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 factor...