Diclofenac for Alcohol Use Disorder

Overseen By Mathew Glassman, MS

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: University of Maryland, Baltimore

Must not be taking: Psychotropics, Anticoagulants, NSAIDs, others

Disqualifiers: Schizophrenia, Bipolar, Cardiovascular, others

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

Compensation: Varies

Number of Visits: 4

Duration: 5 weeks

24 Participants Needed

Trial Summary

What is the purpose of this trial?

The development of efficacious medications for AUD remains a high research priority with current emphases on identifying novel molecular targets and efficiently screening new compounds. Pharmacological modulation of the kynurenine pathway (KP) represents a promising novel target for AUD. The KP is a complex enzymatic cascade with each step producing biologically active metabolites that are critically involved in diverse physiological and pathological processes. Chronic alcohol exposure produces dysregulation of the KP, particularly as evidenced by decreased levels of the neuroprotective metabolite kynurenic acid (KYNA) and increased levels of the neurotoxic metabolite quinolinic acid (QUIN). This metabolic shift is associated with various alcohol-related pathologies in animals and humans. Thus, a medication that targets the KP to restore KYNA and attenuate QUIN levels may be an effective treatment for AUD. The enzyme kynurenine 3- monooxygenase (KMO) is a major gatekeeper of the KP and resultant KYNA levels. KMO inhibition shifts the KP towards KYNA production in brain and away from QUIN production. Critically, KMO inhibition in rodents, through its increase in brain KYNA levels, decreases alcohol self-administration, preference, cue-reactivity, and relapse behaviors. However, KMO-inhibitors have not been tested in humans because of presumed lack of availability. Diclofenac is an FDA-approved Non-Steroidal Anti-Inflammatory Drug that was recently discovered to inhibit KMO activity. Consistent with KMO inhibition, diclofenac increases KYNA levels in the brain and periphery of rodents. However, it remains unknown whether diclofenac increases KYNA levels and affects alcohol-related behaviors in humans at approved, safe dosages. Investigators propose to conduct a human laboratory pilot study to test whether diclofenac can increase KYNA in individuals with AUD, and if so, which of 3 doses (50, 75, or 100 mg) most effectively increases KYNA. Individuals with AUD (n = 24) will complete four sessions where they receive diclofenac (50, 75, or 100 mg) or placebo. Investigators will examine increases in KYA levels and will also assess QUIN levels, alcohol craving, and negative mood.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications that contraindicate the use of diclofenac, such as oral corticosteroids, anticoagulants, lithium, warfarin, aspirin (daily use), methotrexate, cyclosporine, ACE-inhibitors, and certain diuretics. If you are on any of these medications, you may need to stop them to participate in the trial.

Is diclofenac generally safe for humans?

Diclofenac has been used worldwide since 1974 and is generally considered safe, with safety data showing it is better tolerated than aspirin and comparable to ibuprofen and naproxen. Studies involving over 100,000 patients indicate that adverse effects are infrequent and usually mild, and it is safe for long-term use, even in older adults. ^{1 2 3 4 5}

How is the drug Diclofenac unique for treating Alcohol Use Disorder?

Diclofenac is unique for treating Alcohol Use Disorder because it is primarily known as a pain reliever and anti-inflammatory medication, commonly used for conditions like arthritis, rather than for alcohol-related issues. This novel use suggests a different mechanism of action compared to traditional treatments for Alcohol Use Disorder, which typically focus on reducing cravings or withdrawal symptoms. ^{6 7 8 9 10}

Eligibility Criteria

This trial is for individuals with Alcohol Use Disorder (AUD). Participants will undergo four sessions where they'll receive different doses of Diclofenac or a placebo to see if it affects their craving and mood.

Inclusion Criteria

Meet DSM-5 diagnostic criteria for current AUD of any severity (Mild, Moderate, or Severe)

In the 30-day period before enrollment, engage in heavy drinking (5 or more drinks for men, 4 or more drinks for women) 5 times per month or more

I am between 21 and 65 years old.

