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Sabrina Bimonte,1,* Piergiacomo Di Gennaro,2,* Anna Crispo,2 Sergio Coluccia,2 Assunta Luongo,2 Alfonso Amore,3,4 Egidio Celentano,2 Francesco Del Prato,1 Daniela Schiavo,1 Davide Nocerino,1 Marco Cascella,5 Arturo Cuomo1 1Division of Anesthesia and Pain Medicine, Istituto Nazionale Tumori, IRCCS Fondazione G. Pascale, Naples, Italy; 2Epidemiology and Biostatistics Unit, Istituto Nazionale Tumori, IRCCS Fondazione G. Pascale, Naples, Italy; 3Melanoma and Sarcoma Surgery Unit, Istituto Nazionale Tumori, IRCCS Fondazione G. Pascale, Naples, Italy; 4PhD School of Applied Medical-Surgical Sciences, University of Rome Tor Vergata, Rome, Italy; 5Department of Medicine, University of Salerno, Salerno, Italy*These authors contributed equally to this workCorrespondence: Anna Crispo, Epidemiology and Biostatistics Unit, Istituto Nazionale Tumori, IRCCS Fondazione G. Pascale, Via Mariano Semmola 53, Naples, Italy, Tel +39 081 17770298, Email a.crispo@istitutotumori.na.itPurpose: Breakthrough cancer pain (BTcP) is a temporary exacerbation of pain that “breaks through” a phase of adequate pain control by an opioid-based therapy. The non-predictable BTcP (NP-BTcP) subtype occurs in the absence of any specific activity. Evidence showed that gender differences exist in pain response sensitivity and clinical pain risk. This analysis aimed to signify the gender differences for the NP-BTcP phenomenon.Patients and Methods: This is a secondary analysis of the Italian Oncologic Pain multiSetting-Multicentric Survey (IOPS-MS), the largest study on BTcP. The subset of NP-BTcP cases for non-gender-specific cancer was considered. Univariable and multivariate analyses were conducted to identify gender differences for the NP-BTcP profile about its intensity, number of episodes per day, and type. A metastatic status-stratified analysis was performed to compare gender with the main clinical variables among the population with NP-BTcP.Results: Males exhibited a higher occurrence of BTcP in the thorax region compared to females (15% vs 11%, respectively, p = 0.03). Males also had a higher onset of BTcP, a higher BTcP therapy dosage (33% vs 28%, p = 0.04, mean: 201 vs 186, p = 0.02) and a lower Karnofsky score (mean: 46.9 vs 49.2, p = 0.03) compared to females. Similar gender differences were found for metastatic patients in the BTcP site (14% vs 8.5%, respectively; p = 0.01), peak onset (33% vs 27%, p = 0.02), BTcP therapy dosage (199 vs 185, p=0.04), and Karnofsky score (mean 47.5 vs 50.4, p = 0.009). Phenotype 2 was more characterized by non-metastatic males (41% vs 23%, p = 0.020) while non-metastatic females presence was predominant among others.Conclusion: In this study, gender differences according to site, onset and dosage of BTcP were found. The phenotype characterization of BTcP needs to be further investigated for a possible useful function in the management of cancer-related pain in non-metastatic patients.Keywords: non-predictable breakthrough cancer pain, gender cancer pain, cluster analysis

