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Stephan Schug,1,2 Esther Pogatzki-Zahn,3 Lawrence D Phillips,4 Margaret Noyes Essex,5 Feng Xia,5 Alison J Reader,6 Robert Pawinski6 1Discipline of Anaesthesiology and Pain Medicine, Medical School, University of Western Australia, Perth, WA, Australia; 2Department of Anaesthesia and Pain Medicine, Royal Perth Hospital, Perth, WA, Australia; 3Department of Anaesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital of Muenster, Muenster, Germany; 4Department of Management, London School of Economics and Political Science, London, UK; 5Pfizer Inc, New York, NY, USA; 6Pfizer Ltd, Walton Oaks, Tadworth, UKCorrespondence: Margaret Noyes Essex Tel +1 212 733 8018Fax +1 646 441 5967Email margaret.essex@pfizer.comBackground: Identifying the optimal treatment in an acute postoperative setting remains a challenge. Multiple analgesic options are available, but comparing outcomes is limited by a lack of head-to-head trials. In addition, decisions based on efficacy only do not take drug safety into account. In such cases, multi-criteria decision analysis (MCDA) can be utilized to quantify and compare the efficacy and safety data of various drugs.Methodology: The efficacy-safety profiles of eight parenteral, postoperative analgesics (acetaminophen, diclofenac, ketorolac, metamizole, morphine, nefopam, parecoxib, tramadol) widely used in Europe were evaluated using an MCDA model that included 17 criteria: three for efficacy and 14 for safety. Each drug was scored on each criterion on a scale from 0 (worst) to 100 (best), according to published data and the judgment of an expert panel. A weighting process was then applied to standardize the impact of each criterion and adjust drugs’ preference scores accordingly, normalizing them on the 0– 100 scale. Sensitivity analyses were also performed, including a model in which analgesic profiles were compared when opioid sparing effect was set at a zero value for all drugs.Results: In the primary model, efficacy and safety had relative weightings of 64% and 36%, respectively. Efficacy and safety criteria with the highest values were pain relief (relative weight, 29%) and gastrointestinal effects (12%). Parecoxib received the highest overall score (93), followed by diclofenac (80), and ketorolac (75). Morphine scored the lowest (57), due to the lack of an opioid sparing effect. When opioid sparing was given a zero rating, parecoxib remained the highest scoring analgesic (93), followed by diclofenac (80), metamizole (76), and morphine (76). Parecoxib remained the most preferred analgesic in several other sensitivity analyses.Conclusion: This MCDA-based assessment suggests that parecoxib has the most favorable efficacy-safety profile among the assessed postoperative analgesics.Keywords: multi-criteria decision analysis, parenteral analgesics, postoperative pain

Bruce Parsons,1 Rainer Freynhagen,2,3 Stephan Schug,4,5 Ed Whalen,1 Marie Ortiz,1 Pritha Bhadra Brown,1 Lloyd Knapp61Pfizer Inc, New York, NY, USA; 2Department of Anesthesiology, Critical Care Medicine, Pain Therapy & Palliative Care, Pain Center Lake Starnberg, Benedictus Hospital, Tutzing, Germany; 3Department of Anesthesiology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany; 4Discipline of Anaesthesiology and Pain Medicine, Medical School, University of Western Australia, Perth, WA, Australia; 5Department of Anaesthesia and Pain Medicine, Royal Perth Hospital, Perth, WA, Australia; 6Pfizer Inc, Groton, CT, USACorrespondence: Bruce ParsonsPfizer Inc, 235 East 42nd Street, New York, NY, USATel +1 212 573 1649Email bruce.parsons@pfizer.comBackground: Euphoria is a complex, multifactorial problem that is reported as an adverse event in clinical trials of analgesics including pregabalin. The relationship between the reporting of euphoria events and pregabalin early treatment responses was examined in this exploratory post-hoc analysis.Methods: Data were from patients with neuropathic or non-neuropathic chronic pain enrolled in 40 randomized clinical trials, who received pregabalin (75–600 mg/day) or placebo. Reports of treatment-emergent euphoria events were based on the Medical Dictionary of Regulatory Activities preferred term “euphoric mood”. Prevalence rates of euphoria events overall and by indication were assessed. Post-treatment endpoints included ≥30% improvements in pain and sleep scores up to 3 weeks as well as a ≥1-point improvement in daily pain score up to 11 days after treatment.Results: 13,252 patients were analyzed; 8,501 (64.1%) and 4,751 (35.9%) received pregabalin and placebo, respectively. Overall, 1.7% (n=222) of patients reported euphoria events. Among pregabalin-treated patients, a larger proportion who reported euphoria events achieved an early pain response compared with those who did not report euphoria (30% pain responders in week 1 with euphoria events [43.0%], without euphoria events [24.2%]). Results were similar for weeks 2 and 3. For Days 2–11, a larger proportion of pregabalin-treated patients with (relative to without) euphoria events were 1-point pain responders. Findings were similar in pregabalin-treated patients for sleep endpoints (30% sleep responders in week 1 with euphoria events [50.7%], without euphoria events [36.1%]). Similar results were found for weeks 2 and 3. Patients who received placebo showed similar patterns, although the overall number of them who reported euphoria events was small (n=13).Conclusion: In patients who received pregabalin for neuropathic or non-neuropathic chronic pain, those who experienced euphoria events may have better early treatment responses than those who did not report euphoria events.Keywords: euphoria, pain, pregabalin, sleep

