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Low back pain continues to be a major clinical challenge with high direct and indirect societal costs. It is a complex disease with complex pathophysiology both for acute and chronic low back pain. Although there is consistent evidence about multidisciplinary treatment of low back pain, several different approaches and techniques are proposed, with different results often conflicting among them. In fact, even though the multidisciplinary approach is widely accepted, it is generally applied in different steps involving only one health care providing for each approach. This approach not only does not guarantee a real multidisciplinary vision of this disease but also lacks evaluation of the dynamic changes of the disease according to real patients’ needs. In our hospital setting we have developed a “simultaneous multidisciplinary care” of low back pain patients in order to overcome these problems and to satisfy all patients’ needs by evaluating and treating all problems causing and related to low back pain. Starting from the existing literature we propose our approach as a new pathway to treat low back patients with a simultaneous multidisciplinary approach.

Human protein glycosylation is a complex process, and its in vivo regulation is poorly understood. Changes in glycosylation patterns are associated with many human diseases and conditions. Understanding the biological determinants of protein glycome provides a basis for future diagnostic and therapeutic applications. Genome-wide association studies (GWAS) allow to study biology via a hypothesis-free search of loci and genetic variants associated with a trait of interest. Sixteen loci were identified by three previous GWAS of human plasma proteome N-glycosylation. However, the possibility that some of these loci are false positives needs to be eliminated by replication studies, which have been limited so far. Here, we use the largest set of samples so far (4802 individuals) to replicate the previously identified loci. For all but one locus, the expected replication power exceeded 95%. Of the 16 loci reported previously, 15 were replicated in our study. For the remaining locus (near the KREMEN1 gene), the replication power was low, and hence, replication results were inconclusive. The very high replication rate highlights the general robustness of the GWAS findings as well as the high standards adopted by the community that studies genetic regulation of protein glycosylation. The 15 replicated loci present a good target for further functional studies. Among these, eight loci contain genes encoding glycosyltransferases: MGAT5, B3GAT1, FUT8, FUT6, ST6GAL1, B4GALT1, ST3GAL4 and MGAT3. The remaining seven loci offer starting points for further functional follow-up investigation into molecules and mechanisms that regulate human protein N-glycosylation in vivo.

The transition from acute to chronic pain is critically important but not well understood. Here, we investigated the pathophysiological mechanisms underlying the transition from acute to chronic low back pain (LBP) and performed transcriptome-wide analysis in peripheral immune cells of 98 participants with acute LBP, followed for 3 months. Transcriptomic changes were compared between patients whose LBP was resolved at 3 months with those whose LBP persisted. We found thousands of dynamic transcriptional changes over 3 months in LBP participants with resolved pain but none in those with persistent pain. Transient neutrophil-driven up-regulation of inflammatory responses was protective against the transition to chronic pain. In mouse pain assays, early treatment with a steroid or nonsteroidal anti-inflammatory drug (NSAID) also led to prolonged pain despite being analgesic in the short term; such a prolongation was not observed with other analgesics. Depletion of neutrophils delayed resolution of pain in mice, whereas peripheral injection of neutrophils themselves, or S100A8/A9 proteins normally released by neutrophils, prevented the development of long-lasting pain induced by an anti-inflammatory drug. Analysis of pain trajectories of human subjects reporting acute back pain in the UK Biobank identified elevated risk of pain persistence for subjects taking NSAIDs. Thus, despite analgesic efficacy at early time points, the management of acute inflammation may be counterproductive for long-term outcomes of LBP sufferers.

