Sex Differences in Acute Pain and Analgesic Responses: Psychosocial and Genetic I

摘要：疼痛是最昂贵和普遍的公共卫生问题之一，女性和少数民族面临治疗不足和管理不善的风险增加。与男性相比，女性报告更频繁和强烈的疼痛，并且在多种情况下，使人虚弱的疼痛的患病率增加。在每年进行的4000万次门诊和门诊手术中，妇女也占了大多数。急性术后疼痛和治疗不足的疼痛是有充分证据的，会导致恢复时间延长，并有可能发展成慢性长期疼痛状况。尽管在镇痛疗效的性别差异方面发现不一致，但一致的报告显示，与男性相比，女性经历的药物不良反应（adr）多30%-75%。不良反应可导致危及生命的并发症、停止疼痛治疗、恢复时间延长和不遵医嘱。最近的药物基因组学研究表明，基因型可能导致某些药物的药代动力学（PK）和药效学（PD）反应的性别差异。在疼痛研究领域，遗传和非遗传因素对阿片类药物镇痛的性别差异、相关副作用和治疗结果的影响受到有限的关注。本研究将使用一个常见的急性临床疼痛模型来识别和表征导致疼痛感知、镇痛和副作用的性别差异的社会心理、生理和遗传因素。目的1将确定对急性术后疼痛的感知和生理反应的性别差异，并将研究这些差异与遗传、术前心理物理和社会心理因素的关系。目的2将确定阿片类药物镇痛和副作用的性别差异，并将检查解释镇痛反应组差异的遗传、PK、PD和社会心理因素。140名接受第三磨牙拔除的男性和女性患者（年龄16-45岁）将被纳入本研究。术前，我们将评估实验性疼痛反应和社会心理测量。我们将监测术后疼痛水平以及对阿片类芬太尼的PK/PD反应。我们将立即、术后数小时和术后3天检查术后疼痛、镇痛反应和副作用的性别差异。该研究旨在为R01拨款提案奠定基础，以支持独立的临床相关疼痛实验研究。该项目将加强对疼痛的转化研究以及造成疼痛及其治疗方面健康差异的生物心理社会因素的理解，特别是对妇女而言。此外，这项研究将提供复杂的遗传，PK/PD过程参与术后疼痛和镇痛反应，并将阐明疼痛和副作用的性别差异的生物心理社会贡献。最终目标是开展转化研究，通过制定量身定制的干预措施来提高妇女的生活质量，从而减轻妇女临床疼痛日益增加的负担，这与美国国立卫生研究院妇女健康研究办公室的优先事项相一致。公共卫生相关性：疼痛是美国最昂贵和最普遍的公共卫生问题之一，妇女疼痛治疗不足的风险增加。本研究将使用一个常见的急性临床疼痛模型来识别和表征导致疼痛感知、镇痛和副作用的性别差异的社会心理、生理和遗传因素。最终目标是开展转化研究，通过制定量身定制的干预措施来提高妇女的生活质量，从而减轻妇女临床疼痛日益增加的负担，这与美国国立卫生研究院妇女健康研究办公室的优先事项相一致。

DESCRIPTION (provided by applicant): Sex Differences in Acute Pain and Analgesic Responses: Psychosocial and Genetic Influences ABSTRACT: Pain is one of the most costly and pervasive public health problems, with women and minorities facing increased risk for under-treated and mismanaged pain. Women, compared to men, report more frequent and intense pain and have increased prevalence of debilitating pain across a multitude of conditions. Women also represent the majority of the 40 million outpatient and ambulatory surgeries conducted each year. Acute post- operative pain and under-treatment of pain are well-documented and lead to prolonged recovery and potentially to development of chronic long-term pain conditions. Despite incongruent findings of sex differences in analgesic efficacy, consistent reports show that women experience between 30%-75% more adverse drug reactions (ADRs) compared to men. ADRs can lead to life-threatening complications, discontinuation of pain treatment, prolonged recovery and non-compliance. Recent pharmacogenomic studies have demonstrated that genotype may contribute to sex differences in pharmacokinetic (PK) and pharmacodynamic (PD) responses to certain drugs. Genetic and nongenetic contributions to sex differences in opioid analgesia, related side effects and treatment outcome have received limited attention in the field of pain research. This study will use a common acute clinical pain model to identify and characterize psychosocial, physiological and genetic factors that contribute to sex differences in pain perception, analgesia and side effects. Aim 1 will determine sex differences in perceptual and physiological responses to acute post-operative pain and will examine how those are related to genetic, pre-operative psychophysical and psychosocial factors. Aim 2 will determine sex differences in opioid analgesia and side effects and will examine genetic, PK, PD, and psychosocial factors that explain group differences in analgesic responses. 140 male and female patients (age range 16-45) who undergo third molar extraction will be included in this study. Preoperatively, we will assess experimental pain responses and psychosocial measures. We will monitor post-operative pain levels along with PK/PD responses to the opioid fentanyl. We will examine sex differences in post-operative pain, analgesic responses and side effects immediately and for several hours post-surgery and for 3 days post-procedure. The study is designed to build a foundation for a R01 grant proposal supporting an independent line of clinically-relevant experimental pain research. This project will enhance understanding of translational research in pain as well as biopsychosocial factors that contribute to health disparities in pain and its treatment, particularly for women. Additionally, this study will provide insight into the complex genetic, PK/PD processes involved in post- operative pain and analgesic responses and will elucidate biopsychosocial contributions to sex differences in pain and side effects. The ultimate goal is to develop translational research that will reduce the increased burden of clinical pain in women through the development of tailored interventions designed to enhance the quality of life for women, consistent with priorities of the NIH Office of Research on Women's Health. PUBLIC HEALTH RELEVANCE: Pain is one of the most costly and pervasive public health problems in the United States, and women are at increased risk for under-treatment of pain. This study will use a common acute clinical pain model to identify and characterize psychosocial, physiological and genetic factors that contribute to sex differences in pain perception, analgesia and side effects. The ultimate goal is to develop translational research that will reduce the increased burden of clinical pain in women through the development of tailored interventions designed to enhance the quality of life for women, consistent with priorities of the NIH Office of Research on Women's Health.