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Joint pain is a major cause of lameness in animals such as horses and dogs, and it may affect their athletic performance and quality of life. The intra-articular administration of analgesic/antinflammatory drugs is a common practice in veterinary medicine, for both lameness diagnosis and joint pain management. It is used either perioperatively, such as in animals undergoing arthroscopy/arthrotomy, and in osteoarthritic animals. However, evidence regarding efficacy and safety of each drug is limited, and controversies persist in these areas. In particular, it is often uncertain whether a defined treatment is effective by simply relieving the symptomatic pain associated with the joint disease, or whether it has a positive effect on the joint environment. Moreover, there is still much hesitation about treatments for joint diseases, related to the time of their application for the best outcome, and to any possible deleterious side effects. This article includes a review of the literature concerning the main analgesic/antinflammatory drugs used intra-articularly for managing acute and chronic joint pain/inflammation in dogs and horses. Three main issues for each class of drugs are considered, including clinical efficacy, pharmacokinetics, and local cytotoxic effects.

Objectives: To capture evidence of the efficacy and safety of pharmacological analgesia for uncomplicated acute sickle-cell pain in pediatric patients compared to placebo. Sources of data: Searches for key evidence were performed from March 1 to 31, 2018, for randomized controlled trials of pharmacological analgesia compared to placebo for uncomplicated acute sickle-cell pain in a pediatric sample. The authors searched ten scientific databases including, among others, PubMed, MEDLINE, Embase, and Clinicaltrials.gov for this systematic review and meta-analysis. Summary of the findings: Four trials (n = 227) were selected by the inclusion criteria (intranasal fentanyl, intravenous magnesium, arginine, and inhaled nitric oxide). The quality of evidence ranged from low to moderate for each outcome. Meta-analysis of changes in the ladder of pain score (p = 0.72), length-of-stay in hospital (p = 0.65), and amount of narcotics used during the study (p = 0.10) showed non-statistically significant differences and a lack of amelioration provided by pharmaceutical analgesics in treatment group. The adverse events reported that more participants in the intervention arm underwent pain, with statistically significant differences at the drug delivery site in studies using intranasal fentanyl and intravenous magnesium (p = 0.03). Conclusions: Pharmacological analgesia appears to be uncertain in improving the intensity and providing relief of acute pain crisis in pediatric patients with sickle-cell anemia. With respect to clinical advantage, no decisive deduction about the clinical efficacy may be made regarding these medications in acute sickle-cell pain management in the pediatric age group. Resumo: Objetivos: Obter evidências da eficácia e segurança da analgesia farmacológica para dor falciforme aguda não complicada em pacientes pediátricos em comparação com placebo. Fontes de dados: Uma busca de evidências-chave foi feita de 1º a 31 de março de 2018 por ensaios clínicos randomizados controlados de analgesia farmacológica em comparação com placebo para dor aguda falciforme não complicada em uma amostra de pacientes pediátricos. Os autores pesquisaram dez bases de dados científicos que envolveram, entre outras, PubMed, Medline, Embase e Clinicaltrials.gov para esta revisão sistemática e metanálise. Resumo dos dados: Quatro ensaios (n = 227) foram considerados para critérios de inclusão (fentanil intranasal, magnésio intravenoso, arginina e óxido nítrico inalado). As evidências de qualidade variaram de baixas a moderadas para cada desfecho. A metanálise de alterações na escala de dor (p = 0,72), o tempo de internação hospitalar (p = 0,65) e a quantidade de analgésicos usados durante o estudo (p = 0,10) mostraram diferença não estatisticamente significativa e a ausência de melhoria resultante do uso do fármaco analgésico no grupo de tratamento. Os eventos adversos relatados mostraram que no braço de intervenção mais participantes sofreram dor com diferença estatisticamente significativa no local de aplicação do fármaco com o uso de fentanil intranasal e magnésio intravenoso (p = 0,03). Conclusões: A analgesia farmacológica parece ter um efeito incerto na melhoria da intensidade e alívio da crise de dor aguda em pacientes pediátricos com doença falciforme. Em relação à vantagem clínica, ainda é incerta a eficácia clínica desses medicamentos no tratamento da dor aguda falciforme no grupo etário pediátrico. Keywords: Anemia, sickle cell, Sickle cell disease, Acute pain, Analgesic drugs, Pediatrics, Palavras-chave: Anemia falciforme, Doença falciforme, Dor aguda, Drogas analgésicas, Pediatria

