Journal of Gastroenterology

, Volume 47, Issue 3, pp 284–292 | Cite as

Rikkunshito improves symptoms in PPI-refractory GERD patients: a prospective, randomized, multicenter trial in Japan

  • Kazunari Tominaga
  • Ryuichi Iwakiri
  • Kazuma Fujimoto
  • Yasuhiro Fujiwara
  • Mio Tanaka
  • Yasuyuki Shimoyama
  • Eiji Umegaki
  • Kazuhide Higuchi
  • Motoyasu Kusano
  • Tetsuo Arakawa
  • and the GERD 4 Study Group
Original Article—Alimentary Tract



To seek a promising therapeutic regimen for proton pump inhibitor (PPI)-refractory patients with gastroesophageal reflux disease (GERD) after the standard PPI treatment, we compared the efficacies of rikkunshito (a Japanese traditional medication) combined with rabeprazole (RPZ) and a double dose of RPZ in a prospective randomized multicenter trial in Japanese PPI-refractory GERD patients.


One hundred and four patients with GERD symptoms remaining after 4-week treatment with RPZ (10 mg/day) were randomly assigned to 4 weeks of either combination therapy [rikkunshito (7.5 g/day) with a standard dose of RPZ (10 mg/day)] or a double dose of RPZ (20 mg/day). The primary endpoint was the improvement rate, calculated based on the frequency scale for the symptoms of GERD (FSSG) before and after treatment. Subgroup analysis was also performed with respect to each subject’s background factors such as reflux esophagitis (RE)/non-erosive GERD (NERD), age, gender, and body mass index (BMI).


Four-week treatment with rikkunshito combined with RPZ significantly decreased the FSSG score from 17.6 ± 6.5 to 12.0 ± 6.9, similar to the decrease seen on treatment with a double dose of RPZ. Regarding the therapeutic improvement rate, there were also significant effects in both groups. However, in the subgroup analysis based on RE/NERD, the improvement rate of male NERD patients in the rikkunshito group was significantly greater than that of such patients in the other group (P < 0.05). In the rikkunshito group, the treatment was more effective in NERD patients with a low BMI than in those with a high BMI (P < 0.05).


Rikkunshito combined with standard-dose RPZ therapy may be a useful new strategy for PPI-refractory GERD patients.


Heartburn Abdominal discomfort Rikkunshito Acid-suppressive therapy 



We are grateful to the GERD 4 Study Group, as listed below, for their contribution to this study. The GERD 4 Study Group: Shiroishi Kyoritsu Hospital, Kinoshita Clinic, Takashima Hospital, Nagae Pediatric Medicine Clinic, Arita Kyoritsu Hospital, Hiramatsu Hospital, Fujise Clinic, Imamura Clinic, Oda Regional Medical Center, Saga Prefectural Hospital Kouseikan, Jinnouchi Gastrointestinal and Internal Medicine, Kanzaki Clinic in Saga, Sousei Hospital, Taisyo Hospital, Osaka Saiseikai Nakatsu Hospital, Hoshigaoka Koseinenkin Hospital, Osaka City Juso Hospital, and Izumiotsu Municipal Hospital (all in Osaka, Japan).

