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Trial record 1 of 1 for:    NCT02469077
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Reduced Opioid Analgesic Requirements Via Improved Endogenous Opioid Function

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ClinicalTrials.gov Identifier: NCT02469077
Recruitment Status : Completed
First Posted : June 11, 2015
Results First Posted : September 23, 2020
Last Update Posted : September 23, 2020
Sponsor:
Collaborator:
National Institute on Drug Abuse (NIDA)
Information provided by (Responsible Party):
Stephen Bruehl, PhD, Vanderbilt University Medical Center

Brief Summary:
Chronic Pain (CP) management has increasingly utilized long-term opioid analgesic therapy, a change associated with increased opioid abuse (via greater exposure in vulnerable individuals), non-pain health consequences (hormone changes, falls), and a dramatic rise in opioid-related overdoses and deaths. Treatment strategies that minimize the need for chronic high-dose opioids are sorely needed. This project will test the novel hypothesis that effective pain relief can be achieved at lower opioid analgesic doses by increasing levels of endogenous opioids (EOs).

Condition or disease Intervention/treatment Phase
Chronic Pain Behavioral: 6 week aerobic exercise intervention Drug: Placebo Drug: Morphine Drug: naloxone Not Applicable

Detailed Description:

There are three separate goals of the study: 1) test the effects of the intervention (versus control) on clinical outcomes, 2) test for endogenous opioid mechanisms of the intervention (indexed by the difference in laboratory evoked pain response between placebo and naloxone drug conditions), and 3) test the effects of the intervention on morphine responses (indexed by the difference in evoked pain response between placebo and morphine laboratory drug conditions).

This project will determine whether enhancing endogenous opioids (via aerobic exercise training) permits achieving desired levels of analgesia with lower dosages of opioid analgesics, and fewer side effects and abuse-relevant drug effects. This 4 year project will test study hypotheses in a sample of 116 chronic low back pain patients. The study will have two key elements: 1) a randomized, controlled aerobic exercise manipulation in CP patients completing daily electronic pain diaries and 2) laboratory evoked thermal pain protocols pre- and post-exercise permitting direct examination of changes in both opioid analgesic effects (in response to a series of incremental morphine doses) and EO activity (indexed by comparing pain responses after placebo vs. opioid blockade).

The study will use a 6 week supervised aerobic exercise manipulation, with subjects randomly assigned to the exercise protocol or a no exercise control condition.

The study will employ a mixed between/within-subjects design using double-blind, counterbalanced, placebo-controlled administration of both an opioid antagonist (naloxone) and an opioid agonist (morphine). All participants will undergo three identical laboratory pain-induction sessions (each ≈5 days apart) prior to randomization to experimental condition, and again at the end of the 6 week exercise manipulation period (regardless of exercise group assignment) during which they will receive the 3 study drugs and participate in controlled laboratory evaluation of evoked thermal pain responsiveness.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 117 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: Reduced Opioid Analgesic Requirements Via Improved Endogenous Opioid Function
Study Start Date : August 2015
Actual Primary Completion Date : September 2019
Actual Study Completion Date : September 2019


Arm Intervention/treatment
Experimental: 6 week aerobic exercise intervention
Participants randomly assigned to the exercise condition will complete an 18 session aerobic exercise manipulation supervised by an American College of Sports Medicine-certified personal trainer (3 exercise sessions per week for 6 weeks). Immediately before and after participating in this intervention arm, participants will undergo laboratory evoked thermal pain response testing with placebo-controlled morphine and naloxone administration to assess mechanisms of exercise-related changes.
Behavioral: 6 week aerobic exercise intervention

Participants randomly assigned to the 6 week aerobic exercise intervention will complete an 18 session aerobic exercise manipulation supervised by an American College of Sports Medicine-certified personal trainer (3 exercise sessions per week for 6 weeks).

Each exercise session will consist of a 5 minute warm-up, 30 minutes of aerobic exercise, followed by a 5 minute cool-down period. Aerobic exercise will consist of treadmill walking/running, stepping, elliptical, or cycling exercise as preferred by the participant. Duration of exercise will be standardized at 30 minutes with a target exercise intensity between 70-85% Heart Rate Reserve (RPE = 15, hard). Because of the focus on de-conditioned individuals with Chronic Low Back Pain, the duration and intensity of exercise will be progressively increased up to target during the first two weeks to avoid symptom exacerbation and minimize study drop-out.


