Buprenorphine Plus Baclofen to Increase Analgesia in Healthy Volunteers

Study Overview
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Brief Summary
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To determine if baclofen will enhance buprenorphine analgesia for acute pain in healthy volunteers.

Detailed Description
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Abuse of opioids is a significant and growing problem in the United States. In the past two decades, opioid prescriptions have quadrupled while the age of heroin initiation has decreased, suggesting that more individuals are using opioids and transitioning to heroin and potent synthetic opioids than in the past. Further, fatal opioid overdose is now the leading cause of accidental death and is the 5th highest overall cause of mortality in the US. Engaging opioid users in opioid agonist treatments has been shown to lower rates of criminal behavior, lower rates of non-opioid drug use, and increase retention in drug treatment programs, while decreasing mortality and new HIV and hepatitis infections. However, a recent study noted that 68% of patients prescribed buprenorphine had poor medication adherence, which was associated with illicit opioid use. A Cochrane review concluded that buprenorphine was less effective at retaining patients in treatment relative to methadone. One reason for lower treatment retention may be the high comorbidity of opioid use disorder and chronic pain and/or opioid-induced hyperalgesia. Buprenorphine, as a partial mu agonist, provides lower analgesia but an improved safety profile relative to full agonists like methadone. Thus, enhancing the analgesic properties of buprenorphine will provide a safer alternative for opioid use disorder patients with chronic pain/hyperalgesia.

Official Title
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Buprenorphine Plus Baclofen to Increase Analgesia in Healthy Volunteers

Conditions
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Acute Pain, Analgesia

Intervention / Treatment
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* Drug: Placebos
* Drug: Baclofen 5 mg
* Drug: Baclofen 10mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 years or older general good health English speaking Exclusion Criteria: Pregnant or nursing Opioid use disorder or any substance use disorder other than nicotine Prescribed agonist treatment for opioid dependence or prescribed opioids for a medical condition Prescribed naltrexone Known sensitivity to buprenorphine, naloxone, or baclofen Acute or chronic pain condition Trouble breathing or a pulmonary condition Prescribed benzodiazepines or daily use of benzodiazepines Positive drug screen (positive cannabis result allowed) Cognitive impairment or psychiatric disorder requiring treatment Uncontrolled hypertension