Conflict of interest



  1. 1.
    Hiyama T, Yoshihara M, Tanaka S, Haruma K, Chayama K. Strategy for treatment of nonerosive reflux disease in Asia. World J Gastroenterol. 2008;14:3123–8.PubMedCrossRefGoogle Scholar
  2. 2.
    Vakil N, van Zanten SV, Kahrialis P, Dent J, Jones R, Global Consensus Group. The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus. Am J Gastroenterol. 2006;101:1900–20.PubMedCrossRefGoogle Scholar
  3. 3.
    Chiba N, De Gara CJ, Wilkinson JM, Hunt RH. Speed of healing and symptom relief in Grade II to IV gastroesophageal reflux disease: a meta-analysis. Gastroenterology. 1997;112:1798–810.PubMedCrossRefGoogle Scholar
  4. 4.
    Fass R, Shapiro M, Dekel R, Sewell J. Systematic review: proton-pump inhibitor failure in gastro-oesophageal reflux disease. Where next? Aliment Pharmacol Ther. 2005;22:79–94.PubMedCrossRefGoogle Scholar
  5. 5.
    Hershcovici T, Fass R. Nonerosive reflux disease (NERD)—an update. J Neurogastroenterol Motil. 2010;16:8–21.PubMedCrossRefGoogle Scholar
  6. 6.
    Holloway RH, Dent J, Narielval F, Mackinnon AM. Relation between oesophageal acid exposure and healing of oesophagitis with omeprazole in patients with severe reflux oesophagitis. Gut. 1996;38:649–54.PubMedCrossRefGoogle Scholar
  7. 7.
    Coté GA, Howden CW. Potential adverse effects of proton pump inhibitors. Curr Gastroenterol Rep. 2008;10:208–14.PubMedCrossRefGoogle Scholar
  8. 8.
    Futagami S, Iwakiri K, Shindo T, Kawagoe T, Horie A, Shimpuku M, et al. The prokinetic effect of mosapride citrate combined with omeprazole therapy improves clinical symptoms and gastric emptying in PPI-resistant NERD patients with delayed gastric emptying. J Gastroenterol. 2010;45:413–21.PubMedCrossRefGoogle Scholar
  9. 9.
    Kawahara H, Kubota A, Hasegawa T, Okuyama H, Ueno T, Ida S, et al. Effects of rikkunshito on the clinical symptoms and esophageal acid exposure in children with symptomatic gastroesophageal reflux. Pediatr Surg Int. 2007;23:1001–5.PubMedCrossRefGoogle Scholar
  10. 10.
    Hayakawa T, Arakawa T, Kase Y, Akiyama S, Ishige A, Takeda S, et al. Liu-Jun-Zi-Tang, a kampo medicine, promotes adaptive relaxation in isolated guinea pig stomachs. Drugs Exp Clin Res. 1999;25:211–8.PubMedGoogle Scholar
  11. 11.
    Kido T, Nakai Y, Kase Y, Sakakibara I, Nomura M, Takeda S, et al. Effects of rikkunshi-to, a traditional Japanese medicine, on the delay of gastric emptying induced by N(G)-nitro-l-arginine. J Pharmacol Sci. 2005;98:161–7.PubMedCrossRefGoogle Scholar
  12. 12.
    Tominaga K, Kido T, Ochi M, Sadakane C, Mase A, Okazaki H, et al. The traditional Japanese medicine rikkunshito promotes gastric emptying via the antagonistic action of the 5-HT3 receptor pathway in rats. eCAM 2009:1–8. doi: 10.1093/ecam/nep173.
  13. 13.
    Hattori T, Fujitsuka N, Asakawa A, Inui A. A strategy using rikkunshito (Liu-Jun-Zi-Tang), a Japanese traditional medicine, to treat gastrointestinal disease. In: Satoh H, editor. Basics of evidences-based herbal medicine. Kerala: Research Signpost; 2010. p. 149–60.Google Scholar
  14. 14.
    Kusano M, Shimoyama Y, Sugimoto S, Kawamura O, Maeda M, Minashi K, et al. Development and evaluation of FSSG; frequency scale for the symptoms of GERD. J Gastroenterol. 2004;39:888–91.PubMedCrossRefGoogle Scholar
  15. 15.
    Kusano M, Shimoyama Y, Kawamura O, Maeda M, Kuribayashi S, Nagoshi A, et al. Proton pump inhibitors improve acid-related dyspepsia in gastroesophageal reflux disease patients. Dig Dis Sci. 2007;52:1673–7.PubMedCrossRefGoogle Scholar
  16. 16.
    Pehlivanov N, Liu J, Mittal R. Sustained esophageal contraction: a motor correlate of heartburn symptom. Am J Gastroenterol. 2001;281:743–51.Google Scholar
  17. 17.
    Xenos ES. The role of esophageal motility and hiatal hernia in esophageal exposure to acid. Surg Endosc. 2002;16:914–20.PubMedCrossRefGoogle Scholar
  18. 18.