We aimed to characterize the in-hospital analgesic use among total hip or knee arthroplasty (THA or TKA) patients, and to identify possible drug-related challenges. We identified 15 263 patients operated with a THA or TKA between 1 January 2012 and 30 April 2016. The prevalence of analgesic users and patients with potential clinically relevant drug-drug interactions (DDIs), along with the prevalence of readmission among patients with vs. without a DDI, were calculated. A DDI was defined as the combination of (A) a diuretic, an angiotensin-converting enzyme inhibitor or an angiotensin II receptor blocker, and an non-steroidal anti-inflammatory Drug (NSAID); (B) warfarin and an NSAID; and (C) a benzodiazepine or a benzodiazepine-related drug and an opioid. The prevalence of analgesics administered in THA and TKA patients was 99.3% and 99.1% for paracetamol and 93.8% and 98.8% for opioids, respectively. The prevalence of patients who received interaction A, B or C was 8.4%, 2.5% and 40.7%, respectively. Patients with vs. without a DDI had a higher prevalence of 30-day readmission. In conclusion, most THA and TKA patients were administered paracetamol or opioids. The prevalence of 30-day readmission was higher in patients with than in patients without a potential clinically relevant DDI.

Introduction: Drug-drug interactions may lead to poor health outcomes, as well as increased costs and utilization of healthcare services. Unfortunately, real-world data continuously prove high prevalence of potential drug-drug interactions (pDDIs) worldwide. Among identified drivers, ageing, multimorbidity and polypharmacy play a very important role. With these factors being widespread, the need for implementation of strategies minimizing the burden of pDDIs becomes an urgency. This, however, requires a better understanding of the prevalence of pDDIs and the underlying causative factors.Aim of study: To assess the real-world prevalence of pDDIs and its characteristics in the general population of Poland, using analgesic drugs as a model, and to find out whether pDDIs are caused by prescribing coming from the very same prescribers (co-prescribing).Methods: A retrospective analysis of the 2018 dispensation data of the National Health Fund (NHF) - the only Polish public healthcare payer organization with nationwide coverage. We searched for selected pDDIs of non-steroidal anti-inflammatory drugs (NSAIDs) with antihypertensives, other NSAIDs (double use), oral glucocorticoids, oral anticoagulants, selective serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors (SNRIs), and antiplatelet drugs; as well as opioides with SSRIs, SNRIs, gabapentinoids, and benzodiazepines. A pDDI was deemed present if two drugs standing in a possible conflict were dispensed within the same calendar month.Results: Out of 38.4 million citizens of Poland, 23.3 million were dispensed prescribed drugs reimbursed by NHF in 2018. In this cohort, we have identified 2,485,787 cases of analgesic drug pDDIs, corresponding with 6.47% of the Polish population. Out of these, the most prevalent pDDI was caused by “NSAIDs + antihypertensives” (1,583,575 cases, i.e., 4.12% of the Polish population), followed by “NSAIDs + NSAIDs” (538,640, 1.40%) and “NSAIDs + glucocorticoids” (213,504, 0.56%). The most persistent pDDIs among those studied were caused by “Opioids + Gabapentinoids” (2.19, 95%CI: 2.16–2.22 months). On average, 76.63% of all cases of pDDIs were caused by drugs prescribed by the very same prescribers.Conclusion: Based on high-quality, nationwide data, we have found a high prevalence of analgesic drugs-related pDDIs in Poland. Over ¾ of the identified pDDIs were caused by co-prescribing, i.e., prescriptions issued by the same prescribers. The significance of the problem, illustrated with our findings on analgesic drugs-related pDDIs in Poland, deserves much more scientific and policymaker attention.

Background Pain assessment and management are important in postoperative circumstances as overdosing of opioids can induce respiratory depression and critical consequences. We aimed this study to check the reliability of commonly used pain scales in a postoperative setting among Korean adults. We also intended to determine cut-off points of pain scores between mild and moderate pain and between moderate and severe pain by which can help to decide to use pain medication. Methods A total of 180 adult patients undergoing elective non-cardiac surgery were included. Postoperative pain intensity was rated with a visual analog scale (VAS), numeric rating scale (NRS), faces pain scale revised (FPS-R), and verbal rating scale (VRS). The VRS rated pain according to four grades: none, mild, moderate, and severe. Pain assessments were performed twice: when the patients were alert enough to communicate after arrival at the postoperative care unit (PACU) and 30 min after arrival at the PACU. The levels of agreement among the scores were evaluated using intraclass correlation coefficients (ICCs). The cut-off points were determined by receiver operating characteristic curves. Results The ICCs among the VAS, NRS, and FPS-R were consistently high (0.839–0.945). The pain categories were as follow: mild ≦ 5.3 / moderate 5.4 ~ 7.1 /severe ≧ 7.2 in VAS, mild ≦ 5 / moderate 6 ~ 7 / severe ≧ 8 in NRS, mild ≦ 4 / moderate 6 / severe 8 and 10 in FPS-R. The cut-off points for analgesics request were VAS ≧ 5.5, NRS ≧ 6, FPS-R ≧ 6, and VRS ≧ 2 (moderate or severe pain). Conclusions During the immediate postoperative period, VAS, NRS, and FPS-R were well correlated. The boundary between mild and moderate pain was around five on 10-point scales, and it corresponded to the cut-off point of analgesic request. Healthcare providers should consider VRS and other patient-specific signs to avoid undertreatment of pain or overdosing of pain medication.

