Opioids + Benzodiazepines for Substance Abuse

(MAP Trial)

Overseen By Heidi Aguas

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Wayne State University

Must not be taking: Methadone, Buprenorphine, Naltrexone, others

Disqualifiers: Severe psychiatric disorder, Severe substance use, others

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

Compensation: Varies

Number of Visits: 9

24 Participants Needed

Trial Summary

What is the purpose of this trial?

In this study, the investigators will measure affective, neurocognitive and behavioral outcomes related to chronic use of opioids and benzodiazepines (screening phase), and in response to the administration of the opioid morphine, the benzodiazepine alprazolam, morphine then alprazolam, alprazolam then morphine, morphine+alprazolam simultaneously, and placebo (laboratory pharmacology experiment). The latter will enable the investigators to assess the effects of an opioid alone, benzodiazepine alone, concurrent and simultaneous administration of opioid+benzodiazepine, relative to a placebo control.

Do I have to stop taking my current medications for the trial?

The trial does not specify if you must stop all current medications, but you cannot have a past-month benzodiazepine or opioid prescription, and you must not be on methadone, buprenorphine, or naltrexone. Also, you cannot have used contraindicated medications in the past 30 days.

What data supports the idea that Opioids + Benzodiazepines for Substance Abuse is an effective drug?

The available research does not provide evidence that the combination of opioids and benzodiazepines is an effective treatment for substance abuse. Instead, the studies highlight risks associated with this combination, such as increased chances of overdose and drug-related poisonings. For example, one study found that people with opioid use disorder who also take benzodiazepines are at a higher risk for overdose. Another study showed that pharmacist interventions led to a significant reduction in the co-prescribing of these drugs, suggesting that their combined use is generally discouraged due to safety concerns. ^{1 2 3 4 5}

What safety data exists for the use of opioids and benzodiazepines in substance abuse treatment?

The safety data for the combination of opioids and benzodiazepines, such as alprazolam, indicates significant risks. Alprazolam has been associated with disproportionate harm, especially among opioid substitution treatment clients. Studies show that combining opioids like fentanyl with benzodiazepines can enhance reinforcing effects, potentially increasing abuse liability. Regulatory changes in Australia have aimed to mitigate these risks by rescheduling alprazolam to a more controlled category. Additionally, pharmacist interventions have been effective in reducing co-prescribing of these drugs, highlighting the importance of careful management to ensure safety. ^{3 6 7 8 9}

Is the drug Alprazolam, Morphine a promising treatment for substance abuse?

Based on the research, combining Alprazolam (a benzodiazepine) and Morphine (an opioid) is not considered a promising treatment for substance abuse. The studies suggest that using these drugs together is often for recreational purposes and can lead to negative health outcomes, including a higher risk of overdose. Therefore, this combination is not recommended as a treatment for substance abuse. ^{1 2 10 11 12}

Research Team

Mark Greenwald, PhD

Principal Investigator

Wayne State University

Eligibility Criteria

This trial is for adults who have used opioids and sedatives in the past five years, not seeking treatment, and are generally healthy. They may have mild to moderate opioid or sedative use disorder but can't be severely overweight, pregnant, using certain drugs, or have severe mental health issues.

Inclusion Criteria

Must be in current good overall health

As an alternative to the sedative drug exposure requirement, participants must have used alcohol on at least 3 separate days during the past month

I have used opioids or sedatives in the last 10 years, for any reason.

Exclusion Criteria

Body mass index > 38 kg/m2

I have been prescribed benzodiazepines or opioids in the past month.

Alcohol-positive breath sample

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Laboratory Pharmacology Experiment

Participants receive various drug administrations including placebo, morphine, alprazolam, and their combinations to assess affective, neurocognitive, and behavioral outcomes.

3 weeks

6 sessions (in-person)

Follow-up

Participants are monitored for safety and effectiveness after drug administration sessions

4 weeks

2 visits (in-person)

Treatment Details

Interventions

• Alprazolam
• Morphine
• Opioid/Benzodiazepine Polydrug Abuse: Aim 3
• Placebo

Trial Overview The study tests how morphine (an opioid) and alprazolam (a benzodiazepine) affect emotions, thinking, and behavior when taken alone or together compared to a placebo. It aims to understand the impact of these substances on chronic users.

