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) foropioiduse disorder (OUD) for at least 3 months prior to first study drug dose perparticipant s Opioid Treatment Program (OTP) and self-report. However, we will allowflexibility in the dose range during that 3-month period (such as an occasionalmissed methadone dose or a temporarily decreased methadone dose) if, in thejudgement of the MAI, the candidate is stable on methadone overall and has not losttolerance to methadone.

• Willing to miss two to three mornings' doses of methadone (without supplementingwith other opioids), and reporting having done so in the past without severewithdrawal symptoms on the first day-with severe defined here as any of thefollowing: repeated vomiting, repeated bouts of diarrhea, or any other symptoms sopainful or uncomfortable that the participant would not want to experience themseveral times in this study.

• Willing to provide blood samples through an intravenous catheter to either upperextremity.

• For women of childbearing potential: must have a negative serum or urine pregnancytest within 72 hours prior to the first study drug dose (active or placebo) ANDagree 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 ofchildbearing potential include any female who has experienced menarche and who hasnot undergone successful surgical sterilization (hysterectomy, bilateral tuballigation, or bilateral oophorectomy) or is not postmenopausal.

• Adequate methods of contraception for sexually active women are those who havea male sexual partner(s) who is surgically sterilized prior to inclusion; havea sexual partner(s) who is/are exclusively female; is using oral contraceptives (either combined or progesterone only) WITH a single-barrier method ofcontraception consisting of spermicide and condom or diaphragm; is usingdouble-barrier contraception, specifically, a condom plus spermicide AND afemale 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 menopausaland 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 notneed pregnancy testing or contraception. If their FSH level is less than 20, theywill 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 testand 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 additionalpregnancy testing. If their FSH test is less than 20, they will need pregnancytesting and contraception as required by the protocol.

• For men, unless surgically sterilized (vasectomy with documentation ofazoospermia), must agree to practice abstinence or use barrier contraception,and not donate sperm, for a period of 3 months beginning from first dose ofstudy drug.

• Self-report of experiencing noticeable opioid withdrawal after missing just oneor two days of methadone. This will be systematically assessed duringscreening.

• Participants must be able to speak, read, and understand English.Justification: This study uses scales and experimental procedures that arevalidated only in English. This includes the assessments conducted to test theprimary and secondary outcomes and is therefore required to maintain theresearch 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 ontobuprenorphine or another partial or biased agonist, or self-reported prior inabilityto 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, toavoid the risk of physical withdrawal from them. Other DSM-5 criteria for SUDsinvolving alcohol or sedative-hypnotics are not automatically exclusory. The MAIwill determine whether the clinical profile suggests a risk of physical withdrawalfrom alcohol or sedative-hypnotics.

• Inability to pass the NIDA Evaluation of Potential Research Participants Ability toConsent 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 theinvestigators, would compromise safe participation in research, including but notlimited to pulmonary disease, cirrhosis, nephrotic syndrome, thyroid disease,epilepsy, panhypopituitarism, adrenal insufficiency, ischemic heart disease, historyof QTc prolongation, prolonged QTc on screening ECG (men, >450ms; women, >470ms,using the QTcF method), and potential causes of QTc prolongation (electrolyteabnormalities such as hypokalemia, hypomagnesemia, and hypocalcemia; medicationssuch as certain antihistamines, antiemetics, antiarrhythmics, antidepressants,antibiotics, and antipsychotics; and structural or functional heart disease such ascongenital 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 (suchas 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 upperlimit of normal; total bilirubin >2.0mg/dL.

• Any other medical reason or clinical condition that the MAI or designee considersunsafe for participation in the study.