ED-Initiated Naltrexone + Gabapentin for Alcoholism

Overseen By Kathryn Hawk, MD, MHS

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Yale University

Must not be taking: Opioids, Gabapentin, Naltrexone

Disqualifiers: OUD, Cognitive impairment, Psychosis, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Compensation: Varies

Number of Visits: 3

Duration: 4 weeks

240 Participants Needed

Trial Summary

What is the purpose of this trial?

The proposed study will be the first randomized clinical trial to evaluate a comprehensive Emergency Department (ED)-based intervention for moderate to severe Alcohol Use Disorder (AUD) combining Screening, Brief Intervention and Referral to Treatment (SBIRT) with ED-initiated medications for treatment of alcohol use disorder (MAUD). The primary objective of this phase 3 study is to evaluate for differences in treatment engagement 30 days after ED visit between emergency department patients with moderate to severe alcohol use disorder (AUD) who are randomized to initiate medications for the treatment for AUD in the ED in addition to receiving a brief intervention and referral to ongoing treatment, which all participants will receive. The secondary objective of this study is to evaluate the difference in reduction of heavy drinking days between the two ED treatment models during the 30 days post ED visit.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are currently taking gabapentin or naltrexone, or if you have been treated with medications for alcohol use disorder in the past week.

What data supports the effectiveness of the drugs used in the ED-Initiated Naltrexone + Gabapentin for Alcoholism trial?

Research shows that naltrexone and acamprosate are effective drugs for treating alcohol dependence, with naltrexone being particularly effective in reducing alcohol cravings. Gabapentin may help with symptoms like insomnia and mood instability during early abstinence, potentially preventing early relapse. ^{1 2 3 4 5}

Is the combination of naltrexone and gabapentin safe for treating alcohol dependence?

Naltrexone and acamprosate have been shown to be safe in treating alcohol dependence, with naltrexone's injectable form having fewer side effects than the oral form. Gabapentin, when combined with naltrexone, may help reduce symptoms like insomnia and mood instability during early abstinence, suggesting it is generally safe for this use. ^{1 2 5 6 7}

How does the drug combination of naltrexone and gabapentin differ from other treatments for alcoholism?

This treatment is unique because it combines naltrexone, which helps reduce cravings for alcohol, with gabapentin, which may alleviate withdrawal symptoms like insomnia and mood instability, potentially preventing early relapse. This combination targets both the craving and withdrawal aspects of alcohol dependence, which might make it more effective than using naltrexone alone. ^{1 2 3 8 9}

Research Team

Kathryn Hawk, MD, MHS

Principal Investigator

Yale University

Eligibility Criteria

This trial is for adults aged 18-80 with moderate to severe Alcohol Use Disorder not in remission. Participants must be willing and able to follow the study procedures, available for its duration, and speak English well enough to understand it. Women of childbearing age must test negative for pregnancy and agree to effective birth control during the study.

Inclusion Criteria

Clinical Alcohol Withdrawal Scale (CIWA-Ar) ≥ 4

I am between 18 and 80 years old.

Diagnosed with moderate to severe Alcohol Use Disorder

Exclusion Criteria

Current diagnosis of OUD, self-reported past 7 day opioid or opioid pain medication use, or a positive urine opioid screen (opiates, methadone, buprenorphine, oxycodone, hydrocodone, tramadol and fentanyl)

In police custody

History of complicated alcohol withdrawal

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1 week

1 visit (in-person)

Treatment

Participants receive ED-initiated medications for alcohol use disorder, including naltrexone and gabapentin, with a brief intervention and referral to ongoing treatment

4 weeks

1 visit (in-person), daily medication adherence monitoring

Follow-up

Participants are monitored for safety and effectiveness, including treatment engagement and reduction in heavy drinking days

4 weeks

1 visit (in-person), self-reported outcomes

Extension

Participants may continue to receive support and monitoring for ongoing AUD treatment engagement

Long-term

Treatment Details

Interventions

• Brief Negotiation Interview
• Gabapentin Pill
• Naltrexone Injection
• Naltrexone Pill

Trial Overview The trial tests if starting medications (Naltrexone Pill or Injection, Gabapentin Pill) in the emergency department helps people with alcohol use disorder engage better in treatment after 30 days compared to just a brief intervention and referral. It's a phase 3 study where participants are randomly assigned treatments.

Participant Groups

Group I: SBIRT+ED-MAUD Experimental Treatment 4 Interventions

Participants with receive BNI, Referral to Treatment, and MAUD. In the MAUD component, either XR-NTX or oral naltrexone will be provided, supplemented by ancillary treatment with gabapentin. Participants will receive their first doses of XR-NTX (injection) and gabapentin in the ED and will receive 7 days of gabapentin take-home doses. Those who prefer to initiate treatment in ED with oral naltrexone receive their first doses of naltrexone and gabapentin in the ED and receive 29-day take-home doses of naltrexone and 7 days of gabapentin.

Group II: SBIRT Experimental Treatment 1 Intervention

Participants will receive the Brief Negotiation Interview (BNI) and Referral to Treatment. The BNI has four key components: (1) permission to discuss substance use, (2) feedback on the health consequences of ongoing substance use, including making a connection between the ED visit and substance use, (3) motivational enhancement, and (4) negotiation and advice.

Brief Negotiation Interview is already approved in United States, European Union for the following indications:

Approved in United States as Campral for:

• Maintenance of abstinence from alcohol in patients with alcohol dependence

Approved in European Union as Acamprosate for:

• Maintenance of abstinence from alcohol in patients with alcohol dependence

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

In a clinical trial with 150 alcohol-dependent individuals, combining gabapentin with naltrexone significantly improved drinking outcomes during the first 6 weeks of abstinence, leading to longer intervals before heavy drinking and fewer heavy drinking days compared to naltrexone alone.