Sonya Ting,1 Stephan Schug2,3 1Department of Anaesthesia, Sir Charles Gairdner Hospital, Perth, WA, Australia; 2Anaesthesiology Unit, School of Medicine and Pharmacology, University of Western Australia, Perth, WA, Australia; 3Department of Anaesthesia and Pain Medicine, Royal Perth Hospital, University of Western Australia Anaesthesiology Unit, Royal Perth Hospital, Perth, WA, Australia Abstract: Pain is a common symptom that can be complex to treat. Analgesic medications are the mainstay treatment, but there is wide interindividual variability in analgesic response and adverse effects. Pharmacogenomics is the study of inherited genetic traits that result in these individual responses to drugs. This narrative review will attempt to cover the current understanding of the pharmacogenomics of pain, examining common genes affecting metabolism of analgesic medications, their distribution throughout the body, and end organ effects. Keywords: cytochrome P450, COMT, pharmacokinetics, pharmacodynamics, inherited traits

Summary: Video‐assisted thoracoscopic surgery has become increasingly popular due to faster recovery times and reduced postoperative pain compared with thoracotomy. However, analgesic regimens for video‐assisted thoracoscopic surgery vary significantly. The goal of this systematic review was to evaluate the available literature and develop recommendations for optimal pain management after video‐assisted thoracoscopic surgery. A systematic review was undertaken using procedure‐specific postoperative pain management (PROSPECT) methodology. Randomised controlled trials published in the English language, between January 2010 and January 2021 assessing the effect of analgesic, anaesthetic or surgical interventions were identified. We retrieved 1070 studies of which 69 randomised controlled trials and two reviews met inclusion criteria. We recommend the administration of basic analgesia including paracetamol and non‐steroidal anti‐inflammatory drugs or cyclo‐oxygenase‐2‐specific inhibitors pre‐operatively or intra‐operatively and continued postoperatively. Intra‐operative intravenous dexmedetomidine infusion may be used, specifically when basic analgesia and regional analgesic techniques could not be given. In addition, a paravertebral block or erector spinae plane block is recommended as a first‐choice option. A serratus anterior plane block could also be administered as a second‐choice option. Opioids should be reserved as rescue analgesics in the postoperative period. [ABSTRACT FROM AUTHOR]

Summary: Tonsillectomy is one of the most frequently performed surgical procedures; however, pain management remains challenging. Procedure‐specific efficacy as well as specific risks of treatment options should guide selection of pain management protocols based on evidence and should optimise analgesia without harm. The aims of this systematic review were to evaluate the available literature and develop recommendations for optimal pain management after tonsillectomy. A systematic review utilising preferred reporting items for systematic reviews and meta‐analysis guidelines with procedure‐specific postoperative pain management (PROSPECT) methodology was undertaken. Randomised controlled trials published in the English language up to November 2019 assessing postoperative pain using analgesic, anaesthetic or surgical interventions were identified. Out of the 719 potentially eligible studies identified, 226 randomised controlled trials met the inclusion criteria, excluding the studies examining surgical techniques. Pre‐operative and intra‐operative interventions that improved postoperative pain were paracetamol; non‐steroidal anti‐inflammatory drugs; intravenous dexamethasone; ketamine (only assessed in children); gabapentinoids; dexmedetomidine; honey; and acupuncture. Inconsistent evidence was found for local anaesthetic infiltration; antibiotics; and magnesium sulphate. Limited evidence was found for clonidine. The analgesic regimen for tonsillectomy should include paracetamol; non‐steroidal anti‐inflammatory drugs; and intravenous dexamethasone, with opioids as rescue analgesics. Analgesic adjuncts such as intra‐operative and postoperative acupuncture as well as postoperative honey are also recommended. Ketamine (only for children); dexmedetomidine; or gabapentinoids may be considered when some of the first‐line analgesics are contra‐indicated. Further randomised controlled trials are required to define risk and combination of drugs most effective for postoperative pain relief after tonsillectomy. [ABSTRACT FROM AUTHOR]

Summary: Caesarean section is associated with moderate‐to‐severe postoperative pain, which can influence postoperative recovery and patient satisfaction as well as breastfeeding success and mother‐child bonding. The aim of this systematic review was to update the available literature and develop recommendations for optimal pain management after elective caesarean section under neuraxial anaesthesia. A systematic review utilising procedure‐specific postoperative pain management (PROSPECT) methodology was undertaken. Randomised controlled trials published in the English language between 1 May 2014 and 22 October 2020 evaluating the effects of analgesic, anaesthetic and surgical interventions were retrieved from MEDLINE, Embase and Cochrane databases. Studies evaluating pain management for emergency or unplanned operative deliveries or caesarean section performed under general anaesthesia were excluded. A total of 145 studies met the inclusion criteria. For patients undergoing elective caesarean section performed under neuraxial anaesthesia, recommendations include intrathecal morphine 50–100 µg or diamorphine 300 µg administered pre‐operatively; paracetamol; non‐steroidal anti‐inflammatory drugs; and intravenous dexamethasone administered after delivery. If intrathecal opioid was not administered, single‐injection local anaesthetic wound infiltration; continuous wound local anaesthetic infusion; and/or fascial plane blocks such as transversus abdominis plane or quadratus lumborum blocks are recommended. The postoperative regimen should include regular paracetamol and non‐steroidal anti‐inflammatory drugs with opioids used for rescue. The surgical technique should include a Joel‐Cohen incision; non‐closure of the peritoneum; and abdominal binders. Transcutaneous electrical nerve stimulation could be used as analgesic adjunct. Some of the interventions, although effective, carry risks, and consequentially were omitted from the recommendations. Some interventions were not recommended due to insufficient, inconsistent or lack of evidence. Of note, these recommendations may not be applicable to unplanned deliveries or caesarean section performed under general anaesthesia. [ABSTRACT FROM AUTHOR]

