Endogenous Opioid Response to Injections

Official title

Antagonism of Endogenous Opioids: Use in Interpretation of Injections

Overview

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.

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.

Interventions

• Drug 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)
• Drug 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.

Primary outcome measures

• Endogenous opioid-dependent placebo analgesia [Time frame: 10 minutes after naloxone infusion]

Secondary outcome measures (6)

• Saline-reversible analgesia [Time frame: 10 minutes after saline infusion]
• Change in low back pain score after Lumbar Medial Branch Block #2 [Time frame: 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 [Time frame: 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 [Time frame: Baseline, then 6 weeks, 3 months, 6 months after Lumbar Medial Branch Radiofrequency Neurotomy]
• Change in MQS-III after Lumbar Medial Branch Radiofrequency Neurotomy [Time frame: Baseline, then 6 weeks, 3 months, 6 months after Lumbar Medial Branch Radiofrequency Neurotomy]
• Change in Patient-Reported Outcomes Measurement Information System-29 after Lumbar Medial Branch Radiofrequency Neurotomy [Time frame: Baseline, then 6 weeks, 3 months, 6 months after Lumbar Medial Branch Radiofrequency Neurotomy]

Eligibility criteria

Inclusion criteria

• 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

Exclusion criteria

• 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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Diagnostic

Study locations

United States · 1 center

• VA Tennessee Valley Healthcare System — Nashville

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. PMID 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.0b01 PMID 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. PMID 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. PMID 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 PMID 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. PMID 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. PMID 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. PMID 31583358

Identifiers

NCT: NCT06666621 · 1792559 · Foundation Grant

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