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Simona De Gregori,1 Manuela De Gregori,1–4 Nora Bloise,5,6 Dario Bugada,3,4,7 Mariadelfina Molinaro,1 Claudia Filisetti,8 Massimo Allegri,3,9 Michael E Schatman,3,10,11 Lorenzo Cobianchi12,13 1Clinical and Experimental Pharmacokinetics Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; 2Pain Therapy Service, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; 3Study in Multidisciplinary Pain Research Group, Parma, Italy; 4Young Against Pain Group, Parma, Italy; 5Department of Molecular Medicine, Centre for Health Technologies, INSTM UdR of Pavia, University of Pavia, Pavia, Italy; 6Department of Occupational Medicine, Toxicology and Environmental Risks, Istituti Clinici Scientifici Maugeri, IRCCS, Lab of Nanotechnology, Pavia, Italy; 7Emergency and Intensive Care Department – ASST Papa Giovanni XXIII, Bergamo, Italy; 8“V. Buzzi” Children Hospital, Pediatric Surgery, Milan, Italy; 9Anesthesia and Intensive Care Service, IRCCS MultiMedica Hospital, Sesto San Giovanni, Milano, Italy; 10Research and Network Development, Boston Pain Care, Waltham, MA, USA; 11Department of Public Health and Community Medicine, Tufts University School of Medicine, Boston, MA, USA; 12General Surgery Department, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; 13Department of Clinical, Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy Background: The pharmacokinetic properties and clinical advantages of the local anesthetic chloroprocaine are well known. Here, we studied the pharmacokinetic profile of a new hydrogel device loaded with chloroprocaine to investigate the potential advantages of this new strategy for postoperative pain (POP) relief. Materials and methods: We performed both in vitro and in vivo analyses by considering plasma samples of four piglets receiving slow-release chloroprocaine. To quantify chloroprocaine and its inactive metabolite 4-amino-2-chlorobenzoic acid (ACBA), a HPLC–tandem mass spectrometry (HPLC-MS/MS) analytical method was used. Serial blood samples were collected over 108 hours, according to the exposure time to the device. Results: Chloroprocaine was consistently found to be below the lower limit of quantification, even though a well-defined peak was observed in every chromatogram at an unexpected retention time. Concerning ACBA, we found detectable plasma concentrations between T0 and T12h, with a maximum plasma concentration (Cmax) observed 3 hours after the device application. In the in vitro analyses, the nanogel remained in contact with plasma at 37°C for 90 minutes, 3 hours, 1 day, and 7 days. Chloroprocaine Cmax was identified 1 day following exposure and Cmin after 7 days, respectively. Additionally, ACBA reached the Cmax following 7 days of exposure. Conclusion: A thorough review of the literature indicates that this is the first study analyzing both in vivo and in vitro pharmacokinetic profiles of a chloroprocaine hydrogel device and is considered as a pilot study on the feasibility of including this approach to the management of POP. Keywords: postoperative outcome, hydrogel device, chloroprocaine, ACBA, pharmacokinetics

Concetta Dagostino,1,2 Massimo Allegri,2–4 Valerio Napolioni,5 Simona D’Agnelli,1 Elena Bignami,1 Antonio Mutti,1 Ron HN van Schaik6 1Department of Medicine and Surgery, University of Parma, Parma 43126, Italy; 2Study In Multidisciplinary Pain Research (SIMPAR), Milan 20100, Italy; 3Anesthesia and Intensive Care Department, IRCCS Multi Medica Hospital, Milan 20099, Italy; 4Italian Pain Institute, Milan 20100, Italy; 5Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA 94305, USA; 6Department of Clinical Chemistry, Erasmus MC, 3000 Rotterdam, The Netherlands Background: Opioids are widely used for chronic low back pain (CLBP); however, it is still unclear how to predict their effectiveness and safety. Codeine, tramadol and oxycodone are metabolized by CYP/CYP450 2D6 (CYP2D6), a highly polymorphic enzyme linked to allele-specific related differences in metabolic activity.Purpose: CYP2D6 genetic polymorphisms could potentially help to predict the effectiveness and safety of opioid-based drugs in clinical practice, especially in the treatment of CLBP.Patients and methods: A cohort of 224 Italian patients with CLBP treated with codeine or oxycodone was retrospectively evaluated to determine whether adverse reactions and effectiveness were related to CYP2D6 single-nucleotide polymorphisms. CYP2D6 genotyping was performed using the xTAG® CYP2D6 Kit v3 (Luminex) to determine CYP2D6 metabolizer phenotype (poor, intermediate, rapid and ultrarapid). Subjects from the cohort were categorized into two groups according to the occurrence of side effects (Case) or benefit (Control) after chronic analgesic treatment. The impact of CYP2D6 polymorphism on treatment outcome was tested at the metabolizer phenotype, diplotype and haplotype levels.Results: CYP2D6 polymorphism was significantly associated with opioid treatment outcome (Omnibus P=0.018, for both global haplotype and diplotype distribution test). CYP2D6*6 and *9 carriers, alleles characterized by a reduced (*9) or absent (*6) enzymatic activity, were significantly (P

