Assessing a Clinically-meaningful Opioid Withdrawal Phenotype

评估具有临床意义的阿片类药物戒断表型

• 批准号: 10580802
• 负责人: Kelly E Dunn
• 金额: $ 65.48万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-15 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10580802
• 关键词: Attention; Behavioral; Buprenorphine; Categories; Classification; Clinical; Clinical Treatment; Clonidine; Data; Data Set; Development; Drug usage; Enrollment; Evaluation; Exposure to; Goals; Health Services Accessibility; Human; Individual; Individual Differences; Laboratories; Learning; Life Expectancy; Measurement; Morbidity - disease rate; Motivation; Naloxone; Naltrexone; Negative Reinforcements; Opioid; Opioid Antagonist; Opioid agonist; Outcome; Outpatients; Participant; Patients; Persons; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Physiological; Placebos; Positive Reinforcements; Provider; Public Health; Publishing; Reporting; Role; Sampling; Severities; Time; Tramadol; Withdrawal; Withdrawal Symptom; Woman; clinically relevant; design; experience; follow-up; lofexidine; medication for opioid use disorder; men; mortality; novel; opioid epidemic; opioid use disorder; opioid withdrawal; personalized medicine; prescription opioid; prospective; relapse prevention; response; secondary analysis; sex; treatment strategy; treatment trial

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.

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 正在缩短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了预期。 可用治疗时段和治疗途径的数量由于并非所有患者都接受治疗而变得更加复杂 以与我们当前的 OUD 药物疗法类似的方式做出反应，我们是测量和治疗方面的专家。 阿片类药物戒断症状的评估、OUD 治疗新药物的评估以及 我们最近对阿片类药物反应的个体差异进行了评估。 一项更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， 与随后的 RCT 中参与者对 OUD 治疗药物的临床反应相关。 R01 将跟进我们已发布的有希望的初步数据，这些数据表明临床上- 我们建议进行一项严格的、高度控制的人类阿片戒断表型。 实验室+自发戒断研究来验证和调查这些数据将。 表型驱动的阿片类药物戒断预先管理的机会我们将招募同等数量的人。 接受 OUD 参与住院研究的男性和女性参与者将使用阿片类激动剂稳定病情。 在短时间内，他们将使用安慰剂或 OUD 完成两项纳洛酮挑战 药物洛非西定，然后开始临床洛非西定辅助减量并随后过渡到 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。 探索参与者将分为两个潜在类别，这将与表达一致 高或低阿片类药物戒断表型主要目标 2 将决定纳洛酮的程度。 挑战表型与随后的临床减量期间的戒断相关。 纳洛酮挑战期间表型类别的升高将与 SOWS 显着相关 次要目标 1 期间的 AUC 值将确定行为和生理相关性。 我们采取了不同程度的阿片类药物戒断严重程度。 戒断将显示出行为（Subaim 1）或生理（Subaim 2）相关性的差异。 目标 2 将确定性别在戒断表达中的作用。我们发现男性和女性都会有这种情况。 不同的戒断严重程度（目标 1），从纳洛酮挑战会话中戒断将对应于 男性和女性临床减量期间的戒断情况（目标 2），并且男性和女性会有不同的情况 行为和生理与阿片类药物戒断严重程度相关（次要目标 1）。 先前的结果通过确认阿片类药物戒断表型的存在将有助于推进个性化 OUD 的医学方法，并了解导致戒断严重程度的因素（独立于 男性和女性的表型）将更广泛地扩大新药开发的机会。