RESUMO
The Sedation Consortium on Endpoints and Procedures for Treatment, Education, and Research, established by the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks, a public-private partnership with the US Food and Drug Administration, convened a second meeting of sedation experts from a variety of clinical specialties and research backgrounds to develop recommendations for procedural sedation research. The previous meeting addressed efficacy and patient- and/or family-centered outcomes. This meeting addressed issues of safety, which was defined as "the avoidance of physical or psychological harm." A literature review identified 133 articles addressing safety measures in procedural sedation clinical trials. After basic reporting of vital signs, the most commonly measured safety parameter was oxygen saturation. Adverse events were inconsistently defined throughout the studies. Only 6 of the 133 studies used a previously validated measure of safety. The meeting identified methodological problems associated with measuring infrequent adverse events. With a consensus discussion, a set of core and supplemental measures were recommended to code for safety in future procedural clinical trials. When adopted, these measures should improve the integration of safety data across studies and facilitate comparisons in systematic reviews and meta-analyses.
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Ensaios Clínicos como Assunto/métodos , Sedação Consciente/métodos , Determinação de Ponto Final , Hipnóticos e Sedativos/uso terapêutico , Avaliação de Processos e Resultados em Cuidados de Saúde/métodos , Avaliação de Resultados da Assistência ao Paciente , Projetos de Pesquisa , Sedação Consciente/efeitos adversos , Consenso , Humanos , Hipnóticos e Sedativos/efeitos adversos , Segurança do Paciente , Medição de Risco , Fatores de Risco , Resultado do TratamentoRESUMO
The Sedation Consortium on Endpoints and Procedures for Treatment, Education, and Research, established by the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks public-private partnership with the US Food and Drug Administration, convened a meeting of sedation experts from a variety of clinical specialties and research backgrounds with the objective of developing recommendations for procedural sedation research. Four core outcome domains were recommended for consideration in sedation clinical trials: (1) safety, (2) efficacy, (3) patient-centered and/or family-centered outcomes, and (4) efficiency. This meeting identified core outcome measures within the efficacy and patient-centered and/or family-centered domains. Safety will be addressed in a subsequent meeting, and efficiency will not be addressed at this time. These measures encompass depth and levels of sedation, proceduralist and patient satisfaction, patient recall, and degree of pain experienced. Consistent use of the recommended outcome measures will facilitate the comprehensive reporting across sedation trials, along with meaningful comparisons among studies and interventions in systematic reviews and meta-analyses.
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Pesquisa Biomédica/normas , Ensaios Clínicos como Assunto/normas , Determinação de Ponto Final/normas , Hipnóticos e Sedativos/normas , Segurança do Paciente/normas , Assistência Centrada no Paciente/normas , Anestesia/efeitos adversos , Anestesia/normas , Pesquisa Biomédica/métodos , Ensaios Clínicos como Assunto/métodos , Congressos como Assunto/normas , Sedação Consciente/métodos , Sedação Consciente/normas , District of Columbia , Determinação de Ponto Final/métodos , Humanos , Hipnóticos e Sedativos/efeitos adversos , Hipnóticos e Sedativos/uso terapêutico , Satisfação do Paciente , Assistência Centrada no Paciente/métodos , Resultado do TratamentoRESUMO
A B S T R A C T The drugs available for the management of acute orofacial pain have changed very little since the introduction of ibuprofen into practice 40 years ago. Orally effective opioids, acetaminophen, aspirin and NSAIDs remain the mainstay of analgesic therapy. Increased recognition of the societal and personal impact of opioid diversion and abuse requires re-examination of the traditional approach of prescribing an opioid-containing analgesic combination to be administered by the patient "as needed" (PRN) starting postoperatively.
