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Chronic PainNCT02469077

Reduced Opioid Analgesic Requirements Via Improved Endogenous Opioid Function

A study testing 6 week aerobic exercise intervention, Morphine and naloxone in people with Chronic Pain, run by Vanderbilt University Medical Center at 2 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 to 55 years
Conditions the study is for
Chronic Pain
What is being tested?
6 week aerobic exercise intervention, Morphine and naloxone
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
117 participants
Where
2 sitesUnited States
Study dates
Aug 2015to Sep 2019
Phase
Interventional
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 55 years
  • All sexes
  • No healthy volunteers
  • Adult

Who may be able to join

  • 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

Who cannot join

  • 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
Show all 12Show fewer
  • 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

Trial locations and contacts

2 sites in 1 country.

United States2 sites

  • Rush University

    Chicago, Illinois, 60612

  • Vanderbilt University

    Nashville, Tennessee, 37212

Other trials in United States

About this study

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).

Read the 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.

Conditions
Chronic Pain
Being tested
6 week aerobic exercise intervention, Placebo, Morphine, naloxone
Keywords
Chronic Low Back Pain
Medical subject headings
Chronic Pain

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • 6 week aerobic exercise interventionBehavioural

    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.

  • PlaceboDrug

    Also called normal saline 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).

  • MorphineDrug

    Also called Astramorph

    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).

  • naloxoneDrug

    Also called narcan

    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).

Study groups in NCT02469077
Study groupRoleWhat they receive
6 week aerobic exercise interventionExperimentalParticipants 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.
Receives: Behavioral: 6 week aerobic exercise intervention; Drug: Placebo; Drug: Morphine; Drug: naloxone
Normal exercise (control)Active comparatorParticipants 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.
Receives: Drug: Placebo; Drug: Morphine; Drug: naloxone

What is being measured

The primary outcome is the main question the study is designed to answer.

  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

    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.

    Measured: At pre-intervention baseline laboratory assessment and again post-intervention (an expected average of 6 weeks later)

  2. Mean Change in 5-day Electronic Diary Ratings of Low Back Pain Intensity

    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.

    Measured: At pre-intervention baseline and again post-intervention (an expected average of 6 weeks later)

Secondary outcomes (11)

  1. Mean Change in Placebo Condition Ratings of Acute Thermal Pain Intensity on the McGill Pain Questionnaire-Short Form

    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.

    Measured: At pre-intervention baseline laboratory assessment and again post-intervention (an expected average of 6 weeks later)

  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

    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

    Measured: At pre-intervention baseline laboratory assessment and again post-intervention (an expected average of 6 weeks later)

  3. Mean Change in McGill Pain Questionnaire-2 Total Chronic Back Pain Ratings

    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.

    Measured: At pre-intervention baseline laboratory assessment and again post-intervention (an expected average of 6 weeks later)

  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.

    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

    Measured: At pre-intervention baseline laboratory assessment and again post-intervention (an expected average of 6 weeks later)

  5. Mean Change in Positive and Negative Affect Scale-Negative Affect Subscale Ratings.

    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.

    Measured: At pre intervention baseline and again post-intervention (an expected average of 6 weeks later)

  6. Mean Change in Morphine Condition Visual Analog Scale (VAS) Opioid Effects Scale-Euphoria Subscale Ratings

    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.

    Measured: At pre-intervention baseline and again post-intervention (an expected average of 6 weeks later)

  7. Mean Change in Morphine Condition Visual Analog Scale (VAS) Opioid Effects Scale-Sedation Subscale Ratings

    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.

    Measured: At pre-intervention baseline and again post-intervention (an expected average of 6 weeks later)

  8. Mean Change in Morphine Condition Visual Analog Scale (VAS) Opioid Effects - Unpleasantness Subscale Ratings

    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.

    Measured: At pre-intervention baseline and again post-intervention (an expected average of 6 weeks later)

  9. Mean Change in Morphine Condition Drug Effects, Liking, and Take Again (DELTA) -Drug Effect Subscale Ratings

    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.

    Measured: At pre-intervention baseline and again post-intervention (an expected average of 6 weeks later)

  10. Mean Change in Morphine Condition Drug Effects, Liking, and Take Again (DELTA) -Drug Liking Subscale Ratings

    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.

    Measured: At pre-intervention baseline and again post-intervention (an expected average of 6 weeks later)

  11. Mean Change in Morphine Condition Drug Effects, Liking, and Take Again (DELTA) -Take Again Subscale Ratings

    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.

    Measured: At pre-intervention baseline and again post-intervention (an expected average of 6 weeks later)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted11 Jun 2015 (estimated)
  2. Study startAug 2015
  3. Primary completionSep 2019
  4. Study completionSep 2019

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase N/A
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Double blind
Who is masked
Participant, Investigator
Enrolment
117 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02469077
Sponsor's protocol ID
141862
Other IDs
R01DA037891
Status last verified
Sep 2020
First submitted
7 May 2015
Last updated
23 Sep 2020
Data monitoring committee
No
Individual data sharing
No

Publications

  • Bement MK, Sluka KA. Low-intensity exercise reverses chronic muscle pain in the rat in a naloxone-dependent manner. Arch Phys Med Rehabil. 2005 Sep;86(9):1736-40. doi: 10.1016/j.apmr.2005.03.029.

