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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how combining opioids and benzodiazepines affects emotions, thinking, and behavior in individuals who have used these substances. It compares the effects of morphine (an opioid) and alprazolam (a benzodiazepine, also known as Xanax) alone, in sequence, and together, against a placebo. The trial seeks participants who have used opioids or sedatives in the past ten years and are not currently seeking treatment for substance use issues. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group of people.

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.

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

Research has shown that both alprazolam (Xanax) and morphine present safety concerns when used alone. Alprazolam can be safe when taken as prescribed, but misuse may cause serious side effects, including overdose. It is also highly addictive, requiring careful medical supervision. Morphine, a well-known painkiller, carries similar risks. Misuse can lead to addiction, so users must be cautious about dependency.

Combining these two drugs increases the risks. Studies have demonstrated that using opioids like morphine with benzodiazepines such as alprazolam can cause severe side effects, including extreme drowsiness, slowed breathing, and, in some cases, death. Consequently, the FDA has issued warnings about using these medications together.

This study is in phase 2, indicating that early safety checks have been completed, but more information is needed to fully understand the safety, especially for the combination treatment. Always consult healthcare professionals before considering participation in such trials. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are interested in the combination of alprazolam and morphine for treating substance abuse because it explores how these drugs might work together to manage withdrawal symptoms or cravings differently than existing treatments. Unlike traditional options like methadone or buprenorphine, which primarily target opioid receptors, this combination could offer a dual-action approach, affecting both anxiety and pain pathways. By administering these drugs in various sequences or simultaneously, researchers aim to discover the most effective strategy for minimizing abuse potential and improving patient outcomes. This innovative approach could potentially lead to more personalized and effective treatment plans for individuals struggling with substance abuse.

What evidence suggests that this trial's treatments could be effective for substance abuse?

Research shows that taking opioids and benzodiazepines together, such as morphine and alprazolam, poses significant risks. This trial includes several treatment arms to study these effects: one arm administers alprazolam followed by morphine, another morphine followed by alprazolam, and a third combines both simultaneously. This combination can increase drowsiness and the risk of overdose. Studies have found that using these drugs together produces stronger effects than using either one alone, impacting coordination and task performance. While morphine effectively relieves pain, it can be addictive and misused. Alprazolam also carries a risk of misuse and dependency, affecting coordination and cognition. Due to these concerns, combining both drugs requires careful management to minimize the risk of harmful side effects. ^{1 2 6 7 8}

Who Is on the Research Team?

Mark Greenwald, PhD

Principal Investigator

Wayne State University

Are You a Good Fit for This Trial?

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 for a Trial Participant

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)

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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 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]

Citations

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A Review of Alprazolam Use, Misuse, and Withdrawal - PMC CDC prescription death rate data reveal that between 2003 and 2009, alprazolam had the highest death rate increase of all benzodiazepines and second highest ...

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Polydrug abuse: A review of opioid and benzodiazepine ... The two drugs in combination produced stronger psychomotor effects and performance impairment. Yet, alprazolam did not alter abuse liability-related subjective ...

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Xanax: Side Effects, Dangers & Long-Term Impacts The most common adverse effects of alprazolam include impaired coordination, low blood pressure, difficulty speaking, and increased libido.

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Mother's little helper turned a foe: Alprazolam use, misuse, ... This review outlines alprazolam use and misuse, and potential mechanism(s) surrounding tolerance, dependence, and abuse.

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How 'Publication Bias' May Skew Our Understanding of ... Researchers found that when considering unpublished data, only 20 percent of trials showed the drug was beneficial and its success may have been ...

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Signal mining and risk analysis of Alprazolam adverse ... This study aims to evaluate the safety of Alprazolam by analyzing the FAERS database, provide data analysis for monitoring adverse drug reactions.

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Xanax Addiction And Abuse - Addiction to Alprazolam Xanax is a benzodiazepine used to treat anxiety and insomnia. The drug is extremely addictive and should only be used under doctor's orders.

8. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2021/018276s058lbl.pdf

XANAX® (alprazolam) tablets, USP WARNING Abuse, Misuse, and Addiction Inform patients that the use of XANAX, even at recommended dosages, exposes users to risks of abuse misuse and addiction, which ...