Exclusion Criteria

Current (last 12 months) DSM-5 diagnosis of SUD for any psychoactive substances other than alcohol, nicotine, and cannabis (cannabis use disorder, mild severity allowed; moderate and severe excluded)

Lifetime DSM-5 diagnosis of schizophrenia spectrum and other psychotic disorders and bipolar and related disorders

Positive urine toxicology screen for cocaine, opiates, amphetamines, methamphetamine, phencyclidine, barbiturates, benzodiazepine, methadone, and tricyclic antidepressants

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive diclofenac (50, 75, or 100 mg) or placebo across four sessions to assess changes in KYNA and QUIN levels, alcohol craving, and negative mood.

5 weeks

4 sessions

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Diclofenac

Trial Overview The study tests whether Diclofenac, at doses of 50mg, 75mg, or 100mg, can increase KYNA levels in the brain and reduce alcohol-related behaviors compared to a placebo in people with AUD.

Participant Groups

Group I: Diclofenac 50mg Active Control 1 Intervention

In this arm participants will receive 50mg of Diclofenac

Group II: Diclofenac 75mg Active Control 1 Intervention

In this arm participants will receive 75mg of Diclofenac

Group III: Diclofenac 100mg Active Control 1 Intervention

In this arm participants will receive 100mg of Diclofenac

Group IV: Placebo Placebo Group 1 Intervention

Placebo arm

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

Approved in United States as Voltaren for:

• Ankylosing Spondylitis
• Aseptic Necrosis
• Back Pain
• Chronic Pain
• Frozen Shoulder
• Headache
• Migraine
• Muscle Pain
• Osteoarthritis
• Pain
• Period Pain
• Rheumatoid Arthritis
• Sciatica
• Spondyloarthritis

Approved in European Union as Voltaren for:

• Osteoarthritis
• Rheumatoid Arthritis
• Ankylosing Spondylitis
• Migraine
• Pain
• Dysmenorrhea

Approved in Canada as Voltaren for:

• Osteoarthritis
• Rheumatoid Arthritis
• Ankylosing Spondylitis
• Migraine
• Pain
• Dysmenorrhea

Who Is Running the Clinical Trial?

University of Maryland, Baltimore

Lead Sponsor

Trials

729

Recruited

540,000+

Findings from Research

Diclofenac sodium has been used worldwide since 1974, and extensive safety data indicate it is safer and better tolerated than aspirin, with safety comparable to ibuprofen and naproxen.

Clinical trials in the U.S. show that patients taking diclofenac (150 mg daily) experienced fewer adverse reactions compared to those on other nonsteroidal anti-inflammatory drugs, except for naproxen at 500 mg daily.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Worldwide safety experience with diclofenac. Catalano, MA.[2019]

Data from over 100,000 patients indicate that diclofenac is safe and well-tolerated, with adverse effects being infrequent and generally mild, especially when compared to placebo and other NSAIDs.

Long-term use of diclofenac (over a year) has shown no significant increase in adverse effects for older patients compared to younger patients, making it a reliable option for treating various rheumatic conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Worldwide clinical safety experience with diclofenac. Willkens, RF.[2019]

Diclofenac has been shown to be effective in treating conditions like rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis, based on extensive clinical studies worldwide.

Its safety and efficacy are comparable to other NSAIDs, with the added benefit of a short serum half-life and long-lasting effects in synovial fluid, allowing for convenient twice-daily dosing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Diclofenac. Ogle, C.[2013]

Diclofenac (VOLTAREN) is effective for various conditions treated with NSAIDs, showing good tolerability and a favorable balance between COX-2 and COX-1 inhibition, which may reduce side effects.

The drug is available in multiple forms and has a long history of use, but caution is advised for patients at risk of adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Voltaren--the gold standard]. Babić-Naglić, D.[2013]

In a double-blind trial involving hospitalized patients with rheumatoid arthritis, both diclofenac sodium (50 mg b.i.d.) and naproxen (250 mg b.i.d.) effectively reduced morning stiffness, improved grip strength, and alleviated pain, showing no significant difference in clinical efficacy between the two.