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Participants will be randomized to one of three interventions.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Participants randomized to this arm will receive Placebo. | Drug: Placebos<br>* Participants will receive placebo in combination with 0.3 mg of buprenorphine to examine analgesia in acute pain tasks.<br>|
| Experimental: Baclofen 5mg<br>Participants randomized to this arm will receive 5 mg of Baclofen. | Drug: Baclofen 5 mg<br>* Participants will receive 5mg of baclofen in combination with 0.3 mg of buprenorphine to examine analgesia in acute pain tasks.<br>|
| Experimental: Baclofen 10mg<br>Participants randomized to this arm will receive 10 mg of Baclofen. | Drug: Baclofen 10mg<br>* Participants will receive 10mg of baclofen in combination with 0.3 mg of buprenorphine to examine analgesia in acute pain tasks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pain Threshold | Pain threshold refers to the intensity at which a stimulus is first perceived as painful. Heat stimuli will be delivered using a computer-controlled thermal stimulation system with a 30 millimeter X 30 millimeter probe. From a baseline of 32 degrees Celsius, the probe temperature will increase at a rate of .5 degrees Celsius/second until the participant responds by pressing a button on a handheld device. For heat pain threshold, participants will be instructed to press the button when the sensation first becomes painful Pain rating scores will be reflected in scores of 0-100, 0 being the least amount of pain and 100 being the most amount of pain. | Baseline | 
| Pain Threshold | Pain threshold refers to the intensity at which a stimulus is first perceived as painful. Heat stimuli will be delivered using a computer-controlled thermal stimulation system with a 30 millimeter X 30 millimeter probe. From a baseline of 32 degrees Celsius, the probe temperature will increase at a rate of .5 degrees Celsius/second until the participant responds by pressing a button on a handheld device. For heat pain threshold, participants will be instructed to press the button when the sensation first becomes painful Pain rating scores will be reflected in scores of 0-100, 0 being the least amount of pain and 100 being the most amount of pain. | Baseline through one week | 
| Pain tolerance | Pain tolerance refers to the maximum amount of pain produced by a stimulus that a person is able/willing to tolerate. Heat stimuli will again be delivered using the computer-controlled thermal stimulation system. From a baseline of 32 degrees Celsius, the probe temperature will increase at a rate of .5 degrees Celsius/second until the participant responds by pressing a button on a handheld device. For heat pain tolerance, participants will be instructed to press the button when they are no longer willing to tolerate the painful sensation. Pain rating scores will be reflected in scores of 0-100, 0 being the least amount of pain and 100 being the most amount of pain. | Baseline | 
| Pain tolerance | Pain tolerance refers to the maximum amount of pain produced by a stimulus that a person is able/willing to tolerate. Heat stimuli will again be delivered using the computer-controlled thermal stimulation system. From a baseline of 32 degrees Celsius, the probe temperature will increase at a rate of .5 degrees Celsius/second until the participant responds by pressing a button on a handheld device. For heat pain tolerance, participants will be instructed to press the button when they are no longer willing to tolerate the painful sensation. Pain rating scores will be reflected in scores of 0-100, 0 being the least amount of pain and 100 being the most amount of pain. | Baseline through one week | 
| Temporal summation of pain | Temporal summation of pain refers to a form of endogenous pain facilitation characterized by the perception of increased pain despite constant or even reduced peripheral afferent input. Temporal summation is presumed to be the psychophysical manifestation of wind-up. Wind-up is a phenomenon where repetitive stimulation of C primary afferents at rates greater than 0.3 Hertz produces a slowly increasing response of second-order neurons in the spinal cord. Pain rating scores will be reflected in scores of 0-100, 0 being the least amount of pain and 100 being the most amount of pain. | Baseline | 
| Temporal summation of pain | Temporal summation of pain refers to a form of endogenous pain facilitation characterized by the perception of increased pain despite constant or even reduced peripheral afferent input. Temporal summation is presumed to be the psychophysical manifestation of wind-up. Wind-up is a phenomenon where repetitive stimulation of C primary afferents at rates greater than 0.3 Hertz produces a slowly increasing response of second-order neurons in the spinal cord. Pain rating scores will be reflected in scores of 0-100, 0 being the least amount of pain and 100 being the most amount of pain. | Baseline through one week | 
| Conditioned pain modulation | A routinely used quantitative sensory testing protocol for the measurement of endogenous pain inhibition is conditioned pain modulation, which refers to the reduction in pain from one stimulus (the test stimulus) produced by the application of a second pain stimulus at a remote body site (the conditioning stimulus). Conditioned pain modulation is believed to reflect the perceptual manifestation of diffuse noxious inhibitory controls, whereby ascending projections from one noxious stimulus activate supraspinal structures that trigger descending inhibitory projections to the dorsal horn. Pain rating scores will be reflected in scores of 0-100, 0 being the least amount of pain and 100 being the most amount of pain. | Baseline | 
| Conditioned pain modulation | A routinely used quantitative sensory testing protocol for the measurement of endogenous pain inhibition is conditioned pain modulation, which refers to the reduction in pain from one stimulus (the test stimulus) produced by the application of a second pain stimulus at a remote body site (the conditioning stimulus). Conditioned pain modulation is believed to reflect the perceptual manifestation of diffuse noxious inhibitory controls, whereby ascending projections from one noxious stimulus activate supraspinal structures that trigger descending inhibitory projections to the dorsal horn. Pain rating scores will be reflected in scores of 0-100, 0 being the least amount of pain and 100 being the most amount of pain. | Baseline through one week | 
| Suprathreshold pain response | Ratings of pain in response to discrete stimuli with intensities above the pain threshold detection/ patients provide an intensity rating using any number of a 0-100 scale whereby 0=no pain and 100= the most intense pain imaginable | Baseline | 
| Suprathreshold pain response | Ratings of pain in response to discrete stimuli with intensities above the pain threshold detection/ patients provide an intensity rating using any number of a 0-100 scale whereby 0=no pain and 100= the most intense pain imaginable | Baseline through one week | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Opioid Symptom Checklist | Lists True-False questions measuring opioid effects. | One to seven days post baseline | 
| McGill Pain Questionnaire-Short Form | 15 descriptors (11 sensory; 4 affective) using an intensity scaled ranging from 0-3 on pain. 0 being the least amount of pain and 3 being the most amount of pain. | One to seven days post baseline | 
| 26-item Visual Analog Scale (VAS) | Measures subjective and physiological effects of a medication using mood states as well as questions about the dose of medication. | One to seven days post baseline | 
| Drug Effects Questionnaire-5 | Assesses drug effects and uses VAS ratings from Not at all to Very much. | One to seven days post baseline | 
| 26-item Visual Analog Scale (Subjective drug effects) | This 26-item VAS measures subjective and physiological effects of a medication using mood states as well as questions about the dose of medication. | One to seven days post baseline |