Rotator cuff repair can be associated with significant and difficult to treat postoperative pain. We aimed to evaluate the available literature and develop recommendations for optimal pain management after rotator cuff repair. A systematic review using procedure-specific postoperative pain management (PROSPECT) methodology was undertaken. Randomised controlled trials published in English from 1 January 2006 to 15 April 2019 assessing postoperative pain after rotator cuff repair using analgesic, anaesthetic or surgical interventions were identified from MEDLINE, Embase and Cochrane Databases. Out of 322 eligible studies identified, 59 randomised controlled trials and one systematic review met the inclusion criteria. Pre-operative and intra-operative interventions that improved postoperative pain were paracetamol, cyclo-oxygenase-2 inhibitors, intravenous dexamethasone, regional analgesia techniques including interscalene block or suprascapular nerve block (with or without axillary nerve block) and arthroscopic surgical technique. Limited evidence was found for pre-operative gabapentin, perineural adjuncts (opioids, glucocorticoids, or α-2-adrenoceptor agonists added to the local anaesthetic solution) or postoperative transcutaneous electrical nerve stimulation. Inconsistent evidence was found for subacromial/intra-articular injection, and for surgical technique-linked interventions, such as platelet-rich plasma. No evidence was found for stellate ganglion block, cervical epidural block, specific postoperative rehabilitation protocols or postoperative compressive cryotherapy. The analgesic regimen for rotator cuff repair should include an arthroscopic approach, paracetamol, non-steroidal anti-inflammatory drugs, dexamethasone and a regional analgesic technique (either interscalene block or suprascapular nerve block with or without axillary nerve block), with opioids as rescue analgesics. Further randomised controlled trials are required to confirm the influence of the recommended analgesic regimen on postoperative pain relief. [ABSTRACT FROM AUTHOR]

Effective peri-operative pain management is a prerequisite for optimal recovery after surgery. Despite published evidence-based guidelines from several professional groups, postoperative pain management remains inadequate. The procedure-specific pain management (PROSPECT) collaboration consists of anaesthetists and surgeons with broad international representation that provide healthcare professionals with practical and evidence-based recommendations formulated in a way that facilitates clinical decision-making across all stages of the peri-operative period on a procedure-specific basis. The aim of this manuscript is to provide a detailed description of the current PROSPECT methodology with the intention of providing the rigour and transparency in which procedure-specific pain management recommendations are developed. The high methodological standards of the recommendations should improve the quality of clinical practice. [ABSTRACT FROM AUTHOR]

Importance: High-tone pelvic floor dysfunction is a complex condition that is challenging to manage effectively. Pelvic floor physical therapy (PFPT) is often used in the treatment and relies on a coordinated effort between the physician, patient, and physical therapist. Collaboration is crucial for therapy success, but there is limited research that includes personal perspectives from these individuals., Objective: The objective of this qualitative study was to gain further insight from these groups to identify areas for improvement in patient counseling and understanding of the diagnosis of high-tone pelvic floor dysfunction and the role of physical therapy., Study Design: The following participants were recruited: urogynecologists, pelvic floor physical therapists, and patients. Semistructured interviews were conducted exploring participant experiences with therapy and management of the condition and surrounding phenomena., Results: Participants interviewed included 5 urogynecologists, 5 pelvic floor physical therapists, and 15 patients. Similarities in key themes were identified: (1) the usefulness of pelvic models and illustrations in counseling, (2) appropriate descriptions of therapy, (3) motivating factors for patients, and (4) patient barriers to completing therapy. Several emergent themes revealed a misalignment in perspectives, including (1) patients reporting an unclear understanding of PFPT, (2) patient unawareness of the intimacy of therapy, and (3) reports of unsupportive and unempathetic physician providers., Conclusions: There are both similarities and discrepancies in the perspectives among physicians, pelvic floor physical therapists, and patients regarding high-tone pelvic floor dysfunction and PFPT. Acknowledging these comparisons and adapting practices could facilitate patient-centered care and improve patient understanding of their diagnosis., Competing Interests: The authors have declared they have no conflicts of interest., (Copyright © 2023 American Urogynecologic Society. All rights reserved.)

Objective: To describe the use of sublingual ketamine wafers administered by volunteer emergency medical technicians (EMTs) for pain management to patients in rural Western Australia (WA)., Methods: This retrospective cohort study included patients older than 12 years who were attended by volunteer EMTs in Esperance, Lancelin and Kalbarri, WA and received analgesic medications from 2018 to 2021. Patients who received ketamine wafers with/without other analgesics were compared to (i) patients who received only oral paracetamol and (ii) patients who received inhalational methoxyflurane without ketamine wafers with/without paracetamol., Results: The present study included 826 patients, among whom 149 patients received ketamine wafer with/without other analgesics, 82 paracetamol only and 595 methoxyflurane with/without paracetamol. Patients who received ketamine wafers were younger (median age 49 years vs 54 years for the paracetamol group vs 58 years for the methoxyflurane group), required a longer median transport interval (56 min vs 20 min vs 8 min), trauma-related (73% vs 35% vs 54%), and presented higher median initial pain score (9 vs 3 vs 8 out of 10) than those who received paracetamol and those who received methoxyflurane, respectively. Eight in the ketamine wafers group (5.4%) had a record of nausea/vomiting after the administration of ketamine wafers., Conclusions: Sublingual ketamine wafer was administered by volunteer EMTs without any evidence of major adverse events in rural WA and deemed useful as an additional pain management option when long transport to hospital was needed. No other symptoms that may be associated with the use of ketamine were recorded., (© 2023 Australasian College for Emergency Medicine.)

