents new insight on which cognitive mechanisms are influenced by CP with the focus on numerical spatial abilities. It could therefore provide useful knowledge in developing new pain assessment tools specifically for patients suffering from CP.

Objectives To retrospectively analyse experience of radical cystectomy using spinal/epidural anaesthesia and to classify this method using the IDEAL criteria. Methods Data from patients who had undergone radical cystectomy using spinal/epidural anaesthesia were evaluated retrospectively, focusing on clinical data, intraoperative and perioperative parameters and postoperative complications. Current literature reporting on this technique was reviewed and, together with the present study, evaluated according to the IDEAL recommendations. Results Three male patients aged 66-79 years who had undergone radical cystectomy with epidural anaesthesia were identified. The operating time ranged from 159-261 min and only minor complications occurred. Between 2013 and 2015, three published studies reported experiences with radical cystectomy with epidural/spinal anaesthesia; one was prospective and two were retrospective in nature and they included a total of 55 patients. According to the IDEAL classification, the present study corresponds to stage 1 (idea) and overall the surgical technique can be ranked as stage 2a (development). Conclusions Radical cystectomy with epidural anaesthesia is feasible and applicable for those who are not fit for general anaesthesia. The present study confirmed the functional results of this technique, which can be classified as IDEAL stage 2a on the basis of published studies.

Background: In-hospital pain services (IPS) are commonplace, but evidence of efficacy is inadequate, and patients' pain management in any hospital ward remains problematic. This service evaluation aimed to measure the effect of a contemporary IPS, its appropriate use and cost-efficacy., Methods: Records of 249 adults reviewed by the IPS in an inner London Teaching Hospital over an 8-month period were analysed for demographic data, interventions, workload and change in pain intensity measured by numerical rating scale (NRS). Non-parametric tests were used to evaluate differences between initial and final NRS. Spearman's rank correlation analysis was used to create a correlation matrix to evaluate associations between all identified independent variables with the change in NRS. All strongly correlated variables (ρ > 0.5) were subsequently included in a binary logistic regression analysis to identify predictors of pain resolution greater than 50% NRS and improvement rather than deterioration or no change in NRS. Finally, referral practice and cost of inappropriate referrals were estimated. Referrals were thought to be inappropriate when pain was not optimised by the referring team; they were identified using a set algorithm., Results: Initial median NRS and final median NRS were significantly different when a Wilcoxon signed-rank test was applied to the whole cohort; Z = -5.5 (p = 0.000). Subgroup analysis demonstrated no significant difference in the 'mild' pain group; z = -1.1 (p = 0.253). Regression analysis showed that for every unit increase in initial NRS, there was a 62% chance of general and a 33% chance of >50% improvement in final NRS. An estimated annual cost-saving potential of £1546 to £4558 was found in inappropriate referrals and patients experiencing no benefit from the service., Discussion: Results suggest that patients with moderate to severe pain benefit most from IPS input. Also pain management resources are often distributed inefficiently. Future research is required to develop algorithms for easy identification of potential treatment responders., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

The pupillary dilatation reflex may present an objective method of predicting whether sedated patients require additional analgesia for painful procedures. Behavioural pain assessment tools identify pain only once it has occurred and are unable to guide pre-emptive management. The pupillary dilatation reflex response to a tetanic stimulus has been utilised to assess analgesic requirements in patients under anaesthesia and for those with postoperative pain. This tool appears promising to assess pain in the critically ill; however, a number of questions remain unanswered regarding the influence of sedation on this response. These questions require further exploration before the pupillary dilatation reflex can be widely adopted into clinical practice.

Background: Adenosine triphosphate-sensitive potassium (KATP) channels in brain are involved in neuroprotective mechanisms. Pharmacologic activation of these channels is seen as beneficial, but clinical exploitation by using classic K channel openers is hampered by their inability to cross the blood-brain barrier. This is different with the inhalational anesthetic xenon, which recently has been suggested to activate KATP channels; it partitions freely into the brain., Methods: To evaluate the type and mechanism of interaction of xenon with neuronal-type KATP channels, these channels, consisting of Kir6.2 pore-forming subunits and sulfonylurea receptor-1 regulatory subunits, were expressed in HEK293 cells and whole cell, and excised patch-clamp recordings were performed., Results: Xenon, in contrast to classic KATP channel openers, acted directly on the Kir6.2 subunit of the channel. It had no effect on the closely related, adenosine triphosphate (ATP)-regulated Kir1.1 channel and failed to activate an ATP-insensitive mutant version of Kir6.2. Furthermore, concentration-inhibition curves for ATP obtained from inside-out patches in the absence or presence of 80% xenon revealed that xenon reduced the sensitivity of the KATP channel to ATP. This was reflected in an approximately fourfold shift of the concentration causing half-maximal inhibition (IC50) from 26 +/- 4 to 96 +/- 6 microm., Conclusions: Xenon represents a novel KATP channel opener that increases KATP currents independently of the sulfonylurea receptor-1 subunit by reducing ATP inhibition of the channel. Through this action and by its ability to readily partition across the blood-brain barrier, xenon has considerable potential in clinical settings of neuronal injury, including stroke.