BACKGROUND Rapid maxillary expansion (RME) is an orthopaedic procedure indicated for a wide variety of clinical conditions. AIM The aim of the study was to compare the effects of ketoprofen lysine salt (KLS) vs paracetamol/acetaminophen (P) on pain perception during RME. DESIGN One hundred and fifty-one subjects (mean age 8.6 year) were enrolled in this prospective controlled clinical trial according to inclusion criteria: prepuberal stage of development, negative posterior transverse interarch discrepancy, non-concurrent use of other drugs. First phase: n.40 allocated to Group 1 used 40 mg of KLS, n.40 to Group 2 used 250 mg of P, n.36 to Group 3 as control group. Second phase: n.35 allocated to Group 4 used 40 mg ketoprofen lysine salt once a day for the first 3 days of activation. Pain experience was reported on a numeric rating scale (0-4) and a 100-mm visual analogue scale. Pain perception was tested with the Mann-Whitney test (P

Since both anesthesia and sleep depress consciousness, bidirectional relationship between them has been further studied. Earlier findings have shown that they share electroencephalographic features and brain regions that are activated in both state of unconsciousness. Despite these similarities, medication-induced sedation provokes different outcome from natural sleep. Enlisting commonly used analgesic drugs, such as benzodiazepines, intravenous agents, benzodiazepine antagonists, opioids, and other adjuvants, the study is comprised of assorted case studies that are clinically applicable or comparable. Acknowledging potential of analgesic drugs on sleep disorders including sleep deprivation, narcolepsy, circadian rhythm disorder, periodic limb movement disorder, and obstructive sleep apnea, the study underscores the clinical importance of studying both fields, sleep and anesthesia. In conclusion, the aim of this review is explaining the consequences of analgesic agents or sedatives on sleep and sleep disorders.

Purpose: Many elderly people living in nursing homes experience pain and take analgesic medication. The aim of this study was to analyze the prevalence of pain and pharmacological pain treatment among people living in nursing homes in Sweden, in two large, comparable, samples from 2007 to 2013. Methods: Cross-sectional surveys were performed in 2007 and 2013, including all residents in nursing homes in the county of Västerbotten, Sweden. A total of 4933 residents (2814 and 2119 respectively) with a mean age of 84.6 and 85.0 years participated. Of these, 71.1 and 72.4% respectively were cognitively impaired. The survey was completed by the staff members who knew the residents best. Results: The prescription of opioids became significantly more common while the use of tramadol decreased significantly. The staff reported that 63.4% in 2007 and 62.3% in 2013 had experienced pain. Of those in pain, 20.2% in 2007 and 16.8% in 2013 received no treatment and 73.4 and 75.0% respectively of those with pain, but no pharmacological treatment, were incorrectly described by the staff as being treated for pain. Conclusions: There has been a change in the pharmacological analgesic treatment between 2007 and 2013 with less prescribing of tramadol and a greater proportion taking opioids. Nevertheless, undertreatment of pain still occurs and in many cases, staff members believed that the residents were prescribed analgesic treatment when this was not the case.

Introduction In the Neonatal Intensive Care Unit (NICU), prematurely born infants undergo a range of skin breaking and painful procedures. At the same time, the spinal nociceptive system is in a sensitive developmental stage. Both neonatal repetitive painful procedures and their treatment can induce plasticity of the neonatal spinal nociceptive system, causing long-lasting alterations to pain processing and pain reactivity. Methods This review focuses on developmental processes related to the nociceptive network in the spinal dorsal horn and more specifically at mechanisms related to 1. Modulation of afferent systems; 2. The role of interneurons; 3. Descending inhibitory pathways; and 4. The central neuro-immune responses and microglial cell responses. The effects and possible mechanisms underlying the long-term effects of repetitive painful procedures on the developing nociceptive system as well as subsequent pharmacological treatment (acetaminophen, morphine) in early life are discussed. Results Repetitive stimulation of the nociceptive system in a rat model with use of needle pricks in the hind-paw closely mimics the clinical situation for infants in the NICU. Conclusion Activity dependent plasticity in early postnatal life induces long-lasting alterations that then may cause altered pain perception in adulthood. For a future choice of optimal analgesic drugs these considerations have to be taken into account beyond the classical classes of drugs used nowadays.