This review is aimed to summarize the pain-relieving effect of non-drug substances, mostly prescribed as integrators in treatment of pain, including especially in chronic postoperative pain (CPSP) and in chronic back pain after acute episodes. Their use reflects the fact that the current treatments for these syndromes continue to pose problems of unsatisfactory responses in a significant portion of patients and/or of an excess of side effects like those noted in the present opioid crisis. As integrators are frequently introduced into the market without adequate clinical testing, this review is aimed to collect the present scientific evidence either preclinical or clinical for their effectiveness. In particular, we reviewed the data on the use of: B vitamins; vitamin C; vitamin D; alpha lipoic acid (ALA); N-acetylcysteine; acetyl L-carnitine; curcumin; boswellia serrata; magnesium; coenzyme Q10, and palmitoylethanolamide. The combination of preclinical findings and clinical observations strongly indicate that these compounds deserve more careful attention, some of them having interesting clinical potentials also in preventing chronic pain after an acute episode. In particular, examining their putative mechanisms of action it emerges that combinations of few of them may exert an extraordinary spectrum of activities on a large variety of pain-associated pathways and may be eventually used in combination with more traditional pain killers in order to extend the duration of the effect and to lower the doses. Convincing examples of effective combinations against pain are vitamin B complex plus gabapentin for CPSP, including neuropathic pain; vitamin B complex plus diclofenac against low back pain and also in association with gabapentin, and ALA for burning mouth syndrome. These as well as other examples need, however, careful controlled independent clinical studies confirming their role in therapy.

Chronic pain is a debilitating and poorly treated condition whose underlying mechanisms are poorly understood. Nerve injury and inflammation cause alterations in gene expression in tissues associated with pain processing, supporting molecular and cellular mechanisms that maintain painful states. However, it is not known whether transcriptome changes can be used to reconstruct a molecular pathophysiology of pain. In the current study, we identify molecular pathways contributing to chronic pain states through the analysis of global changes in the transcriptome of dorsal root ganglia, spinal cord, brain, and blood in mouse assays of nerve injury- and inflammation-induced pain. Comparative analyses of differentially expressed genes identified substantial similarities between 2 animal pain assays and with human low-back pain. Furthermore, the extracellular matrix (ECM) organization has been found the most commonly regulated pathway across all tested tissues in the 2 animal assays. Examination of human genome-wide association study data sets revealed an overrepresentation of differentially expressed genes within the ECM organization pathway in single nucleotide polymorphisms most strongly associated with human back pain. In summary, our comprehensive transcriptomics analysis in mouse and human identified ECM organization as a central molecular pathway in the development of chronic pain.

A large variation in the severity of disease symptoms is one of the key open questions in COVID-19 pandemics. The fact that only a small subset of people infected with SARS-CoV-2 develop severe disease suggests that there have to be some predisposing factors, but biomarkers that reliably predict disease severity have not been found so far. Since overactivation of the immune system is implicated in a severe form of COVID-19 and the IgG glycosylation is known to be involved in the regulation of different immune processes, we evaluated the association of inter-individual variation in IgG N-glycome composition with the severity of COVID-19. The analysis of 166 severe and 167 mild cases from hospitals in Spain, Italy and Portugal revealed statistically significant differences in the composition of the IgG N-glycome. The most notable difference was the decrease in bisecting N-acetylglucosamine (GlcNAc) in severe patients from all three cohorts. IgG galactosylation was also lower in severe cases in all cohorts, but the difference in galactosylation was not statistically significant after correction for multiple testing. To our knowledge, this is the first study exploring IgG N-glycome variability in COVID-19 severity.

BackgroundMost respiratory viruses show pronounced seasonality, but for SARS-CoV-2 this still needs to be documented.MethodsWe examined the disease progression of COVID-19 in 6,914 patients admitted to hospitals in Europe and China. In addition, we evaluated progress of disease symptoms in 37,187 individuals reporting symptoms into the COVID Symptom Study application.FindingsMeta-analysis of the mortality risk in seven European hospitals estimated odds ratios per one day increase in the admission date to be 0.981 (0.973-0.988, pInterpretationSeverity of COVID-19 in Europe decreased significantly between March and May and the seasonality of COVID-19 is the most likely explanation.

