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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.

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.

Most respiratory viruses show pronounced seasonality, but for SARS-CoV-2, this still needs to be documented. We 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. Meta-analysis of the mortality risk in seven European hospitals estimated odds ratios per 1-day increase in the admission date to be 0.981 (0.973–0.988, < 0.001) and per increase in ambient temperature of 1°C to be 0.854 (0.773–0.944, = 0.007). Statistically significant decreases of comparable magnitude in median hospital stay, probability of transfer to the intensive care unit, and need for mechanical ventilation were also observed in most, but not all hospitals. The analysis of individually reported symptoms of 37,187 individuals in the UK also showed the decrease in symptom duration and disease severity with time. Severity 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 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.

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

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

Background:Low back pain (LBP) is a very frequent condition, affecting most people at some point throughout their life. This cross-sectional study was aimed to investigate a selected panel of cytokines and inflammatory biomarkers in patients with or without LBP.Methods:The study population consisted of 104 patients diagnosed with LBP (52 non-persistent and 52 persistent) and 52 healthy subjects with no LBP. Blood samples were collected for assessment of adiponectin, leptin, monocyte chemoattractant protein-1 (MCP-1) and C reactive protein (CRP). The duration of LBP was categorized as “no pain”, “non-persistent LBP” and “persistent LBP”.Results:Higher values of CRP and lower concentrations of both leptin and MCP-1 were found in LBP patients compared to controls, whereas adiponectin did not differ among groups. MCP-1 was also lower in patients with non-persistent than in those with persistent LBP. Age, leptin (relative risk, 11.8; 95% CI, 3.9–35.8) and MCP-1 (relative risk, 2.7; 95% CI, 1.7–4.4) were independently associated with presence and duration of LBP. The combination of age, leptin and MCP-1 predicted 61% of the risk of LBP duration. The area under the curve of MCP-1 for distinguishing persistent from non-persistent LBP was 0.65 (95% CI, 0.54–0.76).Conclusions:Then results of our study suggest that leptin and MCP-1 may be promising biomarkers for diagnosis of acute LBP and its risk to become chronic.

Regional anesthesia: the best is yet to come

In recent decades, there has been a revision of the role of institutional review boards with the intention of protecting human subjects from harm and exploitation in research. Informed consent aims to protect the subject by explaining all of the benefits and risks associated with a specific research project. To date, there has not been a review published analyzing issues of informed consent in research in the field of genetic/Omics in subjects with chronic pain, and the current review aims to fill that gap in the ethical aspects of such investigation. Despite the extensive discussion on ethical challenges unique to the field of genetic/Omics, this is the first attempt at addressing ethical challenges regarding Informed Consent Forms for pain research as the primary focus. We see this contribution as an important one, for while ethical issues are too often ignored in pain research in general, the numerous arising ethical issues that are unique to pain genetic/Omics suggest that researchers in the field need to pay even greater attention to the rights of subjects/patients. This article presents the work of the Ethic Committee of the Pain-Omics Group (www.painomics.eu), a consortium of 11 centers that is running the Pain-Omics project funded by the European Community in the 7th Framework Program theme (HEALTH.2013.2.2.1-5—Understanding and controlling pain). The Ethic Committee is composed of 1 member of each group of the consortium as well as key opinion leaders in the field of ethics and pain more generally.

Acute pain remains a tremendous clinical and economic burden, as its prevalence and common narcotic-based treatments are associated with poorer outcomes and higher costs. Multimodal analgesia portends great therapeutic promise, but rarely allows opioid sparing, and new alternatives are necessary. Microparticles (MPs) composed of biodegradable polymers [e.g., poly(lactic-co-glycolic acid) or PLGA] have been applied for controlled drug release and acute pain treatment research. However, foreign particles' presence within inflamed tissue may affect the drug release or targeting, and/or cause a secondary inflammatory reaction. We examined how small alterations in the particulate nature of MPs affect both their uptake into and subsequent activation of macrophages. MPs composed of PLGA and chitosan (PLGA-Chi) loaded with bupivacaine (BP) were engineered at different sizes and their opsonization by J774 macrophages was assessed. Uptake of PLGA-Chi by macrophages was found to be size dependent, but they were not cytotoxic or proinflammatory in effect. Moreover, encapsulation of MPs in a thermoresponsive loading gel (pluronic F-127) effectively prevented opsonization. Finally, MPs displayed sustained, tunable release of BP up to 7 days. These results demonstrate our ability to develop a drug delivery system capable of controlled release of local anesthetics to treat acute/subacute pain while concurrently avoiding enhanced inflammation.