Arturo Cuomo,1,* Ileana Parascandolo2,* 1Division of Anesthesia and Pain Medicine, Istituto Nazionale Tumori, IRCCS - Fondazione G Pascale, Naples, Italy; 2Istituto Nazionale Tumori, IRCCS - Fondazione G Pascale, Naples, Italy*These authors contributed equally to this workCorrespondence: Arturo Cuomo, Email a.cuomo@istitutotumori.na.itAbstract: Chronic musculoskeletal pain (CMP), defined as persistent discomfort in musculoskeletal tissues persisting for over 3 months, afflicts an estimated 1.71 billion people globally, leading to significant functional impairments and psychological distress, thereby detrimentally affecting individuals’ quality of life. The objective of this narrative review is to elucidate the complex relationship among dietary habits, sarcopenia, and gut microbiota composition, with an eye toward enhancing patient management and outcomes. Given the burgeoning interest in the influence of diet on CMP, a detailed examination of the current literature is warranted. Nutritional intake is a critical determinant of the gut microbiota profile, which, in turn, is linked to musculature integrity and performance, potentially leading to sarcopenia. The development of sarcopenia can aggravate CMP owing to diminished muscular strength and functionality. Additionally, disruptions in the gut microbiota may directly modulate nociception, intensifying CMP manifestations. Thus, nutritional optimization emerges as a viable approach to CMP management. Emphasizing a diet conducive to a healthy gut microbiome could forestall or mitigate sarcopenia, thereby attenuating CMP intensity. Nevertheless, the domain calls for further empirical exploration to unravel the nuances of these interactions and to forge efficacious dietary strategies for individuals with CMP. Beyond mere analgesia, comprehensive patient care for CMP requires acknowledgment of the complex and multifactorial nature of pain and its foundational elements. Embracing an integrative treatment model allows healthcare practitioners to promise better patient prognoses, enriched life quality, and a decrease in the sustained healthcare costs associated with CMP.Plain Language Summary: Chronic musculoskeletal pain (CMP) is long-lasting pain in the bones, muscles, and joints, and it’s a common problem affecting over 1.7 billion people worldwide. This kind of pain can really disrupt someone’s daily life, making it hard to do everyday things and causing a lot of stress.This review is like a deep dive into how eating habits, muscle loss, and the tiny organisms living in our guts all connect to this pain. As we are becoming more curious about how food affects CMP, it’s important to look closely at what we already know.What we eat can change the tiny bugs in our guts, which has a big impact on our muscles. If our muscles get weak and shrink (a condition called sarcopenia), it can make CMP worse because weak muscles cannot support our bodies well. Also, if the balance of bugs in our gut is off, it might even make us feel pain more intensely. So, changing what we eat might be a good way to tackle CMP. Eating foods that keep our gut bugs happy might help prevent muscle loss and reduce pain. But we still need to do more research to understand this better and to figure out the best foods to eat for this purpose.Treating CMP is not just about getting rid of the pain; it’s about looking at the whole picture and all the things that contribute to the pain. By considering everything — from our diet to our muscles to our gut bugs — doctors can help improve the lives of people with CMP, making them more comfortable and possibly reducing medical costs in the long run.Keywords: chronic musculoskeletal pain, diet, nutrition, treatment, biopsychosocial, holistic

Rossella Di Franco,1 Marco Cascella,2 Mario Fusco,3 Valentina Borzillo,1 Esmeralda Scipilliti,1 Piera Ferraioli,1 Eva Iannacone,1 Giampaolo De Palma,1 Giustino Silvestro,1 Federica Gherardi,1 Sergio Buonopane,1 Domingo Alberti,1 Giuseppe Totaro,1 Roberto Manzo,1 Giovanna Guida,1 Arturo Cuomo,2 Sandro Pignata,4 Marilena Di Napoli,4 Sabrina Rossetti,4 Egidio Celentano,5 Anna Crispo,5 Maria Grimaldi,5 Vincenzo Ravo,1 Paolo Muto1 1Department of Radiation Oncology, Istituto Nazionale Tumori - IRCCS - Fondazione G. Pascale, Napoli, Italia; 2Division of Anesthesia and Pain Medicine, Istituto Nazionale Tumori, IRCCS Fondazione G. Pascale, Napoli, Italia; 3Cancer Registry Unit, ASL Napoli 3 SUD, Napoli, Italia; 4Department of Uro-Gynecological, Istituto Nazionale Tumori - IRCCS - Fondazione G. Pascale, Napoli, Italia; 5Epidemiology and Biostatistics Unit, Istituto Nazionale Tumori - IRCCS - Fondazione G. Pascale, Napoli, ItaliaCorrespondence: Rossella Di Franco, Department of Radiation Oncology, Istituto Nazionale Tumori - IRCCS - Fondazione G. Pascale, Napoli, Italia, Email r.difranco@istitutotumori.na.itBackground: In the Italian Campania Region, 30.517 new cases of solid cancer have been diagnosed, in 2019. Of those, patients with metastatic disease are up to 20%. This class of patients is extremely diversified and copious, and the offer of radiotherapy may vary in different geographical areas within the same region. The aim of this observational multicenter retrospective and prospective trial is to evaluate the occurrence of metastatic metastatic cancer patients candidates for palliative radiotherapy in several areas of a great Italian region, the management of the disease through RT approaches, and its impact on cancer-related pain and overall HRQoL.Methods: This is a multicenter, retrospective and prospective observational investigation. The retrospective part of the study concerns all patients enrolled with a diagnosis of metastatic disease and treated in RT centers within the Campania Region between January 2019 and July 2020. The prospective phase is going to involve all the metastatic patients with an indication of palliative RT. Considering regional epidemiological data, we expect an enrollment of 12.500– 21.000 patients in 5 years.Conclusion: The MAMETIC Trial in an observational study designed for investigating on the use of radiotherapy in patients with advanced disease within a regional area, and for evaluating the local response to the patient’s request. It can be a unique opportunity, not only to highlight possible geographic differences but also to regularly collect and share data to standardize the therapeutic offer within the regional area. ClinicalTrials.gov ID NCT04595032, retrospectively registered.Keywords: palliative care, metastatic disease, radiotherapy, cancer pain, breakthrough cancer pain, quality of life

