Extended-Release Naltrexone vs. Buprenorphine for Opioid Treatment

CTN-0051 assesses the comparative effectiveness of extended release injectable naltrexone (XR-NTX, Vivitrol®), an opioid antagonist recently approved and indicated for the prevention of relapse to opioid dependence, versus buprenorphine-naloxone (BUP-NX, Suboxone®), a high affinity partial agonist indicated for maintenance treatment of opioid dependence, as pharmacotherapeutic aids to recovery. The study is conducted in 8 NIDA Clinical Trials Network affiliated community based treatment programs. Up to 600 eligible participants will be randomized to treatment with XR-NTX or BUP-NX for 24 weeks (sufficient to include 350 participants who are randomized more than 72 hours after their last opioid). The primary goal of the study is to estimate the difference, if one exists, between XR-NTX and BUP-NX in the distribution of the time to relapse (i.e.., loss of persistent abstinence) during the 6-month trial. Secondary objectives are to: (1) compare outcome on XR-NTX versus BUP-NX across a range of clinical safety and secondary efficacy domains, and (2) explore demographic and, clinical, and genetic predictors of successful treatment and moderators of differential effectiveness (i.e., what variables may help clinicians choose which of these treatments is best for a given patient).), and (3) collect a limited dataset to permit analyses of economic costs and benefits of the two treatments.

For opioid-dependent patients in the U.S. and most of the rest of the world, detoxification or detoxification followed by short term residential treatment, with the goal of achieving long-term abstinence from opioid misuse is a mainstay of treatment. Nonetheless, the majority of patients treated in this way will relapse to opioid misuse, leading to a costly and ineffectual cycle of readmission for repeated detoxifications. The overarching goal of CTN-0051 is to foster adoption of new relapse-prevention pharmacotherapies in community-based treatment programs (CTPs) where these could have a substantial public health impact. To this end CTN-0051 assesses the comparative effectiveness of extended release injectable naltrexone (XR-NTX, Vivitrol®), an opioid antagonist recently approved and indicated for the prevention of relapse to opioid dependence, versus buprenorphine-naloxone (BUP-NX, Suboxone®), a high affinity partial agonist indicated for maintenance treatment of opioid dependence, as pharmacotherapeutic aids to recovery. The study is conducted in 8 CTN-affiliated CTPs that provide or partner with detoxification services (inpatient/residential) which have the capacity to maintain participants opioid-free for approximately 3-7 days, have the capacity to provide medication-assisted therapy, and can provide a minimum of one group or individual counseling session per week during the 24-week treatment period. Up to 600 eligible participants will be randomized to treatment with XR-NTX or BUP-NX for 24 weeks (sufficient to include 350 participants who are randomized more than 72 hours after their last opioid). To maximize generalizability, the point of randomization is flexible, from shortly after program admission until just prior to program discharge. A data analysis modification (assessment of whether the early vs. late randomizers have a differential treatment effect and if so, time to relapse will be estimated for early and late randomizers separately) will occur if differential treatment initiation is a problem for cases randomized prior to completing detoxification (i.e., significantly fewer early randomizers are able to complete detoxification and XR-NTX induction). The primary goal of the study is to estimate the difference, if one exists, between XR-NTX and BUP-NX in the distribution of the time to relapse (i.e., loss of persistent abstinence) during the 6-month trial. The primary outcome measure will be the time to the event, with the event called relapse. Secondary objectives are to: (1) compare outcome on XR-NTX versus BUP-NX across a range of clinical safety and secondary efficacy domains, and (2) explore demographic and, clinical, and genetic predictors of successful treatment and moderators of differential effectiveness (i.e., what variables may help clinicians choose which of these treatments is best for a given patient), and (3) collect a limited dataset to permit analyses of economic costs and benefits of the two treatments. Toward the end of the 24-week treatment period, participants are referred for follow-up care in the community (which could include pharmacotherapy if desired and available), and follow-up outcomes are assessed at week 28 and week 36 after randomization. For participants receiving BUP-NX, who do not wish to continue, or for whom community resources are not available, the study provides a two-week BUP-NX taper. In an ancillary genetics study we plan to study functional variants in three genes (OPRM1, OPRK1 and PDYN), known to affect the dynamic response to opioid receptor ligands. These variants will be evaluated in CTN-0051 for their contribution to treatment retention, abstinence, and depression. Blood collection for DNA extraction will occur at the same time that blood is collected for medical safety and liver function evaluation, precluding the need for an additional needle-stick. Coded blood samples for the genetics studies will be sent to the NIDA Center for Genetics Repository.

extended-release naltrexone (Vivitrol), buprenorphine-naloxone (Suboxone), comparative effective, relapse prevention

Relapse occurs if the participant is using any non-protocol prescribed opioids regularly starting at day 21 post-randomization or thereafter. Operationally, relapse is defined as either: (a) four consecutive opioid use weeks, or (b) seven consecutive days of use by self-report. A use week is defined as any week during which a participant self-reports at least one day of use during that week, provides a urine sample positive for non-protocol opioids, or fails to provide a urine sample. Self-report of opioid (heroin or prescription opioids) and other substance use is ascertained at each weekly study visit using the Timeline Follow-Back for each day leading back to the previous visit. Urine is collected at each study visit and tested for opioids. A missed UDS counts as a use week.