Drug: Placebo
In randomized order (crossover) across 3 laboratory sessions each approximately 5 days apart, participants will undergo laboratory evoked thermal pain response testing with: 1) 4 doses of saline placebo (20ml each), 2) an 8mg dose of naloxone (in 20ml saline vehicle), followed by saline, 4mg naloxone, and saline, or 3) morphine sulfate (0.03 mg/kg in 20ml saline vehicle initially, followed by 3 incremental doses of 0.02mg/kg each).
Other Name: normal saline placebo

Drug: Morphine
In randomized order (crossover) across 3 laboratory sessions each approximately 5 days apart, participants will undergo laboratory evoked thermal pain response testing with: 1) 4 doses of saline placebo (20ml each), 2) an 8mg dose of naloxone (in 20ml saline vehicle), followed by saline, 4mg naloxone, and saline, or 3) morphine sulfate (0.03 mg/kg in 20ml saline vehicle initially, followed by 3 incremental doses of 0.02mg/kg each).
Other Name: Astramorph

Drug: naloxone
In randomized order (crossover) across 3 laboratory sessions each approximately 5 days apart, participants will undergo laboratory evoked thermal pain response testing with: 1) 4 doses of saline placebo (20ml each), 2) an 8mg dose of naloxone (in 20ml saline vehicle), followed by saline, 4mg naloxone, and saline, or 3) morphine sulfate (0.03 mg/kg in 20ml saline vehicle initially, followed by 3 incremental doses of 0.02mg/kg each).
Other Name: narcan

Active Comparator: Normal exercise (control)
Participants assigned to the control condition will not undergo any exercise manipulation during this 6 week period, and will be asked to continue their current activity levels and not engage in any additional exercise activity during the study period. Immediately before and after participating in this intervention arm, participants will undergo laboratory evoked thermal pain response testing with placebo-controlled morphine and naloxone administration to assess mechanisms of exercise-related changes.
Drug: Placebo
In randomized order (crossover) across 3 laboratory sessions each approximately 5 days apart, participants will undergo laboratory evoked thermal pain response testing with: 1) 4 doses of saline placebo (20ml each), 2) an 8mg dose of naloxone (in 20ml saline vehicle), followed by saline, 4mg naloxone, and saline, or 3) morphine sulfate (0.03 mg/kg in 20ml saline vehicle initially, followed by 3 incremental doses of 0.02mg/kg each).
Other Name: normal saline placebo

Drug: Morphine
In randomized order (crossover) across 3 laboratory sessions each approximately 5 days apart, participants will undergo laboratory evoked thermal pain response testing with: 1) 4 doses of saline placebo (20ml each), 2) an 8mg dose of naloxone (in 20ml saline vehicle), followed by saline, 4mg naloxone, and saline, or 3) morphine sulfate (0.03 mg/kg in 20ml saline vehicle initially, followed by 3 incremental doses of 0.02mg/kg each).
Other Name: Astramorph

Drug: naloxone
In randomized order (crossover) across 3 laboratory sessions each approximately 5 days apart, participants will undergo laboratory evoked thermal pain response testing with: 1) 4 doses of saline placebo (20ml each), 2) an 8mg dose of naloxone (in 20ml saline vehicle), followed by saline, 4mg naloxone, and saline, or 3) morphine sulfate (0.03 mg/kg in 20ml saline vehicle initially, followed by 3 incremental doses of 0.02mg/kg each).
Other Name: narcan




Primary Outcome Measures :
  1. Mean of the Change in Morphine Dosage (in mg) Required to Achieve 25% Reduction in Thermal Evoked Pain Responses Relative to Baseline (Pre-intervention) Placebo Condition Responses [ Time Frame: At pre-intervention baseline laboratory assessment and again post-intervention (an expected average of 6 weeks later) ]

    At a laboratory testing day pre and post intervention each participant received morphine sulphate (0.3mg/kg in 20ml saline vehicle initially, followed by 3 incremental doses of 0.02 mg/kg each with testing for thermal evoked pain response. Weight adjusted dosing was used by multiplying the weight of each patient in kg by 0.3mg (dose 1 only) or by .02mg (doses 2-4), with all doses infused in 20mL saline vehicle.

    Mean of the change in morphine dosage required to achieve 25 % reduction in thermal evoked pain responses on testing day at baseline (pre-intervention) and post intervention. Positive values for the change in the mean between pre and post intervention indicated decreased morphine requirements post intervention.


  2. Mean Change in 5-day Electronic Diary Ratings of Low Back Pain Intensity [ Time Frame: At pre-intervention baseline and again post-intervention (an expected average of 6 weeks later) ]
    Mean change in 5-day electronic diary ratings of low back pain intensity from pre intervention baseline to post intervention. 9 point pain scale assessing pain intensity with 0 represents no pain and 8 represents worst possible pain. Positive values indicate reduced pain post intervention.