Sabrina Bimonte,1,* Cira Antonietta Forte,1,* Massimiliano Cuomo,2 Gennaro Esposito,1 Marco Cascella,1 Arturo Cuomo1 1Division of Anesthesia and Pain Medicine, Istituto Nazionale Tumori - IRCCS - Fondazione G. Pascale, Naples, Italy; 2S.C. Project Management e Formazione, Istituto Nazionale Tumori - IRCCS - Fondazione G. Pascale, Naples, Italy*These authors contributed equally to this workCorrespondence: Sabrina BimonteDivision of Anesthesia and Pain Medicine, Istituto Nazionale dei Tumori, IRCCS Fondazione G. Pascale, Naples, ItalyEmail s.bimonte@istitutotumori.na.itAbstract: Coronavirus disease-19 (COVID-19) pandemic is currently ongoing worldwide and causes a lot of deaths in many countries. Although different vaccines for the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection have been developed and are now available, there are no effective antiviral drugs to treat the disease, except for Remdesivir authorized by the US FDA to counteract the emergency. Thus, it can be useful to find alternative therapies based on the employment of natural compounds, with antiviral features, to circumvent SARS-CoV-2 infection. Pre-clinical studies highlighted the antiviral activities of epigallocatechin-3-gallate (EGCG), a catechin primarily found in green tea, against various viruses, including SARS-CoV-2. In this review, we summarize this experimental evidence and highlight the potential use of EGCG as an alternative therapeutic choice for the treatment of SARS-CoV-2 infection.Keywords: COVID-19, EGCG, SARS-CoV-2, tea polyphenols, antiviral properties

Alessandro Vittori,1 Emiliano Petrucci,2 Marco Cascella,3 Massimo Innamorato,4 Arturo Cuomo,3 Antonino Giarratano,5 Flavia Petrini,6 Franco Marinangeli7 1Department of Anesthesia and Critical Care, ARCO ROMA, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy; 2Department of Anesthesia and Intensive Care Unit, San Salvatore Academic Hospital of L’Aquila, L’Aquila, Italy; 3Department of Anesthesia and Critical Care, Istituto Nazionale Tumori - IRCCS, Fondazione Pascale, Naples, Italy; 4Department of Neuroscience, Pain Unit, Santa Maria delle Croci Hospital, AUSL Romagna, Ravenna, Italy; 5Department of Surgical, Oncological and Oral Science (Di.Chir.On.S.), Section of Anaesthesia, Analgesia, Intensive Care and Emergency, Policlinico Paolo Giaccone, University of Palermo, Palermo, Italy; 6SIAARTI (Italian Society of Anaesthesia, Analgesia, Reanimation and Intensive Care Medicine), Rome, Italy; 7Department of Anesthesiology, Intensive Care and Pain Treatment, University of L’Aquila, L’Aquila, ItalyCorrespondence: Alessandro VittoriDepartment of Anesthesia and Critical Care, ARCO ROMA, Ospedale Pediatrico Bambino Gesù, IRCCS, Piazza S. Onofrio 4, Rome, 00165, ItalyEmail alexvittori82@gmail.comBackground: Increased attention to the functional impact of chronic pain (CP), as highlighted by the 11th revision of the International Classification of Diseases (ICD-11) and advocated by the International Classification of Functioning, Disability and Health (ICF), is an important step forward for optimizing its management. Evidence about perspectives of Italian physicians on the relevance of musculoskeletal (MSK) pain care to improve patients’ functioning and Quality of Life is scant. The study aimed to investigate the physicians’ perception of the value of functional recovery in severe MSK pain patients, their attitude towards its assessment and achievement in Italy.Methods: A survey was conducted in Italy between October 2020 and January 2021. Specialist centers members of the SIAARTI (n = 395) were sent an online questionnaire encompassing the Italian pain therapy network. Participants rated their agreement to questionnaire items according to a 5-point Likert-type scale.Results: A total of 305 centers (77%) completed the survey. Most physicians rated the recovery of functioning as very relevant in MSK pain treatment and, when they assessed it, devoted great attention to the ability to perform daily activities, pain, ability to ambulate and sleep quality. Multidimensional questionnaires were less employed in favor of physical examination and pain intensity scales. Pharmacological therapy, rehabilitation and lifestyle changes and/or physical exercise were all rated optimal strategies to pursue the recovery of patients’ functioning. When considering pharmacological therapy, weak and strong opioids, either alone or combined with paracetamol, were the most frequently employed analgesics.Conclusion: Clinicians seem to recognize the recovery of functioning as equally important as pain intensity reduction, but there is a need of streamlining available tools to effectively assess both across different MSK pain patients.Keywords: chronic musculoskeletal pain, recovery of functioning, pain care models