Neuropathic pain (NeuP) arises due to injury of the somatosensory nervous system and is both common and disabling, rendering an urgent need for non-addictive, effective new therapies. Given the high evolutionary conservation of pain, investigative approaches from Drosophila mutagenesis to human Mendelian genetics have aided our understanding of the maladaptive plasticity underlying NeuP. Successes include the identification of ion channel variants causing hyper-excitability and the importance of neuro-immune signaling. Recent developments encompass improved sensory phenotyping in animal models and patients, brain imaging, and electrophysiology-based pain biomarkers, the collection of large well-phenotyped population cohorts, neurons derived from patient stem cells, and high-precision CRISPR generated genetic editing. We will discuss how to harness these resources to understand the pathophysiological drivers of NeuP, define its relationship with comorbidities such as anxiety, depression, and sleep disorders, and explore how to apply these findings to the prediction, diagnosis, and treatment of NeuP in the clinic., Calvo et al. discuss how applying genetic techniques, from model organisms to human populations, can help us understand the pathophysiology of neuropathic pain. These strategies could soon reveal novel analgesic drug targets and aid both personalized risk prediction and treatment.

The authors surveyed the clinical data and reviewed the literature on the pain management in elderly patients. The conclusion was made that chronic pain in older age is neglected and analgesia is often insufficient. Data for pharmacokinetic and pharmacodynamic characteristics of widely used analgesic drugs are summarized. The authors provide practical guidelines for pain management of elderly people in outpatients departments. Aging is an inevitable component of life. However, there is no overall accepted definition about an elderly individual. One could be determined as old by physical characteristics, e.g. white or gray hair, changes in social activities, having grandchildren, by changes in occupational status (e.g. being retired) by biological characteristics - e.g. age, etc. An adequate definition should probably contain maximum characteristics of such kind. In this context, it could be assumed that the physiological age can have a more significant impact than the biological one. In the last decades, the age range of all societies has changed to a sustained increase towards older population. According to reliable demographic and sociological calculations, the segment of individuals over the age of 65 in industrial societies will increase from 17.5% in 2000 to 36.3% in 2050 [1]. Retrospective studies performed in the period between years 1983-2003, established that the US population over the age of 65 has increased from 11.7% to 12.4%, and the proportion of individuals over 80 increased from 2.4% to 3.5%. The prognosis is that in 2045 the proportion of these age groups will be 20%, and 7.2% respectively [2]. Within the global population, the proportion of the individuals over 65 increased from 6.9% in 2000 to 7.7% in 2009, and in 2050 will reach 16.7%. The proportion of population aged over 80 is dramatically increasing from 1.2% in 2000 to 1.5% in 2009, and in 2050 will increase more, up to 4.9%. These changes are mainly due to the increased life expectancy, which in 2020 for women will be 80.4 years and for men - 79.5 years [3]. There is a dissonance though between these facts and the data that the raised life expectancy does not actually correlate with wholesome living throughout these years [4]. There is an increased complex co-morbidity in the aging population, among which pain of different variety is a frequent symptom. Epidemiological studies indicate that 40-75% of adult individuals complain of chronic pain of various etiology and pathogenesis, with the largest group composed of elderly women [5]. The prolonged pain is most often a consequence of chronic musculoskeletal disorders, osteoporosis with fractures or fissures, metabolic and neuro-degenerative diseases with neuropathic symptoms, etc. The pharmacotherapy of pain syndromes in adults should be consistent with number of factors complicating the application of conventional analgesic approaches. Adult individuals have reduced nociceptive capabilities, i.e. feel less pain, but tolerate strong and continuous pain syndromes more difficult. They suffer with more than one disease, take many medications of different groups, and rarely report alarming symptoms. Their treatment is complicated by the diminished cognitive capacity in many of them or by the neuropathic pain caused by bone or vertebra fractures, diabetes or other chronic diseases. For the evaluation of pain intensity in elderly patients, different approaches should be used - preferably verbal scales with clear definitions, such as: no-pain, weak-, moderate-, middle-, or severe pain on visual, numerical, picture, mimic and other types of scales [1].

