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Erika A Petersen,1,* Timothy R Deer,2,* Stana Bojanic,3 Lauren R Sankary,4 Natalie H Strand,5 Adnan Al Kaisy,6 Frank Huygen,7 Dawood Sayed,8 Monique Steegers,9 Paul Verrills,10 Michael E Schatman11,12 1Department of Neurosurgery, University of Arkansas for Medical Sciences, Little Rock, AR, USA; 2Spine and Nerve Center of the Virginias, Charleston, WV, USA; 3Department of Neurosurgery, John Radcliffe University Hospitals NHS Trust, Oxford, UK; 4Neuroethics Program, Cleveland Clinic, Cleveland, OH, USA; 5Department of Anesthesiology, Mayo Clinic, Phoenix, AZ, USA; 6The Pain Management and Neuromodulation Centre, Guy’s & St. Thomas’ NHS Foundation Trust, London, UK; 7Department of Anesthesiology, Center of Pain Medicine, Erasmus MC, Rotterdam, the Netherlands; 8Department of Anesthesiology and Pain Medicine, The University of Kansas Medical Center, Kansas City, KS, USA; 9Departments of Anesthesiology and Pain and Palliative Medicine, Amsterdam UMC, Amsterdam, the Netherlands; 10Pain Medicine, Metro Pain Clinic, Melbourne, Australia; 11Department of Anesthesiology, Perioperative Care, and Pain Medicine, NYU Grossman School of Medicine, New York, NY, USA; 12Department of Population Health – Division of Medical Ethics, NYU Grossman School of Medicine, New York, NY, USA*These authors contributed equally to this workCorrespondence: Erika A Petersen, Department of Neurosurgery, University of Arkansas for Medical Science, 4301 West Markham Slot #507, Little Rock, AR, 72205, USA, Tel +15016865270, Email eapetersen@uams.eduAbstract: The COVID-19 pandemic caught many areas of medicine in a state of unpreparedness for conducting research and completing ongoing projects during a global crisis, including the field of pain medicine. Waves of infection led to a disjointed ability to provide care and conduct clinical research. The American Society of Pain and Neuroscience (ASPN) Research Group has created guidance for pragmatic and ethical considerations for research during future emergency or disaster situations. This analysis uses governmental guidance, scientific best practices, and expert opinion to address procedure-based or device-based clinical trials during such times. Current literature offers limited recommendations on this important issue, and the findings of this group fill a void for protocols to improve patient safety and efficacy, especially as we anticipate the impact of future disasters and spreading global infectious diseases. We recommend local adaptations to best practices and innovations to enable continued research while respecting the stressors to the research subjects, investigator teams, health-care systems, and to local infrastructure.Keywords: research, pain, emergency, pandemic, protocols

David J Kopsky,1– 3 Karolina M Szadek,1 Patrick Schober,1 Alexander FJE Vrancken,3 Monique AH Steegers1 1Department of Anesthesiology, Amsterdam University Medical Center, Amsterdam, 1081 HV, the Netherlands; 2Institute for Neuropathic Pain, Amsterdam, 1056 SN, the Netherlands; 3Department of Neurology, Brain Centre University Medical Center Utrecht, Utrecht University, Utrecht, the NetherlandsCorrespondence: David J Kopsky Institute for Neuropathic Pain, Vespuccistraat 64-III, Amsterdam, 1056 SN, the Netherlands Tel +31-6-28671847 Email info@neuropathie.nuAbstract: Enriched enrollment randomized withdrawal (EERW) pain trials are designed to include only responders with considerable pain relief without unacceptable side effects into the randomized phase. There are no recommendations for primary endpoints in such trials. Our objective was to propose recommendations based on assessment of trial characteristics, endpoints and effect sizes in EERW pain trials. We conducted a systematic review by searching electronic databases up to June 2020 for EERW trials comparing an analgesic with a placebo in adults suffering from chronic pain. A total of 28 trials met our criteria, involving 13662 patients in the open or single-blind phase and 7937 patients in the double-blind phase. As primary endpoint 18 trials used pain intensity measured with the visual analogue scale (VAS) or the 11-point numerical rating scale (NRS); 1 trial used a 4-point NRS. Loss of therapeutic response (LTR) was used in 1 trial and time to LTR was used in 8 trials as primary endpoint. Definitions of time to LTR differed considerably between trials. Only 2 out of 8 trials using time to LTR as primary endpoint reported the percentage of patients experiencing a minimum pain relief of 50%, compared to 14 out of 18 trials using NRS or VAS. Due to the complexity and diversity of time to LTR in EERW pain trials, we propose to use the NRS as primary endpoint with conservative imputation methods, and to use time to LTR as secondary endpoint.Keywords: systematic review, pain, EERW trials, analgesics, endpoints

