Overview
- Background
People with opioid-use disorder (OUD) might benefit from having more treatment drugs to choose from. A new drug, TRV734, could be used like methadone to treat OUD. It might not have as many side effects.
- Objective
To test if TRV734 relieves withdrawal symptoms and has fewer side effects than oxycodone in people with OUD.
- Eligibility
People ages 18-75 who have been receiving daily treatment with methadone for opioid use disorder for at least 3 months
- Design
Participants will be screened under Protocol 415. They will be screened with:
Medical, social, and psychiatric history
Physical exam
Electrocardiogram (ECG). For this, sticky pads will be placed on the participant s chest to monitor their heartbeat.
Blood and urine tests
Participants will stay in a residential unit for 13-21 days.
Most days, participants will receive their regular daily dose of methadone.
On 4 or 5 occasions, 3-4 days apart, participants will skip two doses of methadone in a row. About 4 hours after they skip the second dose, they will have an IV catheter inserted with a needle so that blood samples can be taken. They will take capsules of either oxycodone, a placebo, or the study drug. They will have an ECG. They will complete questionnaires. Their blood pressure, pupil size, and alertness will be tested. They will then take their usual dose of methadone.
Participants will give daily urine and breath samples.
Description
Background. Opioid-agonist medications (methadone and buprenorphine) are the most effective treatments available for opioid addiction. However, they are not effective in all cases, and with the vast number of people requiring treatment in the current crisis, even a modest increase in the percentage of people who respond to treatment would represent a substantial benefit in public health. Recent advances in neuropsychopharmacology have led to the discovery of a new class of opioid agonists that are functionally selective. That is, they are biased towards specific post-receptor pathways and in theory can produce therapeutic opioid effects (analgesia, withdrawal relief) while minimizing side effects (sedation, respiratory depression) that can lead people to discontinue treatment with methadone or buprenorphine.
Objective. Our goal is to assess the efficacy and tolerability of a biased opioid agonist for suppressing or reversing opioid withdrawal.
Participant population. Adults who are physically dependent on opioids and already receiving chronic daily methadone treatment (up to 64 enrolled; up to 30 completers, plus at least 3 to complete in an initial unpowered dose-finding pilot). Target enrollment will include 40% women and 60% minorities (mostly African-American), reflecting the demographics of the relevant local population.
Experimental design. A double-blind within-subject randomized placebo-controlled experiment will be used to test whether a biased opioid agonist suppresses withdrawal when given about 52 h after discontinuing methadone. TRV734 (capsule form), a biased opioid agonist with good oral bioavailability, will be compared to placebo and to oxycodone (positive control) in matching capsules. A signal of efficacy and safety in the proposed laboratory study will be our cue to embark on a larger clinical trial.
Methods. Participants in an unpowered dose-finding five-session pilot phase (up to 30 consecutive days, i.e., 29 consecutive nights) will receive placebo, oxycodone, and a range of doses of TRV734, starting on the high side of the analgesic dose range. The highest dose that relieves withdrawal symptoms with no appreciable adverse effects will be used as the higher of two doses for the participants in the main study. These participants will stay at the inpatient unit for up to 30 consecutive days to help ensure that participants use no additional opioids 52-76-hr prior to each test session.
Participants in the main phase will stay at the inpatient unit for up to 21 consecutive days (original timeline, likely to increase after the pilot is completed) to help ensure that participants use no additional opioids 52-76-hr prior to each test session. To help demonstrate that TRV734 s effects are dose-related, we will also select a lower dose with withdrawal-relief efficacy intermediate between placebo and the higher dose. For participants in the main study, there will be four experimental sessions: one each with placebo, oxycodone, and the two doses of TRV734. Safety and research measures will be collected before (baseline) and for 4 hours after administration of study drugs. The participant s usual methadone dose will be administered after each session.
Outcome measures: The primary outcome will be suppression of withdrawal symptoms, to be assessed by the SOWS (Subjective Opioid Withdrawal Scale). Secondary outcomes will include safety, specificity of effects (e.g., absence of psychomotor slowing), tolerability, and suppression of objective signs of withdrawal. Instruments used for these assessments will include the COWS (Clinical Opioid Withdrawal Scale), scales for opioid effects, psychomotor assessments, and differential dropout across sessions. We hypothesize that the higher dose of TRV734 will be superior to placebo in therapeutic effects and have lower adverse effects (including effects on alertness and psychomotor performance) compared to oxycodone.
Eligibility
- 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.
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 operationalized with the 014 Opioid
Withdrawal History Questionnaire, which we wrote specifically for this study
because no suitable published instrument exists.
- 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.