Opioid Mechanisms for Stress Management

Overseen By Gail Mayo

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Vanderbilt University Medical Center

Must not be taking: Benzodiazepines, Opioids

Disqualifiers: Alcohol abuse, PTSD, Cancer, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

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

Compensation: Varies

Number of Visits: 4

Duration: 3 weeks

120 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to see how stress influences the effects of opioid pain medications often used to help relieve back pain. The study will help to learn more about how high stress levels could increase risk for pain medication misuse.

Will I have to stop taking my current medications?

The trial requires that you have not used any opioid pain medications within 3 days of participating in the study. If you are currently using opioids, you will need to stop taking them at least 3 days before joining the trial.

What data supports the effectiveness of the drug for stress management?

Research shows that oxycodone, a component of the drug, is effective in managing severe pain, which may indirectly help with stress by alleviating pain-related stressors. Additionally, the combination of oxycodone with naloxone has been used to manage chronic pain, suggesting potential benefits in stress management through pain relief. ^{1 2 3 4 5}

Is oxycodone generally safe for human use?

Oxycodone is a widely used pain medication that has been studied extensively for its safety and effectiveness. Common side effects include nausea, constipation, and drowsiness, which often decrease over time. It has a potential for abuse, similar to other opioids, and should be used under medical supervision. ^{1 2 6 7 8}

How does the drug Oxycodone work for stress management?

Oxycodone is unique for stress management because it acts on multiple opioid receptors in the brain, which can help modulate stress-related behaviors and reduce the risk of developing conditions like PTSD by inhibiting fear-related memory consolidation. Unlike other treatments, it specifically targets the opioid system to manage stress responses, which is not a standard approach for stress management. ^{7 9 10 11 12}

Research Team

Stephen Bruehl, PhD

Principal Investigator

Vanderbilt University Medical Center

Eligibility Criteria

This trial is for adults over 18 with persistent low back pain lasting at least three months and averaging at least a moderate intensity. Participants must be cognitively intact, able to consent, and proficient in English. Excluded are those who've used opioids or benzodiazepines recently, have significant health issues like heart disease, are pregnant, have kidney or liver problems, a history of substance abuse treatment, chronic pain from cancer/autoimmune diseases, allergies to oxycodone or similar drugs, or certain psychiatric disorders.

Inclusion Criteria

I have had daily lower back pain for at least three months, with a pain level of at least 3 out of 10.

Ability to read and write in English sufficiently to understand and complete study questionnaires (which are only validated in English)

I understand information and can make decisions about my health care.

Exclusion Criteria

You have experienced an allergic reaction or intolerance to oxycodone or similar medications in the past.

I have chronic pain from cancer or an autoimmune disease like rheumatoid arthritis or lupus.

My doctor thinks my heart condition may interfere with the study.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Baseline Assessment

Baseline assessment of stress-related markers

1 week

1 visit (in-person)

Treatment

Participants undergo 3 laboratory sessions with assessments of endocannabinoids, back pain, and exposure to pain stimuli after administration of placebo, naloxone, and oxycodone

3 weeks

3 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Naloxone
• Oxycodone
• Placebo

Trial Overview The study examines the impact of stress on the risk of misusing opioid medications prescribed for chronic back pain relief. It involves testing Oxycodone (a pain reliever), Naloxone (which can block opioid effects), and a placebo to understand how stress might affect their use and potential misuse.

Participant Groups

Group I: Adults with chronic non-cancer low back pain Experimental Treatment 3 Interventions

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

Approved in United States as OxyContin for:

• Moderate to severe pain
• Chronic pain

Approved in European Union as OxyContin for:

• Severe pain
• Cancer pain

Approved in Canada as OxyContin for:

• Moderate to severe pain

Who Is Running the Clinical Trial?

Vanderbilt University Medical Center

Lead Sponsor

Trials

922

Recruited

939,000+

National Institute on Drug Abuse (NIDA)

Collaborator

Trials

2,658

Recruited

3,409,000+

Findings from Research

Oxycodone is an effective opioid analgesic for severe pain, particularly in patients who have not responded to weaker opioids, due to its strong affinity for μ and κ opioid receptors and its ability to cross the blood-brain barrier quickly.