Background: The positive allosteric adenosine receptor modulator, T62 (2-amino-3-(4-chlorobenzoyl)-5,6,7,8-tetrahydrobenzothiophene), has been shown to reduce mechanical allodynia in a rat model of neuropathic pain. However, whether chronic oral T62 retains efficacy in this pain model has not been examined. Therefore, the authors studied antiallodynic effects of chronic oral T62 in spinal nerved-ligated rats, as well as motor and sedative behavioral effects., Methods: Oral T62, 100 mg/kg, or oral oil was applied daily to spinal nerve-ligated rats for 4 weeks, with rat weights examined daily. Sedation, placing and ambulation scores, and withdrawal threshold were observed for 3 h daily for the first 2 weeks and then once a week. At the end of observation, the animals were killed, and the spinal tissues were collected for radioligand binding. In addition, withdrawal thresholds were also observed in rats with 5 days of treatment with 50 mg/kg oral T62. Furthermore, the effects of intrathecal adenosine on rats with oral T62 or oil treatment were compared., Results: Chronic oral T62, at 100 mg/kg, initially returned the withdrawal threshold to mechanical testing to preinjury levels, with minor or no sedative or motor effects. Tolerance was observed, with a 60% loss of most possible effects in antiallodynia within 5 days of daily administration. Similarly, tolerance also occurred with chronic oral T62 at 50 mg/kg but did not alter the effect of intrathecal adenosine. Furthermore, 4 weeks of exposure to 100 mg/kg T62 resulted in a small reduction in spinal cord A1 receptor number., Conclusion: The results imply that chronically administered A1 adenosine modulators lose efficacy over time, partly as a result of receptor down-regulation.

Background: Intrathecal adenosine is antinociceptive under conditions of central sensitization, but not in response to acute stimuli in normals. The reasons for this selective circumstance of action remain unclear, but some evidence links adenosine's antinociceptive effects to release of norepinephrine by terminals in the spinal cord. The purpose of this study was to test whether spinal adenosine induces norepinephrine release selectively in settings of hypersensitivity., Methods: Rats randomly assigned to spinal nerve ligation, sham operation, or no operation were anesthetized. A microdialysis fiber was implanted in the spinal cord dorsal horn at the L5-L6 level and perfused with artificial cerebrospinal fluid. After washout and a baseline sample period, adenosine at various concentrations was infused through the fiber for 150 min, and samples were collected every 15 min., Results: In ligated, but not in sham or normal animals, adenosine perfusion increased norepinephrine in spinal cord microdialysates in a concentration-dependent manner. The effects of adenosine plateaued after 75 min and remained stable until the end of the experiment. Intravenous injection of selective adenosine A1 and A2 receptor antagonists revealed that adenosine's effect on spinal norepinephrine release was A1 receptor mediated., Conclusions: This is the first study to provide direct evidence that adenosine is able to release norepinephrine in spinal cord dorsal horns in living animals. However, this effect was only seen in animals after spinal nerve ligation. These data are consistent with behavioral studies demonstrating that adenosine's antinociceptive effects in rats after spinal nerve ligation is totally dependent on intact spinal noradrenergic terminals and can be blocked by spinal alpha 2-adrenergic receptor antagonists.

Background: Previous studies suggest that the alpha adrenoceptor subtype is the target for spinally administered alpha -adrenergic agonists, clonidine, for pain relief. However, ST 91, a preferential alpha adrenoceptor subtype agonist, induces antinociception, and intrathecally administered alpha antisense oligodeoxynucleotide decreases antinociception induced by clonidine in the rat, suggesting non-A sites may be important as well. Therefore, the authors examined the subtype of alpha adrenoceptor activated by clonidine and ST 91 in normal rats and those with nerve injury-induced hypersensitivity., Methods: The same mechanical stimulus was applied to normal rats and those following spinal nerve ligation, and the effect of intrathecal clonidine and ST 91 on withdrawal threshold to the stimulus was determined. To further examine subtypes, animals were spinally pretreated with vehicle, BRL 44408 (an alpha subtype-preferring antagonist), and ARC 239 (an alpha subtype-preferring antagonist)., Results: In normal animals, clonidine's effect was diminished by pretreatment with either antagonist, whereas ST 91's antinociceptive effect was solely blocked by pretreatment with ARC 239. In nerve-injured animals, the antihypersensitivity action of both clonidine and ST 91 was blocked by administration of ARC 239, whereas BRL 44408 was ineffective., Conclusions: These data agree with previous studies supporting that the alpha adrenoceptor is important to the antinociceptive effect of clonidine in normal animals. Nerve injury alters this and results in a total reliance on alpha adrenoceptors.

