n-Acetylcysteine for Substance Use Disorder

(BED IN 43 Trial)

Recruiting in Palo Alto (17 mi)

+1 other location

Overseen by William W Stoops, Ph.D.

Age: 18 - 65

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase < 1

Recruiting

Sponsor: William Stoops

Must be taking: Hydromorphone

Disqualifiers: Serious physical disease, Schizophrenia, others

Trial Summary

What is the purpose of this trial?

The overarching hypotheses of this protocol are that (1) persistent brain glutamate changes induced by chronic opioid use will exacerbate use of cocaine during opioid physical dependence and withdrawal and (2) n-acetylcysteine (NAC) will ameliorate glutamatergic dysregulation, and thus will reduce both opioid and cocaine demand. These hypotheses will be tested with two specific aims. Specific Aim 1. Determine the reinforcing effects of cocaine in individuals with comorbid opioid and cocaine use disorder with physiological dependence on opioids during NAC maintenance. All subjects will be maintained on oral hydromorphone. They will also be randomly assigned to receive placebo or oral NAC (2.4 g/day), stratified by sex. After dose stabilization, experimental sessions will be conducted in which subjects complete hypothetical cocaine purchase tasks during opioid maintenance and opioid withdrawal. The hypotheses are: 1) cocaine purchasing will be greater during opioid withdrawal and 2) NAC maintenance will attenuate cocaine purchasing across opioid maintenance and withdrawal periods. Specific Aim 2. Evaluate glutamate functionality during periods of opioid maintenance and withdrawal in individuals with comorbid opioid and cocaine use disorder and physiological dependence on opioids during NAC maintenance. Subjects will undergo magnetic resonance spectroscopy to evaluate brain glutamate changes as a function of opioid maintenance/withdrawal state and NAC maintenance. The hypotheses are: 1) glutamate levels will be elevated during opioid withdrawal and 2) NAC maintenance will ameliorate elevated glutamate levels.

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.

What evidence supports the effectiveness of the drug n-Acetylcysteine for Substance Use Disorder?

The research does not provide direct evidence for the effectiveness of n-Acetylcysteine in treating Substance Use Disorder, but hydromorphone, a component of the study, is shown to have analgesic (pain-relieving) properties in patients with chronic pain, which may indirectly support its use in managing symptoms related to substance use. ^{1 2 3 4 5}

How does the drug n-acetylcysteine for Substance Use Disorder differ from other treatments?

The drug n-acetylcysteine (NAC) is unique for Substance Use Disorder as it is primarily known for its antioxidant properties and ability to replenish glutathione levels, which may help reduce cravings and withdrawal symptoms. Unlike traditional opioid treatments, NAC is not an opioid itself and works through a different mechanism, potentially offering a novel approach to managing addiction. ^{6 7 8 9 10}

Research Team

William W Stoops, Ph.D.

Principal Investigator

University of Kentucky

Eligibility Criteria

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.

Trial Timeline

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

Treatment Details

Interventions

• Hydromorphone (Behavioural Intervention)
• n-acetylcysteine (Behavioural Intervention)
• n-acetylcystine (Behavioural Intervention)
• Placebo hydromorphone (Behavioural Intervention)
• Placebo n-acetylcystine (Behavioural Intervention)

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.

Participant Groups

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 Canada for the following indications:

Approved in Canada as Hydromorphone for:

• Moderate to severe pain

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

University of Kentucky Laboratory of Human Behavioral Pharmacology Lexington, KY

University of Kentucky Department of Behavioral Science Lexington, KY

Who Is Running the Clinical Trial?

William Stoops

Lead Sponsor

Trials

9

Recruited

240+

National Institute on Drug Abuse (NIDA)

Collaborator

Trials

2658

Recruited

3,409,000+

Dr. Nora Volkow

National Institute on Drug Abuse (NIDA)

Chief Executive Officer since 2003

MD from National Autonomous University of Mexico

Dr. Nora Volkow

National Institute on Drug Abuse (NIDA)

Chief Medical Officer since 2003

MD from National Autonomous University of Mexico

Findings from Research

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]

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]

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]

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]

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]

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]

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]

References

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

Cost-Effectiveness of Buprenorphine-Naloxone Versus Extended-Release Naltrexone to Prevent Opioid Relapse. [2020]

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

Cyclazocine: comparison to hydromorphone and interaction with cocaine. [2019]

3. United States 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. [2012]

4. England 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. [2020]

5. United States 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. [2022]

6. Ireland pubmed.ncbi.nlm.nih.gov

Acetylcodeine, an impurity of illicitly manufactured heroin, elicits convulsions, antinociception, and locomotor stimulation in mice. [2022]

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

Codeine and 6-acetylcodeine analgesia in mice. [2020]

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

Novel opiates and antagonists. 4. 7-Alkanoylhydromorphones. [2019]

9. Netherlands pubmed.ncbi.nlm.nih.gov

Pharmacological characterization of dihydromorphine, 6-acetyldihydromorphine and dihydroheroin analgesia and their differentiation from morphine. [2013]

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

Stability and Analgesic Efficacy of Di-acetyl Morphine (Diamorphine) Compared with Morphine in Implanted Intrathecal Pumps In Vivo. [2022]