n-Acetylcysteine for Substance Use Disorder

(BED IN 43 Trial)

Recruiting at 1 trial location

Overseen By William W Stoops, PhD

Age: 18 - 65

Sex: Any

Trial Phase: Phase < 1

Sponsor: William Stoops

Must be taking: Hydromorphone

Disqualifiers: Serious physical disease, Schizophrenia, others

Compensation: Varies

Number of Visits: Unknown

24 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how n-acetylcysteine (NAC) might assist individuals with both opioid and cocaine use disorders. Researchers aim to determine if NAC can reduce cocaine cravings, particularly during opioid withdrawal. Participants will receive either NAC or a placebo while also taking hydromorphone, assigned randomly. The trial seeks individuals physically dependent on short-acting opioids who use cocaine but are not currently seeking treatment for drug use. As an Early Phase 1 trial, this research focuses on understanding NAC's effects in people, providing participants an opportunity to contribute to groundbreaking treatment insights.

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 will be maintained on oral hydromorphone during the study. It's best to discuss your current medications with the study team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that n-acetylcysteine (NAC) is generally safe for use. Some studies suggest it can help reduce cravings in individuals with substance use problems, though the effects are not always strong. For instance, one study indicated that NAC might aid in addictions to substances like cocaine, heroin, and tobacco, but the results were inconclusive.

Few reports of serious side effects from using NAC suggest it is relatively safe. However, more research is needed to confirm this. If NAC is already approved for other uses, it provides some reassurance about its safety. Still, individual experiences may vary.

Overall, while NAC appears safe, ongoing trials will help determine its effectiveness and safety in treating substance use disorders. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for substance use disorder, which often involve behavioral therapies and medications like methadone or buprenorphine, n-acetylcysteine offers a fresh approach by targeting the brain's glutamate system. This different mechanism of action could help reduce cravings and withdrawal symptoms more effectively. Researchers are excited because n-acetylcysteine is also known for its safety profile, being a well-tolerated antioxidant used in other medical contexts, which could make it a gentler option for patients.

What evidence suggests that n-acetylcysteine might be an effective treatment for substance use disorder?

Research suggests that n-acetylcysteine (NAC), which participants in this trial may receive, might help reduce cravings for drugs like opioids and cocaine. Although the evidence remains limited, NAC has shown positive results in animal studies, particularly with opioids. Some studies indicate it could help decrease cravings in people with substance use disorders, but further research is needed to confirm this. NAC likely works by balancing glutamate, a brain chemical affected by drug use. While findings are still preliminary, scientists believe NAC may help by addressing this imbalance. ^{6 7 8 9 10}

Who Is on the Research Team?

William W Stoops, Ph.D.

Principal Investigator

University of Kentucky

Are You a Good Fit for This Trial?

This trial is for adults aged 18-55 with both opioid and cocaine use disorders who are not seeking treatment. They must be physically dependent on opioids, have normal lab results, no MRI contraindications, and be in good health otherwise. Women must use effective birth control.

Inclusion Criteria

I am not pregnant and use effective birth control.

Physically dependent on short-acting opioids

I am healthy except for my opioid and cocaine use disorder.

Exclusion Criteria

Meet diagnostic criteria for moderate-severe substance use disorder for substances other than opioids, stimulants, cannabis, or nicotine

I have a serious physical or psychiatric condition, excluding substance use disorders.

I have a close family member with schizophrenia, serious heart disease, or epilepsy.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Stabilization

Participants are stabilized on oral hydromorphone and randomly assigned to receive placebo or oral NAC (2.4 g/day), stratified by sex

7 days

Daily monitoring during inpatient admission

Experimental Sessions

Participants complete hypothetical cocaine and opioid purchase tasks during opioid maintenance and withdrawal, and undergo magnetic resonance spectroscopy to evaluate brain glutamate and GABA changes

10 days

Daily sessions during inpatient admission

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Hydromorphone
• n-acetylcysteine
• n-acetylcystine
• Placebo hydromorphone
• Placebo n-acetylcystine

Trial Overview

The study tests if n-acetylcysteine (NAC) can reduce the desire for cocaine during opioid dependence and withdrawal by balancing brain glutamate levels. Participants will take oral hydromorphone with either NAC or placebo and undergo tasks and MRIs to assess changes.

How Is the Trial Designed?

Group I: n-Acetylcysteine Experimental Treatment 3 Interventions

Subjects will receive 0.6 g oral n-acetylcysteine 4 times per day.

Group II: Placebo Placebo Group 3 Interventions

Subjects will receive oral placebo 4 times per day.

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

Approved in United States as Dilaudid for:

• Moderate to severe pain

Approved in Canada as Hydromorphone for:

• Moderate to severe pain

Approved in European Union as Hydromorphone for:

• Moderate to severe pain

Who Is Running the Clinical Trial?

William Stoops

Lead Sponsor

Trials

9

Recruited

240+

National Institute on Drug Abuse (NIDA)

Collaborator

Trials

2,658

Recruited

3,409,000+

Published Research Related to This Trial

Dihydromorphine and its acetylated derivatives are potent mu-opioid analgesics, showing distinct pharmacological profiles compared to morphine, despite their structural similarities.

These compounds maintain their effectiveness in pain relief even in cases of morphine tolerance, suggesting they may offer alternative therapeutic options for pain management without the same level of cross-tolerance seen with morphine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacological characterization of dihydromorphine, 6-acetyldihydromorphine and dihydroheroin analgesia and their differentiation from morphine. Gilbert, AK., Hosztafi, S., Mahurter, L., et al.[2013]

In a study of 143 individuals with opioid use disorders, treatment with extended-release naltrexone did not increase pain levels compared to those receiving buprenorphine-naloxone, indicating that naltrexone is safe in terms of pain management.

