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Understanding the Mechanistic, Neurophysiological, and Antinociceptive Effects of Transcutaneous Auricular Neurostimulation for Treatment of Chronic Pain

Award Number: RM1NS128787
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2022
PERIOD OF PERFORMANCE END DATE: 07/31/2027

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Understanding the Mechanistic, Neurophysiological, and Antinociceptive Effects of Transcutaneous Auricular Neurostimulation for Treatment of Chronic Pain - Project Summary/Abstract Despite growing urgency to transition many chronic pain patients off prescription opioids, there is limited evidentiary support and mixed success rates for alternative treatment approaches that aim to facilitate discontinuation. Few patients who initiate opioid tapers succeed, and a subset of patients react adversely to dose reductions, experiencing significantly worsened pain and psychological destabilization. This is particularly true with patients on prolonged opioid therapy, in which the effects of physiological dependence alter functioning within the neural pain matrix towards a dysregulated and hypersensitized state. Neuromodulation approaches are particularly well suited for this clinical challenge, offering safe and effective analgesia as well as mitigation of opioid withdrawal syndrome. In particular, the Sparrow Therapy System is an FDA-cleared device that delivers transcutaneous auricular neurostimulation (tAN) to the vagal and trigeminal nerves and is therapeutically indicated for pain during opioid withdrawal. Yet, the mechanisms of action remain poorly understood. The absence of an accepted mechanistic model poses limits on tAN clinical application, as an understanding of the neurophysiological mechanisms supporting analgesia would enable parameter optimization leading to precision implementation and maximized therapeutic benefit. We hypothesize that the effects of our tAN approach are 1) dependent on endogenous opioid neurotransmission, 2) are maximally engaged by simultaneous vagal and trigeminal stimulation, and 3) confer analgesic benefits associated with increased neural activity in brainstem vagal afferents but decreased activation in cortical and subcortical pain network regions. To elucidate these proposed mechanisms, we offer a synergistic series of studies in healthy adults and chronic pain patients. Aim 1 will use an experimental µ-opioid blockade paradigm and a novel concurrent pain and functional magnetic resonance imaging (fMRI) paradigm to assess brain activation and pain thresholds following auricular vagal and trigeminal stimulation presented alone and in combination. Aim 2 will likewise entail a concurrent neurostimulation and fMRI paradigm to observe the direct brain effects of auricular vagus stimulation, auricular trigeminal stimulation, combination stimulation, or sham stimulation. Using a double-blind, sham-controlled clinical mechanistic trial of tAN in pain patients undergoing acute opioid tapering, Aim 3 will establish the specific neurophysiological signature of tAN-based analgesia and differentiate this activation profile from secondary outcomes. Our interdisciplinary approach and diverse scientific team of bioengineers, neuroscientists, and clinical pain and opioid specialists is well suited for accomplishing these goals. Results of this project will deliver specific therapeutic mechanisms of action of an emerging treatment that will expand benefits for a high-need clinical population and lead directly to optimized clinical approaches.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $1,733,153 )
2025	2025	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Drug Use and Addiction Research Programs	001	4	8/4/2025	NON-COMPETING CONTINUATION	$1,733,153
2025	2024	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Drug Use and Addiction Research Programs	000	3	5/1/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $1,733,153

Issue Date FY: 2024 ( Subtotal = $1,753,199 )
2024	2024	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Drug Use and Addiction Research Programs	000	3	7/25/2024	NON-COMPETING CONTINUATION	$1,753,199
														Subtotal = $1,753,199

Issue Date FY: 2023 ( Subtotal = $1,741,775 )
2023	2023	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Drug Use and Addiction Research Programs	000	2	8/7/2023	NON-COMPETING CONTINUATION	$1,741,775
														Subtotal = $1,741,775

Issue Date FY: 2022 ( Subtotal = $1,910,070 )
2022	2022	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Drug Use and Addiction Research Programs	000	1	9/12/2022	NEW	$1,910,070
														Subtotal = $1,910,070

Grand Total All Awards = $7,138,197

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Understanding the Mechanistic, Neurophysiological, and Antinociceptive Effects of Transcutaneous Auricular Neurostimulation for Treatment of Chronic Pain

Award Number: RM1NS128787

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/15/2022

PERIOD OF PERFORMANCE END DATE: 07/31/2027

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