Recent formulations, including controlled-release oxycodone and a combination of prolonged-release oxycodone with naloxone, aim to improve pain management while minimizing adverse effects, such as constipation, which is common with opioid use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of oxycodone and oxycodone/naloxone in cancer pain management. Leppert, W.[2022]

Xtampza® ER (oxycodone DETERx®) is an extended-release opioid formulation designed to deter abuse, and studies show that even when physically manipulated (crushed or chewed), it maintains its extended-release pharmacokinetic profile, making it less likely to be abused compared to immediate-release formulations.

In contrast, when OxyContin is crushed, it loses its extended-release properties and behaves like immediate-release oxycodone, highlighting Xtampza ER's potential as a safer option for patients needing chronic pain management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of physical manipulation on the oral pharmacokinetic profile of Xtampza® ER (oxycodone DETERx® formulation): A review of published studies. Gudin, J.[2020]

In a study involving 40 nondependent recreational opioid users, the new formulation of immediate release oxycodone (IRO-A) resulted in significantly lower subjective ratings of 'drug liking' and 'overall drug liking' compared to the standard immediate release oxycodone (IRO) when both were crushed and administered intranasally.

While both formulations caused common opioid-related side effects, IRO-A was associated with more nasal-related symptoms, suggesting that although it may be less appealing for recreational use, it still carries risks of adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessing subjective and physiologic effects following intranasal administration of a new formulation of immediate release oxycodone HCl (Oxecta™) tablets in nondependent recreational opioid users. Schoedel, KA., Rolleri, RL., Faulknor, JY., et al.[2019]

Oxycodone is an effective opioid analgesic for various types of pain, including acute and chronic conditions, but its mechanism of action is complex due to its low binding potential at μ-opioid receptors compared to its strong analgesic effects.

The drug's efficacy may be enhanced by its active metabolites and its ability to cross the blood-brain barrier, with pharmacogenomics playing a significant role in individual responses to oxycodone compared to morphine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Does the pharmacology of oxycodone justify its increasing use as an analgesic? Olkkola, KT., Kontinen, VK., Saari, TI., et al.[2013]

DORA-12, a dual orexin receptor antagonist, effectively mitigates disruptions in physiological activity caused by oxycodone withdrawal in both male and female rats, suggesting its potential as a treatment for opioid withdrawal symptoms.

The treatment with DORA-12 not only reduced oxycodone-seeking behavior but also normalized food and water intake patterns disrupted by oxycodone, indicating its efficacy in preventing relapse.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daily treatment with the dual orexin receptor antagonist DORA-12 during oxycodone abstinence decreases oxycodone conditioned reinstatement. Illenberger, JM., Flores-Ramirez, FJ., Pascasio, G., et al.[2023]

In a phase III study involving 52 patients aged 65 and older with chronic low back pain, oxycodone DETERx significantly reduced pain intensity from a median score of 7.50 to 2.69 over 12 weeks, demonstrating its efficacy compared to placebo.

The treatment was well tolerated, with 69% of patients completing the study and only 8% discontinuing due to adverse events, indicating a favorable safety profile for elderly patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tolerability, Safety, and Effectiveness of Oxycodone DETERx in Elderly Patients ≥65 Years of Age with Chronic Low Back Pain: A Randomized Controlled Trial. Kopecky, EA., Vaughn, B., Lagasse, S., et al.[2018]

Oxycodone, a μ-opioid receptor agonist, has been extensively studied for its analgesic efficacy in treating acute and chronic pain, but it has also been linked to significant abuse potential, similar to other opioids like heroin and morphine.

Despite its therapeutic benefits, oxycodone's history and pharmacological profile highlight the need for ongoing research to develop alternative opioid analgesics that minimize the risk of abuse.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oxycodone: A Current Perspective on Its Pharmacology, Abuse, and Pharmacotherapeutic Developments. Barrett, JE., Shekarabi, A., Inan, S.[2023]

Oxycodone is an effective semi-synthetic opioid for pain management, with a similar clinical efficacy to morphine but with a more predictable metabolism, making it easier to titrate dosages; it has a rapid onset of action within one hour and a duration of effect lasting up to 12 hours in its controlled-release form.

