Naltrexone for Drug Overdose Prevention

(NOD Trial)

Overseen By Xochitl Luna Marti, MPH

Age: 18+

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: University of California, San Francisco

Must not be taking: Opioids, Anticoagulants

Disqualifiers: Liver disease, Pregnancy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 32

Duration: 24 weeks

100 Participants Needed

Trial Summary

What is the purpose of this trial?

The goal of this clinical trial is to see if an injectable medicine called naltrexone can prevent fentanyl overdose deaths in people who use other drugs (cocaine, methamphetamine). The main questions it aims to answer are: What are the challenges for implementing naltrexone as an overdose prevention strategy? Are injections of naltrexone effective for opioid overdose prevention among people who use stimulants? How often are people who use stimulants and do not intentionally use opioids unintentionally exposed to opioids? Researchers will compare participants to receive the study medication to the usual care group to see if one group experiences fewer opioid overdose events than the other. Participants will be randomized to either receive a monthly injection of naltrexone over six months, or receive usual care. Usual care includes harm reduction supplies. Laboratory procedures will include the collection of urine, blood, and hair samples for various safety and outcome measure testing.

Do I need to stop my current medications to join the trial?

The trial information does not specify if you need to stop taking your current medications. However, if you are using opioids or have been prescribed long-acting injectable naltrexone in the past 30 days, you cannot participate in the trial.

What data supports the effectiveness of the drug Naltrexone for drug overdose prevention?

Research shows that Naltrexone, an opioid blocker, can prevent accidental overdoses by blocking the effects of drugs like heroin. A study found that using a sustained release form of Naltrexone reduced the number of overdoses in people dependent on heroin. ^{1 2 3 4 5}

Is naltrexone safe for humans?

Naltrexone, including its extended-release form (Vivitrol), has been studied for safety in humans, particularly for opioid dependence. It is generally considered safe, but there are concerns about liver health (hepatotoxicity) and the risk of withdrawal symptoms if opioids are used while on treatment. These safety considerations are important for people with conditions like hepatitis C or HIV. ^{1 6 7 8 9}

How does the drug Naltrexone differ from other treatments for drug overdose prevention?

Naltrexone is unique because it is an opioid antagonist, meaning it blocks the effects of opioids, which helps prevent accidental overdoses. Unlike oral forms that require daily intake, it is available as a once-per-month extended-release injection, which can improve adherence and reduce the risk of overdose after stopping the medication. ^{1 2 3 4 8}

Research Team

Ayesha Appa, MD

Principal Investigator

University of California, San Francisco

Eligibility Criteria

This trial is for people who use stimulants like cocaine or methamphetamine and are at risk of unintentional opioid exposure, specifically fentanyl. Participants must be willing to undergo monthly injections and provide urine, blood, and hair samples for testing.

Inclusion Criteria

Able to provide informed consent

Stimulant use disorder (by SCID-5) or positive urine drug test for cocaine, amphetamine, or methamphetamine in last 6 months AND report at least 10 days of stimulant use/month

I am at risk for HIV or currently living with HIV.

Exclusion Criteria

I use opioids, prescribed or not, or have been newly diagnosed with an opioid use disorder.

Buttock implants or fillers

Known hypersensitivity to naltrexone or its diluents

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive monthly injections of naltrexone or usual care over a 6-month period

24 weeks

Monthly visits for injections and assessments

Follow-up

Participants are monitored for safety and effectiveness after treatment

8 weeks

Final study visit at 32 weeks

Treatment Details

Interventions

• Naltrexone

Trial Overview The study tests if injectable naltrexone can prevent opioid overdoses in stimulant users not intentionally using opioids. It compares the effectiveness of monthly naltrexone injections against usual care (harm reduction supplies) over six months.

Participant Groups

Group I: Intervention Experimental Treatment 1 Intervention

Participants assigned to the intervention arm will receive naltrexone injections once a month over 6 months. The naltrexone injection (380mg) will be administered every 4 weeks in the ventrogluteal location.

Group II: Control Active Control 1 Intervention

Participants in the control arm will receive usual care.

Naltrexone is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Vivitrol for:

• Alcohol dependence
• Opioid use disorder

Approved in European Union as Naltrexone for:

• Opioid dependence
• Alcohol dependence

Approved in Canada as Vivitrol for:

• Opioid use disorder
• Alcohol dependence

Who Is Running the Clinical Trial?

University of California, San Francisco

Lead Sponsor

Trials

2,636

Recruited

19,080,000+

National Institute on Drug Abuse (NIDA)

Collaborator

Trials

2,658

Recruited

3,409,000+

Findings from Research

A review of 263 cases related to Vivitrol (extended-release naltrexone) found that 84.6% of fatal overdoses occurred within two months after the last injection, highlighting a critical period for overdose risk.

