Endogenous Opioid Response to Injections

NCT06666621 | Recruiting Phase 4 FDA Drug

• 2 other identifiers: 1792559Foundation Grant
• Study Type: interventional
• Target: 33
• Locations: 1 country
• Sites: 1

Brief 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. 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.

Conditions

Low Back Pain; Zygapophyseal Joint Arthritis

Keywords

low back pain; zygapophysial joint arthritis; endogenous opioids; lumbar medial branch block

Outcome Measures

Primary Outcomes (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

  10 minutes after naloxone infusion

Secondary Outcomes (6)

• Saline-reversible analgesia

  10 minutes after saline infusion

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

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

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

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

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

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

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

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

Other Outcomes (3)

• Fluoroscopy evaluation for procedural integrity - Lumbar Medial Branch Block

  during Lumbar Medial Branch Block procedure

• Fluoroscopy evaluation for procedural integrity, distance - Lumbar Medial Branch Radiofrequency Neurotomy

  during Lumbar Medial Branch Radiofrequency Neurotomy procedure

• Fluoroscopy evaluation for procedural integrity, displacement - Lumbar Medial Branch Radiofrequency Neurotomy

  during Lumbar Medial Branch Radiofrequency Neurotomy procedure

Study Arms (1)

Single arm study: endogenous opioid blockade

OTHER

This 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.

Drug: Normal saline infusion; Drug: Naloxone infusion

Interventions

Normal saline infusion DRUG

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)

Single arm study: endogenous opioid blockade

Naloxone infusion DRUG

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.

Single arm study: endogenous opioid blockade

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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)
• 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

Sponsors & Collaborators

• Middle Tennessee Research Institute: lead
• International Pain and Spine Intervention Society: collaborator

Study Sites (1)

VA Tennessee Valley Healthcare System

Nashville, Tennessee, 37212, United States

RECRUITING

Related Publications (21)

• 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.

  PMID: 8783319 BACKGROUND

• 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.

  PMID: 20613471 BACKGROUND

• 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.

  PMID: 17662665 BACKGROUND

• 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.

  PMID: 17912133 BACKGROUND

• 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.

  PMID: 29847426 BACKGROUND

• 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.

  PMID: 26218947 BACKGROUND

• 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.

  PMID: 10942860 BACKGROUND

• 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.

  PMID: 31583358 BACKGROUND

• 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.

  PMID: 16120776 BACKGROUND

• 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.

  PMID: 32422213 BACKGROUND

• 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.

  PMID: 18923027 BACKGROUND

• 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.

  PMID: 32563287 BACKGROUND

• 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.

  PMID: 30562268 BACKGROUND

• 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.

  PMID: 32569082 BACKGROUND

• 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.

  PMID: 17578917 BACKGROUND

• Wartolowska KA, Gerry S, Feakins BG, Collins GS, Cook J, Judge A, Carr AJ. A meta-analysis of temporal changes of response in the placebo arm of surgical randomized controlled trials: an update. Trials. 2017 Jul 12;18(1):323. doi: 10.1186/s13063-017-2070-9.

  PMID: 28701195 BACKGROUND

• Kaplan M, Dreyfuss P, Halbrook B, Bogduk N. The ability of lumbar medial branch blocks to anesthetize the zygapophysial joint. A physiologic challenge. Spine (Phila Pa 1976). 1998 Sep 1;23(17):1847-52. doi: 10.1097/00007632-199809010-00008.

  PMID: 9762741 BACKGROUND

• Dreyfuss P, Halbrook B, Pauza K, Joshi A, McLarty J, Bogduk N. Efficacy and validity of radiofrequency neurotomy for chronic lumbar zygapophysial joint pain. Spine (Phila Pa 1976). 2000 May 15;25(10):1270-7. doi: 10.1097/00007632-200005150-00012.

  PMID: 10806505 BACKGROUND

• Dreyfuss P, Schwarzer AC, Lau P, Bogduk N. Specificity of lumbar medial branch and L5 dorsal ramus blocks. A computed tomography study. Spine (Phila Pa 1976). 1997 Apr 15;22(8):895-902. doi: 10.1097/00007632-199704150-00013.

  PMID: 9127924 BACKGROUND

• McCormick ZL, Marshall B, Walker J, McCarthy R, Walega DR. Long-Term Function, Pain and Medication Use Outcomes of Radiofrequency Ablation for Lumbar Facet Syndrome. Int J Anesth Anesth. 2015;2(2):028. doi: 10.23937/2377-4630/2/2/1028.

  PMID: 26005713 BACKGROUND

• MacVicar J, Borowczyk JM, MacVicar AM, Loughnan BM, Bogduk N. Lumbar medial branch radiofrequency neurotomy in New Zealand. Pain Med. 2013 May;14(5):639-45. doi: 10.1111/pme.12000. Epub 2012 Dec 28.

  PMID: 23279154 BACKGROUND

MeSH Terms

Conditions

Low Back Pain

Condition Hierarchy (Ancestors)

Back Pain; Pain; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Study Officials

• William E Rivers, DO

  Tennessee Valley Healthcare System VA

  PRINCIPAL INVESTIGATOR

Central Study Contacts

William E Rivers, DO

CONTACT

859-513-9793; william.rivers@va.gov

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NA
• Masking: NONE
• Purpose: DIAGNOSTIC
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: prospective, within-subject

Study Record Dates

• First Submitted: October 23, 2024
• First Posted: October 30, 2024
• Study Start: August 22, 2024
• Primary Completion: October 1, 2025
• Study Completion: February 1, 2026
• Last Updated: May 18, 2025

Record last verified: 2025-05

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)