Assessing a Clinically-meaningful Opioid Withdrawal Phenotype

美国正处于阿片类药物流行之中，阿片类药物相关的发病率和死亡率非常高， 正在降低美国人的平均预期寿命美国目前对OUD治疗的需求远远超过了 可用治疗槽和治疗通路的数量由于并非所有患者 与我们目前的OUD药物疗法有类似的反应。我们是测量专家， 阿片类药物戒断症状的评价，用于OUD治疗的新型药物的评价，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 一项更大规模的RCT表明，患者可分为高戒断表型和低戒断表型， 与参与者在后续RCT中对OUD治疗药物的临床反应相关。这 R 01将跟进我们发表的有希望的初步数据，这些数据表明临床上存在- 有意义的人类阿片类药物戒断表型。我们建议进行一次严格的，高度控制的人类 实验室+自发戒断研究，以验证和研究这些表型。这些数据将 促进表型驱动的阿片类药物戒断管理的机会。我们将招收同等数量的 有OUD的男性和女性进入一个住宅研究。受试者将稳定使用阿片类激动剂 在此期间，他们将用安慰剂或OUD完成两次纳洛酮挑战 药物洛非西定，然后开始临床洛非西定辅助锥度和随后过渡到 复发预防药物纳洛酮。主要目的1将确定阿片类药物戒断表型。我们 假设参与者将分成两个潜在类别，这两个类别与表达 高或低阿片类戒断表型。主要目的2将确定纳洛酮 激发表型与随后临床减量期间的退出相关。我们 假设纳洛酮激发期间表型分类与SOWS显著相关 逐渐减量期间的AUC值。次要目标1将确定行为和生理相关性， 阿片类药物戒断严重程度。我们假设，经历不同水平阿片类药物的参与者 戒断将显示行为（Subaim 1）或生理（Subaim 2）相关性的差异。二次 目标2将确定性别在退缩表达中的作用。我们假设男性和女性 不同的戒断严重程度（目标1），从纳洛酮激发阶段戒断将对应于 男性和女性在临床减量期间退出（目标2），男性和女性将有不同的 行为和生理与阿片类药物戒断严重程度相关（次要目的1）。复制我们的 通过确认阿片类戒断表型的存在，先前的结果将有助于促进个性化治疗。 OUD的医学方法，并了解导致戒断严重程度的因素（独立于 表型）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.