Marco Cascella,1 Alfredo Del Gaudio,2 Alessandro Vittori,3 Sabrina Bimonte,1 Paola Del Prete,4 Cira Antonietta Forte,1 Arturo Cuomo,1 Elvio De Blasio2,5 1Division of Anesthesia and Pain Medicine, Istituto Nazionale Tumori-IRCCS-“Fondazione G. Pascale”, Naples, 80131, Italy; 2DSC Anestesia e Rianimazione 2, IRCCS Casa Sollievo Della Sofferenza, San Giovanni Rotondo, 71013, FG, Italy; 3Department of Anesthesiology and Critical Care, ARCO, Bambino Gesù Children’s Hospital, Rome, Italy; 4Direzione Scientifica, Istituto Nazionale Tumori-IRCCS-“Fondazione G. Pascale”, Naples, 80131, Italy; 5Multidisciplinary Emergency Unit for COVID-19 Campania, Naples, 80100, ItalyCorrespondence: Sabrina BimonteDivision of Anesthesia and Pain Medicine, Istituto Nazionale Tumori-IRCCS-“Fondazione G. Pascale”, Naples, 80131, ItalyTel +39 0815903221Email s.bimonte@istitutotumori.na.itAbstract: Although the respiratory manifestations of COVID-19 are predominant, signs and symptoms of an extra-pulmonary involvement are usually encompassed among the clinical picture of the disease. Several painful manifestations can occur during the acute phase but also as short- or long-term complications. Myalgia, joint pain, sore throat, abdominal pain, chest pain, and headache usually accompany respiratory symptoms, but they can also occur as isolated clinical findings or can be expressed regardless of the severity of COVID-19. On these premises, given the vast spectrum of clinical manifestations and the complexity of their pathogenesis, it would be more appropriate to refer to “COVID-pain”, an umbrella term useful for encompassing all these clinical manifestations in a separate chapter of the disease. In this scenario, we addressed the topic from a molecular perspective, trying to provide explanations for the underlying pathophysiological processes. Consequently, this narrative review is aimed at dissecting the mechanisms of acute and chronic painful manifestations, summarizing fundamental concepts on the matter, controversies, current research gaps, and potential developments in this field.Keywords: COVID-19, SARS-CoV-2, COVID-pain, COVID-19 complications

Stefano De Santis,1 Maria Domenica Simone,2 Sebastiano Mercadante,3 Rocco Domenico Mediati,4 Renato Vellucci,4 Paolo Marchetti,5 Giuseppe Tonini,6 Arturo Cuomo,7 Augusto Caraceni,8 Silvia Natoli,9 Grazia Armento,6 Livio Blasi,10 Massimo Mammucari11 On behalf of the IOPS-MS Study Group1Palliative Care and Oncologic Pain Service, S. Camillo-Forlanini Hospital, Rome, Italy; 2Hematology and BMT Unit, S. Camillo-Forlanini Hospital, Rome, Italy; 3Anesthesia and Intensive Care & Pain Relief and Supportive Care, La Maddalena, Palermo, Italy; 4Palliative Care and Pain Therapy Unit, Careggi Hospital, Florence, Italy; 5Molecular and Clinical Medicine Medical Oncology, La Sapienza University of Rome, Rome, Italy; 6Department of Medical Oncology, Campus Bio-Medico University of Rome, Rome, Italy; 7Anesthesiology, Resuscitation, and Pain Therapy Department, National Cancer Institute, IRCCS Foundation, Naples, Italy; 8Palliative Care, Pain Therapy and Rehabilitation, National Cancer Institute, IRCCS Foundation, Milan, Italy; 9Department of Clinical Science and Translational Medicine – University of Rome Tor Vergata and Department of Emergency, Admission and Critical Area – Policlinic of Tor Vergata, Rome, Italy; 10Medical Oncology Unit, ARNAS Ospedale Civico Di Cristina Benfratelli, Palermo, Italy; 11Primary Care Unit, ASL RM1, Rome, 00165, ItalyCorrespondence: Stefano De Santis Email sdesantis@scamilloforlanini.rm.itBackground: International guidelines recommend moderate-to-severe cancer pain to be treated with strong opioids. However, pain management remains an unsolved matter, at least in the demanding oncology and palliative care setting. Although cancer pain consists of multiple components, which interact in complex ways where combination therapy can better intercept multiple pain characteristics, few studies have used a non-opioid/opioid association to exploit possible synergistic actions. Even the efforts of a recent approach emphasizing appropriate pain assessment and accurate classification to obtain personalized pain management have not produced a satisfactory analgesic strategy.Objective: This analysis was intended to evaluate the effectiveness of the immediate release fixed combination of oxycodone/acetaminophen (OxyIR/Par) for the treatment of moderate-to-severe intensity background pain used alone or in combination with other strong opioids in cancer patients with breakthrough cancer pain (BTcP). This is a secondary analysis of a wider observational, prospective, multicenter study [Italian Oncologic Pain multiSetting Multicentric Survey (IOPS-MS)] performed on 179 patients treated with opioids for cancer pain who received the fixed combination of oxycodone/acetaminophen (OxyIR/Par) for the treatment of background pain (BGP).Results: Cancer patients with breakthrough cancer pain and controlled BGP (Background Pain) were classified according to the presence of analgesic therapy with tablets of fixed combination OxyIR/Par alone (group A, n=120) or tablets of fixed combination OxyIR/Par combined with other strong opioids (group B, n=59). Clinical features of group A were different to group B: higher mean Karnofsky Performance Status Index 70.3% (95% CI=67.2– 73.5; median=70, CI=60– 80) vs 58.3 (95% CI=53.4– 63.2; median=50, CI=45– 70) (P< 0.001), and mainly group A patients were treated in an ambulatory setting (55.0% group A vs 33.9% group B) (p< 0.001). Both groups had managed BGP with similar mean dosages (group A: 12.0, CI=10.5– 13.4; group B: 13.1, CI=11.0– 15.1) and frequencies of OxyIR/Par alone for group A and in association to other opioids for group B, but Breakthrough cancer Pain (BTcP) exhibited different characteristics in the two groups, showing a lower mean intensity numerical rating scale (NRS) of 7.5 (95% CI=7.2– 7.7; median=7, CI=7– 8 group A) vs 7.9 (95% CI=7.6, 8.2; median= 8, CI=7– 9 group B) (P=0.04) and a higher percentage of patients had a faster onset, defined as the maximum intensity reached in less than 10 minutes, 81.7% (N=98) in group A vs 59.3% (n=35) in group B (P=0.002).Conclusion: This is the first analysis about the efficacy of an immediate-release fixed combination of OxyIR/Par in the real world for moderate-to-severe background cancer pain and breakthrough cancer pain. The oral fixed combination OxyIR/Par provided an adequate level of analgesia for moderate–severe background cancer pain, in a different cohort of cancer patients with different performance status, both in ambulatory and palliative settings. The low dosage of fixed combination OxyIR/Par was effective alone or in association with other opioids.Keywords: analgesia, combination of oxycodone/acetaminophen, cancer pain, breakthrough cancer pain