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Dor Aguda/prevenção & controle , Analgésicos/uso terapêutico , Dor Facial/prevenção & controle , Dor Aguda/tratamento farmacológico , Anti-Inflamatórios/uso terapêutico , Combinação de Medicamentos , Dor Facial/tratamento farmacológico , Humanos , Entorpecentes/uso terapêuticoRESUMO
BACKGROUND: A panel convened by the American Dental Association Science and Research Institute, the University of Pittsburgh, and the University of Pennsylvania conducted systematic reviews and meta-analyses and formulated evidence-based recommendations for the pharmacologic management of acute dental pain after simple and surgical tooth extraction(s) and for the temporary management (ie, definitive dental treatment not immediately available) of toothache associated with pulp and periapical diseases in adolescents, adults, and older adults. TYPES OF STUDIES REVIEWED: The panel conducted 4 systematic reviews to determine the effect of opioid and nonopioid analgesics, local anesthetics, corticosteroids, and topical anesthetics on acute dental pain. The panel used the Grading of Recommendations, Assessment, Development and Evaluation approach to assess the certainty of the evidence and the Grading of Recommendations, Assessment, Development and Evaluation Evidence-to-Decision Framework to formulate recommendations. RESULTS: The panel formulated recommendations and good practice statements using the best available evidence. There is a beneficial net balance favoring the use of nonopioid medications compared with opioid medications. In particular, nonsteroidal anti-inflammatory drugs alone or in combination with acetaminophen likely provide superior pain relief with a more favorable safety profile than opioids. CONCLUSIONS AND PRACTICAL IMPLICATIONS: Nonopioid medications are first-line therapy for managing acute dental pain after tooth extraction(s) and the temporary management of toothache. The use of opioids should be reserved for clinical situations when the first-line therapy is insufficient to reduce pain or there is contraindication of nonsteroidal anti-inflammatory drugs. Clinicians should avoid the routine use of just-in-case prescribing of opioids and should exert extreme caution when prescribing opioids to adolescents and young adults.
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Dor Aguda , Analgésicos Opioides , Humanos , Estados Unidos , Idoso , Adolescente , Analgésicos Opioides/uso terapêutico , Odontalgia/tratamento farmacológico , American Dental Association , Dor Aguda/tratamento farmacológico , Anti-Inflamatórios não Esteroides/uso terapêutico , Academias e InstitutosRESUMO
BACKGROUND: A guideline panel convened by the American Dental Association Council on Scientific Affairs, American Dental Association Science and Research Institute, University of Pittsburgh School of Dental Medicine, and Center for Integrative Global Oral Health at the University of Pennsylvania conducted a systematic review and meta-analyses and formulated evidence-based recommendations for the pharmacologic management of acute dental pain after 1 or more simple and surgical tooth extractions and the temporary management of toothache (that is, when definitive dental treatment not immediately available) associated with pulp and furcation or periapical diseases in children (< 12 years). TYPES OF STUDIES REVIEWED: The authors conducted a systematic review to determine the effect of analgesics and corticosteroids in managing acute dental pain. They used the Grading of Recommendations Assessment, Development and Evaluation approach to assess the certainty of the evidence and the Grading of Recommendations Assessment, Development and Evaluation Evidence to Decision framework to formulate recommendations. RESULTS: The panel formulated 7 recommendations and 5 good practice statements across conditions. There is a small beneficial net balance favoring the use of nonsteroidal anti-inflammatory drugs alone or in combination with acetaminophen compared with not providing analgesic therapy. There is no available evidence regarding the effect of corticosteroids on acute pain after surgical tooth extractions in children. CONCLUSIONS AND PRACTICAL IMPLICATIONS: Nonopioid medications, specifically nonsteroidal anti-inflammatory drugs like ibuprofen and naproxen alone or in combination with acetaminophen, are recommended for managing acute dental pain after 1 or more tooth extractions (that is, simple and surgical) and the temporary management of toothache in children (conditional recommendation, very low certainty). According to the US Food and Drug Administration, the use of codeine and tramadol in children for managing acute pain is contraindicated.
