Naloxone for Opioid Overdose and Cardiac Arrest

(NOPACA Trial)

Overseen By Ralph C. Wang, MD, MAS

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of California, San Francisco

Must not be taking: Naloxone

Disqualifiers: Trauma, Choking, Drowning, Pregnancy, others

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: 1

Duration: Immediate (within 5 minutes of CPR initiation)

98 Participants Needed

Trial Summary

What is the purpose of this trial?

The investigator's long-term goal is to conduct Naloxone for Opioid Associated out of Hospital Cardiac Arrest (NOPACA), a randomized, double blind, controlled trial to determine the efficacy of naloxone vs. placebo in Opioid Associated out of Hospital Cardiac Arrest. The investigative team plan to randomize patients in OHCA to early naloxone administration vs. placebo after initial resuscitation and measure ROSC and survival. Challenges to designing NOPACA include uncertainty regarding: 1) the available pool of participants and number of EMS agencies needed to meet enrollment targets; 2) acceptability among patients, EMS and Emergency Medicine provider stakeholders, and 3) estimates of the study outcomes needed for sample size estimates. Toward obtaining the necessary information to design NOPACA, the investigators propose a pilot RCT of participants at high risk for OA-OHCA to verify a reasonable recruitment rate; treatment fidelity and acceptability; and adequate retention and measurement of outcomes at follow up. The investigators propose incorporating hypothesis testing of the feasibility outcomes to determine progression to a definitive trial.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications.

What data supports the effectiveness of the drug naloxone for opioid overdose?

Naloxone is effective in reversing opioid overdoses by quickly counteracting the life-threatening effects, such as respiratory depression (slowed breathing), caused by opioids. It is widely used in emergency settings and has been shown to save lives by reversing the effects of opioid overdose. ^{1 2 3 4 5}

Is naloxone safe for use in humans?

Naloxone has a long history of safe use in treating opioid overdoses, with rare serious adverse reactions. It is generally safe when used as directed, though higher doses can cause withdrawal symptoms in opioid-dependent individuals. ^{3 6 7 8 9}

How is the drug naloxone unique in treating opioid overdose and cardiac arrest?

Naloxone is unique because it is an opioid antagonist (a substance that blocks opioid effects) specifically used to reverse opioid overdoses, and it can be administered via auto-injectors or intranasal systems, making it accessible for emergency use outside of hospitals. Unlike other treatments, naloxone acts quickly to restore normal breathing in individuals experiencing an opioid overdose, although its effects may be shorter than some opioids, requiring careful monitoring and possible additional doses. ^{3 4 10 11 12}

Research Team

Ralph Wang, MD

Principal Investigator

University of California, San Francisco

Eligibility Criteria

This trial is for individuals who have experienced an out-of-hospital cardiac arrest suspected to be due to opioid overdose. Specific details about eligibility criteria are not provided, but typically participants would need to meet certain health conditions and agree to the study's procedures.

Inclusion Criteria

I received advanced life support from EMS for an out-of-hospital cardiac arrest.

I've received CPR, ventilation, and an initial dose of epinephrine.

I am under 50 and had a sudden, unexpected collapse.

Exclusion Criteria

Prior inclusion in the study

Patient has an opt out bracelet or family member states exclusion

Known or apparent pregnancy

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants receive naloxone or placebo administered by EMS personnel immediately following the first dose of epinephrine

Immediate (within 5 minutes of CPR initiation)

1 visit (EMS encounter)

Follow-up

Participants are monitored for survival to hospital discharge and sustained ROSC

Up to 5 days

Hospital monitoring

Outcome Assessment

Assessment of primary and secondary outcomes including survival to hospital discharge and neurologic outcome

Through hospital discharge

Treatment Details

Interventions

• Naloxone

Trial Overview The NOPACA trial is testing whether naloxone (a medication that can reverse the effects of opioids) is more effective than a placebo (saline solution) in improving outcomes after cardiac arrest outside of hospital settings. Participants will be randomly assigned to receive either naloxone or placebo.

Participant Groups

Group I: Naloxone Active Control 1 Intervention

The intervention consists of naloxone 2mg (2ml of 1mg/ml solution) administered by EMS personnel via the IV or IO route. The study intervention will be administered immediately (within 5 minutes) following the first dose of epinephrine.

Group II: Saline Placebo Group 1 Intervention

Saline 2ml will be supplied in pre-filled syringes within numbered trial treatment packs. The trial will be double-blind; patients, investigators, and the clinical team will be blinded. Only the pharmacy providing the numbered syringes will be aware of the allocation but will not be involved with clinical care or outcome evaluation. The saline placebo will be stored in syringes identical to the naloxone syringes without identifying features.

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

Approved in United States as Naloxone for:

• Opioid overdose reversal

Approved in European Union as Naloxone for:

• Opioid overdose reversal

Approved in Canada as Naloxone for:

• Opioid overdose reversal

Who Is Running the Clinical Trial?

