Non-Invasive Vagal Nerve Stimulation Reduces Nausea Rescue Medication in Patients With Gastroparesis and Related Disorders, With Additional Benefits on Multiple Other Associated Symptoms

Introduction: Chronic nausea and vomiting are key symptoms of GP and Functional Dyspepsia (FD). These sensations are relayed to the brain via the vagus nerve and vagal nerve stimulation (VNS) and modulation of its function offers a novel therapeutic approach. Open label studies using the Gammacore(nVNS) device (approved by the FDA for treatment of migraine) have shown promise for the relief of chronic nausea but what has not been explored previously is the utility of nVNS for nausea exacerbations. We therefore hypothesized that nVNS when used on an “as needed” basis may provide an effective and safe alternative to traditional rescue medications. Methods: This pilot study (NCT04857281) included patients aged ≥15 yrs with ongoing GP or FD symptoms for ≥3 months. The primary endpoint was reduction in antinauseant medication requirement by using nVNS as the primary rescue treatment for nausea. Exploratory endpoints included changes in gastrointestinal, autonomic, and psychological symptoms. Patients self-administered a 2-min nVNS using gammaCore as needed for nausea exacerbations randomized to a single neck side (left or right) for 4 wks, followed by a 2-wk washout. Then, they switched to the other side for 4 wks, followed by a final 2-wk washout. Results: 41 patients (38F; age: 35.5 ± 14.8 yrs) were in the total ITT population. To assess the primary endpoint, we excluded 6 patients, (5 who did not report use of rescue medications at baseline and 1 with missing data). All other endpoints were analyzed for 41 subjects. nVNS reduced pills/day by half (Figure 1), sustained during washout periods. The initial side of stimulation had no impact. Exploratory endpoints (Table 1) revealed trends of improvement in GCSI, PAGI-SYM scores for GP and changes in abdominal pain, reflux, indigestion, constipation. Depression levels (Beck Index) improved but anxiety was unaffected. COMPASS-31 showed improvement, mainly in secretomotor and GI domains. HSQ migraine scores improved with fewer headache/migraine pills used. There were no device-related adverse effects. Conclusion: “As needed” nVNS can reduce the use for rescue medications for exacerbations of nausea due to GP or FD, providing an attractive option to patients. In addition, there appears to be several relatively unexpected benefits on a variety of symptoms including pain, constipation, depression, and some autonomic symptoms. These results should inform larger randomized sham-controlled trials in these disorders for which there are few therapeutic alternatives.Figure 1.: Effects of nVNS on the primary endpoint (average number of nausea pills per day; n = 35). Table 1. - Values represent Least Squares Mean at various points in the study Measure Baseline First side Washout Second side Final washout Overall P-value (type 3 F test) Average GCSI-DD 2.56 2.61 2.52 2.47 2.51 0.1 Average GCSI 2.81 2.45 2.43 2.48 2.45 0.08 Average PAGI-SYM 2.47 2.21 2.15 2.21 2.16 0.09 PAGI-SYM Nausea 2.29 1.88 1.99 1.77 1.95 0.04 PAGI-SYM Fullness 3.18 2.86 2.81 2.87 2.97 0.08 PAGI-SYM Bloating 2.94 2.62 2.56 2.78 2.53 0.05 GSRS abdominal pain 4.13 3.50* 3.67 3.62 3.52 < 0.0001 GSRS reflux 3.01 2.78 2.58 2.91 2.35 0.002 GSRS indigestion 3.58 3.07 3.27 3.21 3.18 0.046 GSRS constipation 4.07 3.66 3.62 3.36** 3.30 0.01 Beck depression 17.54 15.37 14.53 14.36 12.17*** 0.02 COMPASS-31 (total) 23.61 21.66 22.54 22.88 20.66 0.11 COMPASS- secretomotor 4.60 3.87 3.94 4.68 4.52 0.01 COMPASS- gastrointestinal 13.18 12.61 13.00 12.63 11.3 0.004 Headache screening questionnaire (HSQ)-migraine 4.98 5.05 4.90 4.27 4.24 0.004 Average number of headache/migraine pills 0.810 0.522 0.604 0.426 0.367 0.06 GCSI = Gastroparesis Cardinal Symptom Index; PAGI-SYM = Patient Assessment of Gastrointestinal Symptoms; GSRS = Gastrointestinal Symptom Rating Scale; COMPASS = Composite Autonomic Symptom Score; HSQ = Headache Screening Questionnaire * P = .0003 compared to baseline (t-test adjusted for multiple comparisons by Tukey-Kramer) ** P = 0.03 compared to baseline (t-test adjusted for multiple comparisons by Tukey-Kramer) ***P = 0.02 compared to baseline (t-test adjusted for multiple comparisons by Tukey-Kramer).