Arturo Cuomo,1 Anna Crispo,2 Andrea Truini,3 Silvia Natoli,4 Orazio Zanetti,5 Paolo Barone,6 Marco Cascella11Division of Anesthesia and Pain Medicine, Istituto Nazionale Tumori, IRCCS Fondazione G. Pascale, Naples, Italy; 2S.C. Epidemiologia e Biostatistica, Istituto Nazionale Tumori, IRCCS Fondazione G. Pascale, Naples, Italy; 3Department of Human Neuroscience, University Sapienza, Rome, Italy; 4Department of Clinical Science and Translational Medicine, Tor Vergata University of Rome, Rome, Italy; 5U.O. Alzheimer, IRCCS Centro San Giovanni di Dio-Fatebenefratelli, Brescia, Italy; 6Center for Neurodegenerative Disease-CEMAND, University of Salerno, Fisciano, ItalyAbstract: In Parkinson’s disease (PD), pain represents a significant issue in terms of prevalence, clinical features, and treatment. Painful manifestations not strictly related to the disease are often amplified by the motor dysfunction. On the other hand, typical pain problems may specifically concern this vulnerable population. In turn, pain may have a deep impact on patients’ health-related quality of life. However, pain treatment in PD remains an unmet need as only about half of patients with pain use analgesics and pain is often managed by simply increasing doses of PD medications. In this complex scenario, pain treatments should follow multimodal approaches through a careful combination of pharmacological agents with non-pharmacological strategies, depending on the type of pain and the clinical context. A multidisciplinary approach involving medical specialists from different disciplines could be a winning strategy to address the issue. This work is aimed to provide practical suggestions useful for different types of clinicians and care professionals for pain management in this vulnerable population.Keywords: Parkinson disease, pain management, pain assessment, opioids, acetaminophen, non-steroidal anti-inflammatory agents

Arturo Cuomo,1,* Sabrina Bimonte,1,* Cira Antonietta Forte,1 Gerardo Botti,2 Marco Cascella1 1Division of Anesthesia and Pain Medicine, Istituto Nazionale Tumori, IRCCS - Fondazione G Pascale, Naples, Italy; 2Scientific Direction, Istituto Nazionale Tumori, IRCCS - Fondazione G Pascale, Naples, Italy *These authors contributed equally to this work Abstract: Chronic pain is described as a manifestation of real or potential tissue damage. It is identified as a perception influenced by the complex interactions of biological, psychological, and social factors. Different types of pain and their comorbidities dramatically affect patients’ quality of life and their families. Due to diverse etiology and pathogenesis, pain management represents a controversial issue in clinical practice. In 1986, the WHO developed a three-step ladder model based on the use of analgesics for pain management according to pain intensity in a linear up or down movement. Despite its huge value for pain relief, this model has some limitations, and some controversies in the pharmacotherapy of pain management have arisen so far. To bypass these difficulties, the concept of WHO analgesic ladder has been contested and changed into a four bidirectional step model which postulates the use of the invasive procedures (neuromodulatory and neurosurgical procedures). Moreover, with the introduction of the neuromatrix theory for dealing the acute and the chronic pain, the WHO model was newly reinterpreted and changed into a platform analgesic model that includes multimodal pharmacological and alternative treatments applicable to all pain conditions, although excludes the precision therapies. Here, we summarize and revise these concepts in order to propose a new model termed “trolley analgesic model” that will allow adopting tailored therapies with dynamic multimodal approaches for pain management according to 1) the pain intensity, 2) the physiopathology of pain, 3) the complexity of symptoms, 4) the presence of comorbidity, and 5) the physiopathological factors and the social context. Keywords: cancer and no-cancer pain management, personalized treatment, analgesic trolley, multimodal approaches