Aims: Patients with chronic health conditions not responding to conventional treatment can access medicinal cannabis (MC) prescriptions from clinicians in Australia. We aimed to assess overall health-related quality of life (HRQL), pain, fatigue, sleep, anxiety, and depression in a large real-world sample of patients accessing prescribed medicinal cannabis. We hypothesized that all patient-reported outcomes (PROs) would improve from baseline to 3-months., Methods: The QUEST Initiative is a large prospective multicenter study of patients with any chronic health condition newly prescribed medicinal cannabis between November 2020 and December 2021. Eligible patients were identified by 120 clinicians at medical centers across six Australian states. Consenting participants completed the EuroQol Group EQ-5D-5L health status questionnaire; European Organization for Research & Treatment of Cancer Quality of Life questionnaire (QLQ-C30); Patient-Reported Outcomes Measurement Information System (PROMIS) Short Forms in Fatigue and Sleep Disturbance, and the Depression Anxiety Stress Scale (DASS-21) before starting therapy, at 2-weeks titration, then monthly for 3-months., Results: Of the 2762 consenting participants, 2327 completed baseline and at least one follow-up questionnaire. Ages ranged between 18-97 years (mean 51y; SD = 15.4), 62.8% were female. The most commonly treated conditions were chronic pain (n = 1598/2327; 68.7%), insomnia (n = 534/2327; 22.9%), generalized anxiety (n = 508/2327; 21.5%), and mixed anxiety and depression (n = 259/2327; 11%). Across the whole cohort both EQ-5D-5L utility scores and QLQ-C30 summary scores showed clinically meaningful improvement in HRQL from baseline to mean follow-up with d = 0.54 (95%CI:0.47 to 0.59) and d = 0.64 (95%CI:0.58 to 0.70) respectively; and clinically meaningful improvement in fatigue (d = 0.54; 95%CI:0.48 to 0.59). There was clinically meaningful reduction of pain for those with chronic pain (d = 0.65; 95%CI:0.57 to 0.72); significant improvements for those with moderate to extremely severe anxiety (X2 = 383; df = 4; p<0.001) and depression (X2 = 395; df = 4; p<0.001); and no changes in sleep disturbance., Conclusions: We observed statistically significant, clinically meaningful improvements in overall HRQL and fatigue over the first 3-months in patients with chronic health conditions accessing prescribed medical cannabis. Anxiety, depression, and pain also improved over time, particularly for those with corresponding health conditions. The study continues to follow-up patients until 12-months to determine whether improvements in PROs are maintained long-term., Trail Registration: Study registration - Australian New Zealand Clinical Trials Registry: ACTRN12621000063819. https://www.australianclinicaltrials.gov.au/anzctr/trial/ACTRN12621000063819., Competing Interests: The University of Sydney received funding from Little Green Pharma Pty Ltd. to support MT and CR to conduct the submitted work; LW is a paid employee of Little Green Pharma Pty Ltd.; no other relationships or activities that could appear to have influenced the submitted work. All authors have completed the ICMJE uniform disclosure form. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Tait et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Abstract: There are few effective treatments for acute whiplash-associated disorders (WADs). Early features of central sensitisation predict poor recovery. The effect of pregabalin on central sensitisation might prevent chronic pain after acute whiplash injury. This double blind, placebo-controlled randomised controlled trial examined feasibility and potential effectiveness of pregabalin compared with placebo for people with acute WAD. Twenty-four participants with acute WAD (<48 hours) and at risk of poor recovery (pain ≥5/10) were recruited from hospital emergency departments in Queensland, Australia, and randomly assigned by concealed allocation to either pregabalin (n = 10) or placebo (n = 14). Pregabalin was commenced at 75 mg bd, titrated to 300 mg bd for 4 weeks, and then weaned over 1 week. Participants were assessed at 5 weeks and 3, 6, and 12 months. Feasibility issues included recruitment difficulties and greater attrition in the placebo group. For the primary clinical outcome of neck pain intensity, attrition at 5 weeks was pregabalin: 10% and placebo: 36% and at 12 months was pregabalin: 10% and placebo: 43%. Pregabalin may be more effective than placebo for the primary clinical outcome of neck pain intensity at 3 months (mean difference: -4.0 [95% confidence interval -6.2 to -1.7]) on an 11-point Numerical Rating Scale. Effects were maintained at 6 months but not 12 months. There were no serious adverse events. Minor adverse events were more common in the pregabalin group. A definitive large randomised controlled trial of pregabalin for acute whiplash injury is warranted. Feasibility issues would need to be addressed with modifications to the protocol., (Copyright © 2021 International Association for the Study of Pain.)

This report provides a summary of the 4 th International Conference on Global Bioequivalence Harmonisation Initiative (GBHI) that was co-organised by the European Federation of Pharmaceutical Sciences (EUFEPS) and the American Association of Pharmaceutical Scientists (AAPS). The goal of the GBHI conference is to offer the most informative and up to date science and regulatory thinking of bioequivalence (BE) in global drug development to support the intended process of a scientific global harmonisation. The workshop provided an open forum for pharmaceutical scientists from academia, industry and regulatory agencies to discuss three BE topics of interest, (a) BE assessment for long-acting injectables and implants, (b) necessity of fed BE studies for immediate-release products and (c) procedures to demonstrate equivalence of orally inhaled products. Moreover, in keynote lectures, a potential road map to an international BE reference product was discussed, and visions and perspectives for future global BE harmonisation activities have been presented. The meeting delivered a cutting-edge insight into the topics in an interactive and at the same time focused way., (Copyright © 2021. Published by Elsevier B.V.)

