The Relationship Between Neuroprotective Activity and Antigenotoxic and Acetylcholinesterase Inhibitory Effects of Glaucium corniculatum Extracts

Abstract The purpose of this study was to investigate the relationship between the acetylcholinesterase (AChE) inhibitory and antigenotoxic effect with the neuroprotective activity of Glaucium corniculatum methanol and water extracts rich in rutin and quercetin flavonoids. Neuroprotective activity in terms of cell survival and development against oxidative damage was measured by MTT assay and microscopic analysis in H2O2-induced NGF-differentiated PC12 (dPC12) cells. QRT-PCR and western blot hybridization method was employed for the determination of AChE inhibition of the extracts in the same cell model, and the genotoxic and antigenotoxic effects were identified with Comet assay with human lymphocytes. H2O2-induced vitality loss in dPC12 cells was inhibited in pre-treated cells with these plant extracts. Moreover, extracts stimulated neurite formation and prevented the oxidative stress-induced reduction in neurite growth. In general, it was determined that G. corniculatum methanol extract containing higher amounts of rutin and quercetin was more effective than water extract in terms of AChE inhibitory, antigenotoxic and also neuroprotective effect. In this study, it was shown for the first time that both AChE inhibitory and antigenotoxic effects of G. corniculatum may be effective in neuroprotection and it's protective and therapeutic effects against neurodegeneration may be related to the flavonoid content.

Cannabinoids versus placebo or no intervention for pain: protocol for a systematic review with meta-analysis and trial sequential analysis.

INTRODUCTION: Pain is a frequent clinical symptom with significant impact on the patient's well-being. Therefore, adequate pain management is of utmost importance. While cannabinoids have become a more popular alternative to traditional types of pain medication among patients, the quality of evidence supporting the use of cannabinoids has been questioned. The beneficial and harmful effects of cannabinoids in patients with pain is unknown. Accordingly, we aim to assess the efficacy, tolerability and safety of cannabinoids (herbal, plant-derived extracts and synthetic) compared with placebo or no intervention for any type of pain. METHODS AND ANALYSES: We will conduct a systematic review of randomised clinical trials with meta-analysis and Trial Sequential Analysis to assess the beneficial and harmful effects of cannabinoids in any dose, formulation and duration. We will accept placebo or no treatment as control interventions. We will include participants with any type of pain (acute and chronic pain, cancer-related pain, headache, neuropathic pain or any other types of pain). We will systematically search The Cochrane Library, MEDLINE, Embase, Science Citation Index and BIOSIS for relevant literature. We will follow the recommendations by Cochrane and the Preferred Reporting Items for Systematic Review and Meta-Analysis statement. The risk of systematic errors (bias) and random errors (play of chance) will be assessed. The overall certainty of evidence will be evaluated using the Grading of Recommendations Assessment, Development and Evaluation approach. ETHICS AND DISSEMINATION: Ethical approval is not a requirement since no primary data will be collected. The findings of this systematic review will be submitted for peer-reviewed publication and disseminated in national and international conferences. DISCUSSION: Although cannabinoids are now being used to manage different pain conditions, the evidence for the clinical effects are unclear. The present review will systematically assess the current evidence for the benefits and harms of cannabinoids to inform practice and future research.

Spiritual Perspectives on Pain in Advanced Breast Cancer: A Scoping Review.

OBJECTIVES: The aim of the present review was to characterize how pain and spirituality have been conceptualized, assessed, and addressed and how these concepts may be related among women with advanced breast cancer. DESIGN: A scoping review was conducted including publications of various methodologies. DATA SOURCES: Searches were conducted in PubMed, CINAHL, PsycINFO, Cochrane Library, OpenGrey, OAIster, and a large university library database (published 2006-2018). REVIEW/ANALYSIS METHODS: Research questions and criteria were formulated at the outset, followed by identification of publications, charting data, and collating results. RESULTS: Forty-two publications met the inclusion criteria. Most (n = 33) focused exclusively on pain, five pain and spirituality, and four exclusively spirituality. Conceptual definitions were not explicitly provided but were implied. Most assessments used the 0-10 Numeric Rating Scale (pain) and qualitative methods (spirituality). Pain management primarily focused on radiotherapy and pharmaceuticals, and two publications identified spiritual interventions. No publications directly examined the impact of spirituality on pain. Findings of qualitative studies including both concepts suggest the potential value of spirituality as a mechanism to cope with pain. CONCLUSIONS: This review identified significant unmanaged pain in women with advanced breast cancer. Women identified dimensions of spirituality as important for coping with their disease. A gap in understanding spirituality and its potential influence on pain in this population was identified.