Diclofenac sodium was associated with fewer unwanted side effects compared to naproxen, with only three patients on diclofenac reporting adverse effects versus seven on naproxen, suggesting it may be a better-tolerated option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Diclofenac sodium (Voltaren) and naproxen in the treatment of rheumatoid arthritis: a comparative double-blind study. Kajander, A., Martio, J.[2019]

Etanercept, the first biological disease-modifying antirheumatic drug approved over 15 years ago, effectively reduces symptoms and improves quality of life in patients with various rheumatic diseases, including rheumatoid arthritis and psoriatic arthritis, with benefits sustained during long-term treatment.

The safety profile of etanercept is consistent with its approved labeling, showing manageable adverse events, making it a cost-effective and central treatment option for autoimmune rheumatic diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Etanercept: a review of its use in autoimmune inflammatory diseases. Scott, LJ.[2022]

Etanercept is an effective treatment for various autoimmune conditions, including rheumatoid arthritis and psoriasis, and is being explored for additional off-label uses, indicating its versatility as a therapeutic option.

While etanercept has rare side effects, both cutaneous and systemic, the overall safety profile suggests it is a promising medication with substantial benefits, likely leading to increased usage in the future.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The medical uses and side effects of etanercept with a focus on cutaneous disease. Scheinfeld, N.[2015]

A total of 344 patients in the UK reported their baseline characteristics and health-related quality of life before starting etanercept, a treatment for various chronic conditions, with a mean age of 53 years and predominantly female participants (62%).

The study highlighted that 56% of patients were treated for rheumatoid arthritis, and notably, 38% of those with rheumatoid arthritis were not on methotrexate, indicating a potential area for further investigation regarding treatment combinations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Baseline characteristics and patient reported outcome data of patients prescribed etanercept: web-based and telephone evaluation. Wade, AG., Crawford, GM., Pumford, N., et al.[2021]

Lisinopril oral solution (Qbrelis) is effective for treating hypertension, heart failure, and acute myocardial infarction, providing a liquid alternative for patients who may have difficulty swallowing pills.

Etanercept-szzs (Erelzi) is used for multiple autoimmune disorders, offering a biosimilar option to patients, while lumacaftor/ivacaftor (Orkambi) is specifically designed to improve lung function in cystic fibrosis patients by targeting the underlying genetic defect.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmaceutical Approval Update. Kaufman, MB.[2020]

In a study involving 77 patients with rheumatoid arthritis or psoriatic arthritis, the AutoTouch™ autoinjector achieved a high success rate of 97.8% for self-injections over 5 weeks, indicating its efficacy for patient use.

In a preference study with 216 patients, 41.7% preferred AutoTouch™ over the SureClick® autoinjector, citing advantages in ease of use and injection monitoring, although SureClick® was favored for fewer steps and less discomfort.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A novel electromechanical autoinjector, AutoTouch™, for self-injection of etanercept: real-world use and benefits. Collier, DH., Bitman, B., Coles, A., et al.[2022]

References

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

Worldwide safety experience with diclofenac. [2019]

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

Worldwide clinical safety experience with diclofenac. [2019]

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

Diclofenac. [2013]

4. Croatia pubmed.ncbi.nlm.nih.gov

[Voltaren--the gold standard]. [2013]

5. Norway pubmed.ncbi.nlm.nih.gov

Diclofenac sodium (Voltaren) and naproxen in the treatment of rheumatoid arthritis: a comparative double-blind study. [2019]

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

Etanercept: a review of its use in autoimmune inflammatory diseases. [2022]

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

The medical uses and side effects of etanercept with a focus on cutaneous disease. [2015]

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

Baseline characteristics and patient reported outcome data of patients prescribed etanercept: web-based and telephone evaluation. [2021]

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

Pharmaceutical Approval Update. [2020]

10. England pubmed.ncbi.nlm.nih.gov

A novel electromechanical autoinjector, AutoTouch™, for self-injection of etanercept: real-world use and benefits. [2022]