Manuela De Gregori,1–3 Inna Belfer,2,4 Roberto De Giorgio,5 Maurizio Marchesini,2,3,6 Carolina Muscoli,7 Mariangela Rondanelli,2,8 Daniela Martini,9 Pedro Mena,9 Laura Isabel Arranz,2,10 Silvia Lorente-Cebrián,2,11 Simone Perna,8 Anna Villarini,12 Maurizio Salamone,2,13,14 Massimo Allegri,2,15 Michael E Schatman2,16,17 1 Pain Therapy Service, Fondazione IRCCS Polclinico San Matteo, Pavia, Italy; 2Study in Multidisciplinary Pain Research Group, Parma, Italy; 3Young Against Pain Group, Parma, Italy; 4Faculty of Dentistry, McGill University, Montreal, QC, Canada; 5Department of Clinical Sciences, Nuovo Arcispedale S. Anna, University of Ferrara, Ferrara, Italy; 6Anesthesia, Intensive Care and Pain Therapy Service, Azienda Ospedaliero, Universitaria of Parma, Parma, Italy; 7Department of Health Sciences, Institute of Research for Food Safety and Health, University “Magna Graecia” of Catanzaro, Parma, Italy; 8Department of Public Health, Section of Human Nutrition and Dietetics, Azienda di Servizi alla Persona di Pavia, University of Pavia, Pavia, Italy; 9Human Nutrition Unit, Department of Food & Drugs, University of Parma, Parma, Italy; 10Department of Nutrition, Food Sciences and Gastronomy, University of Barcelona, Barcelona, Spain; 11Department of Nutrition, Food Science and Physiology, Faculty of Pharmacy, Center for Nutrition Research, University of Navarra, Pamplona, Spain; 12Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; 13Science department, Metagenics Italia srl, Milano, Italy; 14Società internazionale di Neuropsicocardiologia, Trapani, Italy; 15Anesthesia and Intensive Care Service – IRCCS MultiMedica Hospital, Sesto San Giovanni, Milano, Italy; 16Research and Network Development, Boston Pain Care, Waltham, MA, USA; 17Department of Public Health and Community Medicine, Tufts University School of Medicine, Boston, MA, USA Abstract: This review is aimed to summarize the latest data regarding pain and nutrition, which have emerged during the second edition of Feed Your Destiny (FYD). Theme presentations and interactive discussions were held at a workshop on March 30, 2017, in Florence, Italy, during the 9th Annual Meeting of Study in Multidisciplinary Pain Research, where an international faculty, including recognized experts in nutrition and pain, reported the scientific evidence on this topic from various perspectives. Presentations were divided into two sections. In the initial sessions, we analyzed the outcome variables and methods of measurement for health claims pertaining to pain proposed under Regulation EC No 1924/2006 of the European Parliament and of the Council of 20 December 2006 on nutrition and health claims made on foods. Moreover, we evaluated how the Mediterranean diet can have a potential impact on pain, gastrointestinal disorders, obesity, cancer, and aging. Second, we discussed the evidence regarding vitamin D as a nutraceutical that may contribute to pain control, evaluating the interindividual variability of pain nature and nurture, and the role of micro-RNAs (miRNAs), polyunsaturated omega 3 fatty acids, and phenolic compounds, with a final revision of the clinical role of nutrition in tailoring pain therapy. The key take-home message provided by the FYD workshop was that a balanced, personalized nutritional regimen might play a role as a synergic strategy that can improve management of chronic pain through a precision medicine approach. Keywords: chronic pain, multidisciplinary pain management, personalized nutrition, nutritional supplements

