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Supplementary data Supplementary data related to this article can be found at https://doi.org/10.1016/j.jpain.2022.07.014., Neuropathic pain (NP) is a challenging condition to treat, as the need for new drugs to treat NP is an unmet goal. We investigated the analgesic potential of a new sulfated disaccharide compound, named BIS014. Oral administration (p.o.) of this compound induced ameliorative effects in formalin-induced nociception and capsaicin-induced secondary mechanical hypersensitivity in mice, but also after partial sciatic nerve transection (spared nerve injury), chemotherapy (paclitaxel)-induced NP, and diabetic neuropathy induced by streptozotocin. Importantly, BIS014, at doses active on neuropathic hypersensitivity (60 mg/kg/p.o.), did not alter exploratory activity or motor coordination (in the rotarod test), unlike a standard dose of gabapentin (40 mg/kg/p.o.) which although inducing antiallodynic effects on the NP models, it also markedly decreased exploration and motor coordination. In docking and molecular dynamic simulation studies, BIS014 interacted with TRPV1, a receptor involved in pain transmission where it behaved as a partial agonist. Additionally, similar to capsaicin, BIS014 increased cytosolic Ca2+ concentration ([Ca2+]c) in neuroblastoma cells expressing TRPV1 receptors; these elevations were blocked by ruthenium red. BIS014 did not block capsaicin-elicited [Ca2+]c transients, but inhibited the increase in the firing rate of action potentials in bradykinin-sensitized dorsal root ganglion neurons stimulated with capsaicin. Perspective: We report that the oral administration of a new sulfated disaccharide compound, named BIS014, decreases neuropathic pain from diverse etiology in mice. Unlike the comparator gabapentin, BIS014 does not induce sedation. Thus, BIS014 has the potential to become a new efficacious non-sedative oral medication for the treatment of neuropathic pain., Laboratorios Bioibérica (Barcelona), Universidad Autónoma de Madrid (UAM)

The TRPA1 channel is involved in a variety of physiological processes and its activation leads to pain perception and the development of inflammation. Peptide Ms 9a-1 from sea anemone Metridium senile is a positive modulator of TRPA1 and causes significant analgesic and anti-inflammatory effects by desensitization of TRPA1-expressing sensory neurons. For structural and functional analysis of Ms 9a-1, we produced four peptides—Ms 9a-1 without C-terminal domain (abbreviated as N-Ms), short C-terminal domain Ms 9a-1 alone (C-Ms), and two homologous peptides (Ms 9a-2 and Ms 9a-3). All tested peptides possessed a reduced potentiating effect on TRPA1 compared to Ms 9a-1 in vitro. None of the peptides reproduced analgesic and anti-inflammatory properties of Ms 9a-1 in vivo. Peptides N-Ms and C-Ms were able to reduce pain induced by AITC (selective TRPA1 agonist) but did not decrease AITC-induced paw edema development. Fragments of Ms 9a-1 did not effectively reverse CFA-induced thermal hyperalgesia and paw edema. Ms 9a-2 and Ms 9a-3 possessed significant effects and anti-inflammatory properties in some doses, but their unexpected efficacy and bell-shape dose–responses support the hypothesis of other targets involved in their effects in vivo. Therefore, activity comparison of Ms 9a-1 fragments and homologues peptides revealed structural determinants important for TRPA1 modulation, as well as analgesic and anti-inflammatory properties of Ms9a-1.

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

Objectives: To determine the effect of using abdominal binder after cesarean delivery on postoperative wound pain, physical function and analgesic drugs use.Materials and Methods: A randomized controlled trial was conducted between January and April 2018 at KhonKaen Hospital. Fifty women who underwent elective cesarean delivery were randomly allocated to either the abdominal binder group or routine standard care. The primary outcome was postoperative wound pain as measured by a visual analog scale (VAS) scores at 6, 24, and 48 hours after using the binder. The secondary outcomes included physical function as measured by distance 6-minute walk test (6MWT), time to first ambulation, analgesic drugs use and adverse effects.Results: Postoperative wound pain was indicated by a significantly lower VAS score in the binder group with the repeated measures ANOVA (F= 30.78, p < 0.005). The respective postoperative VAS score at 6, 24, and 48 hours was also significantly lower in the binder group (mean ± SD at 6, 24, and 48 hr. = 4.77 ± 1.97, 3.73 ± 1.48, and 2.51 ± 1.63 vs. standard care 6.85 ± 2.26, 5.49 ± 2.34, and 4.66 ± 2.21; p < 0.05). Postoperative opioid drugs use in the binder group was significantly less than in the standard care (5.22 ± 1.20 mg vs. 7.63 ± 2.43 mg; p < 0.01). There were no significant differences in the 6MWT and time to first ambulation between the two groups. No serious adverse effects were reported.Conclusion: Using abdominal binder can reduced pain and analgesic drugs used in postoperative cesarean delivery.