Relapse occurs if the participant is using any non-protocol prescribed opioids regularly starting at day 21 post-randomization or thereafter. Operationally, relapse is defined as either: (a) four consecutive opioid use weeks, or (b) seven consecutive days of use by self-report. A use week is defined as any week during which a participant self-reports at least one day of use during that week, provides a urine sample positive for non-protocol opioids, or fails to provide a urine sample. Self-report of opioid (heroin or prescription opioids) and other substance use is ascertained at each weekly study visit using the Timeline Follow-Back for each day leading back to the previous visit. Urine is collected at each study visit and tested for opioids. A missed UDS counts as a use week.

Binary Y/N assessment of whether the participant was or was not able to initiate their assigned study medication.

Adverse events reported by participants and assessed by clinical staff for relatedness to study medication. These determinations were reviewed by the study medical monitor.

Self report of opioid use by participants using the TLFB. At each visit, the TLFB was completed for dates going back to the last participant encounter.

The Subacute Withdrawal Symptoms Subscale consists of 6 symptoms. Classification of symptoms can be scored as: 0 - absent, 1 - doubtful or trivial, 2 - present. The total range of scores is 0 - 12, and the higher the total score the more severe the depression.

The Alcohol Subscale within ASI is one question that asks how bothered one has been by alcohol problems. The total range of the subscale is 0-4. The higher the score, the bigger the problem.

The Sexual Behavior Subscale consists of 5 questions. Each question is scored from 0-5, for a total score range of 0-25. Higher scores indicate a greater degree of risk-taking behavior.

Trail Making Test Part A consists of 25 circles distributed over a sheet of paper. The circles are number 1-25, and the patient is asked to draw lines to connect the numbers in ascending order. The patient is instructed to connect the circles as quickly as possible, without lifting the pen or pencil from the paper. Higher scores reveal greater impairment.

A urine sample was obtained and tested for opioids at each in person visit; screening, prior to induction onto study medication, weekly through week 24 and at each of the follow up visits.

OCS is a brief 3-item measure used to measure opioid craving. The scale consists of 3 items rated on a visual analogue scale (VAS) from 1-10. The total range of score is 0-30, and a higher score indicates a stronger craver / desire to use opiates.

The Subacute Withdrawal Symptoms Subscale consists of 6 symptoms. Classification of symptoms can be scored as: 0 - absent, 1 - doubtful or trivial, 2 - present. The total range of scores is 0 - 12, and the higher the total score the more severe the depression.

The SOWS is a self-administered scale for grading opioid withdrawal symptoms. It contains 16 symptoms whose intensity the patient rates on a scale of 0 (not at all) to 4 (extremely). The total range of scores is 0-64; the higher the score, the more intense the withdrawal.

The SOWS is a self-administered scale for grading opioid withdrawal symptoms. It contains 16 symptoms whose intensity the patient rates on a scale of 0 (not at all) to 4 (extremely). The total range of scores is 0-64; the higher the score, the more intense the withdrawal.

The Sexual Behavior Subscale consists of 5 questions. Each question is scored from 0-5, for a total score range of 0-25. Higher scores indicate a greater degree of risk-taking behavior.

The Sexual Behavior Subscale consists of 3 questions. Each question is scored from 0-5, for a total score range of 0-15. Higher scores indicate a greater degree of risk-taking behavior.

The Sexual Behavior Subscale consists of 3 questions. Each question is scored from 0-5, for a total score range of 0-15. Higher scores indicate a greater degree of risk-taking behavior.

Trail Making Test Part A consists of 25 circles distributed over a sheet of paper. The circles are number 1-25, and the patient is asked to draw lines to connect the numbers in ascending order. The patient is instructed to connect the circles as quickly as possible, without lifting the pen or pencil from the paper. Higher scores reveal greater impairment.

Part B consists of 25 circles distributed over a sheet of paper. In Part B, the circles include both numbers (1-13) and letters (A-L); the patient draws lines to connect the circles in an ascending pattern, by alternating between the numbers and letters. Results are reported as the number of seconds required to complete the task.

Part B consists of 25 circles distributed over a sheet of paper. In Part B, the circles include both numbers (1-13) and letters (A-L); the patient draws lines to connect the circles in an ascending pattern, by alternating between the numbers and letters. Results are reported as the number of seconds required to complete the task.

The "word card" of the Stoop Test has the names of colors printed in black and white (100 items to be named). The patient's basic score is the total time he/she takes to utter the 100 words on the card.

The "word card" of the Stoop Test has the names of colors printed in black and white (100 items to be named). The patient's basic score is the total time he/she takes to utter the 100 words on the card.

The "color card" contains 100 patches of between 3-5 different colors. The patient's task is to utter the names of the colored patches as rapidly as possible, scanning the rows from left to right. The score is the total time (in seconds) it takes to utter the 100 colors.