Giada Amodeo,1 Dario Bugada,2–4 Silvia Franchi,1 Giorgia Moschetti,1 Stefania Grimaldi,5 Alberto Panerai,1 Massimo Allegri,2 Paola Sacerdote1 1Department of Pharmacological and Biomolecular Sciences, University of Milano, Milano, Italy; 2Study In Multidisciplinary Pain Research Group, 3Department of Anesthesia and ICU, ASST Papa Giovanni XXIII, Bergamo, Italy; 4Department of Anesthesia and ICU, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; 5Department of Anesthesia, IRCCS Humanitas Research Center, Rozzano, Italy Introduction: Impaired immune function during the perioperative period may be associated with worse short- and long-term outcomes. Morphine is considered a major contributor to immune modulation. Patients and methods: We performed a pilot study to investigate postoperative immune function by analyzing peripheral blood mononuclear cells’ functionality and cytokine production in 16 patients undergoing major abdominal surgery. All patients were treated with intravenous (i.v.) patient-controlled analgesia with morphine and continuous wound infusion with ropivacaine+methylprednisolone for 24 hours. After 24 hours, patients were randomized into two groups, one continuing intrawound infusion and the other receiving only i.v. analgesia. We evaluated lymphoproliferation and cytokine production by peripheral blood mononuclear cells at the end of surgery and at 24 and 48 hours postoperatively. Results: A significant reduction in TNF-α, IL-2, IFN-γ and lymphoproliferation was observed immediately after surgery, indicating impaired cell-mediated immunity. TNF-α and IFN-γ remained suppressed up to 48 hours after surgery, while a trend to normalization was observed for IL-2 and lymphoproliferation, irrespective of the treatment group. A significant inverse correlation was present between age and morphine and between age and lymphoproliferation. No negative correlation was present between morphine and cytokine production. We did not find any differences within the two groups between 24 and 48 hours in terms of morphine consumption and immune responses. Conclusion: A relevant depression of cell-mediated immunity is associated with major surgery and persists despite optimal analgesia. Even though morphine may participate in immunosuppression, we did not retrieve any dose-related effect. Keywords: opioids, postoperative pain, cytokines, immunomodulation, lymphoproliferation, surgery

Massimo Allegri,1–3 Pablo M Ingelmo,1,4–7 Michael E Schatman1,8,9 1Consortium of Multidisciplinary Pain Researchers and Clinicians (CIMPARC) Group, Milan, Italy; 2Pain Therapy Service, Policlinico Monza Hospital, Monza, Italy; 3Italian Pain Group, Milan, Italy; 4Department of Anesthesia, McGill University, Montreal, QC, Canada; 5Chronic Pain Service, Montreal Children’s Hospital, Montreal, QC, Canada; 6Shriners Hospital for Children, Montreal, QC, Canada; 7Alan Edwards Centre for Research on Pain, Montreal, QC, Canada; 8Research and Network Development, Boston Pain Care, Waltham, MA, USA; 9Department of Public Health and Community Medicine, Tufts University School of Medicine, Boston, MA, USA

Massimo Allegri,1,2 Dario Bugada,1–3 Manuela De Gregori,2,4 Maria A Avanzini,5 Annalisa De Silvestri,6 Anna Petroni,7 Angelo Sala,7,8 Claudia Filisetti,9–11 Antonia Icaro Cornaglia,12 Lorenzo Cobianchi13,14 1Department of Medicine and Surgery, University of Parma, Parma 2SIMPAR Group (Study in Multidisciplinary PAin Research), 3Department of Anaesthesia and ICU, ASST Papa Giovanni XXIII, Bergamo, 4Pain Therapy Service, Fondazione IRCCS Policlinico San Matteo, 5Laboratory of Transplant Immunology/Cell Factory, IRCCS Foundation Policlinico San Matteo, 6Clinical epidemiology and Biometrics Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, 7Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, 8I.B.I.M., C.N.R., Palermo, 9PhD School, University of Pavia, 10Department of Pediatric Surgery, Fondazione IRCCS Policlinico San Matteo, Pavia, 11Department of Pediatric Surgery, “V. Buzzi” Children’s Hospital, Milan, 12Department of Public Health, Experimental and Forensic Medicine, University of Pavia, 13Department of Surgical, Clinical, Paediatric and Diagnostic Science, University of Pavia, 14General Surgery 1, IRCCS Fondazione Policlinico San Matteo, Pavia, Italy Abstract: Continuous wound infusion (CWI) may protect from inflammation, hyperalgesia and persistent pain. Current local anesthetics display suboptimal pharmacokinetic profile during CWI; chloroprocaine (CP) has ideal characteristics, but has never been tested for CWI. We performed an animal study to investigate the pharmacokinetic profile and anti-inflammatory effect of CP during CWI. A total of 14 piglets received an infusion catheter after pararectal laparotomy and were randomly allocated to one of three groups: 5 mL/h infusion of saline (group A), CP 1.5% (group B) and CP 0.5% (group C). Blood sampling was performed to assess absorption and systemic inflammation at 0, 3, 6, 12, 24, 48, 72, 96, 102 and 108 hours. The wound and contralateral healthy abdominal wall were sampled for histological analyses. Absorption