Background: Evidence supports several countries introducing legislation to allow cannabis-based medicine as an adjunctive treatment for the symptomatic relief of chronic pain, chemotherapy-induced nausea, spasticity in multiple sclerosis (MS), epileptic seizures, depression, and anxiety. However, clinical trial participants do not represent the entire spectrum of disease and health status seen in patients currently accessing medicinal cannabis in practice., Objective: This study aims to collect real-world data to evaluate health-related quality of life in patients prescribed medicinal cannabis oil and describe any differences over time, from before starting therapy to after 3 and 12 months of therapy., Methods: Adult patients newly prescribed medicinal cannabis oil by authorized prescribers and under the Special Access Schemes across Australia will be screened for eligibility and invited to participate. A sample size of 2142 is required, with a 3-month follow-up. All participants will complete the EuroQol 5-Dimension; European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-30; Depression, Anxiety, and Stress Scale-21; Patients' Global Impression of Change; Patient-Reported Outcomes Measurement Information System (PROMIS) Short Form (SF) version 1.0: Sleep Disturbance 8b; and PROMIS SF Fatigue 13a questionnaires. Patients with chronic pain conditions will also complete the PROMIS SF version 1.0: Pain Intensity 3a and PROMIS SF version 1.0: Pain Interference 8a. Patients with movement disorders will also complete Quality of Life in Neurological Disorders (Neuro-QoL) SF version 1.0: Upper Extremity Function (Fine Motor and Activities of Daily Living) and if chorea is indicated, the Neuro-QoL SF version 2.0: Huntington's Disease health-related Quality of LIFE-Chorea 6a. All questionnaires will be administered at baseline, 2 weeks (titration), monthly up to 3 months, and then every 2 months up to 1 year., Results: Recruitment commenced in November 2020. By June 2021, 1095 patients were screened for the study by 69 physicians in centers across 6 Australian states: Australian Capital Territory, New South Wales, Queensland, South Australia, Victoria, and Western Australia. Of the patients screened, 833 (39% of the target sample size) provided consent and completed baseline questionnaires. Results are expected to be published in 2022. Results of this study will show whether patient-reported outcomes improve in patients accessing prescribed medicinal cannabis from baseline to 3 months and whether any changes are maintained over a 12-month period. This study will also identify differences in improvements in patient-reported outcomes among patients with different chronic conditions (eg, chronic pain, MS, epilepsy, Parkinson disease, or cancer)., Conclusions: This protocol contains detailed methods that will be used across multiple sites in Australia. The findings from this study have the potential to be integral to treatment assessment and recommendations for patients with chronic pain and other health indicators for accessing medicinal cannabis., Trial Registration: Australian New Zealand Clinical Trials Registry: ANZCTRN12621000063819; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=380807&isReview=true., International Registered Report Identifier (irrid): DERR1-10.2196/32327., (©Margaret-Ann Tait, Daniel S J Costa, Rachel Campbell, Richard Norman, Stephan Schug, Claudia Rutherford. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 24.11.2021.)

When an action potential arrives at a synapse there is a large probability that no neurotransmitter is released. Surprisingly, simple computational models suggest that these synaptic failures enable information processing at lower metabolic costs. However, these models only consider information transmission at single synapses ignoring the remainder of the neural network as well as its overall computational goal. Here, we investigate how synaptic failures affect the energy efficiency of models of entire neural networks that solve a goal-driven task. We find that presynaptic stochasticity and plasticity improve energy efficiency and show that the network allocates most energy to a sparse subset of important synapses. We demonstrate that stabilising these synapses helps to alleviate the stability-plasticity dilemma, thus connecting a presynaptic notion of importance to a computational role in lifelong learning. Overall, our findings present a set of hypotheses for how presynaptic plasticity and stochasticity contribute to sparsity, energy efficiency and improved trade-offs in the stability-plasticity dilemma., Competing Interests: SS, FB, AS No competing interests declared, (© 2021, Schug et al.)

Abstract: The International Classification of Diseases-11 (ICD-11) chronic pain classification includes about 100 chronic pain diagnoses on different diagnostic levels. Each of these diagnoses requires specific operationalized diagnostic criteria to be present. The classification comprises more than 200 diagnostic criteria. The aim of the Classification Algorithm for Chronic Pain in ICD-11 (CAL-CP) is to facilitate the use of the classification by guiding users through these diagnostic criteria. The diagnostic criteria were ordered hierarchically and visualized in accordance with the standards defined by the Society for Medical Decision Making Committee on Standardization of Clinical Algorithms. The resulting linear decision tree underwent several rounds of iterative checks and feedback by its developers, as well as other pain experts. A preliminary pilot evaluation was conducted in the context of an ecological implementation field study of the classification itself. The resulting algorithm consists of a linear decision tree, an introduction form, and an appendix. The initial decision trunk can be used as a standalone algorithm in primary care. Each diagnostic criterion is represented in a decision box. The user needs to decide for each criterion whether it is present or not, and then follow the respective yes or no arrows to arrive at the corresponding ICD-11 diagnosis. The results of the pilot evaluation showed good clinical utility of the algorithm. The CAL-CP can contribute to reliable diagnoses by structuring a way through the classification and by increasing adherence to the criteria. Future studies need to evaluate its utility further and analyze its impact on the accuracy of the assigned diagnoses., (Copyright © 2021 International Association for the Study of Pain.)