Assuntos
Acetaminofen , Dor Aguda , Estados Unidos , Humanos , Criança , American Dental Association , Saúde Bucal , Odontalgia/tratamento farmacológico , Academias e Institutos , Anti-Inflamatórios não EsteroidesAssuntos
Acetaminofen/uso terapêutico , Analgésicos Opioides/uso terapêutico , Hidrocodona/uso terapêutico , Dente Serotino/cirurgia , Dor Pós-Operatória/prevenção & controle , Padrões de Prática Odontológica/estatística & dados numéricos , Extração Dentária , Dente Impactado/cirurgia , Combinação de Medicamentos , Prescrições de Medicamentos , HumanosRESUMO
BACKGROUND: The role that nitric oxide (NO) plays in modulating pain in the periphery is unclear. We show here, the results of two independent clinical studies (microdialysis and gene expression studies) and a pilot dose finding study (glyceryl trinitrate study), to study the role of NO in the early phase of acute inflammatory pain following oral surgery. The effect of ketorolac on NO production and nitric oxide synthase (NOS) gene expression was also studied. RESULTS: Microdialysis samples showed significantly higher levels of NO at the first 100 min compared to the last 80 minutes in the placebo treated group. In the ketorolac group, on the other hand, NO levels gradually decreased over the first 60 min but were similar to placebo over the later 100-180 min, with no significant change in NO level over time. The levels of NO were negatively correlated to pain intensity scores. Local infusion of the NO donor glyceryl trinitrate at the site of surgery, showed a small analgesic effect that did not reach statistical significance in the sample size used. While the gene expression of iNOS and eNOS were not up-regulated, 3 hours after surgery, nNOS was downregulated in both treatment groups and eNOS gene expression was significantly lower in the ketorolac group compared to the placebo group. Further, there was a positive correlation between the change in gene expression of nNOS and eNOS in the placebo group but not in the ketorolac group. CONCLUSION: We suggest that at this early stage of inflammatory pain in man, NO is analgesic in the periphery. Further, ketorolac down-regulates eNOS gene expression.
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Inflamação/complicações , Inflamação/tratamento farmacológico , Óxido Nítrico/metabolismo , Dor/complicações , Dor/tratamento farmacológico , Doença Aguda , Adolescente , Adulto , Feminino , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Humanos , Isoenzimas/genética , Isoenzimas/metabolismo , Cetorolaco/administração & dosagem , Cetorolaco/farmacologia , Cetorolaco/uso terapêutico , Modelos Lineares , Masculino , Microdiálise , Modelos Biológicos , Doadores de Óxido Nítrico/administração & dosagem , Doadores de Óxido Nítrico/farmacologia , Doadores de Óxido Nítrico/uso terapêutico , Óxido Nítrico Sintase/genética , Óxido Nítrico Sintase/metabolismo , Nitroglicerina/administração & dosagem , Nitroglicerina/farmacologia , Nitroglicerina/uso terapêutico , Adulto JovemRESUMO
BACKGROUND: Kinins play an important role in regulation of pain and hyperalgesia after tissue injury and inflammation by activating two types of G-protein-coupled receptors, the kinin B1 and B2 receptors. It is generally accepted that the B2 receptor is constitutively expressed, whereas the B1 receptor is induced in response to inflammation. However, little is known about the regulatory effects of kinin receptors on the onset of acute inflammation and inflammatory pain in humans. The present study investigated the changes in gene expression of kinin receptors and the levels of their endogenous ligands at an early time point following tissue injury and their relation to clinical pain, as well as the effect of COX-inhibition on their expression levels. RESULTS: Tissue injury resulted in a significant up-regulation in the gene expression of B1 and B2 receptors at 3 hours post-surgery, the onset of acute inflammatory pain. Interestingly, the up-regulation in the gene expression of B1 and B2 receptors was positively correlated to pain intensity only after ketorolac treatment, signifying an interaction between prostaglandins and kinins in the inflammatory pain process. Further, the gene expression of both B1 and B2 receptors were correlated. Following tissue injury, B1 ligands des-Arg9-BK and des-Arg10-KD were significantly lower at the third hour compared to the first 2 hours in both the placebo and the ketorolac treatment groups but did not differ significantly between groups. Tissue injury also resulted in the down-regulation of TRPV1 gene expression at 3 hours post-surgery with no significant effect by ketorolac treatment. Interestingly, the change in gene expression of TRPV1 was correlated to the change in gene expression of B1 receptor but not B2 receptor. CONCLUSIONS: These results provide evidence at the transcriptional level in a clinical model of tissue injury that up-regulation of kinin receptors are involved in the development of the early phase of inflammation and inflammatory pain. The up-regulation of B1 receptors may contribute to acute inflammatory pain through TRPV1 activation.