Background: Spinally injected adenosine induces antinociception in animal models of neuropathic but not acute pain. The reasons for this discrepancy remain unclear. Adenosine receptors are coupled to G proteins, and increased efficiency of adenosine-induced G-protein activity in neuropathic pain could contribute to the antinociceptive effect of adenosine. In this study the authors used [(35)S]guanosine-5'-O-(3-thiotriphosphate) ([(35)S]GTP gamma S) autoradiography in rat spinal cord sections to test this possibility., Methods: The spinal cords of normal animals and those that underwent left L5 and L6 spinal nerve ligation (SNL) were removed and immediately frozen. Horizontal spinal cord sections were cut and mounted on chrom-alum gelatin-subbed slides. Sections were incubated with guanosine diphosphate, [(35)S]GTP gamma S, the adenosine A1 agonist R-N6-phenylisopropyladenosine, and various other drugs, apposed to films, and analyzed., Results: Baseline and R-N6-phenylisopropyladenosine-stimulated [(35)S]GTP gamma S binding was predominantly localized to the superficial dorsal horns of both normal and SNL animals. This binding was significantly increased in SNL compared with normal animals. In contrast, no difference in R-N6-phenylisopropyladenosine-stimulated [(35)S]GTP gamma S binding was observed between SNL and normal animals. Blockade of adenosine A1 receptors by 1,3-dipropyl-8-cyclopentylxanthine, or adenosine destruction by added adenosine deaminase, reduced the increased basal activity in SNL to baseline levels of normal dorsal horns, whereas atropine and naloxone had no effect., Conclusion: This study shows an increased basal G-protein activity in lumbar spinal cords during conditions of SNL. The data suggest that increased adenosine release during conditions of SNL results in an increased basal activity of G proteins in the spinal cord during neuropathic pain.

Background: Intrathecal adenosine produces a remarkably prolonged effect to relieve mechanical hypersensitivity after peripheral nerve injury in animals. The purpose of the current study was to investigate whether this reflected an alteration in kinetics of adenosine in cerebrospinal fluid or in the number of spinal A1 adenosine receptors after nerve injury., Methods: Male rats were anesthetized, and the left L5 and L6 spinal nerves were ligated. Two weeks later, a lumbar intrathecal catheter and intrathecal space microdialysis catheter were inserted. Adenosine, 20 microg, was injected intrathecally in these and in normal rats, and microdialysates of the intrathecal space were obtained. Radioligand binding studies of adenosine A1 receptors were determined in spinal cord tissue from other normal and spinal nerve-ligated rats., Results: Adenosine disappeared from rat cerebrospinal fluid within 30 min after intrathecal injection, with no difference between normal and spinal nerve-ligated animals. A1 adenosine receptor binding sites in the spinal cord were increased after spinal nerve ligation. This increase disappeared when adenosine deaminase was added to the membrane homogenates, suggestive of decreased endogenous adenosine in the membranes of nerve-ligated animals., Conclusion: These data show that prolonged alleviation of hypersensitivity observed with intrathecal adenosine in this animal model of neuropathic pain is not due to prolonged residence in cerebrospinal fluid, although pharmacokinetics in tissues are unknown. Similarly, there is no evidence for up-regulation in spinal A1 adenosine receptors after spinal nerve ligation, and the adenosine deaminase experiment is consistent with a depletion of adenosine in spinal cord tissue after spinal nerve ligation.

Unlabelled: To explore further the role of inflammatory processing on peripheral opioid pharmacology, we examined whether the potency of intraarticular (i.a.) or intrathecal (i.t) morphine in tests of thermal and mechanical nociception changed during the induction of experimental arthritis in the rat. Thermal nociception by i.t. morphine (3, 10, and 50 micrograms) or i.a. morphine (100, 1000, and 3000 micrograms) was assessed by means of a modified Hargreaves box ever) 28 h. Mechanical antinociception was determined for the largest applied doses of morphine using von Frey hairs. Morphine produced dose-dependent thermal antinociception after i.t. or i.a. administration: a 50% increase in maximum antinociceptive thermal response (50% effective dose) was produced by i.t. doses of 9.7 micrograms at the start and 9.1 micrograms at the end of this 28-h observational interval, whereas after i.a. administration, 50% effective dose values were 553 micrograms at the start and 660 micrograms at the end. The largest applied dose of either i.t. or i.a. morphine produced mechanical antinociception. On Day 1, the antinociceptive effect for mechanical nociception (expressed as the area under the curve of the percentage of maximal possible effect values at 0.5, 1, 2, and 4 h) was 68% for i.t. morphine 50 micrograms and 53% for i.a. morphine 3000 micrograms. Neither result differed from the corresponding area under the curve values on Day 2. Naloxone administered either i.t. or i.a. abolished the antinociceptive action of morphine given at the same site. We conclude that, although morphine has a peripheral analgesic site of action in a rat arthritis model, its potency for both i.a. and i.t. routes of administration does not change during the onset of arthritis., Implications: In this animal study, we showed that the administration of morphine modulates thermal and mechanical antinociception at central and peripheral sites in inflammatory pain.