The "color card" contains 100 patches of between 3-5 different colors. The patient's task is to utter the names of the colored patches as rapidly as possible, scanning the rows from left to right. The score is the total time (in seconds) it takes to utter the 100 colors.

The "color-word card" contains the printed names of colors, but printed in an ink of a conflicting color (e.g. the word RED might be printed in green, yellow, or blue). The patient is required to name the colors of the inks while ignoring the conflicting printed color names. The basic score is the total time (in seconds) to utter the 100 colors.

The "color-word card" contains the printed names of colors, but printed in an ink of a conflicting color (e.g. the word RED might be printed in green, yellow, or blue). The patient is required to name the colors of the inks while ignoring the conflicting printed color names. The basic score is the total time (in seconds) to utter the 100 colors.

The Alcohol Subscale within ASI is one question that asks how bothered one has been by alcohol problems. The total range of the subscale is 0-4. The higher the score, the bigger the problem.

The Drug Use Subscale within ASI is one question that asks how bothered one has been by drug use problems. The total range of the subscale is 0-4. The higher the score, the bigger the problem.

The Drug Use Subscale within ASI is one question that asks how bothered one has been by drug use problems. The total range of the subscale is 0-4. The higher the score, the bigger the problem.

The Social Relationship Subscale within ASI contains 2 questions that ask how bothered one has been by family or social problems. The total range of the subscale is 0-8. The higher the score, the bigger the problem.

The Family / Social Relationship Subscale within ASI contains 2 questions that ask how bothered one has been by family or social problems. The total range of the subscale is 0-8. The higher the score, the bigger the problem.

The Legal Status Subscale within ASI is one question that asks how bothered one has been by legal problems. The total range of the subscale is 0-4. The higher the score, the bigger the problem.

The Legal Status Subscale within ASI is one question that asks how bothered one has been by legal problems. The total range of the subscale is 0-4. The higher the score, the bigger the problem.

The Medical Status Subscale within ASI is one question that asks how bothered one has been by medical problems. The total range of the subscale is 0-4. The higher the score, the bigger the problem.

The Medical Status Subscale within ASI is one question that asks how bothered one has been by medical problems. The total range of the subscale is 0-4. The higher the score, the bigger the problem.

The Psychiatric Status Subscale within ASI is one question that asks how bothered one has been by psychiatric or emotional problems. The total range of the subscale is 0-4. The higher the score, the bigger the problem.

The Psychiatric Status Subscale within ASI is one question that asks how bothered one has been by psychiatric or emotional problems. The total range of the subscale is 0-4. The higher the score, the bigger the problem.

Problems related to drug abuse is assessed through this questionnaire, which consists of 5 conditions. Each condition is scored from 0-2 for a total score range of 0-10. The higher the score, the more problems.

Problems related to drug abuse is assessed through this questionnaire, which consists of 5 conditions. Each condition is scored from 0-2 for a total score range of 0-10. The higher the score, the more problems.

Inclusion Criteria Male or female 18 years of age and older Meet DSM-5 criteria for opioid-use disorder (heroin and/or prescription opioids) Have used opioids other than as specifically prescribed within thirty days prior to consent Seeking treatment for opioid dependence and willing to accept "agonist-based" or "antagonist-based" therapy In good-enough general health, as determined by the study physician on the basis of medical history, review of systems, physical exam and laboratory assessments, to permit treatment with XR-NTX or BUP-NX Able to provide written informed consent Able to speak English sufficiently to understand the study procedures and provide written informed consent to participate in the study If female of childbearing potential, be willing to practice an effective method of birth control for the duration of participation in the study Exclusion Criteria Serious medical, psychiatric or substance use disorder that, in the opinion of the study physician, would make study participation hazardous to the participant, or compromise study findings or would prevent the participant from completing the study. Examples include: Disabling or terminal medical illness (e.g., uncompensated heart failure, cirrhosis or end-stage liver disease) as assessed by medical history, review of systems, physical exam and/or laboratory assessments; Severe, untreated or inadequately treated mental disorder (e.g., active psychosis, uncontrolled manic-depressive illness) as assessed by history and/or clinical interview; Current severe alcohol, benzodiazepine, or other depressant or sedative hypnotic use likely to require a complicated medical detoxification (routine alcohol and sedative detoxifications may be included) LFTs (ALT, AST) greater than 5 times upper limit of normal Suicidal or homicidal ideation that requires immediate attention Known allergy or sensitivity to buprenorphine, naloxone, naltrexone, polylactide-co-glycolide, carboxymethylcellulose, or other components of the Vivitrol® diluent Maintenance on methadone at doses of 30mg or greater at the time of signing consent Presence of pain of sufficient severity as to require ongoing pain management with opioids Pending legal action or other reasons that might prevent an individual from completing the study If female, currently pregnant or breastfeeding, or planning on conception Body habitus that, in the judgment of the study physician, precludes safe intramuscular injection of XR-NTX (e.g., BMI>40, excess fat tissue over the buttocks, emaciation)

Data from this study will be available to researchers on the website, http://datashare.nida.nih.gov/ after the study is complete and the data analyzed. This website will not include information that can identify individual study participants.

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