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Inflamação/metabolismo , Dor Pós-Operatória/metabolismo , Receptor B1 da Bradicinina/genética , Receptor B2 da Bradicinina/genética , Doença Aguda , Adolescente , Adulto , Bradicinina/metabolismo , Inibidores de Ciclo-Oxigenase/farmacologia , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Humanos , Inflamação/tratamento farmacológico , Inflamação/fisiopatologia , Cetorolaco/farmacologia , Masculino , Dor Pós-Operatória/tratamento farmacológico , Dor Pós-Operatória/fisiopatologia , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/metabolismo , Canais de Cátion TRPV/genética , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética , Adulto JovemRESUMO
Biomedical science has greatly improved our understanding of pain in recent decades, but few novel molecular entities that address fundamentally new pain mechanisms have entered the clinic, despite dramatically increased pharmaceutical investment. Indeed, virtually all new analgesics approved over the past 25 years are derivatives or reformulations of opioids or aspirin-like drugs, existing drugs given for a new indication or older drugs given by a different route of administration. Here, we discuss factors contributing to this lack of innovation in therapies for pain and advocate public-private partnerships (PPPs) to translate new knowledge into more efficacious and safer treatments.
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Analgésicos , Desenho de Fármacos , Dor/tratamento farmacológico , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Animais , Ensaios Clínicos como Assunto , Modelos Animais de Doenças , Interações Medicamentosas , Quimioterapia Combinada , HumanosRESUMO
Painful peripheral neuropathy is a debilitating complication of the treatment of HIV with nucleoside reverse transcriptase inhibitors (NRTIs). Patients are living longer with these drugs; however many develop excruciating, unremitting, and often treatment-limiting neuropathy that is resistant to conventional pain management therapies. Improving patient comfort and quality of life is paramount and depends on a clearer understanding of this devastating side effect. The mechanisms underlying the development of NRTI-induced neuropathy, however, remain unclear. Using a mouse model of NRTI-induced neuropathy, the authors conducted an unbiased whole-genome microarray screen to identify molecular targets in the spinal dorsal horn, which is the location where integration of ascending sensory transmission and descending modulatory effects occur. Analysis of the microarray data identified a change in the gene giant axonal neuropathy 1 (Gan1). Mutation of this gene has been linked to the development of giant axonal neuropathy (GAN), a rare autosomal recessive condition characterized by a progressive sensorimotor neuropathy. Gan1 has not been previously linked to nerve pathologies in other populations. In this study, downregulation of the Gan1 gene and the gene protein product, gigaxonin, was validated via quantitative polymerase chain reaction ([qPCR] gene expression) and Western blot analyses (protein level). Our report is the first to suggest that Gan1 might be a novel molecular target in the development of NRTI-induced peripheral neuropathy with implications for new therapeutic approaches to preventing or reducing a significant side effect of HIV treatment.
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Proteínas do Citoesqueleto , Modelos Animais de Doenças , Regulação da Expressão Gênica , Doenças do Sistema Nervoso Periférico , Inibidores da Transcriptase Reversa/efeitos adversos , Estavudina/efeitos adversos , Análise de Variância , Animais , Western Blotting , Mapeamento Cromossômico , Proteínas do Citoesqueleto/análise , Proteínas do Citoesqueleto/efeitos dos fármacos , Proteínas do Citoesqueleto/genética , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pesquisa em Enfermagem , Análise de Sequência com Séries de Oligonucleotídeos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/genética , Reação em Cadeia da Polimerase , Análise Serial de Proteínas , Fatores de TempoRESUMO
Since the first draft of the human genome was published 10 years ago, scientists have tried to develop new treatment strategies for various types of diseases based on individual genomes. It is called personalized (or individualized) medicine and is expected to increase efficacy and reduce adverse reactions of drugs. Much progress has been made with newly developed technologies, though individualized pain medicine is still far from realization. Efforts on the integrative genomic analyses along with understandings of interactions between other related factors such as environment will eventually translate complex genomic information into individualized pain medicine.