Objective: For many medical professionals dealing with patients with persistent pain following spine surgery, the term Failed back surgery syndrome (FBSS) as a diagnostic label is inadequate, misleading, and potentially troublesome. It misrepresents causation. Alternative terms have been suggested, but none has replaced FBSS. The International Association for the Study of Pain (IASP) published a revised classification of chronic pain, as part of the new International Classification of Diseases (ICD-11), which has been accepted by the World Health Organization (WHO). This includes the term Chronic pain after spinal surgery (CPSS), which is suggested as a replacement for FBSS., Methods: This article provides arguments and rationale for a replacement definition. In order to propose a broadly applicable yet more precise and clinically informative term, an international group of experts was established., Results: 14 candidate replacement terms were considered and ranked. The application of agreed criteria reduced this to a shortlist of four. A preferred option-Persistent spinal pain syndrome-was selected by a structured workshop and Delphi process. We provide rationale for using Persistent spinal pain syndrome and a schema for its incorporation into ICD-11. We propose the adoption of this term would strengthen the new ICD-11 classification., Conclusions: This project is important to those in the fields of pain management, spine surgery, and neuromodulation, as well as patients labeled with FBSS. Through a shift in perspective, it could facilitate the application of the new ICD-11 classification and allow clearer discussion among medical professionals, industry, funding organizations, academia, and the legal profession., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.)

The classical function of human chorionic gonadotropin (hCG) is its role in supporting pregnancy. hCG is a dimer consisting of two highly glycosylated subunits, alpha (CGA) and beta (CGB). The beta-hCG protein is encoded by CGB3, CGB5, CGB7 and CGB8 genes. CGB3, 5 and 8 code for an identical protein, CGB3/5/8, whereas CGB7 differs in three amino acids from CGB3/5/8. We had observed earlier that CGB7 and CGB3/5/8 display very distinct tissue expression patterns and that the tumor suppressor and transcription factor p53 can activate expression of CGB7 but not of CGB3/5/8 genes. Here, we investigate the glycan structures and possible functional differences of the two CGB variants. To this end, we established a system to produce and isolate recombinant CGA, CGB7 and CGB3/5/8 proteins. We found that N- and O-glycosylation patterns of CGB7 and CGB3/5/8 are quite similar. Functional assays were performed by testing activation of the ERK1/2 pathway and demonstrated that CGB7 and CGB5/5/8 appear to be functionally redundant isoforms, although a slight difference in the kinetics of ERK1/2 pathway activation was observed. This is the first time that biological activity of CGB7 is shown. In summary, the results lead to the hypothesis that CGB7 and CGB3/5/8 do not hold significant functional differences but that timing and cell type of their expression is the key for understanding their divergent evolution.

Objectives: Over two-thirds of older individuals live with multiple chronic conditions, yet chronic diseases are often studied in silos. Taking a lifespan approach to understanding the development of multiple chronic conditions in the older population helps to further elucidate opportunities for targeted interventions that address the complexities of multiple chronic conditions., Methods: Semi-structured interviews were conducted with 38 older adults (age 64+) diagnosed with at least two chronic health conditions. Content analysis was used to build understanding of how older adults discuss the timing of diagnoses and subsequent self-management of multiple chronic conditions., Results: Findings highlight the complex process by which illnesses unfold in the context of individuals' lives and the subsequent engagement and/or disengagement in self-management behaviors. Two primary themes were evident regarding timing of illnesses: illnesses were experienced within the context of social life events and/or health events, and illnesses were not predominantly seen as connected to one another by patients. Self-management behaviors were described in response to onset of each illness., Discussion: Findings provide insight into how older adults understand their experience of multiple chronic conditions and change in self-management behaviors over time. In order for practitioners to ignite behavioral changes, a person's history and life experiences must be considered.

Background: Central sensitization (CS) is a form of neuroplasticity characterized by changes in the neural sensitivity, responsiveness, and/or output that are not contingent on peripheral input nor activity-dependent. CS is characterized by activation of unmyelinated C-fibers resulting in a cascade of events at molecular and cellular levels which eventuate into generation of synaptic currents at rest. CS, therefore, contributes to heightened generalized pain sensitivity, further complicates the process of reaching a diagnosis, and increases the possibility of treatment failure. BODY: Trigeminal nerve is the main sensory supplier of the anterior part of the head, including the intraoral structures. Primary afferent nociceptors of the trigeminal nerve and low threshold mechanoreceptors synapse with wide dynamic range (WDR) neurons in the pons. This multifaceted network of nerve interactions which is further complicated by the modulatory circuits that can suppress or heighten the activity of WDR neurons is one of the main contributors to CS. The importance of CS in orofacial pain disorders is emphasized in the context of chronic pain development. As for all chronic pain conditions, it is crucial to consider the biopsychosocial aspects of chronic orofacial pain in managing this diverse group of conditions. This review highlights current understanding of the biopsychosocial model and central mechanisms contributing to the pathogenesis of chronic orofacial pain., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: Conditioned pain modulation (CPM) and manipulation-induced analgesia (MIA) are 2 forms of endogenous analgesia. Many forms of analgesia can be influenced by the nature of the patient-clinician interaction. The aim of this study was to evaluate the influence of an empathetic and supportive interaction on CPM and MIA in people with lateral epicondylalgia (LE)., Material and Methods: In a double-blind, randomized, controlled trial, 68 participants with LE were assigned to 2 groups: the empathetic and neutral interaction groups. The interactions were carried out by a trained, professional role-play actor, playing the part of a research assistant. The research assistant actor spent 15 minutes before CPM and MIA assessment interacting with the participants in an empathetic or neutral manner. Immediately after the interaction, a blinded assessor measured pressure pain threshold at the symptomatic elbow and ipsilateral wrist during CPM and MIA testing. Linear mixed models were used to evaluate differences in CPM and MIA responses between the interaction groups., Results: There was a significant difference in Consultation and Relational Empathy scores between the groups (P<0.001), indicating that the intervention group experienced a more empathic interaction. Both groups showed a significant increase in pressure pain threshold measures, indicative of a CPM and MIA analgesic response (P<0.001), however, the analgesic responses were greater in the group that had experienced a supportive, empathetic interaction (post CPM, wrist: P<0.001; elbow: P=0.001) (post MIA wrist: P<0.001; elbow: P=0.001)., Discussion: A single session of empathetic interaction positively influenced both CPM and MIA responses in people with LE.