A large variation in the severity of disease symptoms is one of the key open questions in coronavirus disease 2019 (COVID-19) pandemics. The fact that only a small subset of people infected with severe acute respiratory syndrome coronavirus 2 develops severe disease suggests that there have to be some predisposing factors, but biomarkers that reliably predict disease severity have not been found so far. Since overactivation of the immune system is implicated in a severe form of COVID-19 and the immunoglobulin G (IgG) glycosylation is known to be involved in the regulation of different immune processes, we evaluated the association of interindividual variation in IgG N-glycome composition with the severity of COVID-19. The analysis of 166 severe and 167 mild cases from hospitals in Spain, Italy and Portugal revealed statistically significant differences in the composition of the IgG N-glycome. The most notable difference was the decrease in bisecting N-acetylglucosamine in severe patients from all three cohorts. IgG galactosylation was also lower in severe cases in all cohorts, but the difference in galactosylation was not statistically significant after correction for multiple testing.

PubMed: 32118384 [No abstract available]

Background Low back pain (LBP) is the symptom of a group of syndromes with heterogeneous underlying mechanisms and molecular pathologies, making treatment selection and patient prognosis very challenging. Moreover, symptoms and prognosis of LBP are influenced by age, gender, occupation, habits, and psychological factors. LBP may be characterized by an underlying inflammatory process. Previous studies indicated a connection between inflammatory response and total plasma N-glycosylation. We wanted to identify potential changes in total plasma N-glycosylation pattern connected with chronic low back pain (CLBP), which could give an insight into the pathogenic mechanisms of the disease. Methods Plasma samples of 1128 CLBP patients and 760 healthy controls were collected in clinical centers in Italy, Belgium and Croatia and used for N-glycosylation profiling by hydrophilic interaction ultra-performance liquid chromatography (HILIC-UPLC) after N-glycans release, fluorescent labeling and clean-up. Observed N-glycosylation profiles have been compared with a cohort of 126 patients with acute inflammation that underwent abdominal surgery. Results We have found a statistically significant increase in the relative amount of high-branched (tri-antennary and tetra-antennary) N-glycan structures on CLBP patients' plasma glycoproteins compared to healthy controls. Furthermore, relative amounts of disialylated and trisialylated glycan structures were increased, while high-mannose and glycans containing bisecting N-acetylglucosamine decreased in CLBP. Conclusions Observed changes in CLBP on the plasma N-glycome level are consistent with N-glycosylation changes usually seen in chronic inflammation. General significance To our knowledge, this is a first large clinical study on CLBP patients and plasma N-glycome providing a new glycomics perspective on potential disease pathology.

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.

BACKGROUNDPerioperative regional anaesthesia may protect from persistent postsurgical pain (PPSP) and improve outcome after total knee arthroplasty (TKA).OBJECTIVESAim of this study was to evaluate the impact of regional anaesthesia on PPSP and long-term functional outcome after TKA.DESIGNA web-base

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

Objective The transversus abdominis plane (TAP) block is a relatively simple regional anesthesia technique which entails the injection of local anesthetics (LA) into the interfascial plane between the internal oblique and transversus abdominis muscles, where nerves supplying the anterolateral abdominal wall course. It is widely used for acute pain management following abdominal surgical procedures. We describe a series of cases in which TAP blocks were used to aid in the diagnosis and treatment of chronic abdominal wall pain (CAWP). Design Consecutive case series of 5 patients presenting with CAWP. Setting Regional referral Center for Pain Medicine of the academic tertiary hospital of Parma, Italy. Results Five patients received TAP blocks with LA and steroid. Four patients reported ≥50% pain relief within hours of the procedure, and 2 of them maintained low pain intensities at 6 and 12 months’ follow-up calls. Conclusions TAP blocks are a valuable addition to the diagnostic armamentarium of pain physicians confronted with abdominal pain of unclear origin. Although most patients responded to the LA injection, the varying degrees of response duration may have been influenced by the different etiologies underlying each condition and the variable expressions of placebo responses. Once the abdominal wall and/or its nerves are identified as pain generators, the optimal therapeutic management remains to be determined. Available literature as well as our case series show that long-term benefit may be obtained with 1 or more injections, but we speculate that this may only be the case for pain with predominantly neuropathic components. This article is protected by copyright. All rights reserved.