The Role of Pain Classification Systems in Pain Management.

Pain is a multidimensional experience that can significantly impair an individual's quality of life. This article describes the pain classification systems, including anatomic, etiologic, intensity, duration, pathophysiological, and conditions that are not easily classified. A holistic approach is taken by addressing key components to assist with effective pain management, including the psychological and spiritual aspects of care. A case study scenario demonstrates the implementation of pain classifications in pain management. Also discussed are current controversies, potential genetic impacts, and the barriers chronic pain sufferers face, including addiction, diversion, and socioeconomic factors.

Effect of Unmodulated 5-kHz Alternating Currents Versus Transcutaneous Electrical Nerve Stimulation on Mechanical and Thermal Pain, Tactile Threshold, and Peripheral Nerve Conduction: A Double-Blind, Placebo-Controlled Crossover Trial.

OBJECTIVE: To investigate the effect of unmodulated 5-kHz alternating current on mechanical pain threshold (MPT), heat pain threshold (HPT), tactile threshold (TT), and peripheral nerve conduction (PNC) compared with transcutaneous electrical nerve stimulation (TENS) and sham stimulation. SETTING: National referral center. DESIGN: Randomized, double-blind, placebo-controlled crossover trial. PARTICIPANTS: Healthy volunteers (N=38). No dropouts or adverse events were reported. INTERVENTION: TENS, unmodulated 5-kHz currents, and sham stimulation were applied on the radial nerve for 20 minutes with a 24-hour washout period between them and concealed intervention allocation. MAIN OUTCOME MEASURES: Four measures were taken: before, during, and 2 after the interventions. Algometry was used to assess MPT, a Peltier thermode for HPT using the method of limits, Von Frey filaments for TT, and radial nerve compound action potential. RESULTS: No differences were observed on MPT, HPT, and PNC when 5-kHz current and TENS were compared. However, TT increased 56.2mN (95% confidence interval [CI], 28.8-83.6) in the TENS group compared with the 5-kHz current group during intervention. Compared with sham stimulation during intervention, MPT increased 4.7N (95% CI, 0.3-9.2) using 5-kHz current and 10.4N (95% CI, 3.5-17.3) with TENS. TT increased 17.2mN (95% CI, 4.7-29.7) with 5-kHz current and 73.4mN (95% CI, 47.5-99.2) with TENS. However, HPT increased 1.0°C (95% CI, 0.2-2.0) only with TENS. For the PNC, no differences were found among the 3 groups. CONCLUSIONS: Unmodulated 5-kHz current produced an increase in somatosensory thresholds that was greater than placebo but not when compared with TENS; however, participants perceived 5-kHz currents to be more comfortable and showed more habituation to them.

Comparative trial of Aloe vera/olive oil combination cream versus phenytoin cream in the treatment of chronic wounds.

OBJECTIVE: Aloe vera is a medicinal plant that has been traditionally used to accelerate wound healing. Olive oil is also a natural product that may contribute to wound healing owing to its antimicrobial and anti-inflammatory effects. The present study aimed to evaluate the effect of an Aloe vera-olive oil (AVO) combination cream on the healing process of chronic wounds. METHOD: In this randomised, double-blind, comparator-controlled, parallel-group trial, patients with chronic wounds were treated with either AVO cream or phenytoin cream as the standard treatment for a period of 30 days. Wound healing was evaluated using Bates-Jensen assessment tool and the severity of pain was assessed using a visual analogue scale (VAS). RESULTS: After initial assessment, 60 patients with chronic wounds (41 with pressure ulcer, 13 with diabetic wounds and 6 with venous ulcers), were recruited and randomised into 2 groups of 30. After 30 days of treatment, significant improvements in the wound size, depth, and edges; necrotic tissue type and amount; exudate type and amount; colour of wound surroundings; and peripheral tissue oedema score were observed in the AVO cream group (p<0.001). The total score of wound healing showed significant improvement with both AVO (p<0.001) and phenytoin (p<0.01) creams, although AVO was more efficacious (p<0.001). Likewise, although both treatments reduced the initial VAS score, the efficacy of AVO was significantly greater (p<0.001). CONCLUSION: AVO cream significantly accelerates biological healing of chronic wounds and helps to reduce pain severity with a higher efficacy compared with phenytoin cream.