M Cascella,1 CA Forte,1 S Bimonte,1 G Esposito,1 C Romano,2 R Costanzo,2 A Morabito,2 A Cuomo1 1Department of Anesthesia and Pain Medicine, Istituto Nazionale Tumori, IRCCS – Fondazione G Pascale, Naples, Italy; 2Thoracic Medical Oncology, Istituto Nazionale Tumori, IRCCS – Fondazione G Pascale, Naples, Italy Background: Previous studies have shown the efficacy of tapentadol (TP) for chronic cancer pain. We evaluated multiple effectiveness aspects of TP prolonged release on moderate–severe cancer-related pain, neuropathic pain (NeP), patient satisfaction, and quality of life. Methods: An observational prospective study was conducted on 80 cancer patients. Opioid-naïve patients received a starting dose of prolonged-release TP 50 mg twice daily, and opioid-experienced patients were switched to TP, not to exceed 500 mg/day. Treatment response was evaluated at 3, 6, 30–40, and 60–70 days through response rate, numeric rating-scale scoring, survival analysis (time to event for response), pain-intensity difference, TP escalation-index percentage, and effects on NeP. The drug-sparing effect on concomitant therapies was evaluated. Results: Seventy of 80 patients (88%) were responders to treatment (95% CI 78%–94%). Compared to T0, pain-intensity reductions were statistically significant for all intervals (P

Andrea Pozza,1 Christine Lochner,2 Fabio Ferretti,1 Alessandro Cuomo,3 Anna Coluccia1 1Department of Medical Sciences, Surgery and Neurosciences, Santa Maria alle Scotte University Hospital of Siena, Siena, Italy; 2SU/UCT MRC Unit on Anxiety and Stress Disorders, Department of Psychiatry, Stellenbosch University, Cape Town, South Africa; 3Department of Molecular Medicine, University of Siena School of Medicine and Department of Mental Health, University of Siena Medical Center (AOUS), Siena, Italy Background: Obsessive–compulsive disorder (OCD) is one of the leading causes of disability and reduced quality of life (QOL), with impairment in a number of domains. However, there is a paucity of literature on the association between severity of OCD symptoms and QOL, and the data that do exist are inconsistent. In addition, the role of severity in QOL has not been summarized as yet from a cross-generational perspective (ie, across childhood/adolescence and adulthood). Through meta-regression techniques, the current study summarized evidence about the moderator role of severity of OCD symptoms on differences in global QOL between individuals with OCD and controls. Methods: Online databases were searched, and cross-sectional case–control studies comparing participants of all ages with OCD with controls on self-report QOL measures were included. Random-effect meta-regression techniques were used to comment on the role of illness severity in global QOL in individuals with OCD. Results: Thirteen studies were included. A positive significant association emerged between OCD severity and effect sizes on global QOL: in samples with higher severity, there were narrower differences in QOL between patients with OCD and controls than in samples with lower severity. Such positive association was confirmed by a sensitivity analysis conducted on studies including only adults, where the difference in QOL ratings between patients and controls was significantly narrower when OCD severity was higher. Conversely, a negative association between severity and QOL was found in those studies including only children/adolescents, where the difference in QOL was significantly larger between patients and controls when OCD severity was higher. Conclusion: QOL remains an important issue to address in the management of OCD in all age groups, irrespective of illness severity. Even in those with lower severity ratings, QOL may be considered as an important marker of treatment response. Keywords: obsessive–compulsive disorder, quality of life, systematic review, symptoms severity, well-being, meta-regression

BackgroundE-cigarettes have emerged as popular products, especially for younger populations. However, concerns regarding health effects exist and there is a notable gap in understanding the prevalence and nature of adverse events. This study aims to examine the rate of adverse events in individuals who use e-cigarettes in a large sample.MethodsA cross-sectional survey was conducted with a sample of 4695 current and former e-cigarette users with a median age of 34 years. The survey collected data on e-cigarette use, adverse events experienced, product characteristics, related behaviors, sociodemographic factors and presence of medical comorbidities. Statistical analyses were conducted using Pearson's chi-squared tests and logistic regression.ResultsA total of 78.9% of respondents reported experiencing an adverse event within 6 h of using a vaping device, with the most common events being headache, anxiety and coughing. Product characteristics and related behaviors significantly influenced the risk of adverse events. There were also sociodemographic disparities, with Hispanic respondents and those with at least college-level education reporting higher rates of adverse events.ConclusionsOur study found a high rate of adverse events among e-cigarette users. We identified that certain e-cigarette product characteristics, behaviors and medical comorbidities significantly increased the risk of these events.

