Metabolomic analysis of Gyejibongnyeong-Hwan for shoulder pain: A randomized, wait-list controlled pilot trial

In Korea, Gyejibongnyeong-Hwan (GBH), a herbal decoction used to treat blood stasis (BS), is widely used to treat shoulder pain in clinics. Nevertheless, the therapeutic mechanism of GBH in alleviating shoulder pain has not yet been elucidated.In this study, we applied mass spectrometry-based metabolomics to explore the therapeutic mechanism of GBH in BS-induced shoulder pain.We conducted a two-center, randomized, wait-list controlled pilot trial to explore the therapeutic effect of GBH on shoulder discomfort related to BS.A total of 40 participants with shoulder pain were randomly assigned to either the immediate treatment (GBH-Treat; n = 20) or waiting treatment (Wait-List; n = 20) group. A non-targeted metabolomics approach was then applied to investigate the therapeutic mechanism of GBH.After 8 weeks of treatment, the visual analog scale (VAS) scores for shoulder pain decreased significantly in the GBH-Treat and Wait-List groups compared with baseline VAS scores (p = 0.004 and p = 0.013, respectively). However, the VAS and BS scores were significantly more reduced in the GBH-Treat group than in the Wait-List group. The plasma metabolic pattern between GBH-Treat and Wait-List groups also differed significantly, which was shown by the score plot of a partial least-squared-discriminant analysis (R2 = 0.806 and Q2 = 0.229, p = 0.016). Arginine, bilirubin, carnitine, glutamine, maltol, mystic acid, N,N dimethylarginine, trimethylamine N-oxide, valine, kynurenine, and linoleic acid significantly contributed to the different metabolic patterns between the GBH-Treat and Wait-List groups (all p < 0.05). Pathway analysis revealed that these metabolites were involved in arginine biosynthesis and tryptophan metabolism, which are related to pain generation and transmission. We also confirmed that the ratio of kynurenine to tryptophan, one of the indicators for chronic pain and neuro-inflammation, was significantly lower in the GBH-Treat group than in the Wait-List group (p = 0.02).These results demonstrated that GBH may be a potential treatment option for shoulder pain, and it acts by regulating metabolic patterns. In particular, our study provides evidence for the use of GBH treatment for patients with should pain caused by BS, and we believe that our findings can provide evidence for precision medicine based on traditional Chinese medicine (TCM) or traditional Korean medicine (TKM). We also verified that metabolomics studies provide comprehensive understanding of herbal decoctions in TCM or TKM.