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UNLABELLED: A consensus meeting was convened by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) to provide recommendations for interpreting clinical importance of treatment outcomes in clinical trials of the efficacy and effectiveness of chronic pain treatments. A group of 40 participants from universities, governmental agencies, a patient self-help organization, and the pharmaceutical industry considered methodologic issues and research results relevant to determining the clinical importance of changes in the specific outcome measures previously recommended by IMMPACT for 4 core chronic pain outcome domains: (1) Pain intensity, assessed by a 0 to 10 numerical rating scale; (2) physical functioning, assessed by the Multidimensional Pain Inventory and Brief Pain Inventory interference scales; (3) emotional functioning, assessed by the Beck Depression Inventory and Profile of Mood States; and (4) participant ratings of overall improvement, assessed by the Patient Global Impression of Change scale. It is recommended that 2 or more different methods be used to evaluate the clinical importance of improvement or worsening for chronic pain clinical trial outcome measures. Provisional benchmarks for identifying clinically important changes in specific outcome measures that can be used for outcome studies of treatments for chronic pain are proposed. PERSPECTIVE: Systematically collecting and reporting the recommended information needed to evaluate the clinical importance of treatment outcomes of chronic pain clinical trials will allow additional validation of proposed benchmarks and provide more meaningful comparisons of chronic pain treatments.
Assuntos
Ensaios Clínicos como Assunto/métodos , Manejo da Dor , Medição da Dor/métodos , Projetos de Pesquisa , Resultado do Tratamento , HumanosRESUMO
BACKGROUND: In addition to blocking nociceptive input from surgical sites, long-acting local anesthetics might directly modulate inflammation. In the present study, we describe the proinflammatory effects of bupivacaine on local prostaglandin E2 (PGE2) production and cyclooxygenase (COX) gene expression that increases postoperative pain in human subjects. METHODS: Subjects (n = 114) undergoing extraction of impacted third molars received either 2% lidocaine or 0.5% bupivacaine before surgery and either rofecoxib 50 mg or placebo orally 90 min before surgery and for the following 48 h. Oral mucosal biopsies were taken before surgery and 48 h after surgery. After extraction, a microdialysis probe was placed at the surgical site for PGE2 and thromboxane B2 (TXB2) measurements. RESULTS: The bupivacaine/rofecoxib group reported significantly less pain, as assessed by a visual analog scale, compared with the other three treatment groups over the first 4 h. However, the bupivacaine/placebo group reported significantly more pain at 24 h and PGE2 levels during the first 4 h were significantly higher than the other three treatment groups. Moreover, bupivacaine significantly increased COX-2 gene expression at 48 h as compared with the lidocaine/placebo group. Thromboxane levels were not significantly affected by any of the treatments, indicating that the effects seen were attributable to inhibition of COX-2, but not COX-1. CONCLUSIONS: These results suggest that bupivacaine stimulates COX-2 gene expression after tissue injury, which is associated with higher PGE2 production and pain after the local anesthetic effect dissipates.
Assuntos
Anestésicos Locais/efeitos adversos , Bupivacaína/efeitos adversos , Ciclo-Oxigenase 2/biossíntese , Dinoprostona/metabolismo , Lidocaína/efeitos adversos , Mucosa Bucal/efeitos dos fármacos , Procedimentos Cirúrgicos Bucais , Dor Pós-Operatória/induzido quimicamente , Acetaminofen/uso terapêutico , Adolescente , Adulto , Analgésicos não Narcóticos/uso terapêutico , Analgésicos Opioides/uso terapêutico , Codeína/uso terapêutico , Ciclo-Oxigenase 1/biossíntese , Ciclo-Oxigenase 2/genética , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Método Duplo-Cego , Indução Enzimática/efeitos dos fármacos , Feminino , Humanos , Lactonas/uso terapêutico , Masculino , Dente Serotino/cirurgia , Mucosa Bucal/enzimologia , Mucosa Bucal/metabolismo , Medição da Dor , Dor Pós-Operatória/enzimologia , Dor Pós-Operatória/genética , Dor Pós-Operatória/metabolismo , Dor Pós-Operatória/prevenção & controle , Sulfonas/uso terapêutico , Fatores de Tempo , Dente Impactado/cirurgiaRESUMO
OBJECTIVES: To assess the effect of variations in GTP cyclohydrolase gene (GCH1) on pain sensitivity in humans. METHODS: Thermal and cold pain sensitivity were evaluated in a cohort of 735 healthy volunteers. Among this cohort, the clinical pain responses of 221 subjects after the surgical removal of impacted third molars were evaluated. Genotyping was done for 38 single nucleotide polymorphisms (SNPs) whose heterozygosity > 0.2 in GCH1. Influence of the genetic variations including SNPs and haplotypes on pain sensitivity were analyzed. RESULTS: Minor allele frequencies and linkage disequilibrium show significant differences in European Americans, African Americans, Hispanic Americans and Asian Americans. Association analyses in European Americans do not replicate the previously reported important influence of GCH1 variations on pain sensitivity. CONCLUSION: Considering population stratification, previously reported associations between GCH1 genetic variations and pain sensitivity appear weak or negligible in this well characterized model of pain.