This article proposes to consider medieval textbooks, designed for the study of Greek, as major sources for historical sociolinguistic analyses on texts written in (high-register) Medieval Greek. It additionally discusses some aspects of the definition of historical sociolinguistics as a discipline, and stresses the importance of recovering the speech community’s perspective on Medieval Greek.

Marco Fiore,1 Alberto Enrico Maraolo,2 Sebastiano Leone,3 Ivan Gentile,2 Arturo Cuomo,4 Vincenzo Schiavone,5 Sabrina Bimonte,4 Maria Caterina Pace,1 Marco Cascella4 1Department of Anaesthesiological, Surgical and Emergency Sciences, University of Campania “Luigi Vanvitelli”, Naples, Italy; 2Department of Clinical Medicine and Surgery, Section of Infectious Diseases, University of Naples Federico II, Naples, Italy; 3Division of Infectious Diseases, “San Giuseppe Moscati” Hospital, Avellino, Italy; 4Division of Anesthesia, Department of Anesthesia and Pain Medicine, Istituto Nazionale Tumori – IRCCS – Fondazione G. Pascale, Naples, Italy; 5Division of Anesthesia and Intensive Care, Hospital “Pineta Grande”, Castel Volturno, Italy Abstract: Spontaneous peritonitis (SP) is the most common infection among decompensated end-stage liver disease patients. SP is the infection of ascitic fluid (neutrophil ascitic count ≥250/mL) without an alternative focus of abdominal infection. According to the causative agent, clinicians can make the diagnosis of spontaneous bacterial peritonitis or spontaneous fungal peritonitis. The mortality rate is very high, ranging from one-fifth of the patients with spontaneous bacterial peritonitis to four-fifths of the patients with spontaneous fungal peritonitis. An immediate and accurate diagnosis can improve the outcome in end-stage liver disease patients. The aim of this work is to provide physicians with a practical diagnostic guidance for SP diagnosis according to current evidence, in order to improve the management of cirrhotic patients with infected ascitic fluid. Keywords: cirrhosis, spontaneous bacterial peritonitis, spontaneous fungal peritonitis, bacteriascites, fungal ascites

Flaminia Coluzzi,1 Francesca Bifulco,2 Arturo Cuomo,2 Mario Dauri,3 Claudio Leonardi,4 Rita Maria Melotti,5 Silvia Natoli,3 Patrizia Romualdi,6 Gennaro Savoia,7 Antonio Corcione8 1Department of Medical and Surgical Sciences and Biotechnologies, Unit of Anaesthesia, Intensive Care and Pain Medicine, Sapienza University of Rome, Polo Pontino, Latina, 2National Cancer Institute “G Pascale” Foundation, Unit of Anaesthesia, Intensive Care and Pain Medicine, Naples, 3Department of Clinical Science and Translational Medicine, Tor Vergata University of Rome, 4Addiction Disease Department, Local Health Unit (ASL) Rome 2, Rome, 5Department of Medical and Surgical Sciences, 6Department of Pharmacy and Biotechnology, Alma Mater Studiorum University of Bologna, Bologna, 7Department Anesthesia, Fatebenefratelli Hospital, Naples, 8Unit of Anaesthesia and Intensive Care, Dei Colli Hospital, V. Monaldi, Naples, Italy Abstract: The increasing number of opioid users among chronic pain patients, and opioid abusers among the general population, makes perioperative pain management challenging for health care professionals. Anesthesiologists, surgeons, and nurses should be familiar with some pharmacological phenomena which are typical of opioid users and abusers, such as tolerance, physical dependence, hyperalgesia, and addiction. Inadequate pain management is very common in these patients, due to common prejudices and fears. The target of preoperative evaluation is to identify comorbidities and risk factors and recognize signs and symptoms of opioid abuse and opioid withdrawal. Clinicians are encouraged to plan perioperative pain medications and to refer these patients to psychiatrists and addiction specialists for their evaluation. The aim of this review was to give practical suggestions for perioperative management of surgical opioid-tolerant patients, together with schemes of opioid conversion for chronic pain patients assuming oral or transdermal opioids, and patients under maintenance programs with methadone, buprenorphine, or naltrexone. Keywords: opioids, postoperative pain, addiction, abusers, buprenorphine, methadone

