Observational Analgesia Mechanisms for Pain Management
Recruiting in Palo Alto (17 mi)
Overseen byLuana 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?
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.56789
How is the drug Naloxone unique for pain management?
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.
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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 OverviewThe 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
2Treatment groups
Active Control
Placebo Group
Group I: NaloxoneActive Control1 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: SalinePlacebo Group1 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
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
University of MarylandBaltimore, MD
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Who Is Running the Clinical Trial?
University of Maryland, BaltimoreLead Sponsor
References
Buprenorphine: a unique opioid with broad clinical applications. [2019]The analgesic potential of buprenorphine, a high-affinity partial mu agonist, has been a subject of study for several decades. The drug is now widely recognized as being extremely effective in relieving perioperative pain, with little of the addictive potential or risk associated with pure I agonists. Studies have suggested that buprenorphine produces adequate analgesia via almost any route of administration, including transdermal and subcutaneous. It has also been used, with positive results, in the treatment of opioid addiction, and potential remains for research into other roles, e.g., as an anti-inflammatory agent or an antihyperalgesic medication.
Buprenorphine-containing treatments: place in the management of opioid addiction. [2022]Although the synthetic opioid buprenorphine has been available clinically for almost 30 years, its use has only recently become much more widespread for the treatment of opioid addiction. The pharmacodynamic and pharmacokinetic profiles of buprenorphine make it unique in the armamentarium of drugs for the treatment of opioid addiction. Buprenorphine has partial mu-opioid receptor agonist activity and is a kappa-opioid receptor antagonist; hence, it can substitute for other micro-opioid receptor agonists, yet is less apt to produce overdose reactions or dysphoria. On the other hand, buprenorphine can block the effects of opioids such as heroin (diamorphine) and morphine, and can even precipitate withdrawal in individuals physically dependent upon these drugs. Buprenorphine has significant sublingual bioavailability and a long half-life, making administration on a less than daily basis possible. Furthermore, its discontinuation is associated with only a mild withdrawal syndrome. Clinical trials have demonstrated that sublingual buprenorphine is effective in both maintenance therapy and detoxification of individuals addicted to opioids. The introduction of a sublingual formulation combining naloxone with buprenorphine further reduces the risk of diversion to illicit intravenous use. Because of its relative safety and lower risk of illegal diversion, buprenorphine has been made available in several countries for treating opioid addiction in the private office setting, greatly enhancing treatment options for this condition.
Buprenorphine: a primer for emergency physicians. [2013]The recent approval of office-based treatment for opioid addiction and US Food and Drug Administration approval of buprenorphine will expand treatment options for opioid addiction. Buprenorphine is classified as a partial micro opioid agonist and a weak kappa antagonist. It has a high affinity for the micro receptor, with slow dissociation resulting in a long duration of action and an analgesic potency 25 to 40 times more potent than morphine. At higher doses, its agonist effects plateau and it begins to behave more like an antagonist, limiting the maximal analgesic effect and respiratory depression. This "ceiling effect" confers a high safety profile clinically, a low level of physical dependence, and only mild withdrawal symptoms on cessation after prolonged administration. Suboxone contains a mixture of buprenorphine and naloxone. The naloxone is poorly absorbed sublingually and is designed to discourage intravenous use. Subutex, buprenorphine only, will also be available primarily as an initial test dose. Clinicians will be using this drug for detoxification or for maintenance of opioid addiction. Patients with recent illicit opioid use may develop a mild precipitated withdrawal syndrome with the induction of buprenorphine. Acute buprenorphine intoxication may present with some diffuse mild mental status changes, mild to minimal respiratory depression, small but not pinpoint pupils, and relatively normal vital signs. Naloxone may improve respiratory depression but will have limited effect on other symptoms. Patients with significant symptoms related to buprenorphine should be admitted to the hospital for observation because symptoms will persist for 12 to 24 hours.
Baseline- and treatment-associated pain in the X:BOT comparative effectiveness study of extended-release naltrexone versus buprenorphine-naloxone for OUD. [2022]Chronic pain is highly prevalent among patients with opioid use disorder (OUD). However, little is known about how pharmacological treatments for OUD, for example, extended-release naltrexone (XR-NTX) and buprenorphine-naloxone (BUP-NX), affect pain. To begin addressing this question, we performed a secondary analysis of pain data on a large prospective 24-week, open-label, randomized-controlled comparative effectiveness trial of XR-NTX versus BUP-NX (X:BOT trial). Participants' pain status was measured by the EuroQol (EQ-5D). Based on their responses to the pain question at baseline, participants were dichotomized into "Pain" versus "No Pain" categories. Participant's pain status was evaluated every 4 weeks. A mixed effects longitudinal logistic regression model was fitted to examine the differential effect of XR-NTX versus BUP-NX on pain, modelling pain at all available follow-up assessments, adjusted for age, sex, and baseline pain. A total of 474 individuals who were successfully inducted onto their assigned medications were included in this analysis. Among participants endorsing pain at baseline, substantial reductions in pain were observed over the course of the study in both treatment groups. Howecver reduction in pain was slightly greater in the group treated with XR-NTX than the one treated with BUP-NX (OR = 1.60 [95% CI: 1.07-2.40], P = 0.023). Future research using instruments and design specifically focused on pain could extend the present observations and evaluate their clinical significance.
