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Low Back PainPhase 4AEOUI2NCT06666621

Endogenous Opioid Response to Injections

A Phase 4 study testing Normal saline infusion and Naloxone infusion in people with Low Back Pain and Zygapophyseal Joint Arthritis, run by Middle Tennessee Research Institute at 1 site in United States.

Recruiting

Looking for participants now. Contact the study team or a site below to ask about taking part.

Sites and contacts
Official record
Search all trials

Trial summary

This study will study pain relief after spine injections that are used to guide care. Some improvements in pain from a procedure might be from placebo effect rather than the physiological effect of the procedure. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Low Back Pain, Zygapophyseal Joint Arthritis
What is being tested?
Normal saline infusion and Naloxone infusion
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
33 participants
Where
1 siteUnited States
Study dates
22 Aug 2024to Feb 2026
Phase
Phase 4
Are there results?
Not yet: the study is under way

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 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Capable of understanding and providing consent in English and capable of complying with the outcome instruments used
  • ≥3 months low back pain with persistent limiting symptoms despite conventional treatment (physical therapy and oral medications)
  • Low back pain NRS ≥ 4/10 in intensity on 7-day average and at time of lumbar medial branch block

Who cannot join

  • Daily use of opioid medications or recreational drugs, or if using opioids PRN, report of opioid use within the 3 days prior to participating in the protocol
  • Positive urine drug screen for opioid medication on the day of naloxone administration
  • Allergy to naloxone
  • Refusal of or failure to place IV
  • Previous LMBB or LMBRN
  • Known spine condition that may affect the ability to diagnose or treat facet pain or lead to spine surgery (e.g. instability, severe spinal stenosis, radiculopathy, previous spine operation resulting in alteration of anatomy targeted by LMBB or LMBRFN)
Show all 9Show fewer
  • Active medical condition that would limit the safety of naloxone administration (e.g. severe kidney or liver failure, unstable cardiac disease, infection, severe coagulopathy)
  • Psychiatric, medical, neurologic, or pain-related disorder that may compromise the ability of the patient to accurately report changes in low back pain
  • Requirement for procedural sedation to tolerate LMBB

Trial locations and contacts

1 site in 1 country. Contact the study team or a site near you to ask about taking part.

William E Rivers, DO contact

859-513-9793

william.rivers@va.gov

United States1 site, 1 recruiting

  • VA Tennessee Valley Healthcare System

    Nashville, Tennessee, 37212

    William E Rivers, DO, 615-225-6559, william.rivers@va.gov

    Recruiting

Other trials in United States

About this study

Official title: Antagonism of Endogenous Opioids: Use in Interpretation of Injections

This study will study pain relief after spine injections that are used to guide care. Some improvements in pain from a procedure might be from placebo effect rather than the physiological effect of the procedure. The study will use naloxone to reverse the effect of the body's internal placebo system after a spine injection, so the placebo effect and the injection effect can be measured separately. This process may improve the understanding of spine injections and their ability to guide pain care.

Read the detailed description

Nerve blocks are commonly used in pain medicine to diagnose painful conditions and predict response to invasive procedures and surgeries. Placebo responses may cripple clinicians' ability to interpret responses to nerve blocks and guide patient care, when reported pain relief is due to placebo rather than the nerve block.

Existing methods to assess placebo response in clinical practice are limited and indirect. The area that is most explored is in the diagnosis of pain from the facet joints of the spine and relies on an indirect signal from repeated diagnostic injections.

Lumbar medial branch radiofrequency neurotomy (LMBRN) is commonly used to treat low back pain and can lead to large improvements in pain and disability. There is a high failure rate of LMBRN even after a series of controlled prognostic injections called lumbar medial branch nerve blocks (LMBB) with local anesthetic. The discrepancy between response to LMBB and LMBRN has been attributed to the confounding of pain relief from the nerve block with pain relief from the placebo response.

Endogenous opioids (EO), substances produced within the human body that bind to opioid receptors and produce opioid analgesia, are likely responsible for most of the placebo response caused by LMBB.