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.

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.

Amaç: İnferior alveolar sinir bloğu (İASB), mandibular molar dişlerin endodontik tedavisi için en sık kullanılan anestezi tekniğidir, fakat irreversibl pulpitisli hastalarda İASB anestezi başarısı önemli derecede azalmaktadır. Bu çalışmanın amacı, oral preoperatif analjezik ilaçların veya ilaç kombinasyonlarının uygulanmasının, irreversibl pulpitisli mandibular molar dişlerde İASB başarısı üzerine etkisini değerlendirmektir. Gereç ve Yöntem: Bu çift kör, plasebo kontrollü klinik çalışmada, 5 grupta toplam 150 hastaya (n=30) İASB anestezisinden 1 saat önce; plasebo veya 1000 mg asetaminofen, 8 mg lornoksikam, 1000 mg asetaminofen + 50 mg tramadol, 8 mg lornoksikam + 50 mg tramadol ilaçlarından biri verildi. Tüm hastalara 1:80.000 epinefrin içeren 1.8 ml %2'lik lidokain solüsyonu ile standart İASB uygulandı. Tüm hastalar Heft-Parker görsel analog skalasına (HPVAS); ilaç almadan önce (HPVAS-1), ilaç aldıktan 1 saat sonra (HPVAS-2), giriş kavitesi preperasyonu ve kök kanalı enstrümantasyonu sırasında (HPVAS-3) olacak şekilde hissettikleri ağrı skorlarını işaretledi. Elde edilen veriler istatistiksel olarak analiz edildi. Bulgular: Hastaların; yaş, cinsiyet, başlangıç ağrısı ve diş dağılımı arasında istatistiksel olarak anlamlı fark olmadığı gözlendi (p> 0.05). Plasebo, asetaminofen, lornoksikam, asetaminofen + tramadol ve lornoksikam + tramadol için başarı oranları sırasıyla %60, %66, %54, %50 ve %54 idi. Deney gruplar arasında istatistiksel olarak anlamlı fark olmadığı bulundu. (p> 0.05). Sonuç: Bu çalışmanın limitasyonları dâhilinde preoperatif asetaminofen, lornoksikam, asetaminofen + tramadol veya lornoksikam + tramadol uygulamasının, irreversibl pulpitisli mandibular molarlar için İASB'nin başarı oranları üzerinde anlamlı bir etkisi yoktur. İrreversibl pulpitisli hastaların endodontik tedavi sırasındaki konforunu artırmak için farklı analjezik ve analjezik kombinasyonlarıyla ilgili daha fazla premedikasyon çalışması önerilmektedir., Background: The inferior alveolar nerve block (IANB) is the most frequently used anesthetic technique for endodontic treatment of mandibular molar teeth. However anesthetic efficacy of IANB is drastically decreasing patients with irreversible pulpitis. The purpose of this study was to evaluate the effect of the oral administration of preoperative analgesic drugs or drug combinations on the success of IANB in mandibular molars with irreversible pulpitis. Methods: In this double-blind, placebo controlled clinical study, a total of 150 patients in five groups (n=30) with irreversible pulpitis were given placebo, 1000 mg acetaminophen, 8 mg lornoxicam, 1000 mg acetaminophen+50 mg tramadol and, 8 mg lornoxicam+50 mg tramadol medications 1 hour before IANB anesthesia. All patients received standard IANB of 1.8 ml 2% lidocaine solution with 1:80.000 epinephrine. Each patient recorded their pain score on a Heft-Parker visual analog scale before taking medication (HPVAS-1), 1 hour after drug (HPVAS-2), during access cavity preparation and during root canal instrumentation (HPVAS-3). Data were statistically analyzed. Results: There was no statistically significant difference in terms of age, gender, initial pain and distribution of teeth (p>0.05). Overall success rates for placebo, acetaminophen, lornoxicam, acetaminophen + tramadol and lornoxicam + tramadol were 60%, 66%, 54%, 50% and 54%, respectively. There was no significant difference between the groups (p>0.05). Conclusion: Within the limitations of the current study, preoperative administration of acetaminophen, lornoxicam, acetaminophen + tramadol or lornoxicam + tramadol has no significant effect on the success rates of IANB for mandibular molars with irreversible pulpitis. More premedication studies with different analgesic and analgesic combinations are recommended to increase the comfort of endodontic treatment of patients with irreversible pulpitis.

