Observational Analgesia Mechanisms for Pain Management

Overseen By Adria Suhr

Age: 18 - 65

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Maryland, Baltimore

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

Disqualifiers: Cardiovascular, Neurological, Chronic pain, others

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

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

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

Compensation: Varies

Number of Visits: 2

Duration: 2 days

182 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how observing someone else experience pain relief can reduce pain through brain processes. Researchers use naloxone, a medication that blocks opioid effects, and a placebo to study brain changes related to pain perception. The goal is to understand how the brain's response to observation can aid in pain management, potentially reducing opioid use. Individuals free of chronic pain and severe mental health conditions might be suitable participants. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group.

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.

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

Research has shown that naloxone is generally safe for humans and is commonly used to reverse opioid overdoses. Studies confirm that naloxone nasal spray is safe and effective for this purpose, even in children. However, it may cause withdrawal symptoms in those who rely on opioids. These symptoms might be uncomfortable but are usually not dangerous. No reports of serious side effects exist when used by individuals who do not use opioids. In this trial, researchers use naloxone to study brain activity related to pain, but its safety is well-known from other uses. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about this trial because it seeks to understand the mechanisms behind placebo effects in pain management using naloxone. Unlike most pain treatments that primarily focus on reducing pain signals, this trial aims to explore how blocking placebo effects with naloxone, an opioid receptor antagonist, might change brain responses to pain. By using an innovative approach involving fMRI imaging, the study could pave the way for more effective pain management strategies that leverage our understanding of the brain's role in pain perception.

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

Research shows that naloxone effectively stops the effects of opioids, making it crucial for treating opioid overdoses. It quickly reverses the impact of opioids on the brain, preventing overdose deaths. Studies have shown that naloxone is safe and effective when administered by healthcare providers. In this trial, participants will receive either naloxone or saline as part of the study arms. Researchers use naloxone to understand how the brain processes pain relief when observing others experiencing it. While naloxone itself doesn't directly reduce pain, it aids researchers in exploring how the brain might naturally handle pain. ^{6 7 8 9 10}

Who Is on the Research Team?

Luana Colloca, MD/PhD/MS

Principal Investigator

University of Maryland Baltimore School of Nursing

Are You a Good Fit for This Trial?

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 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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Naloxone
• Saline

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.

How Is the Trial Designed?

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 United States, European Union, Canada for the following indications:

Approved in United States as Naloxone for:

• Opioid overdose reversal

Approved in European Union as Naloxone for:

• Opioid overdose reversal

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+

Published Research Related to This Trial

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]

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]

A retrospective study of 199 buprenorphine exposure cases from 2009 to 2018 showed that the majority of incidents were related to suicide attempts and overdoses in individuals with substance abuse issues, but no deaths were reported, indicating a relatively safe profile for buprenorphine.

The study found that while neurological symptoms were common (83%), respiratory symptoms were rare (13%), and the severity of most cases was low, with 80% classified as mild, suggesting that buprenorphine has a lower risk of severe respiratory depression compared to other opioids.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Buprenorphine exposures in adolescents and adults: a 10-year experience of a French Poison Control Center. Boulamery, A., von Fabeck, K., Glaizal, M., et al.[2021]

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]

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]

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]

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]

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]

In a study involving 474 participants with opioid use disorder, both extended-release naltrexone (XR-NTX) and buprenorphine-naloxone (BUP-NX) significantly reduced pain over 24 weeks, as measured by the EuroQol (EQ-5D).

Participants receiving XR-NTX experienced a greater reduction in pain compared to those on BUP-NX, with an odds ratio of 1.60, indicating that XR-NTX may be more effective for managing pain in individuals with opioid use disorder.

NCBI (Pubmed)

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. Wang, AL., Shulman, M., Choo, TH., et al.[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]

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]

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]

Citations

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New York State Department of Health Announces Study ... Researchers reviewed data collected from April of 2023 to March of 2025, examining how many times naloxone was administered, outcomes for ...

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Review of naloxone safety for opioid overdose - PubMed Central Naloxone has a long history of safe and effective use by organized healthcare systems and providers in the treatment of opioid overdose.

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215457Orig1s000 - accessdata.fda.gov Higher doses of naloxone (e.g., 10 mg via the intramuscular. [IM] route) may be more effective in reversing certain opioid overdoses (e.g., ...

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KLOXXADO (naloxone hydrochloride) nasal spray KLOXXADO nasal spray is safe and effective in children for known or suspected opioid overdose. Do not use KLOXXADO nasal spray: • if you are allergic to ...

7. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2015/208411lbl.pdf

NARCAN (naloxone hydrochloride) nasal spray NARCAN Nasal Spray is safe and effective in children for known or suspected opioid overdose. Who should not use NARCAN Nasal Spray? Do not use NARCAN Nasal ...

8. nida.nih.gov nida.nih.gov/publications/drugfacts/naloxone

Naloxone DrugFacts | National Institute on Drug Abuse (NIDA) Overall, naloxone is a safe medicine. But it only reverses an overdose in people with opioids in their systems and will not reverse overdoses ...

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Naloxone (Evzio, Kloxxado) | Davis's Drug Guide Contraindication/Precautions · Cardiovascular disease; · Patients physically dependent on opioids (may precipitate severe withdrawal); · OB: May cause acute ...

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PRODUCT MONOGRAPH NARCAN® NASAL SPRAY Naloxone administration may cause an acute opioid withdrawal syndrome which may be life threatening in opioid dependent neonates if not ...