Pain management during radiotherapy and radiochemotherapy in oropharyngeal cancer patients: single-institution experience.

AIM OF THE STUDY: Radiotherapy (RT) is a radical therapeutic option for patients with oropharyngeal cancer (OPC). It induces an acute postradiation reaction that may cause significant pain. The aim of this study was to analyse pain occurrence and intensity, as well as type and effectiveness of analgesic treatment, in OPC patients undergoing RT or radiochemotherapy (RT-CT). MATERIAL AND METHODS: Retrospective data were obtained for 42 OPC patients at clinical stages I-IVA, treated with adjuvant RT or RT-CT or definite RT or RT-CcT at the Comprehensive Cancer Center in Bialystok, Poland. Pain intensity and type of analgesic treatment during the therapy were analysed and compared with the intensity of the radiation-induced acute reaction, assessed weekly according to the Dische score. RESULTS: Thirty-nine (92.9%) patients received analgesic treatment. Analgesic therapy was started in 27 (64.3%) patients with administration of non-steroidal anti-inflammatory drugs (NSAIDs) and/or paracetamol, in seven (16.7%) with mild opioids and in five (11.9%) with strong opioids. Strong opioids were used during therapy in 21 (50%) patients. Co-analgesics were administered to six patients. Breakthrough pain was observed in 10 (23.8%) patients. CONCLUSIONS: High incidence of pain during RT and RT-CT calls for increased awareness of the importance of pain monitoring and treatment during RT of OPC patients. The analgesic treatment had to be adjusted individually.

Pharmacotherapy for pain: efficacy and safety issues examined by subgroup analyses.

Responses to pharmacotherapy for acute and chronic pain are highly variable, and efficacy is often compromised by some form of toxicity. To increase our understanding of complexities of pharmacotherapy, the authors discuss an approach to identify analgesic responder subgroups and predictors of response. Additionally, analgesic efficacy and toxicity were combined in a single risk-benefit index (utility function) to quantify the probability of side effects in high- vs low-analgesic responders. The subgroup analysis consists of a mathematical description or time series analysis, mixture analysis, and covariate analysis. Applied to ketamine treatment of chronic pain in complex regional pain syndrome and capsaicin 8% patch treatment in post-herpetic neuralgia patients, the analyses yielded homogenous subgroups that differed in distribution frequency between treatments. For capsaicine, a high variability in pretreatment pain reporting was associated with a high probability of falling into a full analgesic subgroup, irrespective of treatment. The utility function was applied to opioid-induced analgesia and respiratory depression. An important observation was that, irrespective of dose, low-analgesic responders to fentanyl had a greater probability of respiratory depression than analgesia while the reverse was true for high-analgesic responders. These data show dissociation between 2 µ-opioid end-points and explain the danger of treating poor analgesic responders with increasingly higher opioid doses. Apart from being valuable in drug development programs, the outlined approach can be used to determine the choice of drug and dose in the treatment of pain in patients with potent and toxic analgesics.

The routine use of the Edmonton Classification System for Cancer Pain in an outpatient supportive care center.