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.

Pain is one of the most prevalent and distressing symptoms in patients with cancer. There is evidence from observational studies that many patients do not get adequate relief. Although data in the literature confirm the effectiveness of most opioid drugs for the treatment of chronic pain, there is limited information about opioid titration.The aim of this study was to evaluate the clinical pharmacokinetics of morphine (M) and their correlation with pharmacodynamic results (effective daily dose of M and side effects) during the M titration phase, in the management of chronic cancer pain. Fifty-two consecutive patients were administered Oramorph (Molteni Farmaceutici, Scandicci, Florence, Italy; beginning with 5 mg every 6 hours), to maintain pain intensity at low levels (visual analog scale4). M, morphine-3-glucuronide (M3G), and morphine-6-glucuronide (M6G) plasma concentrations were determined by a mass spectrometric assay.Expected pharmacokinetic parameters were based on a pharmacokinetic profile extrapolated from 39 patients: M total clearance varied between 1.5 and 6.42 L·h(-1)·kg(-1); the median apparent volume of M distribution was 25.0 L/kg, and the elimination half-life was 4.4 hours. Over the entire period of treatment, a weak correlation between M and M3G or M6G concentrations was found, but the metabolite ratio (M3G/M6G) remained quite stable for each patient and at different sampling times. At the end of titration, the M6G/M ratio was significantly higher in the patients whose effective M concentration was below the median (5.2 ng/mL), than in patients in whom the concentration was above the median (M6G/M: 13.0 and 9.0, respectively).This article presents the pharmacokinetic profiles of M and its metabolites: their concentration ratio could help clinicians to optimize individual therapies and tailor the dose to individual needs. Our results indicate that the relationship between M6G and M could represent a potentially useful parameter to personalize M dosing.

Interstitial cystitis (IC) or bladder pain syndrome (BPS) is defined as supra-pubic pain related to bladder filling. IC is characterized by a particular symptom complex with no identifiable causes; as with bladder hypersensitivity it is usually associated with urinary frequency and urgency with bladder pain. No current treatments have a significant impact on symptoms over time.This systematic review examines the pharmacokinetic aspects and adverse event of present IC therapy to highlight appropriate treatment to improve the symptoms of IC. This article reviews material obtained via Medline, PubMed, and EMBASE literature searches up to October 2013.The correct approach to IC should consider a multidisciplinary team of specialists and a multimodal treatment package that include psychotherapy, behavior change, physical activation, and analgesic treatment. Unfortunately, a single therapeutic target for IC is not yet known. With regard to pathophysiology and therapy, there is more to discover. The first insult damages the bladder urothelium, hence vehicles that lead the drug to penetrate the wall of the bladder might be a novel strategic approach.

To investigate interindividual variability in response to pain treatment, we characterized postoperative patients for morphine metabolism and for COMT, OPRM1 and UGT2B7 polymorphisms.A total of 109 patients treated with morphine were genotyped by DNA sequencing for 12 DNA polymorphisms of the COMT, OPRM1 and UGT2B7 genes. The plasma concentration of morphine and of M3G/M6G metabolites were evaluated by means of reversed phase high-performance liquid chromatography coupled with mass spectrometry.An association between average morphine consumption during the first 24 postoperative hours by patient-controlled analgesia (PCA) and COMT haplotypes was found. Specifically, patients with the diplotype for average pain intensity (APS/APS) required the lowest morphine doses compared to the other subjects (p = 0.011). The APS haplotype contains an adenine corresponding to methionine, instead of valine, at position 158 of the COMT protein. Met/Met homozygous patients consumed significantly lower morphine doses than other subjects (p = 0.014); accordingly, Val158Met genotyping alone might be used in the clinical setting to predict PCA morphine need. Considering both COMT Val158Met and OPRM1 A118G polymorphisms, carriers of both the Met/Met and AA genotypes required less morphine than other subjects, although the difference was not significant. The analysis of UGT2B7 revealed the occurrence of two common haplotypes (G_C_C_A_C and A_T_T_G_T) that did not prove to be related with plasma morphine and M3G/M6G concentration.By considering COMT, OPRM1, and UGT2B7 genotypes, as well as pharmacokinetic results, only COMT polymorphisms appear to be predictive of morphine need in postoperative pain therapy.

