Assessing a Clinically-meaningful Opioid Withdrawal Phenotype

美国正处于阿片类药物流行之中，与阿片类药物相关的发病率和死亡率如此之高，以至于 正在减少美国人的平均预期寿命。目前美国对OUD治疗的需求远远超过 可用治疗槽和治疗通道的数量进一步复杂化，因为并非所有患者 对我们目前的OUD药物疗法做出类似的反应。我们是测量和测量方面的专家 评估阿片类药物戒断症状，评估用于OUD治疗的新药物，以及 评估对阿片类药物反应的个体差异。我们最近进行了一项分析， 一项较大的随机对照试验表明，患者可以分为高戒断表型和低戒断表型，这些表型 与参与者在随后的随机对照试验中对OUD治疗药物的临床反应相关。这 R01将跟进我们公布的有希望的初步数据，这些数据表明，在临床上- 有意义的人类阿片戒断表型。我们建议引导一个严格的、高度受控的人类 实验室+自发戒断研究，以验证和研究这些表型。这些数据将 表型驱动的阿片类药物戒断管理的提前机会。我们将招收同等数量的 男男女女们纷纷走进一间寄宿书房。参与者将被稳定在阿片类激动剂上 在短时间内，他们将用安慰剂或OUD完成两次纳洛酮挑战 药物洛非西定，在开始临床洛非西定辅助的逐渐减少和随后过渡到 预防复发药物纳曲酮。主要目标1将确定阿片类药物戒断表型。我们 假设参与者将分为两个潜在类别，这将与表达 高或低阿片类药物戒断表型。主要目标2将决定纳洛酮治疗的程度 在随后的临床试验中，挑战表型与撤药有关。我们 假设纳洛酮挑战期间的表型等级与母猪显著相关 锥化过程中的AUC值。次要目标1将确定以下行为和生理关联 阿片类药物戒断的严重性。我们假设那些经历了不同程度的阿片类药物的参与者 戒断将在行为(Subaim 1)或生理(Subaim 2)相关方面表现出差异。次要的 目的2将确定性别在戒断表达中的作用。我们假设男人和女人都会有 不同戒断严重程度(目标1)，退出纳洛酮质询会议将符合 男性和女性在临床缩减期间停药(目标2)，男性和女性将有不同 行为和生理与阿片类药物戒断严重程度相关(次要目标1)。复制我们的 先前通过确认阿片类药物戒断表型的存在的结果将有助于推进个性化 OUD的医学方法和对影响戒断严重程度的因素的理解(独立于 在男性和女性中)将更广泛地扩大新药开发的机会。

The US is in the midst of an opioid epidemic with rates of opioid-related morbidity and mortality so high they are decrementing average US life expectancy. The current need in the US for OUD treatment far exceeds the number of available treatment slots and treatment access is further complicated by the fact that not all patients respond in a similar way to our current OUD pharmacotherapies. We are experts in the measurement and evaluation of opioid withdrawal symptoms, the evaluation of novel medications for OUD treatment, and the assessment of individual differences in response to opioid medications. We recently conducted an analysis of a larger RCT that suggested patients could be classified into HIGH and LOW withdrawal phenotypes that were associated with the participant’s clinical response to OUD treatment medications in the subsequent RCT. This R01 will follow up on promising preliminary data we have published that suggests there are clinically- meaningful human opioid withdrawal phenotypes. We propose to conduct a rigorous, highly controlled human laboratory + spontaneous withdrawal study to verify and investigate these phenotypes. These data will advance opportunities for phenotype-driven opioid withdrawal management. We will enroll equal numbers of men and women who have OUD into a residential study. Participants will be stabilized onto an opioid agonist for a brief period, during which they will complete two naloxone challenges with a placebo or the OUD medication lofexidine, before beginning a clinical lofexidine-assisted taper and subsequent transition to the relapse prevention medication naltrexone. Primary aim 1 will identify opioid withdrawal phenotypes. We hypothesize that participants will separate into two latent classes that will be consistent with expressing a HIGH or LOW opioid withdrawal phenotype. Primary aim 2 will determine the degree to which naloxone challenge phenotype is associated with withdrawal during the subsequent clinical taper. We hypothesize that phenotype class during the naloxone challenge will be significantly associated with SOWS AUC values during the taper. Secondary Aim 1 will identify behavioral and physiological correlates of opioid withdrawal severity. We hypothesize that participants who experience varying levels of opioid withdrawal will show differences in behavioral (Subaim 1) or physiological (Subaim 2) correlates. Secondary Aim 2 will determine role of sex in withdrawal expression. We hypothesize that men and women will have different withdrawal severity (Aim 1), that withdrawal from the naloxone challenge session will correspond with withdrawal during the clinical taper in men and women (Aim 2), and that men and women will have different behavioral and physiological correlates with opioid withdrawal severity (Secondary Aim 1). Replicating our previous results by confirming presence of an opioid withdrawal phenotype will help advance personalized medicine approach to OUD, and understanding factors contributing to withdrawal severity (independent of phenotype) in men and women will expand opportunities for new medication development more broadly.