Purpose: Successful embryo implantation into the endometrium depends on embryonic characteristics and proper endometrial development. Reproductive medicine often focuses on embryo quality, whereas reliable diagnostic tests for endometrial receptivity are still needed. We previously found that human chorionic gonadotropin (hCG), one of the earliest proteins secreted by the embryo, was also expressed by the luteal phase endometrium around the implantation window. Here, we tested our hypothesis of endometrial hCG as an implantation marker., Methods: Endometrial biopsies and serum samples were taken from patients undergoing routine infertility diagnostics. Correlations of immunohistochemically detected endometrial hCG expression with adequate endometrial secretory transformation, the infiltration of CD45-positive leukocytes, clinical diagnostic parameters, and endometrial thickness were analyzed., Results: A highly significant correlation between the endometrial score, as a measurement for regular secretory transformation, and the intensity of hCG staining was found. The invasion of CD45-positive leukocytes increased with progressing endometrial secretory transformation and rising endometrial hCG expression. In addition, serum progesterone concentrations correlated with hCG expression by the endometrial glands., Conclusions: Our results suggest endometrial hCG as a possible diagnostic parameter characterizing the endometrial secretory transformation and, thus, possibly also its implantation capability.

Objectives: Conditioned pain modulation (CPM) and manipulation-induced analgesia (MIA) may activate similar neurophysiological mechanisms to mediate their analgesic effects. This study assessed the association between CPM and MIA responses in people with lateral epicondylalgia., Materials and Methods: Seventy participants with lateral epicondylalgia were assessed for CPM followed by MIA. A single assessor measured pressure pain thresholds (PPT) before, during, and after cold water immersion (10°C) of the asymptomatic hand and contralateral lateral glide (CLG) mobilization of the neck. For analyses, linear mixed models evaluated differences in CPM and MIA responses. Pearson partial correlations and regression analyses evaluated the association between CPM and MIA PPT., Results: There was a significant increase (CPM and MIA, P<0.001) in PPT from baseline during the interventions (CPM mean: 195.84 kPa for elbow and 201.87 kPa for wrist, MIA mean: 123.01 kPa for elbow and 126.06 kPa for wrist) and after the interventions (CPM mean: 126.06 kPa for elbow, 114.24 kPa for wrist, MIA mean: 123.50 kPa for elbow and 122.16 kPa for wrist). There were also significant moderate and positive partial linear correlations (r: 0.40 to 0.54, P<0.001) between CPM and MIA measures, controlling for baseline measures. Regression analyses showed that CPM PPT was a significant predictor of MIA PPT (P<0.001) and the models explained between 73% and 85% of the variance in MIA PPT., Discussion: This study showed that CPM and MIA responses were significantly correlated and that the CPM response was a significant predictor of MIA response.

Aim: The principal study objective was to investigate the pharmacokinetic characteristics and determine the absolute bioavailability and tolerability of a new sublingual (SL) buprenorphine wafer., Methods: The study was of open label, two-way randomized crossover design in 14 fasted healthy male and female volunteers. Each participant, under naltrexone block, received either a single intravenous dose of 300 mcg of buprenorphine as a constant infusion over five minutes or a sublingual dose of 800 mcg of buprenorphine in two treatment periods separated by a seven-day washout period. Blood sampling for plasma drug assay was taken on 16 occasions throughout a 48-hour period (predose and at 10, 20, 30, and 45 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24 and 48 hours postdose). The pharmacokinetic parameters were determined by noncompartmental analyses of the buprenorphine plasma concentration-time profiles. Local tolerability was assessed using modified Likert scales., Results: The absolute bioavailability of SL buprenorphine was 45.4% (95% confidence interval = 37.8-54.3%). The median times to peak plasma concentration were 10 minutes and 60 minutes after IV and SL administration, respectively. The peak plasma concentration was 2.65 ng/mL and 0.74 ng/mL after IV and SL administration, respectively. The half-lives were 9.1 hours and 11.2 hours after IV and SL administration, respectively. The wafer had very good local tolerability., Conclusions: This novel sublingual buprenorphine wafer has high bioavailability and reduced Tmax compared with other SL tablet formulations of buprenorphine. The wafer displayed very good local tolerability. The results suggest that this novel buprenorphine wafer may provide enhanced clinical utility in the management of both acute and chronic pain., Background: Buprenorphine is approved for use in pain management and opioid addiction. Sublingual administration of buprenorphine is a simple and noninvasive route of administration and has been available for many years. Improved sublingual formulations may lead to increased utilization of this useful drug for acute and chronic pain management.