This study will use naloxone, an opioid receptor antagonist, to completely block the activity of EOs in patients. First, the pain relief after LMBB will be recorded - this is a combination of the effect of the nerve block and EO released in the placebo response. Normal saline will be infused, as an internal control for the state of receiving an infusion. Naloxone will then be infused, reversing EO-dependent placebo analgesia - the analgesia remaining will be from the nerve block. Finally, clinical outcomes from LMBRN will be collected to determine whether using naloxone with LMBB can improve prediction of outcomes with LMBRN.

Naloxone will be used to probe a mechanism of procedurally-induced endogenous-opioid mediated placebo analgesia. No IND is pursued in this study.

These data will provide detailed parameters of placebo response from LMBB, improving interpretation of LMBB for estimation of prevalence of zygapophyseal joint pain and for prognostication of LMBRN.

Furthermore, if this methodology of EO reversible analgesia is feasible for investigation of placebo from LMBB, it will be more broadly investigated in diagnostic and prognostic injections used in interventional pain management.

Being tested
Normal saline infusion, Naloxone infusion
Keywords
low back pain, zygapophysial joint arthritis, endogenous opioids, lumbar medial branch block
Medical subject headings
Low Back Pain

What participants receive

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

  • Normal saline infusionDrug

    After assessment of response to lumbar medial branch block, 8 ml normal saline will be infused through IV over several minutes. 10 minutes will pass, and response to lumbar medial branch block procedure will be re-assessed.

    After this step, naloxone infusion will occur (see next intervention)

  • Naloxone infusionDrug

    After infusion of normal saline and re-assessment of response to lumbar medial branch block procedure, 8 milligrams of naloxone will be infused over several minutes. Then after 10 minutes, response to lumbar medial branch block procedure will be re-reassessed for the final time.

Study groups in NCT06666621
Study groupRoleWhat they receive
Single arm study: endogenous opioid blockadeOtherThis is a single group study. The participants will undergo two sequential experimental conditions: saline infusion and naloxone infusion. Participants will be identified as candidates for standard of care lumbar medial branch block, consented, and enrolled. Baseline demographics and patient reported clinical measures will be collected. All participants will have IV placed, undergo standard of care lumbar medial branch block, wait 20 minutes, then have their response to procedure assessed. Then normal saline will be infused through the IV over several minutes, 10 minutes will pass, and response to procedure re-assessed. Then naloxone will be infused through the IV over several minutes, 10 minutes will pass, and response to procedure re-assessed for a final time. IV will then be removed. Participants will then follow standard of care clinical practice for second lumbar medial branch block and lumbar medial branch radiofrequency neurotomy treatment.
Receives: Drug: Normal saline infusion; Drug: Naloxone infusion

What is being measured

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

  1. Endogenous opioid-dependent placebo analgesia

    Endogenous opioid-dependent placebo analgesia is defined as change in analgesia after lumbar medial branch block #1 (measured by numeric pain rating scale) after infusing naloxone

    Measured: 10 minutes after naloxone infusion

Secondary outcomes (6)

  1. Saline-reversible analgesia

    Saline-reversible analgesia is defined as change in analgesia after lumbar medial branch block #1 (measured by numeric pain rating scale) after infusing saline

    Measured: 10 minutes after saline infusion

  2. Change in low back pain score after Lumbar Medial Branch Block #2

    Change in Numeric Pain Rating Scale score for low back pain after Lumbar Medial Branch Block #2

    Measured: Approximately 2 weeks after Lumbar Medial Branch Block #1, and before Lumbar Medial Branch Radiofrequency Neurotomy

  3. Change in low back pain score after Lumbar Medial Branch Radiofrequency Neurotomy

    Change in Numeric Pain Rating Scale score for low back pain after Lumbar Medial Branch Neurotomy

    Measured: Baseline, then 6 weeks, 3 months, 6 months after Lumbar Medial Branch Radiofrequency Neurotomy