Participant Groups

Group I: Alprazolam then morphine Active Control 2 Interventions

0.25mg oral alprazolam administered at 9:30 am, then 15mg oral morphine administered at 12:00 pm

Group II: Morphine alone Active Control 1 Intervention

15mg immediate-release oral morphine, administered both at 9:30 am and 12:00 pm

Group III: Alprazolam alone Active Control 1 Intervention

0.25mg oral alprazolam, administered at both 9:30 am and 12:00 pm

Group IV: Morphine then alprazolam Active Control 2 Interventions

15mg oral morphine administered at 9:30 am, then 0.25mg oral alprazolam administered at 12:00 pm

Group V: Morphine+alprazolam simultaneously Active Control 2 Interventions

morphine 15mg + 0.25mg alprazolam at 9:30 am, then morphine 15mg + 0.25mg alprazolam at 12:00 pm

Group VI: Placebo drug Placebo Group 1 Intervention

Lactose, administered both at 9:30 am and 12:00 pm

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

Approved in United States as Xanax for:

• Anxiety disorders
• Panic disorder

Approved in European Union as Xanax for:

• Anxiety disorders
• Panic disorder

Approved in Canada as Xanax for:

• Anxiety disorders
• Panic disorder

Who Is Running the Clinical Trial?

Wayne State University

Lead Sponsor

Trials

318

Recruited

111,000+

Henry Ford Health System

Collaborator

Trials

334

Recruited

2,197,000+

Findings from Research

A study analyzing 1.3 million drug tests found that the combination of opiates and benzodiazepines in patients decreased from 2016 to 2019, suggesting a positive impact of the 2016 CDC prescribing guidelines on reducing polypharmacy.

Despite variability in the use of different opiate pairs, the overall trend indicates fewer patients were using both opiates and benzodiazepines together, which may enhance patient safety by reducing the risk of adverse drug interactions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduction of Drug-Drug Interaction Risk; CDC Guidelines Influence on Opiate Benzodiazepine Prescribing. Pesce, A., Thomas, R., Krock, K., et al.[2021]

Buprenorphine treatment significantly reduces the risk of nonfatal drug-related poisonings by nearly 40% in individuals with opioid use disorder, highlighting its protective effect when compared to non-treatment days.

Conversely, the use of benzodiazepines or Z-drugs is associated with an 88% increase in the risk of drug-related poisonings, especially at higher doses, indicating a need for careful management of these medications in patients receiving buprenorphine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association Between Benzodiazepine or Z-Drug Prescriptions and Drug-Related Poisonings Among Patients Receiving Buprenorphine Maintenance: A Case-Crossover Analysis. Xu, KY., Borodovsky, JT., Presnall, N., et al.[2022]

A study involving 57,748 patients showed that pharmacist-led interventions to recommend discontinuation of concurrent opioid and benzodiazepine prescriptions led to a 65.79% success rate in medication discontinuation, highlighting the effectiveness of this approach in reducing overdose risks.

The study found significant variations in the discontinuation rates of opioids based on patient age and prescriber location, indicating that targeted interventions can be tailored to improve medication safety across different demographics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preliminary Investigation of Pharmacist-Delivered, Direct-to-Provider Interventions to Reduce Co-Prescribing of Opioids and Benzodiazepines among a Medicare Population. Bingham, JM., Taylor, AM., Boesen, KP., et al.[2020]

In a study involving 3 rhesus monkeys with a history of opioid self-administration, neither the α1-sparing compound L-838,417 nor the partial GABAA receptor modulator MRK-696 were self-administered, indicating they lack reinforcing effects.

In contrast, full GABAA receptor modulators like triazolam and lorazepam were self-administered significantly above vehicle levels, suggesting that high efficacy at GABAA receptor subtypes is necessary for reinforcing effects in opioid-experienced subjects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

GABAA Receptor Subtypes and the Reinforcing Effects of Benzodiazepines in Remifentanil-Experienced Rhesus Monkeys. Berro, LF., Rowlett, JK.[2023]

In a study involving Sprague-Dawley rats, the median lethal doses (MLDs) of morphine, buprenorphine, and methadone were determined, showing that buprenorphine had the highest MLD, indicating it may be less lethal than the others when used alone.

The combination of flunitrazepam with buprenorphine and methadone significantly increased their lethality and altered the time to death, suggesting that the interactions between these drugs are complex and warrant further investigation to understand their mechanisms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Flunitrazepam variably alters morphine, buprenorphine, and methadone lethality in the rat. Borron, SW., Monier, C., Risède, P., et al.[2017]

After alprazolam was rescheduled from Schedule 4 to Schedule 8 in Australia, participants in opioid substitution treatment showed a significant reduction in alprazolam use, decreasing from an average of 13.7 days to 7.1 days over 12 months.

The overall use of benzodiazepines also decreased, indicating that the rescheduling was effective in reducing alprazolam consumption without leading to increased use of other substances or unintended harms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alprazolam use and related harm among opioid substitution treatment clients - 12 months follow up after regulatory rescheduling. Deacon, RM., Nielsen, S., Leung, S., et al.[2018]

In a study with 6 rhesus monkeys, fentanyl consistently acted as a positive reinforcer, while alprazolam only reinforced behavior in half of the subjects, indicating variability in response to benzodiazepines.

