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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.

PubMed: 32118384 [No abstract available]

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.

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

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.

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.

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

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.

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.

Breakthrough cancer pain (BTcP) is a frequent event in cancer patients, with a prevalence from 19% to 95%. The reasons for such variability are explained by several factors, including different definitions across studies. In the framework of a wider initiative, we have analyzed the epidemiology of BTcP and identified factors associated with the pattern of care.This study reports the results from a multicenter, prospective, nonrandomized, longitudinal study carried out in Italy between 2006 and 2007 on patients with cancer and pain. Transient exacerbations of pain were assessed with 3 different questions, and 1 composite variable to operationally define BTcP was then used as main outcome. After univariate analysis, a logistic model was also fitted to identify prognostic and predictive factors.One hundred and ten centers recruited 1801 cases of which 40.3% had BTcP at baseline. Most patients did not receive rescue therapy at the time of study inclusion. Univariate analysis identified several associations with clinical variables. A strong association has been also found with the type of recruiting centers, with oncologic wards reporting a somewhat lower proportion of patients with BTcP (-30%) when compared with palliative centers. Patients with BTcP had a high probability of dying (OR=1.4, 95% CI: 1.1-1.7, P-value 0.006) and to change of the opioid with another for analgesic failure or for side effects (OR=1.4, 95% CI: 1.0-1.9, P-value 0.040)These findings confirm the high prevalence of BTcP and substantial undertreatment and identify a few factors associated with prevalence and prognosis.

Laparoscopic procedures have been associated to moderate or severe pain that may require opioids and almost all patients referred shoulder pain. Intraperitoneal instillation of local anaesthetics, as part of a multimodal approach analgesia program, reduces pain intensity and morphine consumption after laparoscopic cholecystectomy. However, direct local anesthetic instillation is not enough to eliminate visceral and shoulder pain. Heated and humidified gas may produce positive effects such as reduction of postoperative pain. Intraperitoneal nebulization, a new technique of drug administration, provides homogeneous spread of drugs allowing a better distribution of local anaesthetics throughout the peritoneum. This technique combines the effects of gas conditioning and the analgesic benefits of local anaesthetic instillation. Nebulization of local anaesthetics during different laparoscopic procedures reduced postoperative pain, morphine consumption and allowed earlier mobilization. Future studies should determine, the optimal dose of local anaesthetics, the effect of local anaesthetic nebulization in different clinical settings and its importance on long term clinical outcomes.

A correct long-term opioid therapy implies the selection of the appropriate opioid and dose for each patient, but it is well demonstrated that the “clinical” approach alone is not sufficient. To this purpose, the literature is stressing that physicians have to focalize even more their attention both on the pharmacokinetic and pharmacodynamic properties of the opioids and on the differences among patients, including the genetic background. Accurate and fast analytical methods (e.g. Tandem Mass Spectrometry) for detecting plasma opioid concentrations represent a useful tool for clinicians to prevent adverse reactions in selected patients. The detection of polymorphisms of several genes involved in opioid absorption, distribution, metabolism, and elimination are promising to customize pain therapy. The success of the chronic opioid therapy also depends on the other drugs co-administered, possibly giving origin to drug-drug interactions; the clinical outcome should be constantly monitored.

Chronic perineal pain syndrome caused by pudendal nerve, is caused by the nerve entrapment between the sacrospinous and sacrotuberous ligaments (interligamentous plane) at the ischial spine and in the Alcock’s canal. Pain therapists approach the problem with peripheral nerve blocks. Needle placement is done by a fluoroscopic, computed tomography (CT) or ultrasound (US) guide. The first is unable to visualize the interligamentous plane and it exposes the patient to potentially harmful ionizing radiations. CT scan allows the visualization of the interligamentous space and of Alcock’s canal, but it is lacking real-time visual control. US alone ensures real-time needle advancement and confirmation of injective spread within the interligamentous plane but it’s usually combined with intraoperative fluoroscopy because at the depth of the ischial spine (usually more than 7 cm) the resolution should be suboptimal. We tried to improve pudendal anesthetic block using fusion real time imaging between US and CT. The system combines, in real time, US imaging with previous magnetic resonance (MR) or CT data. Imaging fusion is possible through the identification of anatomical landmarks of the same patient obtained by the different imaging modalities. Fusion imaging could help to avoid multiple exposures to ionizing radiations, improving costs and quality. We decided to verify the potential of this technique, normally employed to guide interventional imaging, to peripheral anesthetic block, testing its feasibility.