GUNDUZ, Ozgur/0000-0002-2470-3021; Ulugol, Ahmet/0000-0003-4643-1124; Gunaydin, Caner/0000-0002-8304-832X; Gunaydin, Caner/0000-0002-8304-832X WOS: 000385338800008 PubMed: 27685776 Intradermal injection of pruritogens such as serotonin, histamine and compound 48/80 into the skin and then, the evaluation of the scratching behavior is the commonly used animal model to advance pruritic research and drug development. However, predictive validity of this model is poorly documented. There is a close interaction between itch and pain sensations with regard to mediation through an anatomically and functionally identical neuronal pathway. One approach is whether the existing animal model of itch differentiates itch or pain to show efficacy of clinically effective analgesic drugs as a back translation. In this study, we explored the effects of different group of analgesic drugs on serotonin and compound 48/80-induced scratching behavior in Balb-C mice. Serotonin (25 mu g) and compound 48/80 (100 mu g) was injected intradermally in a volume of 50 mu l into the rostra! part of skin on the back of male mice and scratches were counted for a 30-min observation period. Morphine (1, 3, 10 mg/kg), tramadol (20, 40, 80 mg/kg), cannabinoid agonist CP 55,940 (0.1, 0.3, 1 mg/kg), paracetamol (100, 200, 300 mg/kg) and diclofenac (50, 100, 200 mg/kg) were given intraperitoneally 30 min prior to pruritogen injection. The analgesic drugs dose dependently blocked serotonin and compound 48/80-induced straching behavior with exerting complete inhibition at certain doses. Our data suggests that intradermal pruritogen-induced scratching models may not discriminate pain and itch sensations and give false positive results when standard analgesic drugs are used.

This retrospective study evaluates the link between an adverse drug reaction (ADR) or a non-response to treatment and cytochromes P450 (CYP), P-glycoprotein (P-gp) or catechol-O-methyltransferase (COMT) activity in patients taking analgesic drugs for chronic pain. Patients referred to a pain center for an ADR or a non-response to an analgesic drug between January 2005 and November 2014 were included. The genotype and/or phenotype was obtained for assessment of the CYPs, P-gp or COMT activities. The relation between the event and the result of the genotype and/or phenotype was evaluated using a semi-quantitative scale. Our analysis included 243 individual genotypic and/or phenotypic explorations. Genotypes/phenotypes were mainly assessed because of an ADR (n = 145, 59.7%), and the majority of clinical situations were observed with prodrug opioids (n = 148, 60.9%). The probability of a link between an ADR or a non-response and the genotypic/phenotypic status of the patient was evaluated as intermediate to high in 40% and 28.2% of all cases, respectively. The drugs in which the probability of an association was the strongest were the prodrug opioids, with an intermediate to high link in 45.6% of the cases for occurrence of ADRs and 36.0% of the cases for non-response. This study shows that the genotypic and phenotypic approach is useful to understand ADRs or therapeutic resistance to a usual therapeutic dosage, and can be part of the evaluation of chronic pain patients.

Neuropathic pain, a specific type of chronic pain resulting from persistent nervous tissue lesions, is a debilitating condition that affects about 7% of the population. This condition remains particularly difficult to treat because of the poor understanding of its underlying mechanisms. Drugs currently used to alleviate this chronic pain syndrome are of limited benefit due to their lack of efficacy and the elevated risk of side effects, especially after a prolonged period of treatment. Although drugs targeting G protein-coupled receptors (GPCR) also have several limitations, such as progressive loss of efficacy due to receptor desensitization or unavoidable side effects due to wide receptor distribution, the identification of several molecular partners that contribute to the fine-tuning of receptor activity has raised new opportunities for the development of alternative therapeutic approaches. Regulators of G protein signalling (RGS) act intracellularly by influencing the coupling process and activity of G proteins, and are amongst the best-characterized physiological modulators of GPCR. Changes in RGS expression have been documented in a range of models of neuropathic pain, or after prolonged treatment with diverse analgesics, and could participate in altered pain processing as well as impaired physiological or pharmacological control of nociceptive signals. The present review summarizes the experimental data that implicates RGS in the development of pain with focus on the pathological mechanisms of neuropathic pain, including the impact of neuropathic lesions on RGS expression and, reciprocally, the influence of modifying RGS on GPCRs involved in the modulation of nociception as well as on the outcome of pain. In this context, we address the question of the relevance of RGS as promising targets in the treatment of neuropathic pain.

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

The article clarifies that pain in obesity is not obesity and pain. The authors reviewed the literature and surveyed the clinical data about pain in people with abnormal body weight. The conclusion was made that pain in obese patients needs adequate management. Data for pharmacokinetic and pharmacodynamics characteristics of frequently used analgesic drugs are summarized. The authors include useful schemas of pharmacotherapy with non-opioid as well as opioid analgesics and practical guidelines for pain management in clinical ward or outpatient departments.