University of California, San Francisco

Lead Sponsor

Trials

2,636

Recruited

19,080,000+

Findings from Research

Intranasal naloxone is considered the best option for opioid reversal in prehospital settings due to its balance of cost, effectiveness, and safety for the administrator, based on an analysis of 8 studies.

There is no clear consensus on the best route of naloxone administration, as various methods (intramuscular, intranasal, intravenous, and subcutaneous) were evaluated but showed differing results in terms of administration time and efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Naloxone Administration for Opioid Overdose Reversal in the Prehospital Setting: Implications for Pharmacists. Weaver, L., Palombi, L., Bastianelli, KMS.[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]

In a study involving 42 healthy participants, the naloxone auto-injector (NAI) was significantly more effective than the intranasal delivery system (NXN) for administering naloxone during a simulated opioid overdose, with 90.5% success for NAI compared to 0% for NXN before training.

After training, 100% of participants successfully used NAI, while only 57.1% could use NXN, highlighting that NAI is easier to use and requires less training for effective administration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative Usability Study of a Novel Auto-Injector and an Intranasal System for Naloxone Delivery. Edwards, ET., Edwards, ES., Davis, E., et al.[2020]

Current opioid overdose treatment relies on naloxone, which has limitations, especially in mass casualty situations involving synthetic opioids, prompting the need for new alternatives.

Emerging treatments discussed at a 2019 scientific meeting include intranasal nalmefene, which has a longer action than naloxone, and novel strategies like covalent naloxone nanoparticles and detoxifying nanosponge decoy receptors, which could enhance the effectiveness of opioid overdose interventions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Countermeasures for Preventing and Treating Opioid Overdose. France, CP., Ahern, GP., Averick, S., et al.[2021]

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]

The naloxone auto-injector (EZVIO™), approved by the FDA in 2014, is designed for easy use by anyone, including laypersons, to rapidly administer naloxone during an opioid overdose, potentially saving lives.

This device is safe and portable, requiring minimal instruction for use, and should be made widely available to individuals who may encounter opioid users, emphasizing the importance of quick response in overdose situations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessment of the safety and ease of use of the naloxone auto-injector for the reversal of opioid overdose. Merlin, MA., Ariyaprakai, N., Arshad, FH.[2020]

Naloxone is a safe and effective antidote for opioid overdose, with a long history of use by healthcare professionals, and expanding access to it for high-risk individuals and their families is a key public health initiative.

While naloxone is generally safe, its administration can lead to varying levels of adverse reactions, especially with higher doses or intravenous use, highlighting the importance of training for non-healthcare professionals in recognizing overdoses and administering naloxone correctly.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Review of naloxone safety for opioid overdose: practical considerations for new technology and expanded public access. Wermeling, DP.[2020]

Buprenorphine/naloxone has a unique pharmacology that provides a ceiling effect on its cardio-respiratory depressant properties, making it potentially safer than other opioids, especially at higher doses.

Data from various safety monitoring systems indicate that buprenorphine/naloxone has a favorable safety profile compared to other opioids and psychotropic drugs, suggesting it may reduce the risk of overdose-related morbidity and mortality.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Question About the Safety of Buprenorphine/Naloxone and Benzodiazepine Drugs. Howland, RH.[2015]

In a study of 89 emergency department patients who experienced accidental opioid overdoses, 70% reported a history of previous overdoses, highlighting the ongoing crisis of opioid misuse.

Despite the availability of naloxone kits, only 31% of participants had access to one, and most who did reported no change in their opioid use patterns after obtaining naloxone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Naloxone Use Among Emergency Department Patients with Opioid Overdose. Marco, CA., Trautman, W., Cook, A., et al.[2018]

References

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

Naloxone Administration for Opioid Overdose Reversal in the Prehospital Setting: Implications for Pharmacists. [2018]

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

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

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

Comparative Usability Study of a Novel Auto-Injector and an Intranasal System for Naloxone Delivery. [2020]

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

Countermeasures for Preventing and Treating Opioid Overdose. [2021]

5. Ireland pubmed.ncbi.nlm.nih.gov

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

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

Assessment of the safety and ease of use of the naloxone auto-injector for the reversal of opioid overdose. [2020]

7. England pubmed.ncbi.nlm.nih.gov

Review of naloxone safety for opioid overdose: practical considerations for new technology and expanded public access. [2020]

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

A Question About the Safety of Buprenorphine/Naloxone and Benzodiazepine Drugs. [2015]

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

Overdose Risk and Client Characteristics Associated With the Injection of Buprenorphine at a Medically Supervised Injecting Center in Sydney, Australia. [2022]

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

Naloxone Use Among Emergency Department Patients with Opioid Overdose. [2018]

11. England pubmed.ncbi.nlm.nih.gov

Naloxone dosage for opioid reversal: current evidence and clinical implications. [2020]

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

Preliminary evidence of health care provider support for naloxone prescription as overdose fatality prevention strategy in New York City. [2018]