    PubMed 16181935

  • Bruehl S, Burns JW, Gupta R, Buvanendran A, Chont M, Kinner E, Schuster E, Passik S, France CR. Endogenous opioid function mediates the association between laboratory-evoked pain sensitivity and morphine analgesic responses. Pain. 2013 Sep;154(9):1856-1864. doi: 10.1016/j.pain.2013.06.002. Epub 2013 Jun 6.

    PubMed 23748117

  • Bruehl S, Burns JW, Gupta R, Buvanendran A, Chont M, Schuster E, France CR. Endogenous opioid inhibition of chronic low-back pain influences degree of back pain relief after morphine administration. Reg Anesth Pain Med. 2014 Mar-Apr;39(2):120-5. doi: 10.1097/AAP.0000000000000058.

    PubMed 24553304

  • Bruehl S, Chung OY, Burns JW, Biridepalli S. The association between anger expression and chronic pain intensity: evidence for partial mediation by endogenous opioid dysfunction. Pain. 2003 Dec;106(3):317-324. doi: 10.1016/S0304-3959(03)00319-1.

    PubMed 14659514

  • Chatzitheodorou D, Kabitsis C, Malliou P, Mougios V. A pilot study of the effects of high-intensity aerobic exercise versus passive interventions on pain, disability, psychological strain, and serum cortisol concentrations in people with chronic low back pain. Phys Ther. 2007 Mar;87(3):304-12. doi: 10.2522/ptj.20060080. Epub 2007 Feb 6.

    PubMed 17284546

  • Droste C, Meyer-Blankenburg H, Greenlee MW, Roskamm H. Effect of physical exercise on pain thresholds and plasma beta-endorphins in patients with silent and symptomatic myocardial ischaemia. Eur Heart J. 1988 Dec;9 Suppl N:25-33. doi: 10.1093/eurheartj/9.suppl_n.25.

    PubMed 3246253

  • Eriksson SV, Lundeberg T, Lundeberg S. Interaction of diazepam and naloxone on acupuncture induced pain relief. Am J Chin Med. 1991;19(1):1-7. doi: 10.1142/S0192415X91000028.

    PubMed 1654741

  • Ernst M, Lee MH. Influence of naloxone on electro-acupuncture analgesia using an experimental dental pain test. Review of possible mechanisms of action. Acupunct Electrother Res. 1987;12(1):5-22. doi: 10.3727/036012987816358940.

    PubMed 2883837

  • Fritz MS, Mackinnon DP. Required sample size to detect the mediated effect. Psychol Sci. 2007 Mar;18(3):233-9. doi: 10.1111/j.1467-9280.2007.01882.x.

    PubMed 17444920

  • Haier RJ, Quaid K, Mills JC. Naloxone alters pain perception after jogging. Psychiatry Res. 1981 Oct;5(2):231-2. doi: 10.1016/0165-1781(81)90052-4. No abstract available.

    PubMed 6945616

  • Hoffman MD, Shepanski MA, Mackenzie SP, Clifford PS. Experimentally induced pain perception is acutely reduced by aerobic exercise in people with chronic low back pain. J Rehabil Res Dev. 2005 Mar-Apr;42(2):183-90. doi: 10.1682/jrrd.2004.06.0065.

    PubMed 15944883

  • Hutchinson MR, Zhang Y, Shridhar M, Evans JH, Buchanan MM, Zhao TX, Slivka PF, Coats BD, Rezvani N, Wieseler J, Hughes TS, Landgraf KE, Chan S, Fong S, Phipps S, Falke JJ, Leinwand LA, Maier SF, Yin H, Rice KC, Watkins LR. Evidence that opioids may have toll-like receptor 4 and MD-2 effects. Brain Behav Immun. 2010 Jan;24(1):83-95. doi: 10.1016/j.bbi.2009.08.004. Epub 2009 Aug 11.

    PubMed 19679181

  • Janal MN, Colt EWD, Clark CW, Glusman M. Pain sensitivity, mood and plasma endocrine levels in man following long-distance running: effects of naloxone. Pain. 1984 May;19(1):13-25. doi: 10.1016/0304-3959(84)90061-7.

    PubMed 6330643

  • King CD, Goodin B, Kindler LL, Caudle RM, Edwards RR, Gravenstein N, Riley JL 3rd, Fillingim RB. Reduction of conditioned pain modulation in humans by naltrexone: an exploratory study of the effects of pain catastrophizing. J Behav Med. 2013 Jun;36(3):315-27. doi: 10.1007/s10865-012-9424-2. Epub 2012 Apr 26.

    PubMed 22534819

  • Koltyn KF. Analgesia following exercise: a review. Sports Med. 2000 Feb;29(2):85-98. doi: 10.2165/00007256-200029020-00002.

    PubMed 10701712

Questions about this trial

What is this clinical trial studying?

A study testing 6 week aerobic exercise intervention, Morphine and naloxone in people with Chronic Pain, run by Vanderbilt University Medical Center at 2 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 4 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 23 Sep 2020. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

Yes. Results are posted in the registry (first posted 23 Sep 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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)). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02469077, which also lists 29 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 23 Sep 2020.

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