Ansbert S Ndebea,1 Sandra AS van den Heuvel,2 Rogers Temu,3 Mwemezi M Kaino,1 Regina LM van Boekel,2 Monique AH Steegers4 1Department of Anesthesiology, Kilimanjaro Christian Medical Centre, Kilimanjaro, Tanzania; 2Department of Anesthesiology and Pain and Palliative Medicine, Radboud University Medical Centre, Nijmegen, the Netherlands; 3Department of Orthopedic and Trauma, Kilimanjaro Christian Medical Centre, Kilimanjaro, Tanzania; 4Department of Anesthesiology, Amsterdam University Medical Center Location VU, Amsterdam, the NetherlandsCorrespondence: Ansbert S NdebeaDepartment of Anesthesiology, Kilimanjaro Christian Medical Centre, PO Box 3010, Moshi, TanzaniaEmail sweetbert19@gmail.comBackground: In Africa, postoperative pain management is still a major problem with a prevalence of postoperative pain in up to 95.2% of the patients. There are little data on the prevalence and potential risk factors for postoperative pain in Tanzania. Therefore, we aimed to investigate these at Kilimanjaro Christian Medical Centre in Northern Tanzania. Our goal is to optimize pain management.Methods: A prospective cohort study was carried out from December 2016 to April 2017. Patients ≥ 18 years admitted for elective general or orthopedic surgery were included in the study. Demographic data were collected during a pre-operative visit, and pain was assessed with a numerical rating scale (NRS 0– 10) at 4, 24, 36 and 48 hours postoperatively. A NRS > 3 was considered as moderate to severe postoperative pain. Potential risk factors for postoperative pain were identified using univariate and multivariable binary logistic regression analyses.Results: A total of 281 patients were included in the study. The prevalence of postoperative pain was 61%, 73%, 67% and 58% at 4, 24, 36 and 48 hours after surgery, respectively. Pethidine was the most frequently prescribed analgesic for postoperative pain management (85.1%) in the first 24 hours postoperatively; only 1% received paracetamol or diclofenac, and 13% received tramadol. In the multivariable model, general anesthesia and intra-operative analgesia (OR = 3.70, 95% CI 1.70– 8.04) were significant risk factors for postoperative pain.Conclusion: Pain is still inadequately managed at Kilimanjaro Christian Medical Centre leading to a high prevalence (73% on the first day after surgery) of reported postoperative pain in this study. It reflects the need for adequate postoperative analgesia, especially in low- and middle-income countries. Further research identifying risk factors in larger cohorts can be performed if adequate analgesia is given.Keywords: postoperative pain, prevalence, risk factors, Tanzania

Sandra AS van den Heuvel,1 Selina EI van der Wal,1 Ewald M Bronkhorst,2 Michiel C Warlé,3 May Ronday,4 Judith Plat,4 Nens van Alfen,5 Leo AB Joosten,6 Jos GC Lerou,1 Kris CP Vissers,1 Monique AH Steegers7 1Department of Anesthesiology, Pain and Palliative Medicine, Radboud University Medical Centre, Nijmegen, the Netherlands; 2Department of Health Evidence, Radboud University Medical Centre, Nijmegen, the Netherlands; 3Division of Vascular and Transplant Surgery, Department of Surgery, Radboud University Medical Centre, Nijmegen, the Netherlands; 4Department of Anesthesiology, Alexander Monro Breast Cancer Hospital, Bilthoven, the Netherlands; 5Donders Institute for Brain Cognition and Behavior, Department of Neurology, Radboud University Medical Centre, Nijmegen, the Netherlands; 6Department of Internal Medicine and Radboud Centre for Infectious Diseases, Radboud University Medical Centre, Nijmegen, the Netherlands; 7Department of Anesthesiology, Pain