Assuntos
GTP Cicloidrolase/genética , Variação Genética , Limiar da Dor , Dor/genética , Estudos de Coortes , Feminino , Frequência do Gene , Humanos , Desequilíbrio de Ligação , Masculino , Dor/enzimologia , Polimorfismo de Nucleotídeo ÚnicoRESUMO
UNLABELLED: Cyclooxygenase (COX) plays an important role in the induction of pain and inflammation as well as the analgesic actions of NSAIDs and coxibs. This study evaluates the expression of the two isoforms COX-1 and COX-2 in a clinical model in which the surgical removal of impacted third molars is used to evaluate the analgesic activity of anti-inflammatory drugs. A 3-mm punch biopsy was performed on the oral mucosa overlying 1 impacted third molar immediately before extraction of 2 impacted lower third molars. After the second tooth was extracted, a second biopsy was performed adjacent to the surgical site either immediately after surgery or 30, 60, or 120 minutes after surgery. RNA was extracted from the biopsy specimens, and RT-PCR was performed to assess mRNA levels of COX-1, COX-2, and glyceraldehyde-3-phosphate dehydrogenase (G3PDH). The RT-PCR products in the biopsy specimens were normalized to G3PDH and compared with baseline. COX-2 mRNA was progressively increased at 30, 60, and 120 minutes after surgery (P<.05); COX-1 mRNA was transiently decreased at 60 minutes during the postsurgical period (P<.05). The results demonstrate peripheral elevation of COX-2 after tissue injury, which may contribute to increased prostaglandin E(2) at the site of injury, pain onset, and the analgesic activity of both nonselective NSAIDs and selective COX-2 inhibitors. PERSPECTIVE: This clinical study uses a physiologically relevant model to determine the time course of expression of COX-1 and COX-2 in acute inflammation of the human oral mucosa. This study furthers our understanding of the contribution of the COX isoforms to acute pain.
Assuntos
Ciclo-Oxigenase 1/biossíntese , Ciclo-Oxigenase 2/biossíntese , Inflamação/enzimologia , Adolescente , Adulto , Feminino , Regulação Enzimológica da Expressão Gênica/fisiologia , Gliceraldeído-3-Fosfato Desidrogenases/biossíntese , Humanos , Masculino , Dente Serotino/cirurgia , Mucosa Bucal/enzimologia , Dor Pós-Operatória/enzimologia , RNA Mensageiro/biossíntese , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Extração DentáriaRESUMO
Accurate assessment of inappropriate medication use events (ie, misuse, abuse, and related events) occurring in clinical trials is an important component in evaluating a medication's abuse potential. A meeting was convened to review all instruments measuring such events in clinical trials according to previously published standardized terminology and definitions. Only 2 approaches have been reported that are specifically designed to identify and classify misuse, abuse, and related events occurring in clinical trials, rather than to measure an individual's risk of using a medication inappropriately: the Self-Reported Misuse, Abuse, and Diversion (SR-MAD) instrument and the Misuse, Abuse, and Diversion Drug Event Reporting System (MADDERS). The conceptual basis, strengths, and limitations of these methods are discussed. To our knowledge, MADDERS is the only system available to comprehensively evaluate inappropriate medication use events prospectively to determine the underlying intent. MADDERS can also be applied retrospectively to completed trial data. SR-MAD can be used prospectively; additional development may be required to standardize its implementation and fully appraise the intent of inappropriate use events. Additional research is needed to further demonstrate the validity and utility of MADDERS as well as SR-MAD. PERSPECTIVE: Identifying a medication's abuse potential requires assessing inappropriate medication use events in clinical trials on the basis of a standardized event classification system. The strengths and limitations of the 2 published methods designed to evaluate inappropriate medication use events are reviewed, with recommended considerations for further development and current implementation.