of CP from the site of infusion, evaluated as the plasmatic concentrations of CP and its metabolite, 4-amino-2-chlorobenzoic acid (CABA), showed a peak during the first 6 hours, but both CP and its metabolite rapidly disappeared after stopping CP infusion. Local inflammation was reduced in groups B and C (CP-treated p < 0.001), in a CP dose-dependent fashion. While CP inhibited in a dose-dependent manner pig mononuclear cells (MNCs) in vitro proliferation to a polyclonal activator, no effect on systemic cytokines’ concentrations or on ex vivo monocytes’ responsiveness was observed, suggesting the lack of systemic effects, in line with the very short half-life of CP in plasma. CP showed a very good profile for use in CWI, with dose-dependent local anti-inflammatory effects, limited absorption and rapid clearance from the bloodstream upon discontinuation. No cytotoxicity or side effects were observed. CP, therefore, may represent an optimal choice for clinical CWI, adaptable to each patient’s need, and protective on wound inflammatory response (and hyperalgesia) after surgery. Keywords: continuous wound infusion, pig model, chloroprocaine, pharmacokinetics, inflammation, postoperative pain

Guido Fanelli,1,2 Giuliano De Carolis,3 Claudio Leonardi,4 Adele Longobardi,5,6 Ennio Sarli,7,8 Massimo Allegri,1,2 Michael E Schatman9 1Anesthesia, Critical Care and Pain Medicine Unit, Division of Surgical Sciences, Department of Medicine and Surgery, University of Parma, 2Anesthesia, Intensive Care and Pain Therapy Service, Azienda Ospedaliero Universitaria Parma, Parma, 3Pain Therapy Service, Azienda Ospedaliero Universitaria Pisana, Pisa, 4Department of Drug Addiction Diseases, Local Public Health of Rome, Rome, 5Department of Neurosciences, Reproductive and Odontostomatological Sciences, University of Naples “Federico II”, Naples, 6Young Against the Pain (YAP) Group, Parma, 7Progetti Live Surgery, 8PinHub Group, Florence, Italy; 9Department of Public Health and Community Medicine, Tufts University School of Medicine, Boston, MA, USA Background: Despite growing interest in the therapeutic use of cannabis to manage chronic pain, only limited data that address these issues are available. In recent years, a number of nations have introduced specific laws to allow patients to use cannabis preparations to treat a variety of medical conditions. In 2015, the Italian government authorized the use of cannabis to treat several diseases, including chronic pain generally, spasticity in multiple sclerosis, cachexia and anorexia among AIDS and cancer patients, glaucoma, Tourette syndrome, and certain types of epilepsy. We present the first snapshot of the Italian experience with cannabis use for chronic pain over the initial year of its use.Methods: This is a retrospective case series analysis of all chronic pain patients treated with oral or vaporized cannabis in six hubs during the initial year following the approval of the new Italian law (December 2015 to November 2016). We evaluated routes of administration, types of cannabis products utilized, dosing, and effectiveness and safety of the treatment.Results: As only one of the six centers has extensively used cannabinoids for intractable chronic pain (614 patients of 659), only the population from Azienda Ospedaliero Universitaria Pisana (Pisa) was considered. Cannabis tea was the primary mode of delivery, and in almost all cases, it was used in association with all the other pain treatments. Initial and follow-up cannabinoid concentrations were found to vary considerably. At initial follow-up, 76.2% of patients continued the treatment, and

Manuela De Gregori,1–3 Carolina Muscoli,2,4,5 Michael E Schatman,2,6 Tiziana Stallone,2,7 Fabio Intelligente,2,8 Mariangela Rondanelli,2,9 Francesco Franceschi,2,10 Laura Isabel Arranz,2,11 Silvia Lorente-Cebrián,2,12 Maurizio Salamone,2,13,14 Sara Ilari,2,5 Inna Belfer,2,15 Massimo Allegri2,16,17 1Pain Therapy Service, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; 2Study in Multidisciplinary Pain Research Group, 3Young Against Pain Group, Parma, Italy; 4Department of Health Sciences, Institute of Research for Food Safety and Health, University “Magna Graecia” of Catanzaro, Parma, Italy; 5IRCCS San Raffaele Pisana, Roccelletta di Borgia, Catanzaro, Italy; 6US Pain Foundation, Bellevue, WA, USA; 7ENPAB, Rome, 8Chronic Pain Service Anestesia Day-Surgery, IRCCS Humanitas Research Hospital, Rozzano, 9Department of Public Health, Section of Human Nutrition and Dietetics, Azienda di Servizi alla Persona di Pavia, University of Pavia, Pavia, 10Institute of Internal Medicine, Catholic