OBJECTIVE: There is no standardized and universally accepted pain classification system for the assessment and management of cancer pain in both clinical practice and research studies. The Edmonton Classification System for Cancer Pain (ECS-CP) is an assessment tool that has demonstrated value in assessing pain characteristics and response. The purpose of our study was to determine the relationship between negative ECS-CP features and some pain-related variables like pain intensity and opioid use. We also explored whether the number of negative ECS-CP features was associated with higher pain intensity. METHOD: The electronic charts of 100 patients at an outpatient supportive care clinic in a comprehensive cancer center were reviewed for variables like patient characteristics, initial ECS-CP assessment, morphine equivalent daily dose (MEDD), opioid rotation, Edmonton Symptom Assessment Score (ESAS), and use of adjuvant analgesics. RESULTS: Some 91 of the 100 charts were eligible for analysis. The most common primary cancer type was gastrointestinal (22.1%). The median pain intensity was 6, and the median MEDD was 45 mg. Neuropathic pain was associated with higher median pain intensity (7 vs. 5, p = 0.007) and median MEDD requirement (83 vs. 30, p = 0.013). Psychological distress was associated with higher median pain intensity (7 vs. 5, p = 0.042). Incident pain was also associated with a trend toward higher pain intensity (6 vs. 5, p = 0.06). A higher number of negative ECS-CP features was associated with higher pain intensity (p = 0.01). SIGNIFICANCE OF RESULTS: The ECS-CP was successfully completed in the majority of patients, demonstrating its utility in routine clinical practice. Neuropathic pain and psychological distress were associated with higher pain intensity. Also, neuropathic pain was associated with a higher MEDD. A higher sum of negative ECS-CP features was associated with higher pain intensity. Further studies will be needed to verify and explore these observations.

Avaliação da atividade farmacológica do óleo essencial de Piper rivinoides Kunth / Pharmacological activity of the assessment of the essential oil of Piper rivinoides Kunth

A familia Piperaceae é composta por cinco gêneros e suas espécies são utilizadas para vßrios fins medicinais.Objetivo: investigar o efeito antinociceptivo do óleo essencial de Piper rivinoides Kunth (OEPR). Métodologia:Estudo fitoquímico: Foi utilizado o método MDGC(cromatografia a gßs multi-dimensional) para identificar oscomponentes de OEPR. Modelo de Contorção abdominal: camundongos foram estimulados com ßcido acético0,8 por cento ip. As contorções foram contadas durante 10 minutos. Antagonistas adrenérgicos, imidazolínicos e opióidestambém foram usados neste modelo. Modelo de capsaicina: Capsaicina foi injetada na pata posterior direita (1,6mig/pata). Contou-se o tempo de lambedura por 5 minutos. Teste de formalina: Formalina foi injetada na patadireita (20 mig/pata). A contagem foi realizada em duas fases (1¬ - 5 min e 2¬ - após 15 min a 30 min). Tail Flick:A cauda foi exposta a luz (40 W) e avaliada a retirada da cauda. Teste de placa quente: Observou-se a retirada dapata dos animais tratados. Von frey e edema da pata: Carragenina foi injetada na pata direita (300 mig/pata). 1, 3 e6 horas após o estímulo foram avaliados o número de retirada da pata e o edema. Do macerado do coxim da patados experimentos de Von frey e edema foram dosados proteína e citocinas. Rota rod e habituação em campoaberto: camundongos foram colocados no aparelho de rota rod e verificado o tempo de permanência. No campoaberto foi verificada quantidade de crossing e rearing. Indução de úlcera: Os animais foram tratados com etanola 70 por cento e OEPR e quantificado o número de úlceras. Os animais foram tratados (v.o) com OEPR (0,1, 1, 10, 100e 300 mg / kg) ou veículo 1 hora antes. O tratamento com os antagonistas (ip) foram realizados 20 minutos antesde OEPR, veículo ou clonidina. Morfina e diclofenaco foram os fßrmacos padrões. Todos os experimentos foramrealizados de acordo com o CEUA (033/09), com 5 animais/grupo...

The Piperaceae family consists of five genera and their species are used for various medicinal purposes.Objective: To investigate the analgesic effect of the essential oil of Piper rivinoides Kunth (OEPR).Methodology: Phytochemical studies: We used the MDGC method (multi-dimensional gas chromatography) toidentify OEPR compounds. Writhing Model: Mice were challenged with acetic acid (0.8%, ip). The contortionsare counted for 10 minutes. Adrenergic, imidazoline and opioids antagonists were also used in this model.Capsaicin model: Capsaicin was injected into the hind paw (1.6 µg/paw). It was counted the licking time for 5minutes. Formalin test: Formalin was injected into the right paw (20 µg/paw). Counting was done in two stages(1st one for 5 min and 2nd one 15 min after the first, for 15 min). Tail Flick: The tail was exposed to light (40 W)and the withdrawal of the tail was evaluated. Hot plate test: The paw withdrawal from the hot plate was analyzed.Von frey and paw edema: Carrageenan was injected into the right paw (300 µg/paw). 1, 3 and 6 hours after thestimulation the number of paw withdrawal were assessed and edema. Protein and cytokines from paw cushionmash (Von frey and edema experiments) were measured. Rota rod and Open field: mice were placed on the rodroute set and checked the length of permanence on the instrument. The amount of crossing and rearing wasverified in the open field. Induction of ulcers: Animals were treated with 70% ethanol and OEPR and the numberof ulcers were quantified. The animals were treated (po) with OEPR (0.1, 1, 10, 100 and 300 mg/kg) or vehicle 1hour before. Treatment with antagonists (ip) were conducted 20 min before OEPR, vehicle or clonidine.Morphine and diclofenac were standard drugs. All experiments were performed in accordance with the CEUA(033/09), 5 animals/group...