and Palliative Medicine, Amsterdam University Medical Centre, Amsterdam, the NetherlandsCorrespondence: Sandra AS van den HeuvelDepartment of Anesthesiology, Pain and Palliative Medicine, Radboud University Nijmegen Medical Center, Internal mail 630, P.O. Box 9101, Nijmegen 6525 GA, the NetherlandsTel +31 243615244Email Sandra.vandenHeuvel@radboudumc.nlPurpose: An imbalance in perioperative cytokine response may cause acute pain and postoperative complications. Anesthetic drugs modulate this cytokine response, but their role in non-major breast cancer surgery is unclear. In an exploratory study, we investigated whether intravenous lidocaine and dexamethasone could modulate the cytokine response into an anti-inflammatory direction. We also evaluated interrelationships between cytokine levels, pain scores and postoperative complications. Our goal is to develop multimodal analgesia regimens optimizing outcome after breast cancer surgery.Patients and Methods: Forty-eight patients undergoing a lumpectomy were randomly assigned to placebo or lidocaine (1.5 mg⋅kg− 1 followed by 2 mg⋅kg− 1⋅hour− 1) supplemented by dexamethasone zero, 4 or 8 mg, yielding six groups of eight patients. Interleukin (IL)-1β, IL-1Ra, IL-6, IL-10 levels and pain scores were measured at baseline and four hours postoperatively. We assessed postoperative complications occurring within 30 days. We noted persistent pain and infections as potential immune-related complications (PIRC). We used multiple regression to disentangle the effects of the individual study drugs (given by their partial regression coefficients (b)). Odds ratios (OR) estimated the link between pain scores and complications.Results: Dexamethasone 8 mg increased IL-10 (b=12.70 (95% CI=8.06– 17.34), P< 0.001). Dexamethasone 4 mg and 8 mg decreased the ratio IL-6/IL-10 (b=− 2.60 (− 3.93 to − 1.26), P< 0.001 and b=− 3.59 (− 5.04 to − 2.13), P< 0.001, respectively). We could not show modulatory effects of lidocaine on cytokines. High pain scores were linked to the occurrence of PIRC’s (OR=2.028 (1.134– 3.628), P=0.017). Cytokine levels were not related either to acute pain or PIRC.Conclusion: Dexamethasone modulated the perioperative cytokine response into an anti-inflammatory direction. An overall lidocaine effect was not found. Patients with higher pain scores suffered from more 30-day PIRCs. Cytokine levels were not associated with pain or more postoperative complications, even not with PIRC. Larger studies in breast cancer surgery are needed to confirm these explorative results.Keywords: acute pain, anesthetic agents, immune response, lumpectomy, perioperative outcomes

Background Mechanical ventilation ( MV) induces an inflammatory response that may result in (acute) lung injury. Lidocaine, an amide local anesthetic, has anti-inflammatory properties in vitro and in vivo, possibly due to an attenuation of pro-inflammatory cytokines, intracellular adhesion molecule-1 ( ICAM-1), and reduction of neutrophils influx. We hypothesized an attenuation of MV-induced inflammatory response with intravenously administered lidocaine. Methods Lidocaine ( Lido) (2, 4, and 8 mg/kg/h) was intravenously administered during 4 h of MV with a tidal volume of 8 ml/kg, positive end expiratory pressure 1,5 cmH2O and FiO2 0.4. We used one ventilated control ( CON) group receiving vehicle. After MV, mice were euthanized, and lungs and blood were immediately harvested, and cytokine levels and ICAM-1 levels were measured in plasma and lung homogenates. Pulmonary neutrophils influx was determined in LEDER-stained slices of lungs. Anesthetic need was determined by painful hind paw stimulation. Results Lidocaine-treated animals ( Lido 2, 4 and 8 mg/kg/h) showed higher interleukin ( IL)-10 plasma levels compared to control animals. Lidocaine treatment with 8 mg/kg/h ( Lido 8) resulted in higher IL-10 in lung homogenates. No differences were observed in pro-inflammatory cytokines, ICAM-1, and pulmonary influx between the different ventilated groups. Conclusions Intravenously administered lidocaine increases levels of plasma IL-10 with infusion from 2, 4, and 8 mg/kg/h and pulmonary levels of IL-10 with 8 mg/kg/h in a murine mechanical ventilation model. Intravenously administered lidocaine appears to reduce anesthetic need in mice. [ABSTRACT FROM AUTHOR]

