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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how stress affects the impact of oxycodone, a common opioid pain medication, in people with chronic low back pain. Researchers aim to determine if high stress levels increase the risk of misusing these medications. The trial seeks participants who have experienced daily low back pain for at least three months, with a pain intensity of at least 3 out of 10. This study will help determine if stress management could play a role in the safe use of opioid medications. As an unphased trial, it offers participants the opportunity to contribute to important research that could improve pain management strategies.

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.

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

Research has shown that oxycodone, an opioid pain medication, is often used to treat chronic non-cancer pain, such as low back pain. However, studies have identified safety concerns with long-term use. People taking opioids like oxycodone frequently report increased pain and a lower quality of life over time compared to those not using these medications. This suggests that while oxycodone can provide short-term pain relief, it may not be beneficial or manageable over extended periods.

The CDC provides guidelines for prescribing opioids, emphasizing the need for careful monitoring to manage risks such as misuse or dependence. Although the FDA has approved oxycodone for pain relief, its long-term safety remains uncertain, particularly for ongoing conditions. Participants should consider these factors when deciding whether to join a study involving oxycodone. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about oxycodone for managing chronic non-cancer low back pain because it targets opioid receptors, offering a potential alternative to standard non-opioid painkillers like NSAIDs and acetaminophen. Unlike these typical treatments, oxycodone directly addresses pain by altering the way the brain perceives it, which can lead to more significant pain relief for some individuals. Furthermore, the exploration of oxycodone's role in stress management alongside pain control could provide a dual benefit, potentially improving overall quality of life for patients suffering from chronic pain.

What evidence suggests that this trial's treatments could be effective for managing back pain?

This trial will explore the effects of oxycodone for stress management in adults with chronic non-cancer low back pain. Studies have shown that oxycodone can significantly relieve pain in individuals with chronic low back pain. Research suggests that opioids like oxycodone can reduce pain by about 30% in various long-term pain conditions. However, the risks of using opioids for chronic low back pain, such as misuse and addiction, might outweigh the benefits. While oxycodone can aid in pain relief, it may not surpass non-opioid medications in improving functional ability despite the pain. ^{1 3 5 6 7}

Who Is on the Research Team?

Stephen Bruehl, PhD

Principal Investigator

Vanderbilt University Medical Center

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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 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 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]

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]

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]

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]

Citations

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Opioids for low back pain - PMC - PubMed Central - NIH The magnitude of pain relief across chronic non-cancer pain conditions is about 30%. Given the brevity of randomized controlled trials, the long ...

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Opioids for chronic noncancer pain The risks for chronic opioid therapy for some chronic conditions such as headache, fibromyalgia, and chronic low back pain likely outweigh the benefits. Ongoing ...

4. cdc.gov cdc.gov/mmwr/volumes/71/rr/rr7103a1.htm

CDC Clinical Practice Guideline for Prescribing Opioids ... Systematic review of prevalence, correlates, and treatment outcomes for chronic non-cancer pain in patients with comorbid substance use disorder ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S2405844023069153

Risk factors for opioid addiction in chronic non-cancer pain Up to eighteen European countries reported that more than 10% of patients who began treatment with opiates had problems related to their use, the problem not ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8327685/

Naloxone's role in the national opioid crisis - PubMed Central Over the past 25 years, naloxone has emerged as a critical lifesaving overdose antidote. Public health advocates and community activists established early ...

7. wa-provider.kaiserpermanente.org wa-provider.kaiserpermanente.org/static/pdf/public/guidelines/opioid.pdf

Chronic Opioid Therapy Safety Guideline The recommendations in this guideline apply to adult patients who are already on chronic opioid therapy (COT) for the treatment of chronic non-cancer pain.