International audience; Pain in amyotrophic lateral sclerosis (ALS) is paradoxical in this disease of the upper and lower motor neurons. As such, it remains an underestimated and neglected clinical problem because it is poorly identified by physicians, its mechanisms are numerous and its treatments are generally not effective. Pain may be primary in the form of cramps, spasticity and neuropathy, or secondary as nociceptive pain, and may arise before the first motor symptoms. It may also lead to depression and, in all cases, affect patients' daily activities and quality of life. Given the high frequency of pain in ALS, the use of analgesic or sedative drugs is necessary and should reduce the course of the disease. Nevertheless, it is important to understand the pathophysiological mechanisms of pain in ALS, and to train physicians how to detect ALS pain early on and provide dedicated treatments. In France, the implementation of ALS centers is a positive response to the public-health problem resulting from this disorder.

Chronic pain is a debilitating condition with major socioeconomic impact, whose neurobiological basis is still not clear. An involvement of the neurovascular unit (NVU) has been recently proposed. In particular, the blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB), two NVU key players, may be affected during the development of chronic pain; in particular, transient permeabilization of the barrier is suggested by several inflammatory- and nerve-injury-based pain models, and we argue that the clarification of molecular BBB/BSCB permeabilization events will shed new light in understanding chronic pain mechanisms. Possible biases in experiments supporting this theory and its translational potentials are discussed. Moving beyond an exclusive focus on the role of the endothelium, we propose that our understanding of the mechanisms subserving chronic pain will benefit from the extension of research efforts to the NVU as a whole. In this view, the available evidence on the interaction between analgesic drugs and the NVU is here reviewed. Chronic pain comorbidities, such as neuroinflammatory and neurodegenerative diseases, are also discussed in view of NVU changes, together with innovative pharmacological solutions targeting NVU components in chronic pain treatment.

Problem setting. Conducted a comparison of the systems of pharmaceutical provision with pharmaceutical care – providing medical products inUkraine and abroad through the introduction of health insurance and reimbursement of medicines from the state budget. Recent research and publications analysis. Quantitative analysis of the incidence of malignant neoplasms and mortality, the number of pharmacies inUkraine and Kharkiv region; the level of public spending on the program to combat cancer. Noted that the market of voluntary medical insurance inUkraine is underdeveloped (covering only 3% of the population) for a complete provision of population with necessary medicines and medical services. The basic conditions for the successful treatment of cancer. Analyzed legislative framework regulating the circulation of medicines for cancer patients inUkraine. Paper objective. The review violation circulation of medicines, pharmacy made by specialists in providing cancer. Determined that prescription drugs helps minimize forensic pharmaceutical risks (side effects, abuse, etc.). Processed work of scientists ofUkraine and other countries to ensure the cancer drugs of different pharmacological clinical, legal nomenclature and classification of legal groups. Conclusions of the research. Proposed standard-setting initiatives to improve the legal system "doctor-patient-pharmacist" and narcotic drugs for pharmaceutical providing for patients with cancer at discounted prescription from pharmacies in Ukraine and Kharkov region: expanding the definition of "pharmacy"; promoting the opening of pharmacies in rural areas and increase the number of pharmacies that carry out activities related to narcotic drugs

Background: No study has so far addressed whether differences do exist in the management of cancer-related pain in patients admitted to oncology and non-oncology settings. Patients and methods: A multicentre cross-sectional study in 48 Italian hospitals has enrolled 819 patients receiving analgesic therapy for cancer-related pain. Demographics and clinical and analgesic therapy information have been prospectively collected by standardized forms. Adequacy of pain management has been evaluated by the Pain Management Index (PMI). Results: Differences in the analgesic drug administration according to settings of care have been evident, non-opioids more frequently being administered in non-oncology units (19.6% versus 7.0%; P < 0.0001), while strong opioids are more frequently used in the oncology units (69.5% versus 51.9%; P < 0.0001). The number of patients receiving inadequate therapy (PMI < 0) has lowered in oncology compared with non-oncology units (11.3% versus 18.8%; P = 0.0024). Results of multiple logistic regression analysis have shown that the admission to non-oncology setting [odds ratio (OR) = 1.75, 95% confidence interval (CI) = 1.15-2.67; P = 0.0096] and the absence of metastatic disease (OR = 1.60, 95% CI = 1.04-2.44; P = 0.0317) were independent factors associated with an increased risk of receiving an inadequate analgesic therapy. Conclusion: Oncology wards provide the most adequate standard of analgesic therapy for cancer-related pain.