Midwifery students' conceptions of worst imaginable pain.

BACKGROUND: The Visual Analogue Scale (VAS) is one of the most widely used pain assessment scales in clinical practice and research. However, the VAS is used less frequently in midwifery than in other clinical contexts. The issue of how people interpret the meaning of the VAS endpoints (i.e. no pain and worst imaginable pain) has been discussed. The aim of this study was to explore midwifery students' conceptions of 'worst imaginable pain'. METHODS: A sample of 230 midwifery students at seven universities in Sweden responded to an open-ended question: 'What is the worst imaginable pain for you?' This open-ended question is a part of a larger study. Their responses underwent manifest content analysis. RESULTS: Analysis of the midwifery students' responses to the open-ended question revealed five categories with 24 sub-categories. The categories were Overwhelming pain, Condition-related pain, Accidents, Inflicted pain and Psychological suffering. CONCLUSIONS: The midwifery students' conceptions of 'worst imaginable pain' are complex, elusive and diverse.

The impact of integration of dental services on oral health in long-term care: qualitative analysis.

OBJECTIVES: To qualitatively analyse how integration of dental service in long-term care (LTC) impacts residents and their oral health. BACKGROUND: Few studies have attempted to merge inductive and deductive data to clarify the significance of the complex psychosocial environment in LTC facilities. Understanding the subjective oral health experience of LTC residents in their social setting is key to uncovering behavioural patterns that may be limiting the oral care provided to LTC residents. MATERIALS AND METHODS: A cross-sectional study was performed involving 61 residents in three Ontario LTC facilities. Observations and reflective notes were recorded during open-ended interviews using a structured questionnaire to stimulate conversation topics. This ensured that each resident received the same prompting during the interview process. Inductive analysis was used to identify common patterns and themes within field notes and transcriptions. RESULTS: The major themes identified included oral hygiene, oral discomfort, general health, appearance, dental access, and denture related issues. Oral hygiene and discomfort were the dominating categories within the facilities. CONCLUSION: Two of the three LTC centres identified in this study failed to provide appropriate oral care for their residents. Future research needs to be directed at prospective studies assessing the effect of oral health education and mandatory dental examinations o entry within LTC centres utilising qualitative and quantitative analyses.

The effectiveness of manual therapy in supraspinatus tendinopathy.

OBJECTIVES: The aim of this randomized controlled study was to assess the efficacy of manual therapy in the treatment of patients with symptomatic supraspinatus tendinopathy. METHODS: Seventy-seven patients (age range, 30 to 55 years) with supraspinatus tendinopathy, were randomly assigned to one of the three treatment groups: a supervised exercise program (Group 1), a supervised exercise program combined with joint and soft tissue mobilization (Group 2), or a home-based rehabilitation program (Group 3). All patients had rehabilitation for 12 weeks. Pain level was evaluated with a visual analogue scale (VAS) and the range of motion (ROM) was measured with a goniometer. The Modified American Shoulder and Elbow Surgery (MASES) score was used in functional assessment. Flexion, abduction, internal and external rotation strengths were measured with a manual muscle test. All patients were evaluated before, and at the 4th and 12th week of the rehabilitation. RESULTS: All groups experienced significant decrease in pain and an increase in shoulder muscle strength and function by both the 4th and 12th weeks of treatment (p<0.05). There was no significant difference between the groups in terms of function (p>0.05). However, the greatest improvement in functionality was found in Group 2. CONCLUSION: Supervised exercise, supervised and manual therapy, and home-based exercise are all effective and promising methods in the rehabilitation of the patients with subacromial impingement syndrome. The addition of an initial manual therapy may improve the results of the rehabilitation with exercise.

