Observational Analgesia Mechanisms for Pain Management

Recruiting in Palo Alto (17 mi)

Overseen by Luana Colloca, MD/PhD/MS

Age: 18 - 65

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: University of Maryland, Baltimore

Must not be taking: Antidepressants, ADHD medication, Narcotics, others

Disqualifiers: Cardiovascular, Neurological, Chronic pain, others

No Placebo Group

Prior Safety Data

Approved in 3 Jurisdictions

Trial Summary

What is the purpose of this trial?

Placebo effects held an ambivalent place in health care for at least two centuries. On the one hand, placebos are traditionally used as controls in clinical trials to correct for biases and the placebo response is viewed as an effect to be factored out in order to isolate and accurately measure the effects of the treatment. On the other hand, there is scientific evidence that placebo effects represent fascinating psychoneurobiological events involving the contribution of distinct central nervous as well as peripheral physiological mechanisms that influence pain perception and clinical pain symptoms and substantially modulate the response to pain therapeutics. Therefore, placebo effects have shifted from being a challenge for clinical trials to a resource to trigger the reduction of pain based on endogenous mechanisms that can be activated in the brain to promote hypolagesia, self-healing, and well-being. This is relevant in acute pain settings given that chronic opioid users die within approximately 2.5 years of being prescribed their first opioid medication to treat acute pain. The overall hypothesis is that observational learning influences neural pain modulation and cognition systems, including processes associated with mentalizing (the ability to cognitively understand mental states of others), empathy (the ability to share an emotional experience), and expectancy (the anticipation of a benefit). The objective is to determine the brain mechanisms of observationally-induced analgesia using brain mapping approaches that target changes in blood oxygenation and oscillatory activity in the brain, thus enabling investigators to draw inferences about the localization and extent of neurobiological activation underlying hypoalgesia driven by observation. Therefore, the investigators designed innovative experiments using pharmacological fMRI, EEG, and combined EEG-fMRI measurements.

Do I need to stop taking my current medications to join the trial?

Yes, you will need to stop taking certain medications, such as antidepressants, ADHD medication, non-over-the-counter painkillers, methadone, benzodiazepines, barbiturates, and narcotics, if you have used them in the past 3 months.

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

Research shows that buprenorphine, a component of Suboxone, is effective in relieving pain and has a high safety profile. Additionally, a study found that treatments like buprenorphine-naloxone can reduce pain in patients with opioid use disorder. ^{1 2 3 4 5}

Is the treatment generally safe for humans?

The combination of buprenorphine and naloxone, used in treatments like Suboxone, is generally considered safe with a favorable safety profile compared to other opioids. It has less risk of causing severe breathing problems, and studies suggest it is relatively safe even in cases of overdose, with most symptoms being mild and manageable. ^{5 6 7 8 9}

How is the drug Naloxone unique for pain management?

Naloxone is unique in pain management because it is primarily used to counteract opioid overdoses by blocking opioid receptors, rather than directly treating pain. Its use in pain management is more about reducing opioid-related side effects rather than providing analgesia itself. ^{10 11 12 13 14}

Research Team

Luana Colloca, MD/PhD/MS

Principal Investigator

University of Maryland Baltimore School of Nursing

Eligibility Criteria

This trial is for English-speaking adults aged 18-55 without chronic pain, severe psychiatric conditions, or recent hospitalization for mental health issues. Participants must not be pregnant, color-blind, left-handed, have metal implants incompatible with MRI scans, a history of substance abuse or use certain medications recently.

Inclusion Criteria

I am between 18 and 55 years old.

I can speak and write in English.

Exclusion Criteria

Left handed

Color-blindness

I have had an eye injury or might have metal in my eye from work.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants undergo fMRI and EEG measurements with naloxone or saline administration to study neural mechanisms of observationally-induced hypoalgesia

2 days

2 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Naloxone (Opioid Antagonist)
• Saline (Other)

Trial Overview The study investigates how observing others influences our brain's response to pain. It uses saline and naloxone alongside brain imaging techniques like fMRI and EEG to understand the neurobiological activation that leads to reduced pain perception through observation.