Background. Intraperitoneal nebulization of ropivacaine reduces postoperative pain and morphine consumption after laparoscopic surgery. The aim of this multicenter double-blind randomized controlled trial was to assess the efficacy of different doses and dose-related absorption of ropivacaine when nebulized in the peritoneal cavity during laparoscopic cholecystectomy. Methods. Patients were randomized to receive 50, 100, or 150 mg of ropivacaine 1% by peritoneal nebulization through a nebulizer. Morphine consumption, pain intensity in the abdomen, wound and shoulder, time to unassisted ambulation, discharge time, and adverse effects were collected during the first 48 hours after surgery. The pharmacokinetics of ropivacaine was evaluated using high performance liquid chromatography. Results. Nebulization of 50 mg of ropivacaine had the same effect of 100 or 150 mg in terms of postoperative morphine consumption, shoulder pain, postoperative nausea and vomiting, activity resumption, and hospital discharge timing (>0.05). Plasma concentrations did not reach toxic levels in any patient, and no significant differences were observed between groups (P>0.05). Conclusions. There is no enhancement in analgesic efficacy with higher doses of nebulized ropivacaine during laparoscopic cholecystectomy. When administered with a microvibration-based aerosol humidification system, the pharmacokinetics of ropivacaine is constant and maintains an adequate safety profile for each dosage tested.

Glycosylation is a common post-translational modification of proteins. Glycosylation is associated with a number of human diseases. Defining genetic factors altering glycosylation may provide a basis for novel approaches to diagnostic and pharmaceutical applications. Here we report a genome-wide association study of the human blood plasma N-glycome composition in up to 3,811 people measured by Ultra Performance Liquid Chromatography (UPLC) technology. Starting with the 36 original traits measured by UPLC, we computed an additional 77 derived traits leading to a total of 113 glycan traits. We studied associations between these traits and genetic polymorphisms located on human autosomes. We discovered and replicated twelve loci. This allowed us to demonstrate an overlap in genetic control between total plasma protein and IgG glycosylation. The majority of revealed loci contained genes that encode enzymes directly involved in glycosylation (FUT3/FUT6, FUT8, B3GAT1, ST6GAL1, B4GALT1, ST3GAL4, MGAT3, and MGAT5) and a known regulator of plasma protein fucosylation (HNF1A). However, we also found loci that could possibly reflect other, more complex aspects of glycosylation process. Functional genomic annotation suggested the role of several genes including DERL3, CHCHD10, TMEM121, IGH, and IKZF1. The hypotheses we generated may serve as a starting point for further functional studies in this research area.

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.

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 108hours, 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 3hours after the device application. In the in vitro analyses, the nanogel remained in contact with plasma at 37°C for 90minutes, 3hours, 1day, and 7days. Chloroprocaine Cmax was identified 1day following exposure and Cmin after 7days, respectively. Additionally, ACBA reached the Cmax following 7days 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

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

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 24hours. After 24hours, 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 48hours 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 48hours 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 48hours 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&nbsp

Glycosylation is a common post-translational modification of proteins. It is known, that glycans are directly involved in the pathophysiology of every major disease. Defining genetic factors altering glycosylation may provide a basis for novel approaches to diagnostic and pharmaceutical applications. Here, we report a genome-wide association study of the human blood plasma N-glycome composition in up to 3811 people. We discovered and replicated twelve loci. This allowed us to demonstrate a clear overlap in genetic control between total plasma and IgG glycosylation. Majority of loci contained genes that encode enzymes directly involved in glycosylation (FUT3/FUT6, FUT8, B3GAT1, ST6GAL1, B4GALT1, ST3GAL4, MGAT3, and MGAT5). We, however, also found loci that are likely to reflect other, more complex, aspects of plasma glycosylation process. Functional genomic annotation suggested the role of DERL3, which potentially highlights the role of glycoprotein degradation pathway, and such transcription factor as IKZF1.