When combined, fentanyl and alprazolam generally produced additive or even supra-additive reinforcing effects, suggesting that their combination may enhance the potential for abuse, which is important for understanding polydrug addiction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Self-Administration of Fentanyl-Alprazolam Combinations by Rhesus Monkeys Responding under a Progressive-Ratio Schedule. Berro, LF., Zamarripa, CA., Rowlett, JK.[2023]

Oxazepam has a more favorable safety and abuse liability profile compared to other benzodiazepines, likely due to its slower absorption and lack of active metabolites, which prevents accumulation in the body during chronic use.

Its unique pharmacological properties, including binding to the translocator protein and stimulating neurosteroid synthesis, may further reduce the risk of abuse associated with oxazepam.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Abuse Liability of Oxazepam: Is This Benzodiazepine Drug Underutilized? Howland, RH.[2017]

Regulatory changes in Australia, including the up-scheduling of alprazolam to a controlled substance, led to a significant reduction in non-prescribed (from 39% to 17%) and prescribed (from 13% to 4%) use of alprazolam among people who inject drugs (PWID) from 2011 to 2019.

Despite the reduction in use, 17% of PWID still reported non-prescribed use in 2019, indicating the need for additional interventions, such as harm reduction strategies, particularly targeting individuals receiving opioid agonist therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alprazolam use among a sample of Australians who inject drugs: Trends up to six years post regulatory changes. Sutherland, R., Peacock, A., Nielsen, S., et al.[2020]

The co-abuse of opioids and benzodiazepines (BZDs) is widespread, with many users seeking BZDs primarily to enhance the effects of opioids rather than for therapeutic reasons, indicating a significant recreational use.

This combination poses serious health risks, including increased overdose potential, highlighting the need for healthcare providers to adopt more cautious prescribing practices and to be vigilant for signs of abuse among patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Polydrug abuse: a review of opioid and benzodiazepine combination use. Jones, JD., Mogali, S., Comer, SD.[2022]

Patients newly prescribed both opioids and benzodiazepines had a significantly higher risk of all-cause mortality compared to those prescribed only benzodiazepines, only opioids, or neither medication, with an adjusted hazard ratio of 1.52 for benzodiazepine-only users and 1.76 for opioid-only users.

The risk of overdose death was particularly elevated in the concurrent users, with an adjusted subhazard ratio of 2.59 compared to benzodiazepine-only users and 2.58 compared to opioid-only users, indicating a critical safety concern with this combination of medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New Coprescription of Opioids and Benzodiazepines and Mortality Among Veterans Affairs Patients With Posttraumatic Stress Disorder. Hawkins, EJ., Goldberg, SB., Malte, CA., et al.[2023]

In a study of 193 opioid-dependent patients, 61% reported benzodiazepine (BZD) use, highlighting a significant prevalence of misuse among this population.

The research found that childhood traumatic experiences, particularly emotional and physical neglect, were significantly linked to prolonged BZD use, suggesting that addressing these traumas could be crucial for improving treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prolonged use of benzodiazepines is associated with childhood trauma in opioid-maintained patients. Vogel, M., Dürsteler-Macfarland, KM., Walter, M., et al.[2015]

References

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

Reduction of Drug-Drug Interaction Risk; CDC Guidelines Influence on Opiate Benzodiazepine Prescribing. [2021]

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

Association Between Benzodiazepine or Z-Drug Prescriptions and Drug-Related Poisonings Among Patients Receiving Buprenorphine Maintenance: A Case-Crossover Analysis. [2022]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Preliminary Investigation of Pharmacist-Delivered, Direct-to-Provider Interventions to Reduce Co-Prescribing of Opioids and Benzodiazepines among a Medicare Population. [2020]

4. Ireland pubmed.ncbi.nlm.nih.gov

GABAA Receptor Subtypes and the Reinforcing Effects of Benzodiazepines in Remifentanil-Experienced Rhesus Monkeys. [2023]

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

Flunitrazepam variably alters morphine, buprenorphine, and methadone lethality in the rat. [2017]

6. Netherlands pubmed.ncbi.nlm.nih.gov

Alprazolam use and related harm among opioid substitution treatment clients - 12 months follow up after regulatory rescheduling. [2018]

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

Self-Administration of Fentanyl-Alprazolam Combinations by Rhesus Monkeys Responding under a Progressive-Ratio Schedule. [2023]

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

Safety and Abuse Liability of Oxazepam: Is This Benzodiazepine Drug Underutilized? [2017]

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

Alprazolam use among a sample of Australians who inject drugs: Trends up to six years post regulatory changes. [2020]

10. Ireland pubmed.ncbi.nlm.nih.gov

Polydrug abuse: a review of opioid and benzodiazepine combination use. [2022]

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

New Coprescription of Opioids and Benzodiazepines and Mortality Among Veterans Affairs Patients With Posttraumatic Stress Disorder. [2023]

12. Ireland pubmed.ncbi.nlm.nih.gov

Prolonged use of benzodiazepines is associated with childhood trauma in opioid-maintained patients. [2015]