Participant Groups

Group I: Naloxone Active Control 1 Intervention

NARCAN® Naloxone Nasal Spray will be used to block placebo effects during the fMRI experiment. Participants will be stratified for sex and then randomized to naloxone (The dose of naloxone will be 4 mg, so 0.1 mL of 40 mg/ml naloxone solution given intranasally) or saline (0.1 mL 0.9% sodium chloride intranasally), respectively. Investigators, staff, and participants will be blinded to the treatment options.

Group II: Saline Placebo Group 1 Intervention

Saline will be used as a sham comparator for blocking placebo effects during the fMRI experiment. Participants will be stratified for sex and then randomized to naloxone (The dose of naloxone will be 4 mg, so 0.1 mL of 40 mg/ml naloxone solution given intranasally) or saline (0.1 mL 0.9% sodium chloride intranasally), respectively. Investigators, staff, and participants will be blinded to the treatment options.

Naloxone is already approved in Canada for the following indications:

Approved in Canada as Naloxone for:

• Opioid overdose reversal

Who Is Running the Clinical Trial?

University of Maryland, Baltimore

Lead Sponsor

Trials

729

Recruited

540,000+

Dr. Mohan Suntha

University of Maryland, Baltimore

Chief Executive Officer since 2019

MD from Jefferson Medical College, MBA from Wharton School of Business, BA from Brown University

Dr. Taofeek K. Owonikoko

University of Maryland, Baltimore

Chief Medical Officer

MD, PhD

Findings from Research

Buprenorphine is highly effective for relieving perioperative pain and has a lower risk of addiction compared to traditional opioid agonists.

It can be administered through various routes, such as transdermal and subcutaneous, and shows promise for additional uses, including treating opioid addiction and potentially serving as an anti-inflammatory agent.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Buprenorphine: a unique opioid with broad clinical applications. Vadivelu, N., Hines, RL.[2019]

Buprenorphine is a unique treatment for opioid addiction due to its partial agonist activity at mu-opioid receptors and antagonist activity at kappa-opioid receptors, which helps reduce overdose risks while blocking the effects of other opioids.

Clinical trials have shown that sublingual buprenorphine is effective for both maintenance therapy and detoxification, and its combination with naloxone further minimizes the risk of misuse, making it a safer option for outpatient treatment of opioid addiction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Buprenorphine-containing treatments: place in the management of opioid addiction. Robinson, SE.[2022]

Buprenorphine, a partial micro opioid agonist, has a high safety profile due to its 'ceiling effect,' which limits respiratory depression and physical dependence, making it a suitable option for treating opioid addiction.

The combination of buprenorphine and naloxone in Suboxone is designed to discourage misuse, while buprenorphine alone (Subutex) will be used for initial dosing; however, patients with recent opioid use may experience mild withdrawal symptoms upon starting treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Buprenorphine: a primer for emergency physicians. Sporer, KA.[2013]

A survey of intravenous drug users in Helsinki revealed that 73% used buprenorphine as their primary drug, primarily for self-treating addiction or withdrawal symptoms.

The combination of buprenorphine and naloxone (Suboxone) was tried by 68% of respondents, but 80% reported negative experiences, suggesting that while it may help reduce buprenorphine abuse, its acceptance among users is low.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abuse liability of buprenorphine-naloxone tablets in untreated IV drug users. Alho, H., Sinclair, D., Vuori, E., et al.[2015]

Buprenorphine, a semisynthetic opioid, has a unique pharmacological profile that combines effective pain relief with a more favorable safety profile compared to other opioids, reducing the risk of abuse and dependence.

The new transdermal delivery system for buprenorphine allows for consistent and controlled release of the medication, making it an effective and well-accepted option for long-term management of chronic pain with minimal adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transdermal buprenorphine in the management of persistent pain - safety aspects. Likar, R.[2023]

Buprenorphine/naloxone has a unique pharmacology that provides a ceiling effect on its cardio-respiratory depressant properties, making it potentially safer than other opioids, especially at higher doses.

Data from various safety monitoring systems indicate that buprenorphine/naloxone has a favorable safety profile compared to other opioids and psychotropic drugs, suggesting it may reduce the risk of overdose-related morbidity and mortality.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Question About the Safety of Buprenorphine/Naloxone and Benzodiazepine Drugs. Howland, RH.[2015]

Buprenorphine acts on specific opiate receptors, functioning as a partial agonist at the mu receptor and an antagonist at the kappa receptor, which allows it to produce morphine-like effects at low doses while being safer than full agonists at higher doses.