BACKGROUND Every year, more than 1.5 million patients, who undergo cardiac surgery worldwide, are exposed to a series of factors that can trigger acute postoperative pain associated with hemodynamic instability, respiratory complications, and psychological disorders. Through an evaluation of literature data about postoperative pain in cardiac surgery we define unmet needs and potential objectives for future research on this often-underestimated problem. METHODS Following PRISMA Guidelines, a systematic literature search was carried out by two independent researchers on Scopus, CINAHL, the Cochrane Library, and PubMed using the key words: (perioperative OR postoperative) analgesia AND "cardiac surgery." Papers concerning children, or published prior to 2000, were considered ineligible, as well as abstracts, animal studies, and studies written in languages other than English. RESULTS Fifty-four papers were selected and subsequently divided into two main categories: systemic analgesic drugs and regional anesthesia techniques. CONCLUSIONS Over the past 17 years, opioids are still the most extensively used therapy, whereas we found only few trials investigating other drugs (e.g. paracetamol). Regional anesthesia techniques, especially thoracic epidural analgesia and intrathecal morphine administration, can effectively treat pain, but have not yet showed any significant impact on major clinical outcomes, with several concerns related to their potential complications. To date multimodal analgesia with implementation of regional analgesia seems to be the best choice. In the future, better-designed studies should consider other drugs stratifying groups according to comorbidities and risk factors, as well as using standardized units of measurement.

BACKGROUND AND OBJECTIVE Opioid treatments are often prolonged because of the pathology causing pain. We focused on the cognitive functions in patients with chronic pain treated with opioids. This topic is currently controversial, but in practice, the consequences are important in patients' daily lives, social interactions, working ability, and driving. DATABASE AND DATA TREATMENT Medline and Embase databases were searched for eligible articles. We included studies that enrolled patients with chronic noncancer pain, studies with patients receiving opioid treatment, studies with a control group not using opioids, and studies in which cognitive functions were evaluated with specific tests. The cognitive areas examined were as follows: attention, reaction time, executive functions, psychomotor speed, memory, and working memory. From 356 abstracts screened, 9 articles satisfied eligibility criteria and were included in our review: 7 observational and 7 experimental studies. We classified the pain treatments as follows: opioids, other drugs active on the central nervous system (CNS) (antidepressants/anticonvulsants), and treatments not specifically targeted to the CNS. RESULTS Statistically significant differences were seen only with regard to attention between opioids alone and no centrally acting treatment (standardized mean difference [SMD]: -0.53, 95% confidence interval [CI] : -0.91, -0.15; P = 0.007; I2 = 23%) and between opioids combined with antidepressants and/or anticonvulsants and no centrally acting treatment (SMD: -0.62, 95% CI: -1.04, -0.20; P = 0.004; I2 = 0%). No other significant differences were observed. CONCLUSIONS Opioids reduce attention when compared with treatments not targeted on the CNS. If opioids are used together with antidepressants and/or anticonvulsants, this effect increases. SIGNIFICANCE These findings on the neuropsychological effects of opioids could be used to generate strategies to refine pain treatments.