Chronic pain is a major source of suffering. It interferes with daily functioning and often is accompanied by distress. Yet, in the International Classification of Diseases, chronic pain diagnoses are not represented systematically. The lack of appropriate codes renders accurate epidemiological investigations difficult and impedes health policy decisions regarding chronic pain such as adequate financing of access to multimodal pain management. In cooperation with the WHO, an IASP Working Group has developed a classification system that is applicable in a wide range of contexts, including pain medicine, primary care, and low-resource environments. Chronic pain is defined as pain that persists or recurs for more than 3 months. In chronic pain syndromes, pain can be the sole or a leading complaint and requires special treatment and care. In conditions such as fibromyalgia or nonspecific low-back pain, chronic pain may be conceived as a disease in its own right; in our proposal, we call this subgroup "chronic primary pain." In 6 other subgroups, pain is secondary to an underlying disease: chronic cancer-related pain, chronic neuropathic pain, chronic secondary visceral pain, chronic posttraumatic and postsurgical pain, chronic secondary headache and orofacial pain, and chronic secondary musculoskeletal pain. These conditions are summarized as "chronic secondary pain" where pain may at least initially be conceived as a symptom. Implementation of these codes in the upcoming 11th edition of International Classification of Diseases will lead to improved classification and diagnostic coding, thereby advancing the recognition of chronic pain as a health condition in its own right.

The upcoming 11th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD) of the World Health Organization (WHO) offers a unique opportunity to improve the representation of painful disorders. For this purpose, the International Association for the Study of Pain (IASP) has convened an interdisciplinary task force of pain specialists. Here, we present the case for a reclassification of nervous system lesions or diseases associated with persistent or recurrent pain for ≥3 months. The new classification lists the most common conditions of peripheral neuropathic pain: trigeminal neuralgia, peripheral nerve injury, painful polyneuropathy, postherpetic neuralgia, and painful radiculopathy. Conditions of central neuropathic pain include pain caused by spinal cord or brain injury, poststroke pain, and pain associated with multiple sclerosis. Diseases not explicitly mentioned in the classification are captured in residual categories of ICD-11. Conditions of chronic neuropathic pain are either insufficiently defined or missing in the current version of the ICD, despite their prevalence and clinical importance. We provide the short definitions of diagnostic entities for which we submitted more detailed content models to the WHO. Definitions and content models were established in collaboration with the Classification Committee of the IASP's Neuropathic Pain Special Interest Group (NeuPSIG). Up to 10% of the general population experience neuropathic pain. The majority of these patients do not receive satisfactory relief with existing treatments. A precise classification of chronic neuropathic pain in ICD-11 is necessary to document this public health need and the therapeutic challenges related to chronic neuropathic pain.

Background: Tapentadol is a novel atypical opioid. Anecdotal evidence suggests that tapentadol has a lower toxicity than conventional opioids., Objectives: To evaluate all single-drug mortality due to tapentadol and assess serious adverse events caused by tapentadol., Methods: The Preferred Reporting Items for Systematic review and Meta-Analysis Protocols (PRISMA-P) reporting guidelines, an evidence-based minimum set of items for reporting in systematic reviews, were followed in this systematic review., Results:  24 peer-reviewed papers were identified. They indicate that tapentadol toxicity can cause mortality and serious adverse effects., Conclusion(s): At least four confirmed fatalities, and serious adverse effects have been documented for individuals abusing or using tapentadol as prescribed. Serious adverse effects of tapentadol use may include respiratory depression, confusion, coma, hallucination/delusion, seizures, tachycardia, hypertension, agitation, tremor, miosis, hypotension, dyspnea, electrolyte abnormality, atrial fibrillation or severe upper abdominal pain. Tapentadol is unlikely to cause serotonin syndrome. The toxicity of tapentadol is significantly less than pure mu opioids, such as oxycodone.

Chronic postsurgical pain (CPSP) occurs in 12% of surgical populations and is a high priority for perioperative research. Systemic lidocaine may modulate several of the pathophysiological processes linked to CPSP. This systematic review aims to identify and synthesize the evidence linking lidocaine infusions and CPSP. The authors conducted a systematic literature search of the major medical databases from inception until October 2017. Trials that randomized adults without baseline pain to perioperative lidocaine infusion or placebo were included if they reported on CPSP. The primary outcome was the presence of procedure-related pain at 3 months or longer after surgery. The secondary outcomes of pain intensity, adverse safety events, and local anesthetic toxicity were also assessed. Six trials from 4 countries (n = 420) were identified. Chronic postsurgical pain incidence was consistent with existing epidemiological data. Perioperative lidocaine infusions significantly reduced the primary outcome (odds ratio, 0.29; 95% confidence interval, 0.18-0.48), although the difference in intensity of CPSP assessed by the short-form McGill Pain Questionnaire (4 trials) was not statistically significant (weighted mean difference, -1.55; 95% confidence interval, -3.16 to 0.06). Publication and other bias were highly apparent, as were limitations in trial design. Each study included a statement reporting no adverse events attributable to lidocaine, but systematic safety surveillance strategies were absent. Current limited clinical trial data and biological plausibility support lidocaine infusions use to reduce the development of CPSP without full assurances as to its safety. This hypothesis should be addressed in future definitive clinical trials with comprehensive safety assessment and reporting.