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Analgésicos Opioides/uso terapêutico , Ensaios Clínicos como Assunto , Transtornos Relacionados ao Uso de Opioides/diagnóstico , Uso Indevido de Medicamentos sob Prescrição , Ensaios Clínicos como Assunto/métodos , HumanosRESUMO
The outcomes of clinical trials are based on the mean responses of large numbers of subjects but fail to address inter-individual differences. The molecular mechanisms that underlie pain vary among individuals over time and among different types of pain to produce wide inter-individual variations in pain perception and response. Gender, ethnicity, temperament and genetic factors also contribute to individual variation in pain sensitivity and responses to analgesics. Pain measurement scales can be used differently across individuals based on the past pain experiences of individuals. We propose that individual responder analyses could be used in clinical trials to better detect analgesic activity across patient groups and within sub-groups, and to identify molecular-genetic mechanisms that contribute to individual variation.
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Medição da Dor/métodos , Dor/fisiopatologia , Ensaios Clínicos como Assunto/métodos , Ensaios Clínicos como Assunto/tendências , Humanos , Dor/tratamento farmacológico , Medição da Dor/efeitos dos fármacos , Medição da Dor/normas , Reprodutibilidade dos TestesRESUMO
BACKGROUND: Candidate gene studies on the basis of biological hypotheses have been a practical approach to identify relevant genetic variation in complex traits. Based on previous reports and the roles in pain pathways, we have examined the effects of variations of loci in the genes of monoamine neurotransmitter systems including metabolizing enzymes, receptors and transporters on acute clinical pain responses in humans. RESULTS: Variations in the catecholamine metabolizing enzyme genes (MAOA and COMT) showed significant associations with the maximum post-operative pain rating while the serotonin transporter gene (SLC6A4) showed association with the onset time of post-operative pain. Analgesic onset time after medication was significantly associated with the norepinephrine transporter gene (SLC6A2). However, the association between COMT genetic variation and pain sensitivity in our study differ from previous studies with small sample sizes, population stratification and pain phenotype derived from combining different types of pain stimuli. Correcting for multiple comparisons did not sustain these genetic associations between monoamine neurotransmitter systems and pain sensitivity even in this large and homogeneous sample. CONCLUSION: These results suggest that the previously reported associations between genetic polymorphisms in the monoamine neurotransmitter systems and the interindividual variability in pain responses cannot be replicated in a clinically relevant pain phenotype.
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Monoaminas Biogênicas/metabolismo , Química Encefálica/genética , Sistema Nervoso Central/metabolismo , Predisposição Genética para Doença/genética , Dor Pós-Operatória/genética , Polimorfismo Genético/genética , Doença Aguda , Catecol O-Metiltransferase/genética , Catecolaminas/metabolismo , Sistema Nervoso Central/fisiopatologia , Análise Mutacional de DNA , Feminino , Frequência do Gene/genética , Testes Genéticos , Variação Genética/genética , Genótipo , Humanos , Masculino , Monoaminoxidase/genética , Neurotransmissores/metabolismo , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/genética , Limiar da Dor , Dor Pós-Operatória/metabolismo , Dor Pós-Operatória/fisiopatologia , Polimorfismo de Nucleotídeo Único/genética , Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/genéticaRESUMO
BACKGROUND: Cyclooxygenase-2 (COX-2) and COX-2-derived prostaglandins contribute to acute inflammation and pain, as well as resolution of inflammation; inhibition of COX-2 results in persistence of inflammation. Because matrix metalloproteinases (MMPs) play an essential role in inflammatory tissue injury and their activity is regulated by COX-2-derived prostaglandin E2, we evaluated whether COX-2 inhibition is associated with MMP overexpression during acute inflammation. METHODS: A total of 102 oral mucosal biopsy specimens were taken from 51 healthy volunteers who required extraction of impacted third molars. Subjects randomly received either rofecoxib (50 mg daily), ibuprofen (400 mg 4 times per day), or placebo 90 minutes before surgery and up to 48 hours after surgery. Total ribonucleic acid extracted from each biopsy specimen was used to analyze changes in gene expression related to the MMP pathway after tissue injury and drug treatments by use of microarray and quantitative real-time polymerase chain reaction in this clinical model of acute inflammation. RESULTS: Following tissue injury, rofecoxib increased the expression of genes associated with degradation of the extracellular matrix, including MMP-1 (64.7 +/- 6.5, P = .010), MMP-3 (41.7 +/- 4.8, P = .007), PLAT (encoding tissue plasminogen activator) (10.9 +/- 4.6, P = .032), and IL8 (encoding interleukin 8) (8.3 +/- 6.7, P = .020), and decreased the expression of TIMP3 (encoding tissue inhibitor of metalloproteinase 3) (6.2 +/- 2.8, P = .027). Ibuprofen produced similar effects on the expression of MMP-1 (23.4 +/- 5.0, P = .016) and MMP-3 (26.3 +/- 4.2, P = .003). In contrast, the expression of these genes was not statistically changed after tissue injury in the placebo group. The microarray data were in concordance with the changes in gene expression confirmed by quantitative real-time polymerase chain reaction. CONCLUSION: These findings provide evidence at the transcriptional level that inhibition of COX-2, in the presence of acute inflammation, induces changes in gene expression related to the MMP pathway. These changes may contribute to the adverse effects attributed to COX-2 inhibition by interfering with resolution of inflammation.
