Noninvasive Vagal Nerve Stimulation for Opioid Use Disorder

Review Article

Ann Depress Anxiety. 2023; 10(1): 1117.

Noninvasive Vagal Nerve Stimulation for Opioid Use Disorder

J Douglas Bremner, MD1,2,3*; Asim H Gazi, BS4; Tamara P Lambert, MPH, MEng5; Afra Nawar, BS4; Anna B Harrison, MS4; Justine W Welsh, MD1; Viola Vaccarino, MD, PhD6,7; Kevin M Walton, PhD8; Nora Jaquemet, BS1; Kellen Mermin-Bunnell, BS1; Hewitt Mesfin, BS1; Trinity A Gray, BS1; Keyatta Ross, BS1; Georgia Saks BS5; Nikolina Tomic, MS4; Danner Affadzi, BS1; Marom Bikson, PhD9; Amit J Shah, MD, MSCR3,6,7; Kelly E Dunn, PhD10; Nicholas A Giordano, PhD, RN11; Omer T Inan, PhD4,5

1Department of Psychiatry & Behavioral Sciences, Emory University School of Medicine, Atlanta GA

2Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta GA

3Atlanta Veterans Affairs Healthcare System, Decatur GA

4School of Electrical and Computer Engineering, Georgia Institute of Technology, Atlanta, GA

5Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA

6Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA

7Department of Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta GA

8Clinical Research Grants Branch, Division of Therapeutics and Medical Consequences, National Institute on Drug Abuse, Bethesda, MD

9Department of Biomedical Engineering, The City College of New York, New York, NY

10Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore MD

11Nell Hodgson Woodruff School of Nursing, Emory University, Atlanta, GA

Corresponding author: J Douglas Bremner, MD Department of Psychiatry, 12 Executive Park DR NE, Rm 333, Atlanta, GA Tel: (404) 712-9569-8083 Email: [email protected]

Received: June 29, 2023 Accepted: July 26, 2023 Published: August 02, 2023


Background: Opioid Use Disorder (OUD) is an escalating public health problem with over 100,000 drug overdose-related deaths last year most of them related to opioid overdose, yet treatment options remain limited. Non-invasive Vagal Nerve Stimulation (nVNS) can be delivered via the ear or the neck and is a non-medication alternative to treatment of opioid withdrawal and OUD with potentially widespread applications.

Methods: This paper reviews the neurobiology of opioid withdrawal and OUD and the emerging literature of nVNS for the application of OUD. Literature databases for Pubmed, Psychinfo, and Medline were queried for these topics for 1982-present.

Results: Opioid withdrawal in the context of OUD is associated with activation of peripheral sympathetic and inflammatory systems as well as alterations in central brain regions including anterior cingulate, basal ganglia, and amygdala. NVNS has the potential to reduce sympathetic and inflammatory activation and counter the effects of opioid withdrawal in initial pilot studies. Preliminary studies show that it is potentially effective at acting through sympathetic pathways to reduce the effects of opioid withdrawal, in addition to reducing pain and distress.

Conclusions: NVNS shows promise as a non-medication approach to OUD, both in terms of its known effect on neurobiology as well as pilot data showing a reduction in withdrawal symptoms as well as physiological manifestations of opioid withdrawal.


Opioid Use Disorder (OUD) is a national epidemic with devastating consequences. Deaths from opioid overdose, including prescription opiates like OxyContin and Percocet, as well as heroin and other illegal opiates, increased five-fold from 1999 to 2016 [1]. Opioid overdose is now the leading cause of accidental death in the United States [2]. In 2021, there were over 100,000 drug overdose-related deaths, most of which were due to opioids [3]. The standard of care for treating Opioid Use Disorder (OUD) are Medications for Opioid Use Disorder (MOUD), which includes opioid receptor agonists and antagonists; however, the barriers to MOUD care are high, including lack of access to MOUDs with proven benefit, like opioid agonists, methadone and buprenorphine [4-9]. Most OUD patients will relapse without medication, and about half relapse even after treatment with the gold standard opioid-agonist, methadone [10]. Many patients don’t want to take opioid agonists, but treatment with naltrexone, an opioid receptor antagonist, requires an extended period of detoxification during which the risk of relapse and overdose-related death is high [11-13]. During this period of detoxification there is an increase in both the probability of relapse (due to withdrawal symptoms) and the risk of overdose-related death due to a loss of tolerance [4,14,15]. Management of withdrawal during the treatment of OUD is crucial when initiating OUD treatment protocols that will maintain long-term efficacy in prevention of relapse. Non-pharmacological methods that treat withdrawal could provide a bridge to facilitate effective implementation and continuation of opioid antagonist pharmacological therapies. Additionally, the initial induction period when opioid agonist dose adjustment occurs is often associated with symptoms of opioid withdrawal that can increase the risk of relapse and/overdose. Additional interventions to use as adjuncts to FDA-approved treatments of opioid withdrawal, such as lofexidine [16-18], will also be useful. This paper describes the use of a form of neuromodulation called Non-invasive Vagal Nerve Stimulation (nVNS), and outlines its potential usefulness for the treatment of OUDs in the context of its effects on neurobiology and how this may intersect with the neurobiology of OUD and opioid withdrawal.