Hans Timmerman,1 Oliver HG Wilder-Smith,1,2 Monique AH Steegers,3 Kris CP Vissers,3 André P Wolff4 1Department of Anesthesiology, Pain and Palliative Medicine, Radboud University Medical Center, Nijmegen, the Netherlands; 2Center for Sensory-Motor Interaction, Aalborg University, Aalborg, Denmark; 3Department of Anesthesiology, Pain and Palliative Medicine, Radboud University Medical Center, Nijmegen, the Netherlands; 4Department of Anesthesiology, Pain Center, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands Background: The assessment of a neuropathic pain component (NePC) to establish the neurological criteria required to comply with the clinical description is based on history taking, clinical examination, and quantitative sensory testing (QST) and includes bedside examination (BSE). The objective of this study was to assess the potential association between the clinically diagnosed presence or absence of an NePC, BSE, and the Nijmegen–Aalborg screening QST (NASQ) paradigm in patients with chronic (≥3 months) low back and leg pain or with neck shoulder arm pain or in patients with chronic pain due to suspected peripheral nerve damage.Methods: A total of 291 patients participated in the study. Pain (absence or presence of neuropathic pain) was assessed independently by two physicians and compared with BSE (measurements of touch [finger, brush], heat, cold, pricking [safety pin, von Frey hair], and vibration). The NASQ paradigm (pressure algometry, electrical pain thresholds, and conditioned pain modulation) was assessed in 58 patients to generate new insights.Results: BSE revealed a low association of differences between patients with either absent or present NePC: heat, cold, and pricking sensations with a von Frey hair were statistically significantly less common in patients with present NePC. NASQ did not reveal any differences between patients with and without an NePC.Conclusion: Currently, a standardized BSE appears to be more useful than the NASQ paradigm when distinguishing between patients with and without an NePC. Keywords: quantitative sensory testing, NASQ, Nijmegen–Aalborg screening QST, clinical assessment, diagnostic accuracy

Fleur Meijer,1 Petra Cornelissen,2 Corina Sie,3 Michel Wagemans,4 Anja Mars,5 Tiny Hobma,1,6 Marieke Niesters,1 Albert Dahan,1 J Seppe Koopman,6 Monique AH Steegers2 1Department of Anesthesiology, Leiden University Medical Centre, Leiden, the Netherlands; 2Department of Anesthesiology Pain and Palliative Medicine, Radboud University Medical Centre, Nijmegen, the Netherlands; 3Department of Anesthesiology, Erasmus Medical Centre, Rotterdam, the Netherlands; 4Department of Anesthesiology and Pain Medicine, Reinier de Graaf Hospital, Delft, the Netherlands; 5Department of Anesthesiology and Acute Pain Service, Alrijne Hospital, Leiderdorp, the Netherlands; 6Department of Anesthesiology, Maasstad Hospital, Rotterdam, the Netherlands Background: The sublingual sufentanil tablet system (SSTS) is a novel hand-held patient-controlled analgesia device developed for treatment of moderate-to-severe postoperative pain. Here we present the first results of its clinical use. Methods: Adult patients undergoing major surgery in five hospitals in the Netherlands received the SSTS for postoperative pain relief as part of multimodal pain management that further included paracetamol and a nonsteroidal anti-inflammatory drug (NSAID). The following variables were collected: postoperative pain scores using the 11-point numerical rating score (NRS) at rest, number of tablets used, occurrence of nausea, and patient satisfaction scores. Results: We included 280 patients in the study; the majority underwent laparoscopic abdominal (49%) or orthopedic (knee replacement) surgery (34%). The median NRS was 3.5 (interquartile range 2.3–4.0) on the day of surgery, 3.3 (2.3–4.0) on the first postoperative day, and 2.8 (2.0–4.0) on the second postoperative day; pain scores did not differ between surgery types. Mean number of tablets used was 19 (range 0–86). Nausea occurred in 34% of patients, more often in women (45% vs 19%). Overall satisfaction was high in 73% of patients. Satisfaction was correlated with pain relief (p