Abuse liability of buprenorphine-naloxone tablets in untreated IV drug users. [2015]Buprenorphine (Subutex) is widely abused in Finland. A combination of buprenorphine plus naloxone (Suboxone) has been available since late 2004, permitting a comparison of the abuse of the two products among untreated intravenous (IV) users. A survey was distributed to attendees at a Helsinki needle exchange program over 2-weeks in April, 2005, At least 30% were returned anonymously. Survey variables included: years of prior IV opioid abuse, years of buprenorphine abuse, frequency, dosage, route of administration and reasons for use, concomitant IV abuse of other substances and amount paid on the street for both buprenorphine and buprenorphine+naloxone. Buprenorphine was the most frequently used IV drug for 73% of the respondents. More than 75% said they used IV buprenorphine to self-treat addiction or withdrawal. Most (68%) had tried the buprenorphine+naloxone combination IV, but 80% said they had a "bad" experience. Its street price was less than half that of buprenorphine alone. The buprenorphine+naloxone combination appears to be a feasible tool, along with easier access to addiction treatment, for decreasing IV abuse of buprenorphine.
Transdermal buprenorphine in the management of persistent pain - safety aspects. [2023]By virtue of their efficacy, opioid analgesics have long been used for the treatment of both acute and chronic pain. Concerns regarding their safety and tolerability have frequently prevented this class of drugs achieving their full therapeutic potential, and their reported association with drug abuse and dependence has led to a reduced acceptance by many patients. Indeed, there is a variety of opioid-like side effects which are common to all members of the class, but some opioids have a more favourable safety profile than others. Buprenorphine is a semisynthestic opioid with a mu-agonistic and kappa-antagonistic receptor-binding profile. Studies over the past two decades have shown buprenorphine to have a complex and unique pharmacological profile, which results in enhanced therapeutic benefits combined with a favourable safety profile. Having been underused before, the development of a new transdermal drug delivery system for buprenorphine has revived interest in this substance. Transdermal buprenorphine (Gruenenthal GmbH, Aachen, Germany) provides a noninvasive method of rate-controlled drug release ensuring constant and predictable serum buprenorphine levels over a prolonged period. This preparation has been shown to be advantageous for long-term treatment of chronic pain patients providing reliable pain control, few adverse events, and good patient acceptance.
Buprenorphine exposures in adolescents and adults: a 10-year experience of a French Poison Control Center. [2021]Buprenorphine has been used in pain and opioid addiction management for nearly 25 years. Compared to methadone, buprenorphine is thought to exhibit less side effects and respiratory depression in case of accidental or suicidal overdose. The aim was to describe the characteristics of exposures reported to a French Poison Control Center (PCC). We conducted a retrospective study including all buprenorphine exposures for which advice of our PCC was required between 2009 and 2018. After data extraction from the electronic medical files and anonymous transfer to an Access base, a statistical descriptive analysis was performed focusing on adolescents over 10 years old and adults. One hundred and ninety-nine cases were analyzed. The major circumstances of exposure were suicide attempts and overdoses in patients with previously identified substance abuse. Buprenorphine exposures have been reduced by 50% between 2009 and 2018. Coingestions, often with benzodiazepines or antidepressants, were almost systematic and 79% of all the series exhibited at least one symptom. Among the symptomatic cases, neurological effects were the most frequent (83%) and respiratory symptoms occurred in 13%. No deaths were registered. Severity did not exceed PSS1 in 80% of all the cases. Treatment was mainly symptomatic even though naloxone was required in at least 5% of the symptomatic cases. Within 24 h after exposure, 120 patients were discharged from the emergency department. Despite loss to follow-up, our results suggest that buprenorphine is relatively safe.
A Question About the Safety of Buprenorphine/Naloxone and Benzodiazepine Drugs. [2015]Drug overdose is the leading cause of injury death in the United States, and most deaths are related to prescription drugs. A substantial proportion of these deaths involve opioid or benzodiazepine drugs, and many overdoses include a combination of both drug classes. Buprenorphine/naloxone has an unusual pharmacology that distinguishes it from other opioid drugs. Animal and human studies have found that buprenorphine is associated with a ceiling to its cardio-respiratory depressant effect at higher doses, such that it may have a wider safety margin compared to other opioid drugs. Compared to buprenorphine alone, buprenorphine/naloxone is associated with less cardiorespiratory depression. Drug safety data from the National Poison Data System, Drug Abuse Warning Network, and other sources suggest that the safety of buprenorphine/naloxone is favorable compared to the morbidity and mortality associated with other opioid drugs and other classes of psychotropic drugs.