Changes in Neurobiological Systems in OUD

OUD is characterized by alterations in multiple neurobiological systems [19]. Opioid withdrawal is associated with uncomfortable symptoms including headache, nausea and vomiting, diarrhea, sweating, fatigue, anxiety, and sleep disturbance. These symptoms are driven by activation of the sympathetic nervous system with release of inflammatory biomarkers and alterations in dopaminergic reward systems that play a critical role in both addiction and relapse risk [20]. Mesocortical and mesolimbic dopaminergic pathways from the ventral tegmentum area to the medial prefrontal cortex and ventral striatum (nucleus accumbens) play an important role in OUD, and stress and substance use have similar effects on these systems [21-30]. Repeated exposure to opioids, both prescription and illicit, among individuals living with OUD are linked to increased risks for developing pain sensitivity and centralization due, in part to, increased activation of NMDA receptors leading to sensitization of spinal neurons [31]. Compared to controls, persons with OUD show increased cortisol, heart rate and blood pressure response to both drug cues [32] and to a laboratory-based stress task involving public speaking [33]. Persons with OUD have also shown increased drug craving after exposure to drug cues compared to controls [32] although laboratory-based mental stress did not potentiate drug craving over exposure to drug cues alone [33]. Women with OUD showed a pattern of lower cortisol response and experienced more subjective stress during public speaking than men with OUD [34]. Patients with PTSD and either cocaine or alcohol substance use disorders showed increased drug craving following both trauma and drug-related cues [35]. Patients with PTSD experience higher pain levels and have increased instance of substance use disorders than non-PTSD patients, although pain is not a mediator of the increased substance use rates in these patients [36]. These studies show that drug cues activate neurobiological systems that underlie craving, and that responses to this activation differ by gender.

Treatment of OUD with MOUDs

Standard treatments for OUD are medications that act on opioid receptor, including buprenorphine, methadone, and naltrexone. Methadone is a long-acting full opioid agonist of the mu opioid receptor. Buprenorphine is a partial agonist of the mu opioid receptor and an antagonist of the kappa opioid receptor. Methadone must be administered in a specialized clinic, and access to buprenorphine, although it is effective in reducing the risk of relapse and overdose and can be taken at home, is limited. A recent “secret shoppers” study in which volunteers called medical clinics seeking treatment for an OUD showed that only 27% of individuals were able to be seen in a clinic and obtain a buprenorphine prescription if they were not willing to pay cash for treatment [7]. Fifty percent of clinics listed as available for buprenorphine treatment either did not have a working phone number or a physician or practitioner with the necessary specialized certifications to prescribe, and of those, 30% outright refused to treat non-cash paying patients [7]. Thus, buprenorphine treatment, with costs upwards of $350, is cost prohibitive for most people, further precluding access for OUD patients in need of care [9].

Naltrexone is an antagonist of the opioid receptor that is an alternative to opioid agonist therapy that is also effective for OUD [5,11,15,37,38]. Long--acting naltrexone is superior to treatment as usual including non-pharmacological counseling for relapse prevention [12]. Once safely initiated, long-acting naltrexone has equivalent or increased efficacy in relapse prevention as compared to buprenorphine [13]. Naltrexone is an effective long-term treatment for OUD, but the required opioid abstinence and subsequent withdrawal period prior to initiation represents a key barrier to treatment [39]. Interventions during the period of opioid withdrawal to reduce symptoms and prevent relapse, allowing patients to complete the period of abstinence required before the initiation of long-acting naltrexone treatment may both benefit patients with OUD in recovery maintenance and reduce overdose-related deaths during this critical period [39].

Neuroimaging and Neurobiology of OUD

Advancements in neuroimaging have allowed for identification of brain regions and specific neural circuits that are implicated in OUD [40]. The major pathways that play an important role in addiction and relapse are dopaminergic mesolimbic and mesocortical pathways from the ventral tegmentum to the ventral striatum (nucleus accumbens) and medial prefrontal cortex (anterior cingulate) [20,41] and the amygdala [40,42,43]. Release of dopamine in the nucleus accumbens (ventral striatum) is associated with pleasure and reward and is accepted as playing a role in addiction [19,20,44-47]. The medial prefrontal cortex plays an important role in modulation of emotion that is relevant to relapse and addiction [40,42,43] as well as drug craving. The amygdala mediates anxiety and fear reactions and plays a key role in OUD [40,42,43].