The study suggests that there may be a link between Vivitrol discontinuation and increased overdose risk, indicating the need for further investigation and monitoring during this time frame.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Review of Case Narratives from Fatal Overdoses Associated with Injectable Naltrexone for Opioid Dependence. Saucier, R., Wolfe, D., Dasgupta, N.[2019]

In a study of 46,846 individuals with opioid use disorder, buprenorphine treatment significantly reduced the risk of opioid-related overdose compared to no treatment, with an adjusted hazard ratio of 0.40.

In contrast, both extended-release injectable and oral naltrexone did not show a significant reduction in overdose risk, indicating that buprenorphine may be a more effective option for preventing overdoses in patients undergoing treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Overdose following initiation of naltrexone and buprenorphine medication treatment for opioid use disorder in a United States commercially insured cohort. Morgan, JR., Schackman, BR., Weinstein, ZM., et al.[2022]

The sustained release naltrexone implant significantly reduced opioid overdoses in a cohort of 361 heroin-dependent individuals, with no overdoses reported in the 6 months following treatment, compared to 21 overdoses in the 6 months prior.

While the implant effectively prevented opioid overdoses, there was an increase in sedative overdoses shortly after treatment, highlighting the need for comprehensive management of poly-substance use among heroin users.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reducing hospital presentations for opioid overdose in patients treated with sustained release naltrexone implants. Hulse, GK., Tait, RJ., Comer, SD., et al.[2018]

Heroin overdoses have become more common, with risk factors including recent abstinence and polydrug use, highlighting the urgent need for effective prevention strategies.

Naloxone is a safe and effective treatment for reversing heroin overdose effects, as it quickly counteracts respiratory depression and sedation, making it a crucial tool for overdose prevention in communities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prescription naloxone: a novel approach to heroin overdose prevention. Sporer, KA., Kral, AH.[2022]

A study involving 250 opioid-dependent patients, many of whom had chronic hepatitis C virus (HCV) and HIV, found that intramuscular extended-release naltrexone (XR-NTX) did not significantly increase liver enzyme levels compared to a placebo, indicating its safety in this population.

Even though some patients experienced elevated liver enzymes, these levels improved over time, and no specific symptoms were linked to these elevations, suggesting that XR-NTX can be safely administered to patients with mild to moderate chronic HCV and/or HIV.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hepatic safety of injectable extended-release naltrexone in patients with chronic hepatitis C and HIV infection. Mitchell, MC., Memisoglu, A., Silverman, BL.[2019]

In a 1-year open-label extension study involving 114 patients, injectable extended-release naltrexone (XR-NTX) demonstrated long-term efficacy, with 50.9% of participants remaining abstinent from opioids throughout the study.

The treatment was generally safe, with only 21.1% of patients reporting adverse events and no severe adverse events noted, although 16.7% experienced elevated liver function tests.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Injectable extended-release naltrexone for opioid dependence: an open label study of long-term safety and efficacy]. Krupitsky, EM., Nunes, EV., Ling, W., et al.[2016]

Induction success for extended-release naltrexone (XR-NTX) is significantly lower in individuals requiring opioid detoxification (62.6%) compared to those already detoxified (85.0%), indicating that detoxification status is crucial for treatment initiation.

Adherence to XR-NTX is relatively low, with only 44.2% of individuals completing all scheduled injections, and adherence rates are notably higher in controlled research settings compared to routine care, which limits the overall effectiveness of XR-NTX in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Extended-release injectable naltrexone for opioid use disorder: a systematic review. Jarvis, BP., Holtyn, AF., Subramaniam, S., et al.[2019]

References

1. New Zealand pubmed.ncbi.nlm.nih.gov

Review of Case Narratives from Fatal Overdoses Associated with Injectable Naltrexone for Opioid Dependence. [2019]

2. Ireland pubmed.ncbi.nlm.nih.gov

Overdose following initiation of naltrexone and buprenorphine medication treatment for opioid use disorder in a United States commercially insured cohort. [2022]

3. Ireland pubmed.ncbi.nlm.nih.gov

Reducing hospital presentations for opioid overdose in patients treated with sustained release naltrexone implants. [2018]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Prevention of suicide by naltrexone in a recently detoxified heroin addict. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

Prescription naloxone: a novel approach to heroin overdose prevention. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Hepatic safety of injectable extended-release naltrexone in patients with chronic hepatitis C and HIV infection. [2019]

7. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[Injectable extended-release naltrexone for opioid dependence: an open label study of long-term safety and efficacy]. [2016]

8. England pubmed.ncbi.nlm.nih.gov

Extended-release injectable naltrexone for opioid use disorder: a systematic review. [2019]

9. England pubmed.ncbi.nlm.nih.gov

Precipitated withdrawal during maintenance opioid blockade with extended release naltrexone. [2013]