Sabrina Bimonte,1,* Marco Cascella,1,* Vincenzo Schiavone,2 Farrokh Mehrabi-Kermani,3 Arturo Cuomo1 1Division of Anesthesia and Pain Medicine, Istituto Nazionale Tumori – IRCCS – “Fondazione G. Pascale”, Naples, Italy; 2Division of Anesthesia and Intensive Care, Hospital “Pineta Grande”, Castel Volturno, Caserta, Italy; 3Division of Neurosurgery, Hospital “Pineta Grande”, Castel Volturno, Caserta, Italy *These authors contributed equally to this work Abstract: Neuropathic pain (NP) is a complex and chronic disease caused by lesions or defects of the somatosensory nervous system. The treatments normally used for managing NP usually lack efficacy. Several animal models of NP have been engineered in order to understand the molecular mechanisms underlying NP and to find alternative molecules to use as new therapeutic agents. Preclinical in vivo studies identified the epigallocatechin-3-gallate (EGCG), a main active component of green tea (Camellia sinensis), as a possible therapeutic molecule for NP treatment due to its anti-inflammatory and antioxidant properties. Interestingly, it has been shown that EGCG reduced bone cancer pain. The purpose of this article is to discuss the potential use of EGCG for control and treatment of NP, by reviewing the preclinical studies reported in the literature and by shedding light on the potential schemes based on EGCG’s application in clinical practices. Keywords: epigallocatechin-3-gallate, EGCG, natural compound, neuropathic pain, animal models of neuropathic pain, cancer bone pain

Background: Illicit substance sales facilitated by social media platforms are a growing public health issue given recent increases in overdose deaths, including an alarming rise in cases of fentanyl poisoning. However, little is known about how online users evaluate what features of social media posts convey safety, which can influence their intent to source illicit substances. Objectives: This study adapts conjoint analysis which assessed how attributes of social media posts (i.e., features) influence safety evaluations of mock posts selling illicit substances. 440 participants were recruited online for self-reporting use or purchase of controlled substances or prescription medicines recreationally. The following attributes were tested: drug packaging, drug offerings, profile photo of seller, payment info provided, and use of emojis. Results: Packaging was ranked the most important attribute (Average Importance =43.68, Offering=14.94, Profile=13.86, Payment=14.11, Emoji=13.41), with posts that displayed drugs in pill bottles assessed as the most safe. Attribute levels for advertising multiple drugs, having a blank profile photo, including payment information, and including emojis also ranked higher in perceived safety. Rankings were consistent across tested demographic factors (i.e., gender, age, and income). Survey results show that online pharmacies were most likely to be perceived as safe for purchasing drugs and medications. Additionally, those who were younger in age, had higher income, and identified as female were more likely to purchase from a greater number of platforms. Conclusions: These findings can assist in developing more precise content moderation for platforms seeking to address this ongoing threat to public safety.

BACKGROUND: Many clinical trials fail because of poor recruitment and enrollment which can directly impact the success of biomedical and clinical research outcomes. Options to leverage digital technology for improving clinical trial management are expansive, with potential benefits for improving access to clinical trials, encouraging trial diversity and inclusion, and potential cost-savings through enhanced efficiency. OBJECTIVES: This systematic review has two key aims: (1) identify and describe the digital technologies applied in clinical trial recruitment and enrollment and (2) evaluate evidence of these technologies addressing the recruitment and enrollment of racial and ethnic minority groups. METHODS: We conducted a cross-disciplinary review of articles from PubMed, IEEE Xplore, and ACM Digital Library, published in English between January 2012 and July 2022, using MeSH terms and keywords for digital health, clinical trials, and recruitment and enrollment. Articles unrelated to technology in the recruitment/enrollment process or those discussing recruitment/enrollment without technology aspects were excluded. RESULTS: The review returned 614 results, with 21 articles (four reviews and 17 original research articles) deemed suitable for inclusion after screening and full-text review. To address the first objective, various digital technologies were identified and characterized, which included articles with more than one technology subcategory including (a) multimedia presentations (19%, n = 4); (b) mobile applications (14%, n = 3); (c) social media platforms (29%, n = 6); (d) machine learning and computer algorithms (19%, n = 4); (e) e-consenting (24%, n = 5); (f) blockchain (5%, n = 1); (g) web-based programs (24%, n = 5); and (h) virtual messaging (24%, n = 5). Additionally, subthemes, including specific diseases or conditions addressed, privacy and regulatory concerns, cost/benefit analyses, and ethnic and minority recruitment considerations, were identified and discussed. Limited research was found to support a particular technologys effectiveness in racial and ethnic minority recruitment and enrollment. CONCLUSION: Results from this review illustrate that several types of technology are currently being explored and utilized in clinical trial recruitment and enrollment stages. However, evidence supporting the use of digital technologies is varied and requires further research and evaluation to identify the most valuable opportunities for encouraging diversity in clinical trial recruitment and enrollment practices.