Assuntos
Inibidores de Ciclo-Oxigenase 2/farmacologia , Ciclo-Oxigenase 2/efeitos dos fármacos , Lactonas/farmacologia , Metaloproteinases da Matriz/efeitos dos fármacos , Sulfonas/farmacologia , Adolescente , Adulto , Ciclo-Oxigenase 2/genética , Inibidores de Ciclo-Oxigenase 2/administração & dosagem , Feminino , Regulação da Expressão Gênica , Humanos , Ibuprofeno/administração & dosagem , Ibuprofeno/farmacologia , Interleucina-8/genética , Interleucina-8/metabolismo , Lactonas/administração & dosagem , Masculino , Metaloproteinase 1 da Matriz/efeitos dos fármacos , Metaloproteinase 1 da Matriz/genética , Metaloproteinase 3 da Matriz/efeitos dos fármacos , Metaloproteinase 3 da Matriz/genética , Inibidores de Metaloproteinases de Matriz , Metaloproteinases da Matriz/genética , Período Pós-Operatório , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sulfonas/administração & dosagem , Inibidor Tecidual de Metaloproteinase-3/efeitos dos fármacos , Inibidor Tecidual de Metaloproteinase-3/genética , Ativador de Plasminogênio Tecidual/efeitos dos fármacos , Ativador de Plasminogênio Tecidual/genéticaRESUMO
BACKGROUND: Wide interindividual variation in responses to cyclooxygenase (COX) inhibitory drugs limits their clinical utility and safety. METHODS: To better understand the molecular responses to COX inhibition, we analyzed the gene expression level of the genes encoding enzymes related to prostaglandin production including the COX-1 gene (PTGS1) and the COX-2 gene (PTGS2), as well as their genetic polymorphisms, and the analgesic response to COX inhibitory drugs such as ibuprofen or rofecoxib or to placebo after minor surgery. RESULTS: Notable heterogeneity in global gene expression was evident between subjects. At 2 to 4 hours after surgery, PTGS1 expression was slightly decreased (36%, P < .001) and PTGS2 expression was markedly increased (300%, P < .001) with wide interindividual variation; at 48 hours after surgery, little detectable change in PTGS1 and PTGS2 expression was found in the control group. However, ibuprofen and rofecoxib treatment significantly increased PTGS2 expression at 48 hours (P = .001 and P = .049, respectively). At 2 to 4 hours after surgery, patients with the G/G allele at the nucleotide position of -765G>C in PTGS2 showed a significantly higher increase in PTGS2 expression (P = .012) compared with G/C and C/C patients, although all of them showed an increase in PTGS2 expression (P < .001 and P = .043, respectively). Among G/G patients, rofecoxib administration resulted in significantly lower pain intensity on a visual analog scale (7.2 +/- 2.5 mm) (P = .008) at 48 hours after surgery, as compared with ibuprofen administration (31.3 +/- 6.7 mm). The finding regarding pain intensity at 48 hours in G/C and C/C patients was opposite (P = .002), being greater in the rofecoxib group (37 +/- 6.8 mm) compared with the ibuprofen group (7 +/- 1.9 mm). CONCLUSIONS: These results suggest that wide variability in gene expression and functional polymorphisms in PTGS2 may explain part of the interindividual variations in acute pain and the analgesic efficacy of nonsteroidal anti-inflammatory drugs and selective COX-2 inhibitors; this may be useful to define individual responders on the basis of genetic variations to predict patient risk and benefit to drugs.