Study Results
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Basic Information
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RECRUITING
PHASE4
33 participants
INTERVENTIONAL
2024-08-22
2026-02-28
Brief Summary
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Detailed Description
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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.
Conditions
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Study Design
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NA
SINGLE_GROUP
DIAGNOSTIC
NONE
Study Groups
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Single arm study: endogenous opioid blockade
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.
Normal saline infusion
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 infusion
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.
Interventions
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Normal saline infusion
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 infusion
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.
Eligibility Criteria
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Inclusion Criteria
* ≥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
Exclusion Criteria
* 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
18 Years
ALL
No
Sponsors
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International Pain and Spine Intervention Society
UNKNOWN
Middle Tennessee Research Institute
OTHER
Responsible Party
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Principal Investigators
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William E Rivers, DO
Role: PRINCIPAL_INVESTIGATOR
Tennessee Valley Healthcare System VA
Locations
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VA Tennessee Valley Healthcare System
Nashville, Tennessee, United States
Countries
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Central Contacts
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Facility Contacts
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References
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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.
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.
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.
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.
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.
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.
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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.
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.
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.
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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.
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.
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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.
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.
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.
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.
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Other Identifiers
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Foundation Grant
Identifier Type: OTHER
Identifier Source: secondary_id
1792559
Identifier Type: -
Identifier Source: org_study_id
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