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BACKGROUND: As pharmacological treatments are the primary option for opioid use disorder, neuromodulation has recently demonstrated efficacy in managing opioid withdrawal syndrome (OWS). This study investigated the safety and effectiveness of transcutaneous auricular neurostimulation (tAN) for managing OWS. METHODS: This prospective inpatient trial included a 30-minute randomized, sham-controlled, double-blind period followed by a 5-day open-label period. Adults with physical dependence on opioids were randomized to receive active or sham tAN following abrupt opioid discontinuation. The Clinical Opiate Withdrawal Scale (COWS) was used to determine withdrawal level, and participants were required to have a baseline COWS score ≥ 13 before enrollment. The double-blind period of the study occurred during the first 30-minutes to assess the acute effects of tAN therapy compared to a sham control. Group 1 received active tAN during both the 30-minute double-blind period and the 5-day open-label period. Group 2 received passive sham tAN (no stimulation) during the double-blind period, followed by active tAN during the 5-day open-label period. The primary outcome was change in COWS from baseline to 60-minutes of active tAN (pooled across groups, accounting for 30-minute delay). Secondary outcomes included difference in change in COWS scores between groups after 30-minutes of active or sham tAN, change in COWS scores after 120-minutes of active tAN, and change in COWS scores on Days 2-5. Non-opioid comfort medications were administered during the trial. RESULTS: Across all thirty-one participants, the mean (SD) COWS scores relative to baseline were reduced by 7.0 (4.7) points after 60-minutes of active tAN across both groups (p < 0.0001; Cohen's d = 2.0), demonstrating a significant and clinically meaningful reduction of 45.9%. After 30-minutes of active tAN (Group 1) or sham tAN (Group 2), the active tAN group demonstrated a significantly greater COWS score reduction than the sham tAN group (41.7% vs. 24.1%; p = 0.036). Participants across both groups achieved an average COWS reduction up to 74.7% on Days 2-5. CONCLUSION: Results demonstrate tAN is a safe and effective non-opioid approach for reducing symptoms of OWS. This study supported an FDA clearance. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov/ct2/show/NCT04075214 , Identifier: NCT04075214, Release Date: August 28, 2019.
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Maternal opioid use during pregnancy is a growing national problem and can lead to newborns developing neonatal opioid withdrawal syndrome (NOWS) soon after birth. Recent data demonstrates that nearly every 15 min a baby is born in the United States suffering from NOWS. The primary treatment for NOWS is opioid replacement therapy, commonly oral morphine, which has neurotoxic effects on the developing brain. There is an urgent need for non-opioid treatments for NOWS. Transcutaneous auricular neurostimulation (tAN), a novel and non-invasive form of electrostimulation, may serve as a promising alternative to morphine. tAN is delivered via a multichannel earpiece electrode worn on and around the left ear, targeting two cranial nerves-the vagus and trigeminal nerves. Prior research suggests that auricular neurostimulation exerts an anxiolytic effect on the body by releasing endogenous opioids and reduces withdrawal symptoms in adults actively withdrawing from opioids. In this first-in-human prospective, open-label trial, we investigated tAN as an adjuvant to morphine therapy in eight infants >33 weeks gestational age suffering from NOWS and receiving oral morphine treatment. Infants received tAN for 30 min 1 h before receiving a morphine dose. tAN was delivered at 0.1 mA below perception intensity at two different nerve targets on the ear: Region 1, the auricular branch of the vagus nerve; and Region 2, the auriculotemporal nerve. tAN was delivered up to four times daily for a maximum of 12 days. The primary outcome measures were safety [heart rate monitoring, Neonatal Infant Pain Scale (NIPS), and skin irritation] and morphine length of treatment (LOT). tAN was well-tolerated and resulted in no unanticipated adverse events. Comparing to the national average of 23 days, the average oral morphine LOT was 13.3 days (median 9 days) and the average LOT after tAN initiation was 7 days (median 6 days). These preliminary data suggest that tAN is safe and may serve as a promising alternative adjuvant for treating NOWS and reducing the amount of time an infant receives oral morphine.
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BACKGROUND: Energy metabolism is emerging as a driving force for cellular events underlying cognitive processing. The hypothalamus integrates metabolic signals with the function of centers related to cognitive processing such as the hippocampus. OBJECTIVE/HYPOTHESIS: Hypothalamic activity can influence molecular systems important for processing synaptic plasticity underlying cognition in the hippocampus. The neurotrophin BDNF may act as a mediator for the effects of energy metabolism on synaptic plasticity and cognitive function. METHODS: The hypothalamus of rats confined to a respiratory chamber was electrically stimulated, and energy expenditure (EE) was assessed via indirect calorimetry. MRNA levels for BDNF and molecules related to synaptic plasticity and control of cellular energy metabolism were assessed in the hippocampus. RESULTS: Electrical stimulation of the rat hypothalamus elevates mRNA levels of hippocampal BDNF. BDNF mRNA levels increased according to the metabolic rate of the animals, and in proportion to the mRNA of molecules involved in control of cellular energy metabolism such as ubiquitous mitochondrial creatine kinase (uMtCK). CONCLUSIONS: Results show a potential mechanism by which cellular energy metabolism impacts the substrates of cognitive processing, and may provide molecular basis for therapeutic treatments based on stimulation of deep brain structures.
