Testing the efficacy of transcutaneous auricular neurostimulation (TAN) to improve symptoms associated with naloxone-precipitated withdrawal. - in medical settings, naloxone-precipitated opioid…

The National Institute on Drug Abuse awarded a cooperative agreement totaling $717,986 to Research Foundation For Mental Hygiene, Inc. on May 15, 2026, to test the efficacy of transcutaneous auricular neurostimulation (TAN) in reducing naloxone-precipitated opioid withdrawal symptoms under the Drug Use and Addiction Research Programs (CFDA 93.279).

The award funds a randomized, double-blind, sham-controlled clinical trial examining whether non-invasive TAN stimulation of the vagus and trigeminal nerves attenuates withdrawal induced by intranasal naloxone. During the UG3 phase, investigators will evaluate the effects of various TAN stimulation frequencies relative to the FDA-cleared setting of 15 and 100 hertz, with participants randomly assigned to sham TAN, active TAN at low frequencies (5 and 50 hertz), or active TAN at the FDA-cleared frequencies following a 4-milligram intranasal naloxone dose. Prior research demonstrated a 45.9 percent reduction in withdrawal scale scores using TAN following abrupt opioid discontinuation, but naloxone-precipitated withdrawal differs in time course, severity, and symptomology. The trial will determine whether adjusted stimulation frequencies improve effectiveness in managing this acute withdrawal scenario in both medical and out-of-hospital settings.

Research Foundation For Mental Hygiene, Inc., operating through its New York State Psychiatric Institute division and located in New York, New York, serves as the recipient. The period of performance runs through April 30, 2028.

Testing the efficacy of transcutaneous auricular neurostimulation (TAN) to improve symptoms associated with naloxone-precipitated withdrawal. - in medical settings, naloxone-precipitated opioid withdrawal following an overdose reversal can lead to adverse patient reactions and increase discharge against medical advice. In out-of-hospital settings, the fear of inducing withdrawal may preclude or delay the use of naloxone (NLX) by laypersons. Insufficient management of withdrawal in both environments can lead to opioid-seeking, resulting in additional overintoxication. Non- invasive neuromodulation has demonstrated efficacy in managing abstinence-induced opioid withdrawal with minimal side effects. The sparrow ascent ® transcutaneously stimulates branches of the vagus (15 HZ) and trigeminal nerves (100 HZ) on and around the ear to increase parasympathetic activation and release of endorphins. In a randomized, double-blind, sham-controlled trial, non-invasive transcutaneous auricular neurostimulation (TAN) using sparrow ® led to significant reductions (45.9%) in withdrawal scale scores following abrupt opioid discontinuation. Though findings with abstinence-induced withdrawal suggest clinical efficacy for precipitated withdrawal, these two forms of withdrawal vary in time course, severity, symptomology, and response to medications. Furthermore, adjusting the TAN stimulation frequencies could improve effectiveness. The goal of this UG3-UH3 proposal is to test the efficacy of non-invasive TAN of the vagus and trigeminal nerves to attenuate withdrawal induced by naloxone. During the UG3 phase, the investigators will evaluate the effects of various TAN stimulation frequencies on naloxone-precipitated withdrawal (4 MG, intranasal), relative to the FDA-cleared frequency of 15 & 100 HZ. Participants will be randomly assigned to one of four testing conditions: 1. NLX 4.0MG→ sham TAN 2. NLX 4.0MG→ active TAN 5 & 50 HZ (low) 3. NLX 4.0MG→ active TAN 15 & 100 HZ (FDA cleared setting) and 4. NLX 4.0MG→ active TAN 25 & 150 HZ (HIGH), (N=20 per group). Non-treatment-seeking, illicit opioid users will be tested in an ecological validity, naloxone- challenge model. Following naloxone administration, clinical and subjective opiate withdrawal scales (cows and sows, respectively) will be administered for 60 minutes. The 1° aim of the UG3 phase is to determine the most efficacious stimulation frequency as measured by the change in cows (1°) and sows (2°). Go/no-go criterion: a ≥15% reduction in cows score (active VS sham TAN) must be observed to progress to the UH3 phase. The UH3 phase will test the most efficacious stimulation frequency in comparison to lofexidine (0.54 MG: double-blind, double-dummy) with an extended period of observation (4 hours). The 1° aim of the UH3 phase is to assess the ability of TAN of the vagus and trigeminal nerves to produce acute and sustained reductions in withdrawal, compare the side effects profile to lofexidine (2°) and observe for combined treatment effects (2°). The investigation will also explore the ability of TAN to attenuate opioid craving, as preclinical research has found that vagus nerve stimulation inhibits CUE-induced reinstatement of opioid-seeking. Devices treating withdrawal could be implemented in settings where pharmacotherapies are not available.