The maintenance of addiction and relapse is often related to craving precipitated by conditioned responses to exposure to drug cues in patients with OUD [48]. These neural circuits allow for the development and maintenance of such conditioned responses in patients with OUD [40,42,43]. The amygdala likely plays a role in symptoms of anxiety associated with opioid addiction and withdrawal [49]. The medial prefrontal cortex is implicated in the appraisal and regulation of emotions. By inhibiting amygdala activity through extinction mechanisms [50] the medial prefrontal cortex plays a critical role in the acquisition of fear memories as shown in both animal studies [51,52] and brain imaging studies in humans [53-63], highlighting its role in anxiety which is a part of the opioid withdrawal response [19]. Changes in these brain areas are reversible with treatment in patients with OUD [46].

The Locus Coeruleus (LC), located in the pons, is the major source of noradrenergic cell bodies in the brain [64]. Noradrenergic neurons project to multiple areas in the brain, including amygdala, medial prefrontal cortex, hippocampus, ventral striatum, and other areas of the cerebral cortex [64]. Release of norepinephrine, which occurs under both stress and opioid withdrawal, causes an increase in attention and vigilance behaviors, and activates the cardiovascular system [23,24,64]. Inputs to the LC come from the nucleus paragigantocellularis and nucleus prepositus hypoglossi, and endogenous opiates in this brain area are inhibitory to LC neurons [65,66]. Withdrawal of opioids in animals addicted to methadone causes a rebound increase in LC activity, resulting in increased norepinephrine release in the amygdala that subsequently activates the cardiovascular system and drives symptoms of withdrawal [65]. Opioids in the LC initially inhibit of production of adenylyl cyclase and Cyclic Adenosine Monophosphate (cAMP) [67,68]. With prolonged dependence there is eventually an increase in adenylyl cyclase and cAMP resulting in increased cAMP dependent response element binding protein (CREB). This upregulation likely represents a compensatory mechanism for the initial inhibitory effects of opioids [67,68]. Upregulation in the cAMP cascade in the LC is hypothesized to represent a component of tolerance, as well as the mechanism of opioid dependence and withdrawal [67,68]. Norepinephrine and the LC therefore play a central role in opioid addiction and symptoms of withdrawal due to rebound sympathetic activation.

Positron Emission Tomography (PET) studies in patients with OUD implicate similar neurobiological systems and circuits as seen in animal models [46,69]. Morphine acutely reduces brain metabolic activity in the superior frontal gyrus, paracentral lobule, supramarginal gyrus, anterior cingulate, caudate (striatum), gyrus rectus, and middle temporal gyrus [70]. Functional Magnetic Resonance Imaging (fMRI) studies showed abnormal connectivity in OUD in ventral striatum, medial prefrontal cortex (anterior cingulate), amygdala and insula [71]. Functional imaging studies of brain blood flow and metabolism using PET showed increased activation of ventral striatum and medial prefrontal cortex (anterior cingulate) during opioid [46] and nicotine [72,73] craving. Patients with OUD who are exposed to emotional pictures during heroin abstinence had increased connectivity as measured with resting state fMRI between left amygdala and left fusiform gyrus and right amygdala and right orbitofrontal cortex, this normalized after administration of heroin [74].

Chronic opioid use is associated with a decrease in binding of the Dopamine Transporter (DAT) [75] and D-2 receptor binding measured with PET and the radiolig and [C-11] raclopride [40,69,76]. This may reflect a decrease in endogenous dopamine release following chronic overstimulation with opioids and/or decreased transporter and/or receptor binding [40]. DAT uptake was not associated with heroin craving in abstinent OUD patients [75]. These findings implicate dopaminergic pathways in the ventral striatum and medial prefrontal cortex in OUD.

Effects of Early Trauma on Vulnerability to OUD

Early life trauma plays a critical role in the development and maintenance of OUD in many patients [77-83]. Individuals with a high number of Adverse Childhood Experiences (ACEs) have a 10-fold increase in risk for the use of injected drugs, mostly opioids [77,84,85], and there are important links between OUD and Posttraumatic Stress Disorder (PTSD) [36,79,80,86-93]. Recurrent stressors and exposure to triggers of traumatic memories in everyday life is a common precipitator of relapse in patients with OUD [22,89,94], especially for women using prescription opioids [95]. There is a great deal of overlap in brain circuits mediating OUD and PTSD (Figure 1). The fact that nVNS modulates many of these brain regions suggests that it could be useful for both disorders as well as the complex co-morbid conditions that are often seen in patients with OUD.