Brain Imaging for Alcoholism

(Mu Kappa Trial)

Overseen By Marc Grasso

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: Yale University

Must not be taking: Antidepressants, Antipsychotics, Anxiolytics, others

Disqualifiers: Neurological, Cardiovascular, Psychiatric, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

100 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not require participants to stop taking their current medications. However, if you regularly use prescription, psychoactive, or herbal medications that could affect the study data, you may not be eligible to participate.

What data supports the effectiveness of the drug nalmefene in treating alcoholism?

Research shows that nalmefene can significantly reduce alcohol consumption and the number of heavy drinking days in people with alcohol dependence. It works by modulating opioid receptors in the brain, which helps to decrease the urge to drink and improve mood. ^{1 2 3 4 5}

Is nalmefene safe for human use?

Nalmefene is generally well tolerated in humans, with common side effects including nausea, dizziness, and insomnia. Most adverse events are mild or moderate, but it should not be used with opioids as it can cause withdrawal symptoms. ^{2 3 4 6 7}

How does the drug nalmefene differ from other treatments for alcoholism?

Nalmefene is unique because it acts as a partial agonist for the κ-opioid receptor and a pure antagonist for the δ and µ receptors, which helps to reduce alcohol consumption by modulating dopamine levels in the brain. This mechanism can alleviate negative emotional states associated with alcohol dependence, unlike naltrexone, which is a pure antagonist at all these receptors. ^{1 2 3 5 8}

What is the purpose of this trial?

The primary objective of this multimodal positron emission tomography (PET) study is to use PET brain imaging to measure both MOR (Mu-Opioid receptors) and KOR (kappa-opioid receptors) in participants with alcohol use disorder (AUD) and to quantify the relationships between MOR and KOR, separately and jointly, to key clinical outcomes (e.g., craving, mood, withdrawal, time to lapse) during a quit attempt.

Research Team

Kelly Cosgrove, PhD

Principal Investigator

Yale University

Eligibility Criteria

This trial is for adults with Alcohol Use Disorder (AUD) who drink heavily and are diagnosed according to DSM-5 criteria. Men must consume more than 14 drinks weekly, exceeding 4 per day twice a week; women over 7 weekly, exceeding 3 per day twice. Participants must be willing to try quitting alcohol and can read/write English.

Inclusion Criteria

You have a current diagnosis of alcohol use disorder (AUD) according to specific criteria outlined in the DSM-5.

I am willing to try quitting alcohol.

I don't have a history of alcohol or significant substance abuse and drink less than 5 alcoholic drinks per week.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

Up to 3 months

Detoxification

Participants with AUD undergo a detoxification program for 1-3 days before PET imaging

1-3 days

Daily meetings (in-person)

Early Abstinence

Participants with AUD are monitored for changes in MOR and KOR availability during early abstinence

6 days

Daily meetings (in-person)

Outpatient Quit Attempt

Participants continue abstinence with outpatient support and contingency management

3 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

3-6 weeks

1 visit (in-person) for PET and MRI scans

Treatment Details

Interventions

• CFN
• Detoxification Program
• PKAB

Trial Overview The study uses PET brain imaging to measure Mu-Opioid and Kappa-Opioid receptors in people with AUD during a quit attempt. It aims to understand how these receptors relate to cravings, mood, withdrawal symptoms, and the time until they lapse back into drinking.

Participant Groups

Group I: Healthy Control population Experimental Treatment 2 Interventions

Subjects will be asked to complete both a 90 minute \[11C\]CFN and a 90 minute \[11C\]PKAB PET Imaging.

Group II: Alcohol Use Disorder population completing Detoxification Experimental Treatment 3 Interventions

Subjects will be asked to complete both 90 minute \[11C\]CFN and 90 minute \[11C\]PKAB PET Imaging after 1-3 days of a detoxification program.

Detoxification Program is already approved in European Union, United States for the following indications:

Approved in European Union as Selincro for:

• Reduction of alcohol consumption in adults with alcohol dependence

Approved in United States as Revex for:

• Complete or partial reversal of opioid drug effects, including respiratory depression, induced by either natural or synthetic opioids

Who Is Running the Clinical Trial?

Yale University

Lead Sponsor

Trials

1,963

Recruited

3,046,000+

National Institute on Alcohol Abuse and Alcoholism (NIAAA)

Collaborator

Trials

865

Recruited

1,091,000+

Findings from Research

Chronic ethanol intake leads to significant functional and structural changes in neurons, which are linked to impaired mental function, highlighting the need for effective treatments for alcohol dependence.

Nalmefene, a partial agonist for κ opioid receptors and antagonist for δ and µ receptors, has been shown to effectively reduce ethanol intake in dependent patients by modulating dopamine levels in the brain, alleviating negative emotional states associated with alcohol withdrawal.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Neurobiology of alcohol and pharmacological aspects of nalmefene]. Biggio, G.[2016]

Nalmefene, an opioid receptor modulator, has been shown to significantly reduce heavy drinking days and total alcohol consumption in alcohol-dependent patients when used as needed, based on a phase 3 study involving Japanese patients.