Psychological treatments for pediatric headache.

Headache is the most common pain problem in children and adolescents and, in a considerable proportion, a source of suffering and disability. Medical intervention mainly relies on abortive pharmacological agents (analgesics and antimigraine drugs). Psychological therapies aim at the prevention of headache episodes and the modifications of cognitive-emotional and cognitive-behavioral processes influencing pain. Three main forms of therapy have been evaluated in randomized controlled trials and reviewed in meta-analyses: relaxation training, biofeedback and multimodal cognitive-behavioral therapy. So far there is only scarce evidence on hypnosis and acceptance and commitment therapy, although they seem to be promising. Evidence demonstrates that psychological therapies are efficacious, and that clinically relevant improvement is found in approximately 70% of the treated children at follow-up examination. Future research needs to focus on mechanisms of change, and to extend its view of effects induced by therapy beyond headache improvement to indicators of quality of life.

Antinociceptive effects of MSVIII-19, a functional antagonist of the GluK1 kainate receptor.

The ionotropic glutamate receptor subunit, GluK1 (GluR5), is expressed in many regions of the nervous system related to sensory transmission. Recently, a selective ligand for the GluK1 receptor, MSVIII-19 (8,9-dideoxy-neodysiherbaine), was synthesized as a derivative of dysiherbaine, a toxin isolated from the marine sponge Lendenfeldia chondrodes. MSVIII-19 potently desensitizes GluK1 receptors without channel activation, rendering it useful as a functional antagonist. Given the high selectivity for GluK1 and the proposed role for this glutamate receptor in nociception, we sought to test the analgesic potential of MSVIII-19 in a series of models of inflammatory, neuropathic, and visceral pain in mice. MSVIII-19 delivered intrathecally dose-dependently reduced formalin-induced spontaneous behaviors and reduced thermal hypersensitivity 3 hours after formalin injection and 24 hours after complete Freund's adjuvant-induced inflammation, but had no effect on mechanical sensitivity in the same models. Intrathecal MSVIII-19 significantly reduced both thermal hyperalgesia and mechanical hypersensitivity in the chronic constriction injury model of neuropathic pain, but had no effect in the acetic acid model of visceral pain. Peripheral administration of MSVIII-19 had no analgesic efficacy in any of these models. Finally, intrathecal MSVIII-19 did not alter responses in Tail-flick tests or performance on the accelerating RotaRod. These data suggest that spinal administration of MSVIII-19 reverses hypersensitivity in several models of pain in mice, supporting the clinical potential of GluK1 antagonists for the management of pain.

Differential distribution of activated spinal neurons containing glycine and/or GABA and expressing c-fos in acute and chronic pain models.

The inhibitory transmitters GABA and glycine play an important role in modulating pain transmission, both in normal and in pathological situations. In the present study we have combined in situ hybridization for identifying spinal neurons that use the transmitter(s) glycine and/or GABA (Gly/GABA neurons) with immunohistochemistry for c-fos, a marker for neuronal activation. This procedure was used with acute pain models induced by the injection of capsaicin or formalin; and chronic pain models using Complete Freund's Adjuvant (CFA, chronic inflammation), and the spared nerve injury (SNI) model (neuropathic pain). In all models Gly/GABA neurons were activated as indicated by their expression of c-fos. The pattern of Gly/GABA neuronal activation was different for every model, both anatomically and quantitatively. However, the averaged percentage of activated neurons that were Gly/GABA in the chronic phase (≥20h survival, 46%) was significantly higher than in the acute phase (≤2h survival, 34%). In addition, the total numbers of activated Gly/GABA neurons were similar in both phases, showing that the activation of non-Gly/GABA (presumed excitatory) neurons in the chronic phase decreased. Finally, morphine application equally decreased the total number of activated neurons and activated Gly/GABA neurons. This showed that morphine did not specifically activate Gly/GABA neurons to achieve nociceptive inhibition. The present study shows an increased activity of Gly/GABA neurons in acute and chronic models. This mechanism, together with mechanisms that antagonize the effects of GABA and glycine at the receptor level, may determine the sensitivity of our pain system during health and disease.