Long-term use of oxycodone may result in less toxicity compared to morphine, and it is associated with fewer side effects like nausea and hallucinations, making it a potentially safer option for patients, especially in managing cancer pain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oxycodone: a pharmacological and clinical review. Ordóñez Gallego, A., González Barón, M., Espinosa Arranz, E.[2022]

Early life stress and adult psychosocial stress are linked to psychiatric disorders like depression and anxiety, as well as increased sensitivity to pain, indicating a complex relationship between stress and mental health.

Endogenous opioid signaling plays a crucial role in these conditions, with alterations in opioid receptor expression affecting stress responses and pain sensitivity, suggesting potential targets for therapeutic interventions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stress-Induced Changes in the Endogenous Opioid System Cause Dysfunction of Pain and Emotion Regulation. Nakamoto, K., Tokuyama, S.[2023]

Different types of stress can trigger various behavioral responses, such as pain relief (analgesia) and reduced movement (motor suppression), which are influenced by multiple opioid receptor systems in the brain.

Both mu- and delta- or kappa-opioid receptors are involved in stress-induced analgesia, and the interaction between opioid and non-opioid systems is crucial, with dynorphins and enkephalins playing key roles in these responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stress-induced behavioral responses and multiple opioid systems in the brain. Yamada, K., Nabeshima, T.[2019]

Endogenous opioids, like β-endorphins, play a crucial role in managing stress by inhibiting the HPA axis, which helps prevent the development of PTSD after traumatic events.

Chronic stress can increase dynorphin levels, leading to negative effects such as learned helplessness and depression, while also influencing how stress affects the response to morphine, potentially increasing its addictive properties.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stress and opioids: role of opioids in modulating stress-related behavior and effect of stress on morphine conditioned place preference. Bali, A., Randhawa, PK., Jaggi, AS.[2019]

In a clinical trial involving 124 adults with opioid use disorder, an escalating naltrexone dosing regimen (starting from 50 μg to 12.5 mg) resulted in significantly lower stress responses and withdrawal symptoms compared to a single 12.5 mg dose.

The single dose led to higher levels of cortisol and ACTH, indicating increased stress, while the escalating dose maintained hormone levels at or below baseline, suggesting a safer and more tolerable approach to opioid antagonist induction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dose Escalation of Naltrexone to Reduce Stress Responses Associated With Opioid Antagonist Induction: A Double-blind Randomized Trial. Badaras, R., Jovaisa, T., Lapinskiene, I., et al.[2021]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Role of oxycodone and oxycodone/naloxone in cancer pain management. [2022]

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

Effect of physical manipulation on the oral pharmacokinetic profile of Xtampza® ER (oxycodone DETERx® formulation): A review of published studies. [2020]

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

Assessing subjective and physiologic effects following intranasal administration of a new formulation of immediate release oxycodone HCl (Oxecta™) tablets in nondependent recreational opioid users. [2019]

4. England pubmed.ncbi.nlm.nih.gov

Does the pharmacology of oxycodone justify its increasing use as an analgesic? [2013]

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

Daily treatment with the dual orexin receptor antagonist DORA-12 during oxycodone abstinence decreases oxycodone conditioned reinstatement. [2023]

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

Tolerability, Safety, and Effectiveness of Oxycodone DETERx in Elderly Patients ≥65 Years of Age with Chronic Low Back Pain: A Randomized Controlled Trial. [2018]

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

Oxycodone: A Current Perspective on Its Pharmacology, Abuse, and Pharmacotherapeutic Developments. [2023]

8. Italy pubmed.ncbi.nlm.nih.gov

Oxycodone: a pharmacological and clinical review. [2022]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Stress-Induced Changes in the Endogenous Opioid System Cause Dysfunction of Pain and Emotion Regulation. [2023]

10. Netherlands pubmed.ncbi.nlm.nih.gov

Stress-induced behavioral responses and multiple opioid systems in the brain. [2019]

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

Stress and opioids: role of opioids in modulating stress-related behavior and effect of stress on morphine conditioned place preference. [2019]

12. Netherlands pubmed.ncbi.nlm.nih.gov

Dose Escalation of Naltrexone to Reduce Stress Responses Associated With Opioid Antagonist Induction: A Double-blind Randomized Trial. [2021]