Secondary Outcome Measures :
  1. Mean Change in Placebo Condition Ratings of Acute Thermal Pain Intensity on the McGill Pain Questionnaire-Short Form [ Time Frame: At pre-intervention baseline laboratory assessment and again post-intervention (an expected average of 6 weeks later) ]
    Mean change in placebo condition ratings of acute thermal pain intensity using the McGill Pain Questionnaire-Short Form on 3 testing days at baseline (per intervention) and post intervention. The score ranges from 0-33 where 0 represents no pain and 33 represents most intense pain. Positive change values indicate decreased pain responsiveness post intervention.

  2. Mean Within-participant Changes From Pre- to Post-intervention in Opioid Blockade Effects (Within-participant Difference Between Naloxone and Placebo Conditions) for Ratings of Acute Thermal Pain Intensity on the McGill Pain Questionnaire-Short Form [ Time Frame: At pre-intervention baseline laboratory assessment and again post-intervention (an expected average of 6 weeks later) ]

    Between-participant (aerobic exercise vs. control group) comparison of mean changes from pre- to post-intervention in opioid blockade effects for ratings of acute thermal pain intensity on the McGill Pain Questionnaire-Short Form based on 3 laboratory testing days at baseline (pre-intervention) and post intervention. The score ranges from 0-33 where 0 represents no pain and 33 represents more intense pain. Positive values indicate increased endogenous opioid analgesia post intervention.

    This measure will test for endogenous opioid mechanisms of the exercise (versus control) intervention as indexed by changes in opioid blockade effects (the difference in laboratory evoked pain response evoked between placebo and naloxone drug conditions).

    This is a mixed within-between subject design. Per the study protocol, the intent of outcome measures 4 and 6 was to capture opioid blockade effects (within-participant placebo-naloxone condition difference scores) at both the pre- and post-in


  3. Mean Change in McGill Pain Questionnaire-2 Total Chronic Back Pain Ratings [ Time Frame: At pre-intervention baseline laboratory assessment and again post-intervention (an expected average of 6 weeks later) ]
    Mean change in McGill Pain Questionnaire-2 total chronic back pain ratings on 3 testing days at baseline (pre intervention) and post intervention. The score ranges from 0-10 where 0 represents no pain and 10 represents most intense pain. Positive values indicate decreased back pain post intervention.

  4. Mean Within-participant Changes From Pre- to Post-intervention in Opioid Blockade Effects (Within-participant Difference Between Naloxone and Placebo Conditions) for McGill Pain Questionnaire-2 Total Ratings of Back Pain. [ Time Frame: At pre-intervention baseline laboratory assessment and again post-intervention (an expected average of 6 weeks later) ]

    Between-participant (aerobic exercise vs. control group) comparison of mean changes from pre- to post-intervention in opioid blockade effects for McGill Pain Questionnaire-2 Total ratings of back pain based on 3 laboratory testing days at baseline (pre intervention) and post intervention. The score ranges from 0-10 where 0 represents no pain and 10 represents most intense pain. Positive values indicate increased endogenous opioid analgesia post intervention.

    This measure will test the effects of the exercise (versus control) intervention on clinical outcomes as indexed by changes in opioid blockade effects (the difference in laboratory evoked pain response evoked between placebo and naloxone drug conditions).

    This is a mixed within-between subject design. Per the study protocol, the intent of outcome measures 4 and 6 was to capture opioid blockade effects (within-participant placebo-naloxone condition difference scores) at both the pre- and post-intervention lab assessments, an


  5. Mean Change in Positive and Negative Affect Scale-Negative Affect Subscale Ratings. [ Time Frame: At pre intervention baseline and again post-intervention (an expected average of 6 weeks later) ]
    Mean change in Positive and Negative Affect Scale-Negative Affect subscale ratings on 3 testing days at baseline (pre intervention) and post intervention. . Scale ratings range from 10 to 50 where 10 represents lowest negative affect possible and 50 represents highest negative affect possible. Positive values indicate decreased negative affect post intervention.

  6. Mean Change in Morphine Condition Visual Analog Scale (VAS) Opioid Effects Scale-Euphoria Subscale Ratings [ Time Frame: At pre-intervention baseline and again post-intervention (an expected average of 6 weeks later) ]
    Mean change in morphine condition VAS Opioid Effects-Euphoria subscale ratings on 3 testing days at baseline (pre intervention) and post intervention. The score ranges from 0-300 where 0 means no euphoria and 300 means most euphoria possible. Positive values indicate decreased euphoria post intervention.

  7. Mean Change in Morphine Condition Visual Analog Scale (VAS) Opioid Effects Scale-Sedation Subscale Ratings [ Time Frame: At pre-intervention baseline and again post-intervention (an expected average of 6 weeks later) ]
    Mean change in morphine condition VAS Opioid Effects-Sedation subscale ratings on 3 testing days at baseline (pre intervention) and post intervention. The score ranges from 0-300 where 0 means no sedation and 300 means most sedation possible. Positive values indicate decreased sedation post intervention.