The benefits of adding gabapentin diminished after the first 6 weeks, indicating that while it can help manage early abstinence symptoms, its effects do not persist once treatment is stopped.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gabapentin combined with naltrexone for the treatment of alcohol dependence. Anton, RF., Myrick, H., Wright, TM., et al.[2022]

Acamprosate and naltrexone are the only two medications approved for treating alcohol use disorders (AUDs) that have strong evidence from numerous clinical trials, making them effective options for patients.

Several off-label medications, such as topiramate and gabapentin, show promise for treating AUDs, but more research is needed to confirm their efficacy and safety in this context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacotherapy of alcoholism - an update on approved and off-label medications. Soyka, M., Müller, CA.[2018]

Acamprosate and naltrexone, both effective in treating alcohol dependence, can be safely combined without significant adverse effects, as shown by pharmacokinetic studies that indicate increased acamprosate levels when used together.

The combination of these two medications may enhance clinical benefits, suggesting that further large-scale trials are warranted to explore their efficacy and safety in treating alcohol dependence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rationale for combining acamprosate and naltrexone for treating alcohol dependence. Mason, BJ.[2019]

In a study of 169 alcohol-dependent individuals over 12 weeks, naltrexone showed a significant benefit in preventing relapse for those with low levels of depression and alcohol dependence, while acamprosate did not demonstrate any efficacy.

Overall, there were no significant differences in drinking outcomes between naltrexone, acamprosate, and placebo, indicating that naltrexone may be more effective for specific subgroups rather than the general population of alcohol-dependent individuals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Naltrexone versus acamprosate in the treatment of alcohol dependence: A multi-centre, randomized, double-blind, placebo-controlled trial. Morley, KC., Teesson, M., Reid, SC., et al.[2022]

Acamprosate, an oral medication for alcohol dependence, has been shown to effectively restore normal glutamatergic neurotransmission disrupted by chronic alcohol use, making it a valuable treatment option.

The drug has an excellent safety profile and has been validated through multiple Phase I, II, and III clinical trials, indicating its suitability for a wide range of alcohol-dependent patients when used alongside psychosocial interventions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The neurobiology, clinical efficacy and safety of acamprosate in the treatment of alcohol dependence. Mason, BJ., Heyser, CJ.[2018]

Injectable formulations of naltrexone, such as Vivitrex/Vivitrol and Naltrel, show promise in treating alcohol dependence with potentially fewer side effects compared to oral naltrexone, which has limitations like a small treatment effect size and plasma level fluctuations.

Vivitrex/Vivitrol has been effective in reducing heavy drinking in alcohol-dependent males, while Naltrel has been shown to promote abstinence and reduce relapse rates, indicating that these depot formulations may offer improved therapeutic options for alcohol dependence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Naltrexone long-acting formulation in the treatment of alcohol dependence. Johnson, BA.[2021]

Acamprosate significantly improves abstinence rates and cumulative abstinence duration in individuals with alcohol dependence, making it particularly effective for achieving complete abstinence.

Naltrexone effectively reduces relapse rates in the short term but does not significantly increase abstinence rates; it is better suited for programs focused on controlled drinking. Both medications are generally safe and well-tolerated, but compliance remains a challenge.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of naltrexone and acamprosate in the treatment of alcohol dependence: a systematic review. Bouza, C., Angeles, M., Muñoz, A., et al.[2018]

In a study involving 24 healthy adult volunteers, the combination of acamprosate and naltrexone was found to enhance the absorption of acamprosate, leading to a 33% increase in its maximum plasma concentration without affecting naltrexone's pharmacokinetics.

The co-administration of these two medications showed no negative interactions on safety or cognitive function, suggesting that they can be safely used together in treating alcohol dependence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A pharmacokinetic and pharmacodynamic drug interaction study of acamprosate and naltrexone. Mason, BJ., Goodman, AM., Dixon, RM., et al.[2018]

In a study of 160 patients with alcoholism, both naltrexone and acamprosate were found to be significantly more effective than placebo in preventing relapse over a 12-week period.

The combination of naltrexone and acamprosate resulted in the lowest relapse rates compared to placebo and acamprosate alone, indicating that using both medications together enhances their effectiveness in relapse prevention.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparing and combining naltrexone and acamprosate in relapse prevention of alcoholism: a double-blind, placebo-controlled study. Kiefer, F., Jahn, H., Tarnaske, T., et al.[2019]

References

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

Gabapentin combined with naltrexone for the treatment of alcohol dependence. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Pharmacotherapy of alcoholism - an update on approved and off-label medications. [2018]

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

Rationale for combining acamprosate and naltrexone for treating alcohol dependence. [2019]

4. England pubmed.ncbi.nlm.nih.gov

Naltrexone versus acamprosate in the treatment of alcohol dependence: A multi-centre, randomized, double-blind, placebo-controlled trial. [2022]

5. England pubmed.ncbi.nlm.nih.gov

The neurobiology, clinical efficacy and safety of acamprosate in the treatment of alcohol dependence. [2018]

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

Naltrexone long-acting formulation in the treatment of alcohol dependence. [2021]

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

Efficacy and safety of naltrexone and acamprosate in the treatment of alcohol dependence: a systematic review. [2018]

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

A pharmacokinetic and pharmacodynamic drug interaction study of acamprosate and naltrexone. [2018]

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

Comparing and combining naltrexone and acamprosate in relapse prevention of alcoholism: a double-blind, placebo-controlled study. [2019]