Buprenorphine in the treatment of opiate dependence: its pharmacology and social context of use in the U.S. [2022]Buprenorphine's physiological effects are produced when it attaches to specific opiate receptors that are designated mu, kappa, or delta. Buprenorphine, a partial agonist at the mu receptor and an antagonist at the kappa receptor, produces typical morphine-like effects at low doses. At higher doses, it produces opiate effects that are less than those of full opiate agonists. Knowledge of the physiological effects of opiate receptors and the way they interact with opiate agonists, partial opiate agonists, and opiate antagonists is fundamental to understanding the safety and efficacy of buprenorphine in treatment of pain and opiate addiction. Knowledge of the historical and social context of opiate agonist treatment of opiate dependence is fundamental to understanding how nonpharmacological factors may limit the clinical adoption and utility of a safe and effective medication in treatment of opiate dependence. This article reviews the pharmacology of sublingual buprenorphine and the historical context of opiate agonist therapy; delineates classes of opiate receptors and their interaction with opiate agonists, partial agonists, and antagonists; and describes the commercially available pharmaceutical formulations of buprenorphine. It focuses on sublingual buprenorphine tablets, Subutex and Suboxone, the FDA-approved formulations of buprenorphine for treatment of opiate dependence. Sublingual buprenorphine, and the combination of sublingual buprenorphine/naloxone, have unique pharmacological properties that make them a logical first-line intervention in the treatment of opioid dependence.
Pain management protocol implementation and opioid consumption in critical care: an interrupted time series analysis. [2022]To evaluate the impact of an opioid-sparing pain management protocol on overall opioid consumption and clinical outcomes.
Current developments in opioid therapy for management of cancer pain. [2022]Pain remains a highly prevalent problem for patients with cancer and typically falls into one of 3 types: visceral, somatic, and neuropathic. A mechanistic, pathophysiologic approach to pain management involves a good assessment of the type of pain, followed by tailoring of the treatment based on the diagnosis. This pain management strategy can provide rapid pain control with a lower incidence of complications and side effects than other methods. Furthermore, pharmacogenetics may play an important role in individualizing therapies in the future, but for now this type of data offers explanations for phenomena commonly observed in clinical practice, such as (1) differences in individual analgesic and side-effect responses to various opioid agents, (2) incomplete cross-tolerance seen when switching between mu opioid analgesics, and (3) why opioid rotation can be beneficial for patients after an opioid therapy loses efficacy or becomes associated with intolerable side effects. Especially for difficult-to-manage pain patients, additions to the opioid analgesic armamentarium can potentially better individualize pain management, and provide another option to be used for opioid rotation. Among the most recent Food and Drug Administration-approved opioid analgesics for acute pain and persistent pain are oral immediate-release and extended-release formulations of oxymorphone, whereas for breakthrough pain, the ultrarapid-acting opioid, fentanyl effervescent buccal tablets, has newly been developed and indicated within the United States.
New opioids. [2014]Despite the skilled use of opioid analgesics, which is crucial to the relief of cancer pain, there is a lack of evidence to support many aspects of current clinical practice. Therefore, there is a significant need for more effective treatment options. New opioids have been marketed in the past years, including hydrocodone and oxymorphone. Moreover, mixed opioids with combined mechanisms of action have been developed; one such agent, tapentadol, is a centrally acting oral analgesic that possesses a combined mechanism of action: μ-opioid receptor activation with norepinephrine reuptake inhibition. Drug development strategies involving naloxone have been initiated to reduce peripheral opioid-related adverse effects. The rationale is based on the local antagonist activity of naloxone in intestinal opioid receptors and the negligible oral bioavailability of naloxone, particularly in a prolonged-release formulation. New delivery systems have been developed to provide rapid analgesia with potent opioid drugs such as fentanyl. Despite the upcoming availability of these new drugs and technologies that will add to existing types of opioid medication, their benefits and liabilities will ultimately need to be determined by the individual physician and individual patient experiencing pain.
Clinical pharmacology of opioids for pain. [2022]The pharmacological effects of the opioid analgesics are derived from their complex interactions with three opioid receptor types (mu, delta, and kappa; morphine is an agonist at the mu opioid receptor). These receptors are found in the periphery, at presynaptic and postsynaptic sites in the spinal cord dorsal horn, and in the brain stem, thalamus, and cortex, in what constitutes the ascending pain transmission system, as well as structures that comprise a descending inhibitory system that modulates pain at the level of the spinal cord. The cellular effects of opioids include a decrease in presynaptic transmitter release, hyperpolarization of postsynaptic elements, and disinhibition. The endogenous opioid peptides are part of an endogenous pain modulatory system. A number of opioids are available for clinical use, including morphine, hydromorphone, levorphanol, oxymorphone, methadone, meperidine, oxycodone, and fentanyl, and their advantages and disadvantages for the management of pain are discussed. An understanding of the pharmacokinetic properties, as well as issues related to opioid rotation, tolerance, dependence, and addiction are essential aspects of the clinical pharmacology of opioids for pain.
Increasing deaths from opioid analgesics in the United States: an evaluation in an interventional pain management practice. [2019]To assess the prevalence of opioid-related deaths in patients in an interventional pain management tertiary referral center.