Participants who switched from buprenorphine-naloxone to naltrexone after 12 weeks reported no increase in pain intensity, suggesting that long-acting naltrexone does not aggravate existing mild-to-moderate chronic pain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

No increased pain among opioid-dependent individuals treated with extended-release naltrexone or buprenorphine-naloxone: A 3-month randomized study and 9-month open-treatment follow-up study. Latif, ZE., Solli, KK., Opheim, A., et al.[2020]

In a study involving 343 patients with moderate to severe pain, the conversion to extended-release hydromorphone hydrochloride (ER hydromorphone HCl) from other opioids using an 8:1 conversion ratio was effective, with 70% of patients stabilizing their pain levels after titration.

The study reported common side effects such as nausea, somnolence, and constipation, indicating that while ER hydromorphone HCl is effective for pain management, monitoring for these adverse events is important during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multicenter, open-label, prospective evaluation of the conversion from previous opioid analgesics to extended-release hydromorphone hydrochloride administered every 24 hours to patients with persistent moderate to severe pain. Weinstein, SM., Shi, M., Buckley, BJ., et al.[2022]

Acetylcodeine has similar antinociceptive effects to codeine but is less effective in stimulating locomotor activity, indicating it has a comparable pain-relieving effect but a different profile in terms of stimulating behavior.

Importantly, acetylcodeine can enhance the convulsant effects of diacetylmorphine, suggesting it may contribute to the increased risk of seizures and potentially fatal outcomes in heroin users.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acetylcodeine, an impurity of illicitly manufactured heroin, elicits convulsions, antinociception, and locomotor stimulation in mice. O'Neal, CL., Poklis, A., Lichtman, AH.[2022]

The study developed a series of 7-alkanoyl-substituted hydromorphone derivatives, with the most potent compound (6i) showing agonist activity comparable to buprenorphine, indicating potential for effective pain relief.

The N-cyclopropylmethyl-substituted derivatives demonstrated similar structure-activity relationships for analgesia and narcotic antagonism as seen in endo-ethanotetrahydrooripavines, suggesting a promising avenue for further research in pain management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel opiates and antagonists. 4. 7-Alkanoylhydromorphones. Quick, J., Herlihy, P., Razdan, RK., et al.[2019]

In a pooled analysis of 11 studies involving 1251 opioid-tolerant patients, once-daily OROS hydromorphone ER showed a safety profile consistent with known opioid safety, with a high incidence of adverse events (76.9%), including nausea (23.2%) and constipation (22.4%).

Despite the high incidence of adverse events, no treatment-related deaths were reported, indicating that OROS hydromorphone ER can be a tolerable option for managing chronic pain in opioid-tolerant patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Tolerability of Once-Daily OROS(®) hydromorphone extended-release in opioid-tolerant adults with moderate-to-severe chronic cancer and noncancer pain: pooled analysis of 11 clinical studies. Nalamachu, SR., Kutch, M., Hale, ME.[2012]

6-acetylcodeine is an effective analgesic that works through mu opioid receptors, showing a potency about one-third that of codeine, and is effective in various pain relief contexts (systemically, supraspinally, and spinally).

Unlike other mu opioid analgesics, 6-acetylcodeine has a unique pharmacological profile, as it is sensitive to specific mu receptor gene probes but does not respond to certain antagonists that affect other opioids like heroin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Codeine and 6-acetylcodeine analgesia in mice. Milo, S., Ansonoff, M., King, M., et al.[2020]

Di-acetyl morphine, when used in implanted intrathecal drug delivery systems, shows similar analgesic efficacy to morphine over a period of at least ten weeks, with no significant changes in pain scores between the two groups of patients.

The study found that di-acetyl morphine decays to mono-acetyl morphine and then to morphine, with a half-life of 50 days, indicating its stability and potential as a more soluble alternative opioid for pain management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stability and Analgesic Efficacy of Di-acetyl Morphine (Diamorphine) Compared with Morphine in Implanted Intrathecal Pumps In Vivo. Raphael, JH., Palfrey, SM., Rayen, A., et al.[2022]

In a study involving 570 adults with opioid use disorder, buprenorphine-naloxone was found to be more cost-effective than extended-release naltrexone, being preferred in 97% of cases at 24 weeks and 85% at 36 weeks based on quality-adjusted life-years (QALYs).

The analysis suggests that buprenorphine-naloxone is the better first-line treatment option, especially for patients needing detoxification before starting extended-release naltrexone, although the study had limitations such as a relatively short follow-up period.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cost-Effectiveness of Buprenorphine-Naloxone Versus Extended-Release Naltrexone to Prevent Opioid Relapse. Murphy, SM., McCollister, KE., Leff, JA., et al.[2020]

In a study involving 13 experienced opiate and cocaine users, cyclazocine showed only modest effects as a kappa-opioid agonist and did not significantly alter the response to cocaine, suggesting limited efficacy in reducing cocaine's effects.

Despite the modest effects, participants exhibited lower responses to cocaine after four days of cyclazocine pretreatment, indicating potential for kappa-opioid drugs in diminishing acute cocaine effects, although results were not strongly conclusive.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cyclazocine: comparison to hydromorphone and interaction with cocaine. Preston, KL., Umbricht, A., Schroeder, JR., et al.[2019]

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