University of Rome, Rome, Italy; 11Department of Nutrition, Food Sciences and Gastronomy, University of Barcelona, Barcelona, 12Department of Nutrition, Food Science and Physiology, Center for Nutrition Research, University of Navarra, Pamplona, Spain; 13Metagenics Italia srl, Milano, 14Italian Lifestyle Medicine Association, Bari, Italy; 15Faculty of Dentistry, McGill University, Montreal, QC, Canada; 16Department of Surgical Sciences, University of Parma, 17Anesthesia, Intensive Care and Pain Therapy Service, Azienda Ospedaliero, Universitaria of Parma, Parma, Italy Abstract: Recently, attention to the lifestyle of patients has been rapidly increasing in the field of pain therapy, particularly with regard to the role of nutrition in pain development and its management. In this review, we summarize the latest findings on the role of nutrition and nutraceuticals, microbiome, obesity, soy, omega-3 fatty acids, and curcumin supplementation as key elements in modulating the efficacy of analgesic treatments, including opioids. These main topics were addressed during the first edition of the Study In Multidisciplinary Pain Research workshop: “FYD (Feed Your Destiny): Fighting Pain”, held on April 7, 2016, in Rome, Italy, which was sponsored by a grant from the Italian Ministry of Instruction on “Nutraceuticals and Innovative Pharmacology”. The take-home message of this workshop was the recognition that patients with chronic pain should undergo nutritional assessment and counseling, which should be initiated at the onset of treatment. Some foods and supplements used in personalized treatment will likely improve clinical outcomes of analgesic therapy and result in considerable improvement of patient compliance and quality of life. From our current perspective, the potential benefit of including nutrition in personalizing pain medicine is formidable and highly promising. Keywords: pain, personalized nutrition, nutritional supplements

Many countries are using health insurance to advance progress towards universal health coverage (UHC). India launched the Pradhan Mantri Jan Arogya Yojana (PM-JAY) health insurance scheme in 2018. We examine the political economy context around PM-JAY policy formulation, by examining the perspectives of policy stakeholders shaping decisions around the reform. More specifically, we focus on early policy design at the central (national) level. We use a framework on the politics of UHC reform proposed by Fox and Reich (The politics of universal health coverage in low- and middle-income countries: A framework for evaluation and action. J. Health Polit. Policy Law 2015; 40 :1023–1060), to categorize the reform into phases and examine the interactions between actors, institutions, interests, ideas and ideology which shaped reform decisions. We interviewed 15 respondents in Delhi between February and April 2019, who were either closely associated with the reform process or subject experts. The ruling centre-right government introduced PM-JAY shortly before national elections, drawing upon policy legacies from prior and state insurance schemes. Empowered policy entrepreneurs within the government focused discourse around ideas of UHC and strategic purchasing, and engaged in institution building leading to the creation of the National Health Authority and State Health Agencies through policy directives, thereby expanding state infrastructural and institutional power for insurance implementation. Indian state inputs were incorporated in scheme design features like mode of implementation, benefit package and provider network, while features like the coverage amount, portability of benefits and branding strategy were more centrally driven. These balanced negotiations opened up political space for a cohesive, central narrative of the reform and facilitated adoption. Our analysis shows that the PM-JAY reform focused on bureaucratic rather than ideological elements and that technical compromises and adjustments accommodating the interests of states enabled the political success of policy formulation. Appreciating these politics, power and structural issues shaping PM-JAY institutional design will be important to understand how PM-JAY is implemented and how it advances UHC in India. [ABSTRACT FROM AUTHOR]