While nalmefene is generally safe, with most side effects being mild to moderate, common adverse events included nausea and dizziness, occurring more frequently than in the placebo group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Pharmacological profile and clinical findings of nalmefene (Selincro&#174;) for reducing alcohol consumption in patients with alcohol dependence]. Tadori, Y.[2020]

Nalmefene, an opioid system modulator, has been shown to significantly reduce heavy drinking days and total alcohol consumption in alcohol-dependent adults when used as needed, based on results from two multinational trials (ESENSE 1 and ESENSE 2) and a longer-term study (SENSE).

The treatment was generally well tolerated, with common side effects including nausea, insomnia, and dizziness, making nalmefene a promising option for managing alcohol dependence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nalmefene: a review of its use in the treatment of alcohol dependence. Keating, GM.[2022]

Nalmefene is the first drug approved in the E.U. specifically to reduce alcohol consumption in alcohol-dependent patients, showing significant efficacy over 6 months by reducing total alcohol intake by an average of 7.6 g/day and heavy drinking days by 2 days per month.

The drug is generally well tolerated with good compliance rates (over 80% adherence) among patients using it as needed, making it a promising new approach in treating alcohol dependence alongside brief psychosocial interventions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nalmefene and its use in alcohol dependence. Gual, A., Bruguera, P., López-Pelayo, H.[2017]

Nalmefene, an opioid receptor antagonist, significantly reduced mortality from ethanol-induced neurotoxicity in male adolescent rats, decreasing mortality from 71% to 14% when pretreatment was administered before ethanol exposure.

PET imaging with the radioligand [18 F]DPA-714 revealed that nalmefene pretreatment alleviated the neuroinflammatory response in the brain caused by ethanol, indicating its potential as a protective strategy against binge drinking effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nalmefene alleviates the neuroimmune response to repeated binge-like ethanol exposure: A TSPO PET imaging study in adolescent rats. Tournier, N., Pottier, G., Caillé, F., et al.[2021]

Nalmefene, an opioid receptor antagonist approved for reducing alcohol consumption, has been associated with 200 documented adverse drug reactions globally, highlighting the need for careful monitoring.

In 10.5% of cases, nalmefene was used alongside opioids, leading to withdrawal symptoms, indicating that this combination should be avoided to ensure patient safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Nalmefene and Opioid Withdrawal Syndrome: Analysis of the Global Pharmacovigilance Database for Adverse Drug Reactions]. Dahmke, H., Kupferschmidt, H., Kullak-Ublick, GA., et al.[2015]

Nalmefene, an opioid system regulator approved for treating alcohol dependence, was associated with fatigue and deep sleepiness in two patients after just two days of treatment.

Symptoms resolved quickly after discontinuing the drug, highlighting the need for careful monitoring of adverse effects when prescribing nalmefene for alcohol use disorder.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical experience about an unexpected adverse event during nalmefene treatment in two patients with alcohol use disorder. Milano, G., Zavan, V., Natta, WM., et al.[2016]

A study using multi-modal MRI on Marchigian-Sardinian rats showed that just one month of alcohol consumption led to distinct brain changes that could be identified even after a week of abstinence, indicating potential biomarkers for early diagnosis of alcohol use disorders.

Treatment with naltrexone during early abstinence resulted in specific brain changes, suggesting that this medication may aid in the recovery process from alcohol-induced brain alterations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multi-modal MRI classifiers identify excessive alcohol consumption and treatment effects in the brain. Cosa, A., Moreno, A., Pacheco-Torres, J., et al.[2018]

References

1. Italy pubmed.ncbi.nlm.nih.gov

[Neurobiology of alcohol and pharmacological aspects of nalmefene]. [2016]

2. Japan pubmed.ncbi.nlm.nih.gov

[Pharmacological profile and clinical findings of nalmefene (Selincro&#174;) for reducing alcohol consumption in patients with alcohol dependence]. [2020]

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

Nalmefene: a review of its use in the treatment of alcohol dependence. [2022]

4. Spain pubmed.ncbi.nlm.nih.gov

Nalmefene and its use in alcohol dependence. [2017]

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

Nalmefene alleviates the neuroimmune response to repeated binge-like ethanol exposure: A TSPO PET imaging study in adolescent rats. [2021]

6. Switzerland pubmed.ncbi.nlm.nih.gov

[Nalmefene and Opioid Withdrawal Syndrome: Analysis of the Global Pharmacovigilance Database for Adverse Drug Reactions]. [2015]

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

Clinical experience about an unexpected adverse event during nalmefene treatment in two patients with alcohol use disorder. [2016]

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

Multi-modal MRI classifiers identify excessive alcohol consumption and treatment effects in the brain. [2018]