In recent years there has been a wide use of the epidural technique not only during surgery to provide anesthesia and analgesia, but also for obstetric and trauma as well as acute, chronic and cancer pain states. Nowadays there is an increase in the number of the epidural drugs. Local anesthetics and opioids are still the pharmacological agents more widely used epidurally, nevertheless other drugs from different pharmacological classes are administered as adjuvant to local anesthetics and opioids or are in various early stages of investigation. Regarding to local anesthetics, the most recent literature focuses on the new enantiomers, ropivacaine and levobupivacaine, the efficacy of which is similar to that of bupivacaine with a reduced risk of cardiotoxicity. About opioids, the other class of drugs mainly used, the debate, in the last years, concerned the physicochemical properties of morphine and of the more recent lipophilic agents, fentanyl and sufentanil, in order to explain the main differences in efficacy and safety. Other categories of agents have been investigated for epidural administration, such as alpha(2)-adrenergic agonists clonidine and dexmedetomidine. They are being used increasingly as adjuvants to local anesthetics and opioids. Ketamine and neostigmine, the more recent studied drugs for epidural use, are still under investigation and are not part of routine clinical practice.

International audience; BACKGROUND: The use of analgesics can lead to cases of drug abuse and dependence. It can also cause pseudo-addiction in patients suffering from pain. What is the actual situation in patients suffering from severe sickle-cell disease, exposed to acute pain during vaso-occlusive crises? Evaluation of the use of analgesics, on the basis of Diagnostic and Statistical Manual of Mental Disorders criteria for substance abuse and dependence, makes it possible to differentiate the symptoms occurring only in a context of pain, in the aim of managing the pain, and thus describing pseudo-addiction, from symptoms also occurring when there is no pain, and more in favour of true addiction. Currently there is no data available in France on this problem, and no studies have been carried out in children or adolescents with sickle-cell disease. The purpose of the study is to evaluate the prevalence of problematic use of equimolar mixture of oxygen and nitrous oxide and other analgesic drugs in a population of subjects with severe sickle-cell disease in France. METHODS/DESIGN: PHEDRE (Pharmacodépendance Et DREpanocytose-drug dependence and sickle-cell disease) is an observational, descriptive and transversal study. Patients under the age of 26 with sickle-cell disease are included in the study by the doctors looking after them in sickle-cell disease centres. The patients are then contacted by a trained researcher for a telephone interview, including an evaluation of the Diagnostic and Statistical Manual of Mental Disorders criteria for abuse and dependence to equimolar mixture of oxygen and nitrous oxide and for each of the analgesic drugs taken by the patient. The data are also completed using the subject's medical record. DISCUSSION: This study will make it possible to provide an initial quantitative and qualitative evaluation of problematic use of equimolar mixture of oxygen and nitrous oxide and analgesic drugs in the sickle-cell disease population. The results will be used firstly to provide additional data essential for monitoring the risk of overdose, abuse, dependence and misuse of these products, and to begin awareness-raising and to provide information for health care professionals, in order to significantly improve the management of sickle-cell disease-related pain. TRIAL REGISTRATION: Clinical Trials.gov ID: NCT02580565 registered 16 October 2015 Unique Protocol ID: RC14\₀344.

Intraoperative remifentanil has been associated with postoperative hyperalgesia, higher visual analogic pain scores, and increased postoperative morphine consumption. However, this has not been investigated from patient's perspective by using a patient-reported outcomes (PROs) approach with a validated questionnaire.We joined the largest prospective observational study on postoperative pain, PAIN OUT Project (NCT02083835), and collected data for 2 years. We studied the effects of remifentanil (R+) vs nonremifentanil (R-) anesthesia on PROs regarding their pain management after elective thyroidectomy. We selected 5 primary PROs (worst pain experienced, time spent in severe pain, relief received by treatment, satisfaction about pain management, wish for more pain treatment) and five secondary PROs (drowsiness, itching, nausea, dizziness, waking up due to pain) from the validated International Pain Outcomes questionnaire.The analysis included 317 patients, 208 in the R+ group (65.6%) and 109 in the R- group (34.4%), the latter receiving fentanyl as intraoperative opioid. Although the R+ group received more frequently intraoperative nonopioids (202/208, 97.1% vs 86/109, 78.9%; P.0001) and opioids (184/208, 88.5% vs 38/109, 34.9%; P.001), it reported higher worst pain (5.1±2.1 vs 4.3±2.1, P.005), lower satisfaction (7.4±2.0 vs 8.1±2.1, P.001), and worse results in 4 secondary PROs. A sensitivity analysis performed matching 67 couples of patients yielded similar results in primary PROs.Our study suggests that remifentanil-based anesthesia is associated with worse pain-related PROs in patients undergoing thyroidectomy despite more frequent intraoperative analgesic administration. This study adds further evidence to the growing literature about opioid- and remifentanil-induced hyperalgesia.