Systemic inflammation participates to the complex healing process occurring after major surgery, thus directly affecting the surgical outcome and patient recovery. Total plasma N-glycome might be an indicator of inflammation after major surgery, as well as an anti-inflammatory therapy response marker, since protein glycosylation plays an essential role in the inflammatory cascade. Therefore, we assessed the effects of surgery on the total plasma N-glycome and the association with self-administration of postoperative morphine in two cohorts of patients that underwent major abdominal surgery. We found that plasma N-glycome undergoes significant changes one day after surgery and intensifies one day later, thus indicating a systemic physiological response. In particular, we observed the increase of bisialylated biantennary glycan, A2G2S[3,6]2, 12 hours after surgery, which progressively increased until 48 postoperative hours. Most changes occurred 24 hours after surgery with the decrease of most core-fucosylated biantennary structures, as well as the increase in sialylated tetraantennary and FA3G3S[3,3,3]3 structures. Moreover, we observed a progressive increase of sialylated triantennary and tetraantennary structures two days after surgery, with a concomitant decrease of the structures containing bisecting N-acetylglucosamine along with bi- and trisialylated triantennary glycans. We did not find any statistically significant association between morphine consumption and plasma N-glycome.

Chronic low back pain (CLBP) is a chronic pain syndrome in the lower back region, lasting for at least 3 months. CLBP represents the second leading cause of disability worldwide being a major welfare and economic problem. The prevalence of CLBP in adults has increased more than 100% in the last decade and continues to increase dramatically in the aging population, affecting both men and women in all ethnic groups, with a significant impact on functional capacity and occupational activities. It can also be influenced by psychological factors, such as stress, depression and/or anxiety. Given this complexity, the diagnostic evaluation of patients with CLBP can be very challenging and requires complex clinical decision-making. Answering the question “what is the pain generator” among the several structures potentially involved in CLBP is a key factor in the management of these patients, since a mis-diagnosis can generate therapeutical mistakes. Traditionally, the notion that the etiology of 80% to 90% of LBP cases is unknown has been mistaken perpetuated across decades. In most cases, low back pain can be attributed to specific pain generator, with its own characteristics and with different therapeutical opportunity. Here we discuss about radicular pain, facet Joint pain, sacro-iliac pain, pain related to lumbar stenosis, discogenic pain. Our article aims to offer to the clinicians a simple guidance to identify pain generators in a safer and faster way, relying a correct diagnosis and further therapeutical approach.

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

ERAS approach (Enhanced Recovery After Surgery) is a multimodal, perioperative pathway designed to achieve early recovery after surgery. ERAS has shown documented efficacy in elective surgery, and the concept of “multimodal” and “multidisciplinary” approach seems still to be of higher importance than each single item within ERAS protocols. New perspectives include the use of ERAS in emergency surgery, where efficacy and safety on outcome have been documented, and flexibility of traditional items may add benefits for traditionally high-risk patients. Obstetric surgery, as well, may open wide horizons for future research, since extremely poor data are currently available, and ERAS benefits may translate even on the baby. Finally, the concept of “outcome” may be extended when considering the specific setting of cancer surgery, in which variables like cancer recurrence, early access to adjuvant therapies, and, finally, long-term survival are as important as the reduced perioperative complications. In this perspective, different items within ERAS protocols should be reinterpreted and eventually integrated towards “protective” techniques, to develop cancer-specific ERAS approaches keeping pace with the specific aims of oncologic surgery.

10.2217/pmt.16.2 © 2016 Future Medicine Ltd Time for omics to challenge pain The concept of omics refers to the largescale structural and functional investigation of multiple measured biological variables and has become firmly rooted in contemporary biomedical studies. This reflects both the advances in the development of high-throughput techniques for simultaneous analysis of biological processes and entities and a trend toward employing a more holistic view on the control and regulation of biological systems and its implication for medicine. A web-based omics encyclopedia lists hundreds of ‘omes’ and ‘omics’ including customary ones, such as genomics or transcriptomics, and quite extravagant ones such as killifishomics or opiniomics. Attempts are being made to integrate different omics into a single pipeline for better understanding of biological pathways and to boost translational studies [1,2]. The advancement in omics technologies has facilitated the study of groups of chronic pain phenotypes allowing novel groupings of clinical manifestations previously considered separately. The phenotypes include both clinical syndromes of chronic pain, such as chronic low back pain (LBP), and chronic widespread pain (CWP)/fibromyalgia. In addition, objective measures of pain sensitivity known as quantitative sensory testing (QST), such as heat pain sensitivity, may provide a proxy for capturing the biological variation in the manifestation of pain. Whether QST relates to the mechanisms of the development of pain diseases and syndromes remains to be seen. Chronic pain, either as an individual chronic pain syndrome COMMENTARY