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 first marine natural products that served as leads or scaffolds for medicines were discovered in the middle of last century: the arabinosyl glycosides from the marine sponge Tectitethya crypta. Synthesis and modifications of the natural molecules generated antiviral and antileukemic drugs developed in the 1970’s and in the following decades, including the first effective treatment against HIV infection. With the improvement of techniques for the elucidation of chemical structure of the molecules, as well as chemical synthesis, especially from the 1990’s, there was an increase in the number of bioactive natural products characterized from marine organisms. New chemical structures with high specificity towards molecular targets in cells allowed the development of new drugs with indication for the treatment of several illnesses, from cancer to new antibiotics, and even neurological disorders. Currently there are at least 13 molecules derived from marine natural products on advanced clinical trials, and nine were approved to be used as medicines. Considering that in the past eight years, more than 1000 new compounds from marine organisms were described, per year, the expectation is that many more drugs will be derived from marine natural products in a near future.

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, Проведено сравнение систем фармацевтического обеспечения предоставления фармацевтической помощи в Украине и за рубежом, проанализированы количественные показатели заболеваемости злокачественными новообразованиями, количество аптек в Украине и Харьковской области. Изучено нарушение правил обращения лекарственных средств, допущеных для обеспечения онкобольных. Предложены нормотворческие инициативы для усовершенствования системы правоотношений «врач–пациент–провизор» и оборота наркотических лекарственных средств для фармацевтического обеспечения онкобольных по льготным рецептам в аптечных учреждениях Украины и Харьковского региона, Проведено порівняння систем фармацевтичного забезпечення надання фармацевтичної допомоги в Україні та за кордоном, проаналізовано кількісні показники захворюваності на злоякісні новоутворення, кількість аптек в Україні та в Харківській області. Вивчено порушення правил обігу лікарських засобів, допущених для забезпечення онкохворих. Запропоновано нормотворчі ініціативи для удосконалення системи правовідносин «лікар–пацієнт–провізор» та обігу наркотичних лікарських засобів для фармацевтичного забезпечення онкохворих за пільговими рецептами в аптечних закладах України та Харківського регіону

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

Se realizó un estudio descriptivo y transversal en el Consultorio Médico de la Familia No. 28 perteneciente al Policlínico Universitario y Docente "Dr. Mario Muñoz Monroy" desde el 1ro. de junio al 31 de diciembre de 2008, con el objetivo de detectar las reacciones adversas más frecuentes provocadas por el consumo de antiinflamatorios no esteroideos. El universo estuvo constituido por 105 pacientes que asistieron a consulta en el tiempo de estudio y de estos se seleccionó una muestra de 60 pacientes, a quienes se les aplicó un cuestionario de preguntas donde se recogieron las variables de análisis. .Las mujeres resultaron las que más antiinflamatorios consumieron y en el rango de edades de 31-59 años. Las reacciones adversas que más se reportaron fueron la epigastralgia y la hipertensión arterial, así mismo se comprobó la automedicación en algunos pacientes.A descriptive cross-sectional study was conducted in the family physician´s office No. 28 attached to "Dr Mario Muñoz Monroy" university teaching polyclinics from June 1st to December 31st 2008. The objective was to detect the most common adverse reactions caused by non-steroidal anti-inflammatory drugs. The universe of study was made up of 105 patients who attended the physician´s office during the study and from this number, a sample of 60 patients was selected. They were administered a questionnaire including analysis variables. The females aged 31-59 years consumed more antinflammatory drugs. The most reported adverse reactions were epigastralgia and blood hypertension; besides, self-medication was confirmed.

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.