Sublingual formulations of buprenorphine, such as Subutex and Suboxone, are effective first-line treatments for opioid dependence due to their unique pharmacological properties, which help manage addiction while minimizing risks associated with full agonist opioids.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Buprenorphine in the treatment of opiate dependence: its pharmacology and social context of use in the U.S. Wesson, DR.[2022]

The implementation of an opioid-sparing pain management protocol significantly reduced fentanyl consumption in the intensive care unit, with a decrease of 128 units immediately following the intervention.

Patients under this protocol experienced a shorter duration of mechanical ventilation, with a median reduction of 1 day, indicating improved clinical outcomes associated with the new pain management strategy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pain management protocol implementation and opioid consumption in critical care: an interrupted time series analysis. Besen, BAMP., Nassar Júnior, AP., Lacerda, FH., et al.[2022]

A tailored approach to cancer pain management, which assesses the type of pain (visceral, somatic, or neuropathic), can lead to quicker pain relief and fewer complications compared to standard methods.

Recent FDA-approved opioids, such as oxymorphone and fentanyl effervescent buccal tablets, offer new options for managing acute and breakthrough pain, potentially improving individualized treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current developments in opioid therapy for management of cancer pain. de Leon-Casasola, OA.[2022]

New opioids like tapentadol, which combines μ-opioid receptor activation with norepinephrine reuptake inhibition, offer a novel mechanism of action that may improve pain management in cancer patients.

Innovative drug delivery systems and formulations, such as those involving naloxone to mitigate side effects, are being developed to enhance the safety and efficacy of opioid analgesics, but their effectiveness will depend on personalized treatment approaches.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New opioids. Mercadante, S., Porzio, G., Gebbia, V.[2014]

Opioid analgesics, like morphine, work by interacting with three types of opioid receptors (mu, delta, and kappa) located in various parts of the nervous system, which helps modulate pain both by transmitting and inhibiting pain signals.

The clinical use of opioids involves understanding their pharmacokinetics and the potential for tolerance, dependence, and addiction, which are crucial for effective and safe pain management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical pharmacology of opioids for pain. Inturrisi, CE.[2022]

In a study of 2,965 patients receiving opioids at a pain management center from 2003 to 2006, there were 12 opioid-related deaths, indicating a low prevalence of 0.46 to 1.78 deaths per 1,000 patients during this period.

Of the total deaths, only 5 were definitively linked to prescription opioids, suggesting that while opioid use carries risks, the direct relationship to prescribed medications in this population was relatively low.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Increasing deaths from opioid analgesics in the United States: an evaluation in an interventional pain management practice. Manchikanti, KN., Manchikanti, L., Damron, KS., et al.[2019]

References

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

Buprenorphine: a unique opioid with broad clinical applications. [2019]

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

Buprenorphine-containing treatments: place in the management of opioid addiction. [2022]

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

Buprenorphine: a primer for emergency physicians. [2013]

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

Baseline- and treatment-associated pain in the X:BOT comparative effectiveness study of extended-release naltrexone versus buprenorphine-naloxone for OUD. [2022]

5. Ireland pubmed.ncbi.nlm.nih.gov

Abuse liability of buprenorphine-naloxone tablets in untreated IV drug users. [2015]

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

Transdermal buprenorphine in the management of persistent pain - safety aspects. [2023]

7. England pubmed.ncbi.nlm.nih.gov

Buprenorphine exposures in adolescents and adults: a 10-year experience of a French Poison Control Center. [2021]

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

A Question About the Safety of Buprenorphine/Naloxone and Benzodiazepine Drugs. [2015]

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

Buprenorphine in the treatment of opiate dependence: its pharmacology and social context of use in the U.S. [2022]

10. Brazil pubmed.ncbi.nlm.nih.gov

Pain management protocol implementation and opioid consumption in critical care: an interrupted time series analysis. [2022]

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

Current developments in opioid therapy for management of cancer pain. [2022]

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

New opioids. [2014]

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

Clinical pharmacology of opioids for pain. [2022]

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

Increasing deaths from opioid analgesics in the United States: an evaluation in an interventional pain management practice. [2019]