  4. Change in McGill Pain Questionnaire-2 after Lumbar Medial Branch Radiofrequency Neurotomy

    Change in McGill Pain Questionnaire-2 score after Lumbar Medial Branch Radiofrequency Neurotomy

    Measured: Baseline, then 6 weeks, 3 months, 6 months after Lumbar Medial Branch Radiofrequency Neurotomy

  5. Change in MQS-III after Lumbar Medial Branch Radiofrequency Neurotomy

    Change in MQS-III score after Lumbar Medial Branch Radiofrequency Neurotomy

    Measured: Baseline, then 6 weeks, 3 months, 6 months after Lumbar Medial Branch Radiofrequency Neurotomy

  6. Change in Patient-Reported Outcomes Measurement Information System-29 after Lumbar Medial Branch Radiofrequency Neurotomy

    Change in Patient-Reported Outcomes Measurement Information System-29 score after Lumbar Medial Branch Radiofrequency Neurotomy

    Measured: Baseline, then 6 weeks, 3 months, 6 months after Lumbar Medial Branch Radiofrequency Neurotomy

Timeline

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

  1. First posted30 Oct 2024
  2. Study start22 Aug 2024
  3. Primary completionOct 2025 (estimated)
  4. Study completionFeb 2026 (estimated)

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 4
Primary purpose
Diagnosis
Allocation
Not applicable
Intervention model
Single group
Model description
prospective, within-subject
Masking
None (open label)
Enrolment
33 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT06666621
Sponsor's protocol ID
1792559
Other IDs
Foundation Grant
Acronym
AEOUI2
Status last verified
May 2025
First submitted
23 Oct 2024
Last updated
18 May 2025
Results posted
No
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No: Individual Participant Data will only be accessed and analyzed by primary research team.

Publications

  • Benedetti F. The opposite effects of the opiate antagonist naloxone and the cholecystokinin antagonist proglumide on placebo analgesia. Pain. 1996 Mar;64(3):535-543. doi: 10.1016/0304-3959(95)00179-4.

    PubMed 8783319

  • Cohen SP, Williams KA, Kurihara C, Nguyen C, Shields C, Kim P, Griffith SR, Larkin TM, Crooks M, Williams N, Morlando B, Strassels SA. Multicenter, randomized, comparative cost-effectiveness study comparing 0, 1, and 2 diagnostic medial branch (facet joint nerve) block treatment paradigms before lumbar facet radiofrequency denervation. Anesthesiology. 2010 Aug;113(2):395-405. doi: 10.1097/ALN.0b013e3181e33ae5.

    PubMed 20613471

  • Cohen SP, Stojanovic MP, Crooks M, Kim P, Schmidt RK, Shields CH, Croll S, Hurley RW. Lumbar zygapophysial (facet) joint radiofrequency denervation success as a function of pain relief during diagnostic medial branch blocks: a multicenter analysis. Spine J. 2008 May-Jun;8(3):498-504. doi: 10.1016/j.spinee.2007.04.022. Epub 2007 Jun 18.

    PubMed 17662665

  • Manchukonda R, Manchikanti KN, Cash KA, Pampati V, Manchikanti L. Facet joint pain in chronic spinal pain: an evaluation of prevalence and false-positive rate of diagnostic blocks. J Spinal Disord Tech. 2007 Oct;20(7):539-45. doi: 10.1097/BSD.0b013e3180577812.

    PubMed 17912133

  • Cohen SP, Doshi TL, Constantinescu OC, Zhao Z, Kurihara C, Larkin TM, Griffith SR, Jacobs MB, Kroski WJ, Dawson TC, Fowler IM, White RL, Verdun AJ, Jamison DE, Anderson-White M, Shank SE, Pasquina PF. Effectiveness of Lumbar Facet Joint Blocks and Predictive Value before Radiofrequency Denervation: The Facet Treatment Study (FACTS), a Randomized, Controlled Clinical Trial. Anesthesiology. 2018 Sep;129(3):517-535. doi: 10.1097/ALN.0000000000002274.