The pain management in pediatric surgery is a very complex and relevant problem with many clinical implications. Pain in children requires special considerations due to physical and psychological immaturity. The enhancement in pain management results in a reduction of recovery time and complications. Few studies are available in the literature focused on postoperative pain and analgesia requirements in children following surgical procedures. In the present brief review we summarize the current strategies of pain management in pediatric surgery and we envision the new hypothetical horizons in this field.

Neuropathic pain is caused by a lesion or disease affecting the somatosensory system and is difficult to manage, often proving refractory to existing treatments. In more than half of cases, it is localized and affects a specific, clearly circumscribed area of the body (localized neuropathic pain, or LNP). A recently developed screening tool enables patients with probable neuropathic pain/LNP to be identified quickly and easily. In view of the conflicting current treatment recommendations, an advisory board of pain specialists met in June 2015 to develop a complementary treatment guidance algorithm, for use in the primary care setting and by non-pain specialists. The starting point of the algorithm is a diagnosis of LNP and there was consensus that first-line treatment should be a topical analgesic agent, because the benefit/risk ratios are far better than for systemic agents. Topical application offers site-specific delivery, a lower total systemic dose and avoidance of first-pass metabolism, reducing the risk of adverse events and drug/drug interactions. The 5% lidocaine medicated plaster has most evidence supporting its use in LNP, producing effective analgesia and reducing the associated area of allodynia, but other topical agents include capsaicin, clonidine and botulinum toxin type A. Treatment should be commenced with the topical agent of choice, and the patient re-assessed after an appropriate period. Where the response is good the topical agent is continued, with a re-evaluation after 3-6 months. A systemic agent (e.g. gabapentin, pregabalin, duloxetine, venlafaxine) is added if there is only a partial response, or substituted if there is no response, and the patient re-assessed after a month. If there is poor or no response to the systemic agent the patient should be switched to an alternative one and, if this also proves ineffective, referred to a pain specialist.

High interindividual variability in postoperative opioid consumption is related to genetic and environmental factors. We tested the association between morphine consumption, postoperative pain, and single nucleotide polymorphisms (SNPs) within opioid receptor μ 1 ( OPRM1 ), catechol-O-methyltransferase ( COMT ), uridine diphosphate glucose-glucuronosyltransferase-2B7, and estrogen receptor ( ESR1 ) gene loci to elucidate genetic prediction of opioid consumption. We analyzed 20 SNPs in 201 unrelated Caucasian patients who underwent abdominal surgery and who were receiving postoperative patient-controlled analgesia-administered morphine. Morphine consumption and pain intensity were dependent variables; age and sex were covariates. A haplotype of 7 SNPs in OPRM1 showed significant additive effects on opioid consumption ( P = .007); a linear regression model including age and 9 SNPs in ESR1 , OPRM1 , and COMT explained the highest proportion of variance of morphine consumption (10.7%; P = .001). The minimal model including 3 SNPs in ESR1 , OPRM1 , and COMT explained 5% of variance ( P = .007). We found a significant interaction between rs4680 in COMT and rs4986936 in ESR1 ( P = .007) on opioid consumption. SNPs rs677830 and rs540825 of OPRM1 and rs9340799 of ESR1 were nominally associated with pain Numeric Rating Scale scores. Combinations of genetic variants within OPRM1 , COMT , and ESR1 better explain variability in morphine consumption than single genetic variants. Our results contribute to the development of genetic markers and statistical models for future diagnostic tools for opioid consumption/efficacy. Perspective This article presents the efforts dedicated to detect correlations between the genetic polymorphisms and the clinical morphine effect self-administered by patients using a patient-controlled analgesia pump after major surgery. The clinical effect is expressed in terms of morphine consumption and pain scores. Registered on ClinicalTrials.gov NCT01233752.

