OBJECTIVES: Noninvasive vagus nerve stimulation (nVNS) has not only shown antinociceptive effects, but also demonstrated anti-inflammatory and antidepressant effects. These effects could be beneficial in chronic pancreatitis (CP) patients suffering from chronic abdominal pain, even though the underlying central mechanisms remain unclear. The aim was to investigate the effect of cervical nVNS in patients with painful CP on brain functional connectivity and cerebral metabolites. MATERIALS AND METHODS: In a randomized double-blind, sham-controlled crossover trial, we used resting-state functional magnetic resonance imaging to investigate functional connectivity changes of limbic structures (seed-based analysis) after two weeks cervical nVNS treatment (GammaCore) as compared with two weeks sham treatment. Similarly, magnetic resonance spectroscopy was performed in the anterior cingulate cortex (ACC) with assessment of glutamate/creatine (Glu/cre) and N-acetylaspartate/creatine (NAA/cre). RESULTS: Sixteen CP patients (mean age 56.6 ± 9.4 years) completed the trial. nVNS induced reduced functional connectivity compared to sham treatment between 1) bilateral thalamus and bilateral superior frontal gyrus, 2) ACC and putamen, and 3) posterior cingulate cortex and right thalamus (all p < 0.05). No changes were observed in Glu/cre (p = 0.96) and NAA/cre (p = 0.43) levels between the nVNS and sham treatments. CONCLUSION: In our population of CP patients, cervical nVNS compared with sham treatment induced reduced functional connectivity of limbic structures, as also observed in other patient groups. The findings are relevant, since we have previously demonstrated an effect on pain scores in CP patients for both nVNS and sham treatment. Our results elucidate the effects in the central nervous system following nVNS treatment of CP patients, pointing at potential beneficial effects in this patient group.