  8. Mean Change in Morphine Condition Visual Analog Scale (VAS) Opioid Effects - Unpleasantness Subscale Ratings [ Time Frame: At pre-intervention baseline and again post-intervention (an expected average of 6 weeks later) ]
    Mean change in morphine condition VAS Opioid Effects - Unpleasantness subscale ratings on 3 testing days at baseline (pre intervention) and post intervention. The score ranges from 0-300 where 0 represents no unpleasantness and 300 represents most unpleasantness possible. Positive values indicate decreased unpleasantness post intervention.

  9. Mean Change in Morphine Condition Drug Effects, Liking, and Take Again (DELTA) -Drug Effect Subscale Ratings [ Time Frame: At pre-intervention baseline and again post-intervention (an expected average of 6 weeks later) ]
    Mean change in morphine condition Drug Effects, Liking, and Take Again (DELTA) -Drug Effect subscale ratings on 3 testing days at baseline (pre intervention) and post intervention. The score ranges from 1-5 where 1 represents no effect and 5 represents very strong effect. Positive values indicate decreased overall drug effects post intervention.

  10. Mean Change in Morphine Condition Drug Effects, Liking, and Take Again (DELTA) -Drug Liking Subscale Ratings [ Time Frame: At pre-intervention baseline and again post-intervention (an expected average of 6 weeks later) ]
    Mean change in morphine condition Drug Effects, Liking, and Take Again (DELTA) -Drug Liking subscale ratings on 3 testing days at baseline (pre intervention) and post intervention. The score ranges from 0-100 where 0 represents dislike a lot and 100 represents like a lot. Positive values indicate decreased drug liking post intervention.

  11. Mean Change in Morphine Condition Drug Effects, Liking, and Take Again (DELTA) -Take Again Subscale Ratings [ Time Frame: At pre-intervention baseline and again post-intervention (an expected average of 6 weeks later) ]
    Mean change in morphine condition Drug Effects, Liking, and Take Again (DELTA) -Take Again subscale ratings on 3 testing days at baseline (pre intervention) and post intervention. The score ranges from 0-100 where 0 represents definitely would not take again and 100 represents definitely would take again. Positive values indicate decreased desire to take the drug again post intervention.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Intact cognitive status and ability to provide informed consent
  • Ability to read and write in English sufficiently to understand and complete study questionnaires
  • Age 18-55 inclusive
  • Presence of persistent daily low back pain of at least three months duration and of at least a 3/10 in average intensity

Exclusion Criteria:

  • Engagement in > 2 days/wk and > 60 min/wk of moderate or vigorous intensity activity based on responses to 6 validated survey questions at screening (CDC BRFSS)
  • History of renal or hepatic dysfunction
  • Current or past alcohol or substance dependence
  • A history of PTSD, psychotic, or bipolar disorders
  • Chronic pain due to malignancy (e.g., cancer), autoimmune disorders (e.g., rheumatoid arthritis, lupus), or fibromyalgia
  • Recent daily opiate use
  • Use of any opioid analgesic medications within 72 hours of study participation (confirmed through rapid urine screening conducted prior to study participation)
  • Females who are pregnant
  • History of cardiovascular disease (including myocardial infarction)
  • History of seizure disorder
  • Prior allergic reaction/intolerance to morphine or its analogs
  • Presence of cardiac disease or any other medical condition that would make engaging in the aerobic exercise manipulation unsafe

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02469077


Locations
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United States, Illinois
Rush University
Chicago, Illinois, United States, 60612
United States, Tennessee
Vanderbilt University
Nashville, Tennessee, United States, 37212
Sponsors and Collaborators
Vanderbilt University Medical Center
National Institute on Drug Abuse (NIDA)
Investigators
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Principal Investigator: Stephen Bruehl, PhD Vanderbilt University Medical Center
  Study Documents (Full-Text)

Documents provided by Stephen Bruehl, PhD, Vanderbilt University Medical Center:
Informed Consent Form  [PDF] November 6, 2018

Publications:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Stephen Bruehl, PhD, Professor of Anesthesiology, Vanderbilt University Medical Center
ClinicalTrials.gov Identifier: NCT02469077    
Other Study ID Numbers: 141862
R01DA037891 ( U.S. NIH Grant/Contract )
First Posted: June 11, 2015    Key Record Dates
Results First Posted: September 23, 2020
Last Update Posted: September 23, 2020
Last Verified: September 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by Stephen Bruehl, PhD, Vanderbilt University Medical Center:
Chronic Low Back Pain
Additional relevant MeSH terms:
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Chronic Pain
Pain
Neurologic Manifestations
Morphine
Naloxone
Analgesics, Opioid
Narcotics
Central Nervous System Depressants
Physiological Effects of Drugs
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Narcotic Antagonists