Poor acute pain control and inflammation are important risk factors for Persistent Postsurgical Pain (PPSP). The aim of the study is to investigate, in the context of a prospective cohort of patients undergoing hernia repair, potential risk factors for PPSP. Data about BMI, anxious-depressive disorders, neutrophil-tolymphocyte ratio (NLR), proinflammatory medical comorbidities were collected. An analysis for correlation between comorbidities and PPSP was performed in those patients experiencing chronic pain at 3 months after surgery. Tramadol resulted less effective in pain at movement in patients with a proinflammatory status. Preoperative hypertension and NLR > 4 were correlated with PPSP intensity. Regional anesthesia was significantly protective on PPSP when associated with ketorolac. Patients with pain at 1 month were significantly more prone to develop PPSP at 3 months. NSAIDs or weak opioids are equally effective on acute pain and on PPSP development after IHR, but Ketorolac has better profile in patients with inflammatory background or undergoing regional anesthesia. Drug choice should be based on their potential side effects, patient’s profile (comorbidities, preoperative inflammation, and hypertension), and type of anesthesia. Close monitoring is necessary to early detect pain conditions more prone to progress to a chronic syndrome.

The use of ultrasound (US), despite some limitations, has been demonstrated as a valuable imaging technique for loco-regional anesthesia (LRA). It can be used also for chronic pain treatment, both as a therapeutic and diagnostic tool, particularly to perform diagnostic selective blocks. In our paper we discuss US-guided LRA techniques to be used for chronic pain treatment, both nociceptive and neuropathic, as an assistance to nerve lesion techniques.

Opioids are widely used in treatment of acute and chronic pain patients, and today a lot of efforts are put into individualize these therapies. Physicians would like to reduce deaths, minimize side effects and prevent toxicity, but – nevertheless PCA could represent a solution – up to date it is not yet completely reliable. A sustaining pharmacokinetic approach gives significant contribution, in particular in treatment of special populations (e.g. infants, elderly, and patients with renal/liver failure), which have a unique opioids pharmacokinetic profile to be taken into account, in order to maximize analgesic efficacy and reduce the risk of adverse events.

Pain, be it acute, chronic, or any permutation thereof, is a universal problem affecting greater than 1.5 billion people worldwide, with over 116 million in the US, and over 164 million people in Europe and Israel combined. The economic cost to society is staggering, estimated around $560–635 billion annually in the US alone for direct medical treatment costs and lost productivity. Additional complications may include over-prescribing of opiates and other potentially habit-forming substances with life-threatening side effects, as well as drug diversion and the social problems associated with substance abuse and addiction, such as illegal “pill mills,” which contributed to the approximate 600% increase in opioid prescribing in the United States from 1997 to 2007, and a 300% increase in the number of deaths related to prescription opioids. However, the greatest cost of pain rests on the individual who, in addition to his or her pain, is fraught with anxiety, depression, sleep disturbances, and deteriorating interpersonal relationships, resulting in a severely diminished quality of life. While efforts are continuing to unlock the environmental and intrinsic causes and contributors to pain, there are still a great number of unmet needs throughout the realm of pain management, including imaging, drug monitoring, objective pain assessment tools, and of course, therapeutic interventions. As the technological revolution of 21st century medicine continues its ascent, nanomedicine offers unprecedented opportunities in the development of novel pain assessment, diagnostic, and therapeutic delivery mechanisms that will address many of the global unmet needs in pain management, and change the frowning face of pain to a smile of relief. Successful integration of nanomedicine into the clinical milieu requires multi- and interdisciplinary collaboration from every facet, including healthcare professionals, engineers, scientists and researchers, government and regulatory agencies as well as academia.

Intravesical instillations of hyaluronic acid (HA) and chondroitin sulfate (CS) may lead to regeneration of the damaged glycosaminoglycan layer in interstitial cystitis/bladder pain syndrome (IC/BPS).Twenty-two patients with IC/BPS received intravesical instillations (40 ml) of sodium HA 1.6% and CS 2.0% in 0.9% saline solution (IALURIL, IBSA) once weekly for 8 weeks, then once every 2 weeks for the next 6 months.The score for urgency was reduced from 6.5 to 3.6 (p = 0.0001), with a reduction in pain scores from an average of 5.6 to 3.2 (p = 0.0001). The average urine volume increased from 129.7 to 162 ml (p0.0001), with a reduction in the number of voids in 24 h, from 14 to 11.6 (p0.0001). The IC Symptom and Problem Index decreased from 25.7 to 20.3 (p0.0001), and the Pain Urgency Frequency score, from 18.7 to 12.8 (p0.0001).The treatment appeared to be effective and well tolerated in IC/BPS in this initial experience.