Laura Zorzetto,1 Paola Brambilla,1 Elena Marcello,1 Nora Bloise,2 Manuela De Gregori,3 Lorenzo Cobianchi,4,5 Andrea Peloso,4,5 Massimo Allegri,6 Livia Visai,2,7 Paola Petrini1 1Department of Chemistry, Materials and Chemical Engineering ‘G. Natta’, Politecnico di Milano, Milan, 2Department of Molecular Medicine, Centre for Health Technologies (CHT), INSTM UdR of Pavia, University of Pavia, 3Pain Therapy Service, IRCCS Foundation Policlinico San Matteo Pavia, Pavia, 4General Surgery Department, IRCCS Foundation Policlinico San Matteo, Pavia, 5Departments of Clinical, Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, 6Department of Surgical Sciences, University of Parma, Parma, 7Department of Occupational Medicine, Toxicology and Environmental Risks, S. Maugeri Foundation, IRCCS, Lab of Nanotechnology, Pavia, Italy Abstract: Local anesthetics block the transmission of painful stimuli to the brain by acting on ion channels of nociceptor fibers, and find application in the management of acute and chronic pain. Despite the key role they play in modern medicine, their cardio and neurotoxicity (together with their short half-life) stress the need for developing implantable devices for tailored local drug release, with the aim of counterbalancing their side effects and prolonging their pharmacological activity. This review discusses the evolution of the physical forms of local anesthetic delivery systems during the past decades. Depending on the use of different biocompatible materials (degradable polyesters, thermosensitive hydrogels, and liposomes and hydrogels from natural polymers) and manufacturing processes, these systems can be classified as films or micro- or nanostructured devices. We analyze and summarize the production techniques according to this classification, focusing on their relative advantages and disadvantages. The most relevant trend reported in this work highlights the effort of moving from microstructured to nanostructured systems, with the aim of reaching a scale comparable to the biological environment. Improved intracellular penetration compared to microstructured systems, indeed, provides specific drug absorption into the targeted tissue and can lead to an enhancement of its bioavailability and retention time. Nanostructured systems are realized by the modification of existing manufacturing processes (interfacial deposition and nanoprecipitation for degradable polyester particles and high- or low-temperature homogenization for liposomes) or development of novel strategies (electrospun matrices and nanogels). The high surface-to-volume ratio that characterizes nanostructured devices often leads to a burst drug release. This drawback needs to be addressed to fully exploit the advantage of the interaction between the target tissues and the drug: possible strategies could involve specific binding between the drug and the material chosen for the device, and a multiscale approach to reach a tailored, prolonged drug release. Keywords: pain management, microparticle, microencapsulation, nanoparticle production, nanogels, liposomes

Manuela De Gregori,1-3,* Valeria Scotti,4,* Annalisa De Silvestri,4 Moreno Curti,4 Guido Fanelli,2,5,6 Massimo Allegri,2,5,6 Michael E Schatman,2,7 1Pain Therapy Service, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; 2Study In Multidisciplinary PAin Research Group, Parma, Italy; 3Young Against Pain Group, Parma, Italy; 4Center for Scientific Documentation and Biometry Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; 5Anesthesia, Critical Care, and Pain Medicine, Department of Surgical Sciences, University of Parma, Italy; 6Anesthesia, Intensive Care and Pain Therapy Service, Azienda Ospedaliero, Universitaria di Parma, Parma, Italy; 7US Pain Foundation, Bellevue, WA, USA *These authors contributed equally to this work. Abstract: In this study, we investigated the impact of scientific publications of the Italian SIMPAR (Study In Multidisciplinary PAin Research) group by using altmetrics, defined as nontraditional metrics constituting an alternative to more traditional citation-impact metrics, such as impact factor and H-index. By correlating traditional and alternative metrics, we attempted to verify whether publications by the SIMPAR group collectively had more impact than those performed by its individual members, either in solo publications or in publications coauthored by non-SIMPAR group investigators (which for the purpose of this study we will refer to as “individual publications”). For all the 12 members of the group analyzed (pain therapists, biologists, and pharmacologists), we created Open Researcher and Contributor ID and Impact Story accounts, and synchronized these data. Manually, we calculated the level metrics for each article by dividing the data obtained from the research community by those obtained from the public community. We analyzed 759 articles, 18 of which were published by the SIMPAR group. Altmetrics demonstrated that SIMPAR group publications were more likely to be saved (77.8% vs 45.9%), discussed (61.1% vs 1.1%, P