    PubMed 29847426

  • Boswell MV, Manchikanti L, Kaye AD, Bakshi S, Gharibo CG, Gupta S, Jha SS, Nampiaparampil DE, Simopoulos TT, Hirsch JA. A Best-Evidence Systematic Appraisal of the Diagnostic Accuracy and Utility of Facet (Zygapophysial) Joint Injections in Chronic Spinal Pain. Pain Physician. 2015 Jul-Aug;18(4):E497-533.

    PubMed 26218947

  • Kaptchuk TJ, Goldman P, Stone DA, Stason WB. Do medical devices have enhanced placebo effects? J Clin Epidemiol. 2000 Aug;53(8):786-92. doi: 10.1016/s0895-4356(00)00206-7.

    PubMed 10942860

  • Finniss D, Nicholas M, Brooker C, Cousins M, Benedetti F. Magnitude, response, and psychological determinants of placebo effects in chronic low-back pain: a randomised, double-blinded, controlled trial. Pain Rep. 2019 Jun 7;4(3):e744. doi: 10.1097/PR9.0000000000000744. eCollection 2019 May-Jun.

    PubMed 31583358

  • Zubieta JK, Bueller JA, Jackson LR, Scott DJ, Xu Y, Koeppe RA, Nichols TE, Stohler CS. Placebo effects mediated by endogenous opioid activity on mu-opioid receptors. J Neurosci. 2005 Aug 24;25(34):7754-62. doi: 10.1523/JNEUROSCI.0439-05.2005.

    PubMed 16120776

  • Bagley EE, Ingram SL. Endogenous opioid peptides in the descending pain modulatory circuit. Neuropharmacology. 2020 Aug 15;173:108131. doi: 10.1016/j.neuropharm.2020.108131. Epub 2020 May 15.

    PubMed 32422213

  • Petrovic P, Pleger B, Seymour B, Kloppel S, De Martino B, Critchley H, Dolan RJ. Blocking central opiate function modulates hedonic impact and anterior cingulate response to rewards and losses. J Neurosci. 2008 Oct 15;28(42):10509-16. doi: 10.1523/JNEUROSCI.2807-08.2008.

    PubMed 18923027

  • Colloca L. Placebo effects in pain. Int Rev Neurobiol. 2020;153:167-185. doi: 10.1016/bs.irn.2020.04.001. Epub 2020 Jun 9.

    PubMed 32563287

  • Bruehl S, Burns JW, Morgan A, Koltyn K, Gupta R, Buvanendran A, Edwards D, Chont M, Kingsley PJ, Marnett L, Stone A, Patel S. The association between endogenous opioid function and morphine responsiveness: a moderating role for endocannabinoids. Pain. 2019 Mar;160(3):676-687. doi: 10.1097/j.pain.0000000000001447.

    PubMed 30562268

  • Bruehl S, Burns JW, Koltyn K, Gupta R, Buvanendran A, Edwards D, Chont M, Wu YH, Qu'd D, Stone A. Are endogenous opioid mechanisms involved in the effects of aerobic exercise training on chronic low back pain? A randomized controlled trial. Pain. 2020 Dec;161(12):2887-2897. doi: 10.1097/j.pain.0000000000001969.

    PubMed 32569082

  • Wager TD, Scott DJ, Zubieta JK. Placebo effects on human mu-opioid activity during pain. Proc Natl Acad Sci U S A. 2007 Jun 26;104(26):11056-61. doi: 10.1073/pnas.0702413104. Epub 2007 Jun 19.

    PubMed 17578917

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Normal saline infusion and Naloxone infusion in people with Low Back Pain and Zygapophyseal Joint Arthritis, run by Middle Tennessee Research Institute at 1 site 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 3 inclusion and 9 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: looking for participants now, as of the sponsor's last update on 18 May 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site 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.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

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

Contact William E Rivers, DO (859-513-9793, william.rivers@va.gov), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Endogenous opioid-dependent placebo analgesia (time frame: 10 minutes after naloxone infusion). 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 NCT06666621, which also lists 21 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 18 May 2025.

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