Biased Opioid Agonists for Treatment of Opioid Withdrawal in OUD

* INCLUSION CRITERIA: Participants will be eligible for inclusion in the study if they meet the following criteria: * Age between 18 and 75. * Currently receiving daily treatment with methadone (dose range 60-150 mg/day) for opioiduse disorder (OUD) for at least 3 months prior to first study drug dose per participant s Opioid Treatment Program (OTP) and self-report. However, we will allow flexibility in the dose range during that 3-month period (such as an occasional missed methadone dose or a temporarily decreased methadone dose) if, in the judgement of the MAI, the candidate is stable on methadone overall and has not lost tolerance to methadone. * Willing to miss two to three mornings' doses of methadone (without supplementing with other opioids), and reporting having done so in the past without severe withdrawal symptoms on the first day-with severe defined here as any of the following: repeated vomiting, repeated bouts of diarrhea, or any other symptoms so painful or uncomfortable that the participant would not want to experience them several times in this study. * Willing to provide blood samples through an intravenous catheter to either upper extremity. * For women of childbearing potential: must have a negative serum or urine pregnancy test within 72 hours prior to the first study drug dose (active or placebo) AND agree to use an adequate method of contraception1 to avoid pregnancy for a period of 3 months beginning from 30 days prior to first dose of study drug. Women of childbearing potential include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not postmenopausal. * Adequate methods of contraception for sexually active women are those who have a male sexual partner(s) who is surgically sterilized prior to inclusion; have a sexual partner(s) who is/are exclusively female; is using oral contraceptives (either combined or progesterone only) WITH a single-barrier method of contraception consisting of spermicide and condom or diaphragm; is using double-barrier contraception, specifically, a condom plus spermicide AND a female diaphragm or cervical cap; or is using an approved intrauterine device (IUD) with established efficacy. Standard NIH Clinical Center criteria for menopause: * Women over age 55 who have not had a period for 1 year will be considered menopausal and do not need a pregnancy test, FSH test, or contraception. * Women between 50 55, who have not had a period for 1 year, should have an FSH test. If their FSH level is more than 20, they will be considered menopausal and do not need pregnancy testing or contraception. If their FSH level is less than 20, they will need pregnancy testing and contraception as required by the protocol. * Women between 45 50 who have not had a period for 1 year will need both an FSH test and a pregnancy test. If they are not pregnant and their FSH level is more than 20, they will be considered menopausal, and will not require contraception or additional pregnancy testing. If their FSH test is less than 20, they will need pregnancy testing and contraception as required by the protocol. * For men, unless surgically sterilized (vasectomy with documentation of azoospermia), must agree to practice abstinence or use barrier contraception, and not donate sperm, for a period of 3 months beginning from first dose of study drug. * Self-report of experiencing noticeable opioid withdrawal after missing just one or two days of methadone. This will be systematically assessed during screening. * Participants must be able to speak, read, and understand English. Justification: This study uses scales and experimental procedures that are validated only in English. This includes the assessments conducted to test the primary and secondary outcomes and is therefore required to maintain the research integrity of the study. EXCLUSION CRITERIA: Applicants will not be eligible if they meet any of the following criteria: * A history of precipitated withdrawal after stopping opioid use and initiation onto buprenorphine or another partial or biased agonist, or self-reported prior inability to tolerate a moderate level of opioid withdrawal symptoms * History of DSM-5 psychotic or bipolar disorder * Current uncontrolled DSM-5 Major Depressive Disorder diagnosis. * Current physical dependence on alcohol or sedative-hypnotic, e.g. benzodiazepine, to avoid the risk of physical withdrawal from them. Other DSM-5 criteria for SUDs involving alcohol or sedative-hypnotics are not automatically exclusory. The MAI will determine whether the clinical profile suggests a risk of physical withdrawal from alcohol or sedative-hypnotics. * Inability to pass the NIDA Evaluation of Potential Research Participants Ability to Consent questionnaire ( consent quiz ) for 20-DA-N014. * Any condition that interferes with urine or blood sampling. * Clinically significant medical illness or medication use that, in the view of the investigators, would compromise safe participation in research, including but not limited to pulmonary disease, cirrhosis, nephrotic syndrome, thyroid disease, epilepsy, panhypopituitarism, adrenal insufficiency, ischemic heart disease, history of QTc prolongation, prolonged QTc on screening ECG (men, \>450ms; women, \>470ms, using the QTcF method), and potential causes of QTc prolongation (electrolyte abnormalities such as hypokalemia, hypomagnesemia, and hypocalcemia; medications such as certain antihistamines, antiemetics, antiarrhythmics, antidepressants, antibiotics, and antipsychotics; and structural or functional heart disease such as congenital long QT syndrome). * Medications that could alter the effects of the opioid agonists being studied, including strong CYP3A4 inhibitors or inducers, or regular use of medications (such as alpha-2 agonists) that could attenuate signs or symptoms of opioid withdrawal. * For women: pregnancy or breastfeeding. * Any of the following lab values: Hb \< 10.5 g/dl; Cr \>2.0mg/dL; AST or ALT \>3x upper limit of normal; total bilirubin \>2.0mg/dL. * Any other medical reason or clinical condition that the MAI or designee considers unsafe for participation in the study.