Roberto Casale,1,2 Yuriy Romanenko,2,3 Massimo Allegri4–6 1Department of Clinical Neurophysiology and Pain Rehabilitation Unit, Foundation "Salvatore Maugeri", Research and Care Institute, IRCCS, Pavia, Italy; 2EFIC Montescano Pain School, Montescano, Italy; 3Department of Neurology, Lugansk City Hospital 4, Lugansk, Ukraine; 4Department of Clinical, Surgical, Diagnostic and Pediatric Sciences University of Pavia, Pavia, Italy; 5Pain Therapy Service Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; 6SIMPAR group, Pavia, Italy Abstract: Localized neuropathic pain (LNP) is a type of neuropathic pain that is characterized by “consistent and limited area(s) of maximum pain associated with negative or positive sensory signs and/or spontaneous symptoms characteristic of neuropathic pain”. This definition encompasses a huge number of neuropathic orofacial pain syndromes. We present a case report of a patient who was affected with sleep apnea syndrome treated with nocturnal oxygen mask delivery, in whom orofacial LNP hampered the wearing of a mask due to unbearable burning and throbbing pain. The application of 5% lidocaine medicated plaster during the night led to an impressive reduction of both the pain level and the size of the painful area due to the plaster's pharmacological mechanisms, which were associated with a secondary benefit due to its mechanical protective action. This case report shows how these two factors could be of clinical value and have to be considered more systematically in the treatment of LNP in reducing pain and the size of the painful area. Keywords: trigeminal pain, localized neuropathic pain, topical treatment, 5% lidocaine medicated plaster

Roberto Casale,1,2 Maria Di Matteo,3,7 Cristina E Minella,4,7 Guido Fanelli,5,7 Massimo Allegri4,6,71Department of Clinical Neurophysiology and Pain Rehabilitation Unit, Foundation Salvatore Maugeri, IRCCS, Pavia, 2EFIC Montescano School, Montescano, 3Anesthesia and Intensive Care I, 4Pain Therapy Service, Fondazione IRCCS Policlinico San Matteo, Pavia, 5Department of Anesthesia, Intensive Care and Pain Therapy, Azienda Ospedaliera Universitaria Parma, University of Parma, Parma, 6Department of Clinical, Surgical, Diagnostic and Pediatric Science, University of Pavia, Pavia, 7Study In Multidisciplinary Pain Research Group, Parma, ItalyAbstract: Post-herpetic neuralgia (PHN) is neuropathic pain persisting after an acute episode of herpes zoster, and is associated with severe pain and sensory abnormalities that adversely affect the patient's quality of life and increase health care costs. Up to 83% of patients with PHN describe localized neuropathic pain, defined as “a type of neuropathic pain characterized by consistent and circumscribed area(s) of maximum pain”. Topical treatments have been suggested as a first-line treatment for localized neuropathic pain. Use of 5% lidocaine medicated plaster could reduce abnormal nervous peripheral discharge and via the plaster could have a “protective” function in the affected area. It has been suggested that use of this plaster could reduce pain as well as the size of the painful area. To evaluate this possible outcome, we retrospectively reviewed eight patients with PHN, treated using 5% lidocaine medicated plaster. During a follow-up period of 3 months, we observed good pain relief, which was associated with a 46% reduction in size of the painful area after one month (from 236.38±140.34 cm2 to 128.80±95.7 cm2) and a 66% reduction after 3 months (81.38±59.19 cm2). Our study cohort was composed mainly of elderly patients taking multiple drugs to treat comorbidities, who have a high risk of drug–drug interactions. Such patients benefit greatly from topical treatment of PHN. Our observations confirm the effectiveness of lidocaine plasters in the treatment of PHN, indicating that 5% lidocaine medicated plaster could reduce the size of the painful area. This last observation has to be confirmed and the mechanisms clarified in appropriate larger randomized controlled trials.Keywords: localized neuropathic pain, topical treatment, chronic pain, drug–drug interactions, patient's outcome