La Organización Mundial de la Salud define el cuidado paliativo como el cuidado total y activo en aquellos pacientes que no responden a un tratamiento curativo. El control del dolor, otros síntomas y los problemas psicológicos, sociales y espirituales son de fundamental importancia. La meta del cuidado paliativo es brindar la mejor calidad de vida a los pacientes y a sus familias. En el cuidado paliativo es necesario el manejo multidisciplinario. Nuevas estrategias como rotación de opioides y sus diferentes vías de administración pueden ofrecer analgesia con pocos efectos adversos. The World Health Organisation defines palliative care as the active total care of patients whose disease is not responsive to curative treatment. Control of pain, of other symptoms, and of psychological, social and spiritual problems, is paramount. The goal of palliative care is achievement of the best quality of life for patients and their families. Palliative care is necessarily multidisciplinary. New strategies such as the switching opioids and/or their route of administration may offer improved analgesia with fewer adverse effects, thus providing therapeutic alternatives for the clinical community.

Gençer, Nahit (Balikesir Author), The in vitro effects of the injectable form of analgesic drugs, dexketoprofen trometamol, dexamethasone sodium phosphate, metamizole sodium, diclofenac sodium, thiocolchicoside, on the activity of purified human carbonic anhydrase I and II were evaluated. The effect of these drugs on erythrocyte hCA I and hCA II was compared to recombinant hCA I and hCA II expressed in Ecoli. IC50 values of the drugs that caused inhibition were determined by means of activity percentage diagrams. The IC50 concentrations of dexketoprofen trometamol and dexamethasone sodium phosphate on hCA I were 683 mu M and 4250 mu M and for hCA II 950 mu M and 6200 mu M respectively. Conversely, the enzyme activity was increased by diflofenac sodium. In addition, thiocolchicoside has not any affect on hCA I and hCA II. The effect of these drugs on erythrocyte hCA I and hCA II were consistent with the inhibition of recombinant enzymes.

Objetivo: El objetivo de este trabajo ha sido realizar un estudio de utilización de analgésicos opiáceos en el Hospital Universitario La Paz (Madrid) en el año 2008 para conocer cómo se está utilizando este grupo de medicamentos y cuál es la tendencia del consumo. Para ello, se presentan los datos de uso de opiáceos en pacientes ingresados de forma global, por hospitales y por servicios clínicos. Se exponen los datos de consumo de los 5 últimos años y se ha cuantificado el uso del resto de principios activos empleados como analgésicos en nuestro hospital. Material y métodos: Haciendo uso de la metodología recomendada por la Organización Mundial de la Salud para los estudios de utilización de medicamentos en hospitales, presentamos nuestros datos en dosis diarias definidas (DDD) por 100 estancias. Los datos de consumo se han obtenido del programa de gestión de medicamentos del Servicio de Farmacia Farma Tools (Dominion®) Resultados: El valor global de utilización de opiáceos en 2008 ha sido de 8,1 DDD/100 estancias. Los principios activos más consumidos han sido la morfina parenteral y el fentanilo transdérmico, y entre los 2 representan el 83% del consumo total de opiáceos. En el análisis por hospitales apreciamos que el Hospital General y el de Traumatología son los que presentan un mayor empleo de opiáceos y siguen el mismo patrón de utilización que el global. Los servicios más representativos del consumo de opiáceos han sido las reanimaciones del Hospital General y de Traumatología, los Servicios de Oncología, Cuidados paliativos y Hematología. En estos últimos 5 años se ha producido un incremento global del consumo de aproximadamente el 20%, viéndose implicados todos los principios activos. Con relación al consumo total de analgésicos, los datos reflejan una amplia utilización en el hospital (104 DDD/100 estancias). Los opiáceos representan un 7,4% del consumo total de analgésicos, siendo el paracetamol y el metamizol los analgésicos más ampliamente utilizados. Conclusiones: Los datos de nuestro estudio reflejan una tendencia al incremento del consumo de opiáceos en el hospital, lo que consideramos una mejora en el tratamiento del dolor, tanto agudo como crónico, pues en este incremento se ven involucrados todos los principios activos opiáceos. En un hospital con elevada actividad y complejidad asistencial como el Hospital La Paz, este tipo de estudios constituyen una herramienta que nos permite conocer y comparar el uso de opiáceos en los distintos hospitales y servicios clínicos. Nos permiten conocer la evolución del consumo así como detectar posibles desviaciones e implementar acciones de mejora en los diferentes servicios clínicos implicados en el tratamiento del dolor. Objective: The aim of this study was to analyze opioid analgesic use in the La Paz University Hospital in 2008 in order to identify patterns of use and consumption. To that end, data from inpatients were analyzed overall, as well as by hospitals and departments. We analyzed data on consumption in the previous 5 years and quantified the use of the remaining active principles administered as analgesics in our hospital. Materials and methods: Following the Wold Health Organization's guidelines for studieson medication use in hospitals, data are shown as defined daily dose (DDD) per 100 hospital stays. Data on drug use were obtained from the drug management program, Farma Tools (Dominion®), which is used by the Pharmacy Service at La Paz Hospital. Results: The overall value of opioid utilization in 2008 was 8.1 DDD per 100 hospital stays. The most widely used active principles were parenteral morphine and transdermal fentanyl. Together, these drugs represented 83% of total opioid consumption. Analysis by hospital revealed that the General and Traumatology Hospitals showed the highest opioid drug consumption and followed the same utilization pattern as overall use. The services most representative of opioid consumption in inpatients were the Recovery Room in the General and Traumatology Hospitals, Critical Care, Oncology, Hematology and Palliative Care. In the last 5 years of the study, the overall use of these drugs increased by 20%, irrespective of the active principles involved. Analysis of analgesic intake at La Paz Hospital showed widespread use (104 DDD per 100 hospital stays). Opioids represented 7.4% of total analgesic consumption, the most frequently used analgesics being acetaminophen and metamizol. Conclusions: The results of our study show an increasing trend in opioid consumption in this hospital. We believe this increase reflects an improvement in the management of both acute and chronic pain, since the use of all opioid active ingredients increased. In hospitals with very high activity and complex clinical work, such as La Paz Hospital, this kind of study constitutes a specific tool that allows opioid use in distinct services and hospitals to be compared. This type of study also allows patterns of consumption and possible deviations to be identified and improvements to be made in the distinct clinical services involved in treating pain.