Pain is the symptom that leads most patients to ask for medical intervention; if not controlled, pain may become a very costly item in the Italian Health Care system. Proper referral to a second level specialist pain center can extensively decrease the duration of a painful condition, prevent the onset of more pain and of the so-called pain syndromes, and also reduce the improper use of analgesic drugs or pain surgery. Patients should be referred to a specialist pain center when their pain is uncontrolled. In this observational study we analyzed the clinical and demographic data of a population referred for the first time to a specialist pain center (Fondazione Salvatore Maugeri, Pavia) in the year 2008 to define patient characteristics and to understand who makes referrals and after which kind of pharmacological and interventional treatment. Our results indicate that in Italy patients are referred to a pain center very late, which increases the duration of pain syndromes and the cost of pain management.

Local anesthetics and opioids are the most commonly used drugs in regional anesthesia. Several other drugs are used as adjuvants in addition to local anesthetics. We will review the drugs currently used in regional anesthesia. In April 2009 we searched the PubMed database and found 143 articles related to the clinical use of drugs in regional anesthesia; we divided them into 3 major chapters: local anesthetics, opioids and adjuvants. Among local anesthetics, ropivacaine and levobupivacaine can be considered the drugs of choice in neuraxial and peripheral techniques because their toxicity is low even in large volume administration; mepivacaine can be considered the drug of choice in peripheral techniques when a shorter blockade is needed. Sufentanil is the opioid of choice in both neuraxial and peripheral techniques because it appears to improve the quality of anesthesia and to prolong sensory blockade in the postoperative period. Among the adjuvants to local anesthetics, clonidine is by far the most used drug in regional anesthesia; its yield in improving and prolonging the effects of local anesthetics is apparent in neuraxial techniques. Other drugs have been studied as adjuvants to local anesthetics but clinical evidence of their benefit is controversial in many cases and further trials are unquestionably warranted. In conclusion, since many different drugs are available for regional anesthesia, we must choose wisely the one that exhibits the best safety-efficacy profile and that suits the chosen technique and type of anesthesia/analgesia best.

Chronic pain is a situation that bring patients to ask for a medical intervention and can be originated from many different pathologic conditions. Nowadays, recent advancements in pain treatment have made possible to control pain in many patients, allowing them to return to daily activities. Anaesthesiologists are the modern pain specialists, and must know and define the origin of pain in every case: the comprehension of pain mechanisms gives them the possibility for a planned strategy of treatment. In this work we perform a overview about the “state of the art” of pain treatment in Italy analyzing what are the problems that require to focalize our attention. Therefore, sometimes many visits are necessary for a correct diagnosis and successful therapy. Pain management is still a young speciality, and the Italian pain specialist is often a self made expert who needs proper structures and dedicated people: the result is a different treatment not only between the hospitals but also in the same pain conditions. Although it seems that many of the new techniques used to control pain are successful, few studies and controlled trials have been done to verify long-term efficacy and potential adverse effects.

The availability of new local anaesthetics and the improvement of regional techniques has caused a great increase of central and peripheral blockades for anaesthesia as well as for postoperative pain. The increase of these blockades tends to increase the rate of complications. In a Pubmed research we found more than 400 articles about this topic. In the analysis of the literature we divided two major chapters: severe complications after central blockades and after peripheral nerve blocks. Analysis of the literature showed a lower incidence of serious complications associated with neuroaxial anaesthesia. It is important to underline that authors stressed the importance of predisposing factors like pre-existing peripheral or central neurological disease, arteriosclerotic disease, osteoporosis and spinal stenosis, diabetes, cancer, chronic alcohol abuse and steroid therapy. Otherwise, the most concern about peripheral nerve blocks is nerve injury and/or neuropathy due to potential toxicity of local anaesthetics or due a nerve lesion for needle trauma or infection. Even if the incidence of severe side effects is rare, it is very important that we approach this technique knowing well the risks (even if low) so that we can prevent them improving the outcome of patients. Nevertheless, there is again the need to have a large prospective study to investigate the real incidence of severe complications of central and peripheral blocks.