Carmelo Gigliuto,1 Manuela De Gregori,2 Valentina Malafoglia,3 William Raffaeli,3 Christian Compagnone,4 Livia Visai,5,6 Paola Petrini,7 Maria Antonietta Avanzini,9 Carolina Muscoli,8 Jacopo Viganò,11 Francesco Calabrese,11 Tommaso Dominioni,11 Massimo Allegri,2,10 Lorenzo Cobianchi111Anaesthesia and Intensive Care, University of Pavia, Pavia, 2Pain Therapy Service, Fondazione IRCCS Policlinico San Matteo, Pavia, 3ISAL Foundation, Institute for Research on Pain, Torre Pedrera, Rimini, 4Department of Anaesthesia, Intensive Care and Pain Therapy, Azienda Ospedaliera Universitaria Parma, University of Parma, Parma, 5Department of Molecular Medicine, Center for Tissue Engineering (CIT), INSTM UdR of Pavia, University of Pavia, Pavia, 6Department of Occupational Medicine, Ergonomy and Disability, Laboratory of Nanotechnology, Salvatore Maugeri Foundation, IRCCS, Veruno, 7Dipartimento di Chimica, Materiali e Ingegneria Chimica 'G Natta' and Unità di Ricerca Consorzio INSTM, Politecnico di Milano, Milan, 8Department of Health Science, University Magna Grecia of Catanzaro and Centro del Farmaco, IRCCS San Raffaele Pisana, Roma, 9Laboratory of Transplant Immunology/Cell Factory, Fondazione IRCCS Policlinico "San Matteo", Pavia, 10Department of Clinical, Surgical, Diagnostic and Paediatric Sciences, University of Pavia, Pavia, 11University of Pavia, Department of Surgical, Clinical, Paediatric and Diagnostic Science, General Surgery 1, IRCCS Fondazione Policlinico San Matteo, Pavia, ItalyAbstract: In the last two decades, animal models have become important tools in understanding and treating pain, and in predicting analgesic efficacy. Although rodent models retain a dominant role in the study of pain mechanisms, large animal models may predict human biology and pharmacology in certain pain conditions more accurately. Taking into consideration the anatomical and physiological characteristics common to man and pigs (median body size, digestive apparatus, number, size, distribution and communication of vessels in dermal skin, epidermal–dermal junctions, the immunoreactivity of peptide nerve fibers, distribution of nociceptive and non-nociceptive fiber classes, and changes in axonal excitability), swines seem to provide the most suitable animal model for pain assessment. Locomotor function, clinical signs, and measurements (respiratory rate, heart rate, blood pressure, temperature, electromyography), behavior (bright/quiet, alert, responsive, depressed, unresponsive), plasma concentration of substance P and cortisol, vocalization, lameness, and axon reflex vasodilatation by laser Doppler imaging have been used to assess pain, but none of these evaluations have proved entirely satisfactory. It is necessary to identify new methods for evaluating pain in large animals (particularly pigs), because of their similarities to humans. This could lead to improved assessment of pain and improved analgesic treatment for both humans and laboratory animals.Keywords: pain assessment, experimental model, translational research

Elisa Mura,1 Stefano Govoni,1 Marco Racchi,1 Valeria Carossa,1 Guglielmina Nadia Ranzani,2 Massimo Allegri,3,4 Ron HN van Schaik5 1Department of Drug Sciences, Centre of Excellence in Applied Biology, University of Pavia, Pavia, Italy; 2Department of Biology and Biotechnology, University of Pavia, Pavia, Italy; 3Pain Therapy Service, Foundation IRCCS San Matteo Hospital, Pavia, Italy; 4Department of Clinical, Surgical Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy; 5Department of Clinical Chemistry, Erasmus University Medical Center, Rotterdam, The Netherlands Abstract: The 118A>G single nucleotide polymorphism (SNP) in the µ-opioid receptor (OPRM1) gene has been the most described variant in pharmacogenetic studies regarding opioid drugs. Despite evidence for an altered biological function encoded by this variant, this knowledge is not yet utilized clinically. The aim of the present review was to collect and discuss the available information on the 118A>G SNP in the OPRM1 gene, at the molecular level and in its clinical manifestations. In vitro biochemical and molecular assays have shown that the variant receptor has higher binding affinity for ß-endorphins, that it has altered signal transduction cascade, and that it has a lower expression compared with wild-type OPRM1. Studies using animal models for 118A>G have revealed a double effect of the variant receptor, with an apparent gain of function with respect to the response to endogenous opioids but a loss of function with exogenous administered opioid drugs. Although patients with this variant have shown a lower pain threshold and a higher drug consumption in order to achieve the analgesic effect, clinical experiences have demonstrated that patients carrying the variant allele are not affected by the increased opioid consumption in terms of side effects. Keywords: µ-opioid receptor, opioids, pharmacogenetics, pain, analgesia