15 pages, 7 figures.-- PMID: 18615132 [PubMed].-- PMCID: PMC2430674., The identification and cloning of the vanilloid receptor 1 (TRPV1) represented a significant step for the understanding of the molecular mechanisms underlying the transduction of noxious chemical and thermal stimuli by peripheral nociceptors. TRPV1 is a non-selective cation channel gated by noxious heat, vanilloids and extracellular protons. TRPV1 channel activity is remarkably potentiated by pro-inflammatory agents, a phenomenon that is thought to underlie the peripheral sensitisation of nociceptors that leads to thermal hyperalgesia. Cumulative evidence is building a strong case for the involvement of this receptor in the etiology of both peripheral and visceral inflammatory pain, such as inflammatory bowel disease, bladder inflammation and cancer pain. The validation of TRPV1 receptor as a key therapeutic target for pain management has thrust intensive drug discovery programs aimed at developing orally active antagonists of the receptor protein. Nonetheless, the real challenge of these drug discovery platforms is to develop antagonists that preserve the physiological activity of TRPV1 receptors while correcting over-active channels. This is a condition to ensure normal pro-prioceptive and nociceptive responses that represent a safety mechanism to prevent tissue injury. Recent and exciting advances in the function, dysfunction and modulation of this receptor will be the focus of this review., We thank all members of our group and colleagues of collaboration groups for their fundamental contribution to the results herein presented. We are indebted to the Financial support from the MEC, FIS, GVA, and Fundació La Caixa.

Objective: The use of analgesic drugs in patients admitted to Italian intensive care units (ICUs) was assessed. Methods: An observational, prospective, cohort study was conducted, involving all adult patients admitted during a 1-month period in 128 Italian general ICUs. The use of analgesic drugs was evaluated for the first 2 postoperative days in surgical patients who stayed in ICU for at least 2 days. Results: We observed 661 postoperative patients who underwent elective (72%) or emergency surgery. Of the patients with an ICU stay of at least 2 days, 49% did not receive any opioids in the first 48 postoperative hours, and more than 35% did not receive any analgesic at all. The most used opioid was fentanyl, followed by morphine and buprenorphine. Among the 336 patients who received at least one opioid, as many as 42% had only a single bolus per day. Pain control was reported as the reason for drug use in 54.5% of opioid administrations, while control of anxiety covered 10.3% of them. The probability of receiving an opioid was lower for patients in coma. Conclusion: Management of postoperative pain in Italian ICUs was insufficient, particularly in neurosurgical and comatose patients. A general lack of knowledge about pain and misconceptions about pain drugs may be at the basis of these results.

Background: Pain is an indication for total hip arthroplasty (THA) and it should be resolved post-surgery. Because patients' pain is typically treated pharmacologically we tested whether opioid use can be used as a surrogate for patient-reported pain and as an indicator for early surgical failure. Specifically, we evaluated whether the amount of opioids taken within the year after THA was associated with one and five years risk of revision surgery. Methods: A cohort of 9943 THAs (01/2001-12/2012) was evaluated. Post-operative opioid use was the exposure of interest and cumulative daily oral morphine equivalent (OME) amounts were calculated. Total OMEs/90-day periods were categorised into quartiles. Revisions within one and five years were the outcomes of interest. Results: Of the THAs, 2.0 % (N = 200) were revised within one year and 4.2 % (N = 413) within five years. After adjustments for gender, age, surgical indication, co-morbidities, and other analgesics, revision was associated with amount of OMEs in the second quarter after THA (days 91-180 after discharge). Patients on medium-high amounts of OME (400-1119 mg) had higher risk of one (hazard ratio (HR) = 2.22, 95 % CI 1.08-4.56) and five year (HR = 1.66, 95 % CI 1.08-2.56) revision than a patient not taking opioids. During the same period, patients taking the highest amounts of OMEs (≥1120 mg) had a 2.64 (95 % CI 1.03-6.74) times higher risk of one year and a 2.11 (95 % CI 1.13-3.96) times higher risk of five year revision. Conclusions: Opioid use 91-180 days post-surgery is associated with higher risk of revision surgery and therefore is an early and useful indicator for surgical failure. Refereed/Peer-reviewed