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

Study objective The study objective is to identify differences in postoperative pain management according to different analgesic treatments, targeting 2 main pathways involved in pain perception. Design The design is a randomized, parallel groups, open-label study. Setting The setting is in an operating room, postoperative recovery area, and surgical ward. Patients There are 200 patients undergoing open inguinal hernia repair (IHR) with tension-free technique (mesh repair). Interventions The intervention is a randomization to receive ketorolac (group K) or tramadol (group T) for 3 days after surgery. Measurements The measurements are differences in analgesic efficacy (numeric rating scale [NRS]) in the postoperative (up to 5 days) period, chronic pain incidence (1 and 3 months), side effects, and complications. Main results We found no differences in analgesic efficacy (NRS value ≥4 in the first 96 hours: 26% in group K vs 32% in group T, P = .43); the proportion of patients with NRS ≥4 was similar in both groups, and the time trajectories were not significantly different ( P for interaction=.24). Side effects were higher (12% vs 6%) in the tramadol group, although not significantly ( P = .14), with a case of bleeding in the ketorolac group and higher incidence of constipation in tramadol group. One patient in each group developed chronic pain. Conclusions Ketorolac or weak opioids are equally effective on acute pain and on persistent postsurgical pain development after IHR, and drug choice should be based on their potential side effects and patient's comorbidities. Further studies are needed to standardize the most rational approach to prevent persistent postsurgical pain after IHR.

BACKGROUND: Epidural infusion of levobupivacaine and ropivacaine provides adequate postoperative pain management by minimizing side effects related to IV opioids and improving patient outcome. The safety profile of different drugs can be better estimated by comparing their pharmacokinetic profiles than by considering their objective side effects. Because levobupivacaine and ropivacaine have different pharmacokinetic properties, our aim was to investigate whether there is a difference in the pharmacokinetic variability of the 2 drugs in a homogeneous population undergoing continuous epidural infusion. This double-blind, multicenter, randomized, controlled trial study was designed to compare the pharmacokinetics of continuous thoracic epidural infusion of levobupivacaine 0.125% or ropivacaine 0.2% for postoperative pain management in adult patients who had undergone major abdominal, urological, or gynecological surgery. This study is focused on the evaluation of the coefficient of variation (CV) to assess the equivalence in the systemic exposure and interindividual variability between levobupivacaine and ropivacaine and, therefore, the possible differences in the predictability of the plasmatic concentrations of the 2 drugs during thoracic epidural infusion. METHODS: One hundred eighty-one adults undergoing major abdominal surgery were enrolled in the study. Patients were randomized to receive an epidural infusion of levobupivacaine 0.125% + sufentanil 0.75 μg/mL or of ropivacaine 0.2% + sufentanil 0.75 μg/mL at 5 mL/h for 48 hours. The primary end point of this study was to analyze the variability of plasma concentration of levobupivacaine and ropivacaine via an area under the curve within a range of 15% of the CV during 48 hours of continuous epidural infusion. The CV shows how the concentration values of local anesthetics are scattered around the median concentration value, thus indicating the extent to which plasma concentration is predictable during infusion. Secondary end points were to assess the pharmacologic profile of the local anesthetics used in the study, including an analysis of mean peak plasma concentrations, and also to assess plasma clearance, side effects, pain intensity (measured with a verbal numeric ranging score, i.e., static Numeric Rating Scale [NRS] and dynamic NRS]), and the need for rescue doses. RESULTS: The comparison between the 2 CVs showed no statistical difference: the difference between area under the curve was within the range of 15%. The CV was 0.54 for levobupivacaine and 0.51 for ropivacaine (P = 0.725). The plasma concentrations of ropivacaine approached the Cmax significantly faster than those of levobupivacaine. Clearance of ropivacaine decreases with increasing patient age. There were no significant differences in NRS, dynamic NRS scores, the number of rescue doses, or in side effects between groups. CONCLUSIONS: Considering the CV, the interindividual variability of plasma concentration for levobupivacaine and ropivacaine is equivalent after thoracic epidural infusion in adults. We found a reduction in clearance of ropivacaine depending on patient age, but this finding could be the result of some limitations of our study. The steady-state concentration was not reached during the 48-hour infusion and the behavior of plasma concentrations of ropivacaine and levobupivacaine during continuous infusions lasting more than 48 hours remains to be investigated, because they could reach toxic levels. Finally, no differences in the clinical efficacy or in the incidence of adverse effects between groups were found for either local anesthetic., Published ahead of print May 14, 2015

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: 5mL/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 108hours. 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 6hours, 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