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

In the last two decades, animal models have become important tools in understanding and treating pain, and in predicting analgesic efficacy. Although rodent models retain a dominant role in the study of pain mechanisms, large animal models may predict human biology and pharmacology in certain pain conditions more accurately. Taking into consideration the anatomical and physiological characteristics common to man and pigs (median body size, digestive apparatus, number, size, distribution and communication of vessels in dermal skin, epidermal–dermal junctions, the immunoreactivity of peptide nerve fibers, distribution of nociceptive and non-nociceptive fiber classes, and changes in axonal excitability), swines seem to provide the most suitable animal model for pain assessment. Locomotor function, clinical signs, and measurements (respiratory rate, heart rate, blood pressure, temperature, electromyography), behavior (bright/quiet, alert, responsive, depressed, unresponsive), plasma concentration of substance P and cortisol, vocalization, lameness, and axon reflex vasodilatation by laser Doppler imaging have been used to assess pain, but none of these evaluations have proved entirely satisfactory. It is necessary to identify new methods for evaluating pain in large animals (particularly pigs), because of their similarities to humans. This could lead to improved assessment of pain and improved analgesic treatment for both humans and laboratory animals.

Spinal cord stimulation (SCS) is believed to be effective in treating refractory angina. The need for SCS-related chest paresthesia, however, has hitherto made impossible placebo-controlled trials. Subliminal (non paresthesic) SCS, however, might be also effective on anginal pain. In this trial we compared subliminal SCS with paresthesic SCS and with sham SCS. Twenty-five refractory angina patients, who had never received SCS before, underwent SCS device implantation and were randomized to three groups: paresthesic SCS (group PS; n=10), subliminal SCS (group SS; n=7) or "sham" SCS (group NS; n=8). After 1month group NS patients were randomized to either group PS or SS. After 1month, changes in angina episodes (p=0.016), nitroglycerin use (p=0.015), angina class (p=0.02), quality of life score (p=0.05), and items 2 (p=0.008) and 3 (p=0.009) of Seattle angina questionnaire differed significantly among groups. Group PS showed significant improvement in outcomes compared to group NS, whereas there were no significant differences between groups SS and NS; furthermore, only nitroglycerin use differed significantly between groups PS and SS. At 3months, a significant difference between groups PS and SS was observed in angina attacks (p=0.002), but not in other variables. Thus, in this study, paresthesic, but not subliminal SCS was superior to sham SCS in improving clinical status in refractory angina patients. The lack of significant differences between PS and SS groups in this small study suggests that a possible role for subliminal SCS in individual patients deserves to be assessed in larger trials with appropriate statistical power.

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

When peripheral neuropathic pain affects a specific, clearly demarcated area of the body, it may be described as localized neuropathic pain (LNP). Examples include postherpetic neuralgia and painful diabetic neuropathy, as well as post-surgical and post-traumatic pain. These conditions may respond to topical treatment, i.e., pharmaceutical agents acting locally on the peripheral nervous system, and the topical route offers advantages over systemic administration. Notably, only a small fraction of the dose reaches the systemic circulation, thereby reducing the risk of systemic adverse effects, drug-drug interactions and overdose. From the patient's perspective, the analgesic agent is easily applied to the most painful area(s). The 5% lidocaine-medicated plaster has been used for several years to treat LNP and is registered in approximately 50 countries. Many clinical guidelines recommend this treatment modality as a first-line option for treating LNP, particularly in frail and/or elderly patients and those receiving multiple medications, because the benefit-to-risk ratios are far better than those of systemic analgesics. However, some guidelines make only a weak recommendation for its use. This paper considers the positioning of the 5% lidocaine-medicated plaster in international treatment guidelines and how they may be influenced by the specific criteria used in developing them, such as the methodology employed by randomized, placebo-controlled trials. It then examines the body of evidence supporting use of the plaster in some prevalent LNP conditions. Common themes that emerge from clinical studies are: (1) the excellent tolerability and safety of the plaster, which can increase patients' adherence to treatment, (2) continued efficacy over long-term treatment, and (3) significant reduction in the size of the painful area. On this basis, it is felt that the 5% lidocaine-medicated plaster should be more strongly recommended for treating LNP, either as one component of a multimodal approach or as monotherapy.