La Organización Mundial de la Salud define el cuidado paliativo como el cuidado total y activo en aquellos pacientes que no responden a un tratamiento curativo. El control del dolor, otros síntomas y los problemas psicológicos, sociales y espirituales son de fundamental importancia. La meta del cuidado paliativo es brindar la mejor calidad de vida a los pacientes y a sus familias. En el cuidado paliativo es necesario el manejo multidisciplinario. Nuevas estrategias como rotación de opioides y sus diferentes vías de administración pueden ofrecer analgesia con pocos efectos adversos. The World Health Organisation defines palliative care as the active total care of patients whose disease is not responsive to curative treatment. Control of pain, of other symptoms, and of psychological, social and spiritual problems, is paramount. The goal of palliative care is achievement of the best quality of life for patients and their families. Palliative care is necessarily multidisciplinary. New strategies such as the switching opioids and/or their route of administration may offer improved analgesia with fewer adverse effects, thus providing therapeutic alternatives for the clinical community.

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.

New sensitive and rapid spectrophotometric methods for the determination of four analgesic drugs namely, nalbuphine (NALB), naltrexone (NALT), morphine (MORF) and tramadol (TRAM) in pharmaceutical formulations were developed and optimized. The proposed methods involve the addition of a measured excess of N-bromosuccinimide in acid medium followed by determination of unreacted NBS by reacting with either a fixed amount of methyl orange and measuring the absorbance at 508 nm (Method A), or orange G and measuring the absorbance at 478 nm (Method B). In both methods, the amount of NBS reacted corresponds to the amount of drugs. Under the optimum conditions, Beer’s law limit, molar absorptivity and Sandell’s sensitivity were calculated. The limits of detection and quantification were also reported for both methods. Statistical evaluation of the methods was examined by determining intra-day and inter-day precisions. The methods were successfully applied to the assay of drugs in their pharmaceutical formulations. No interference was observed from common additives and the validity of the methods was tested.

To demonstrate that pain affects the goodness of breastfeeding.Seventy-nine patients were interviewed regarding satisfaction in breastfeeding, tiredness, uterine pain, nipple and other pain, and analgesic use at day three and at first, second, third, and fourth week after birth. Data regarding the mode of delivery were recorded from medical charts. Milk formula supplements, bottle use, pacifier use, and nipple shields use were considered as variables suggesting unsuccessful breastfeeding.At third day after delivery, it appeared that analgesic use was significantly associated with milk formula supplementing, bottle use, less satisfaction in breastfeeding, and more tiredness. At first week after delivery, the presence of pain differing from nipple and uterine pain, was more likely associated with milk formula supplementing, bottle use, pacifier use, less satisfaction in breastfeeding, and more tiredness. At third week after delivery, nipple pain was directly related to tiredness, while it increased the odds of adding milk formula and using a bottle.Pain affects the goodness of breastfeeding.

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