    Vela MF, Tutuian R, Katz PO, Castell DO. Baclofen decreases acid and non-acid post-prandial gastro-oesophageal reflux measured by combined multichannel intraluminal impedance and pH. Aliment Pharmacol Ther. 2003;17:243–51.PubMedCrossRefGoogle Scholar
  19. 19.
    Fass R, Naliboff B, Higa L, Johnson C, Kodner A, Munakata J, et al. Differential effect of long-term esophageal acid exposure on mechanosensitivity and chemosensitivity in humans. Gastroenterology. 1998;115:1363–73.PubMedCrossRefGoogle Scholar
  20. 20.
    Sifrim D, Mittal R, Fass R, Smout A, Castell D, Tack J, et al. Acidity and volume of the refluxate in the genesis of gastro-oesophageal reflux disease symptoms. Aliment Pharmacol Ther. 2007;25:1003–15.PubMedCrossRefGoogle Scholar
  21. 21.
    Miwa H, Minoo T, Hojo M, Yaginura R, Nagahara A, Kawabe M, et al. Oesophageal hypersensitivity in Japanese patients with non-erosive gastro-oesophageal reflux diseases. Aliment Pharmacol Ther. 2004;20:112–7.PubMedCrossRefGoogle Scholar
  22. 22.
    Kawahara H, Mitani Y, Nomura M, Nose K, Yoneda A, Hasegawa T, et al. Impact of rikkunshito, an herbal medicine, on delayed gastric emptying in profoundly handicapped patients. Pediatr Surg Int. 2009;25:978–90.CrossRefGoogle Scholar
  23. 23.
    Tatsuta M, Iishi H. Effect of treatment with Lui-Jun-Zi-Tang (TJ-43) on gastric emptying and gastrointestinal symptoms in dyspeptic patients. Aliment Pharmacol Ther. 1993;7:459–62.PubMedCrossRefGoogle Scholar
  24. 24.
    Kusunoki H, Haruma K, Hata J, Ishii M, Kamada T, Yamashita N. Efficacy of rikkunshito, a traditional Japanese medicine (Kampo), in treating functional dyspepsia. Intern Med. 2010;49:2195–202.PubMedCrossRefGoogle Scholar
  25. 25.
    Tomono H, Ito Y, Watanabe T. Successful antiemetics treatment of TSUMURA rikkunshito extract granules for ethical use in addition to other antiemetics agents in neoadjuvant chemotherapy for an advanced breast cancer patient (in Japanese with English abstract). Jpn J Cancer Chemother. 2006;33:1129–31.Google Scholar
  26. 26.
    Takahashi T, Endo S, Nakajima K, Souma Y, Nishida T. Effect of rikkunshito, a Chinese herbal medicine, on stasis in patients after pylorus-preserving gastrectomy. World J Surg. 2009;33:296–302.PubMedCrossRefGoogle Scholar
  27. 27.
    Matsumura T, Arai M, Yonemitsu Y, Maruoka D, Tanaka T, Suzuki T, et al. The traditional Japanese medicine rikkunshito increases the plasma level of ghrelin in humans and mice. J Gastroenterol. 2010;45:300–7.PubMedCrossRefGoogle Scholar
  28. 28.
    Takeda H, Sadakane C, Hattori T, Katsurada T, Ohkawara T, Nagai K, et al. Rikkunshito, an herbal medicine, suppresses cisplatin-induced anorexia in rats via 5-HT2 receptor antagonism. Gastroenterology. 2008;134:2004–13.PubMedCrossRefGoogle Scholar
  29. 29.
    Yakabi K, Sadakane C, Noguchi M, Ohno S, Ro S, Chinen K, et al. Reduced ghrelin secretion in the hypothalamus of rats due to cisplatin-induced anorexia. Endocrinology. 2010;151:3773–82.PubMedCrossRefGoogle Scholar
  30. 30.
    Kamiya T, Adachi H, Hirako M, Shikano M, Matsuhira E, Wada T, et al. Impaired gastric motility and its relationship to reflux symptoms in patients with nonerosive gastroesophageal reflux disease. J Gastroenterol. 2009;44:183–9.PubMedCrossRefGoogle Scholar
  31. 31.
    Ruth M, Hamelin B, Röhss K, Lundell L. The effect of mosapride, a novel prokinetic, on acid reflux variables in patients with gastro-oesophageal reflux disease. Aliment Pharmacol Ther. 1998;12:35–40.PubMedCrossRefGoogle Scholar
  32. 32.
    Kim YS, Kim TH, Choi CS, Shon YW, Kim SW, Seo GS, et al. Effect of itopride, a new prokinetic, in patients with mild GERD: A pilot study. World J Gastroenterol. 2005;22:4210–4.Google Scholar
  33. 33.
    Miwa H, Koseki J, Oshima T, Kondo T, Tomita T, Watari J, et al. Rikkunshito, a traditional Japanese medicine, may relieve abdominal symptoms in rats with experimental esophagitis by improving the barrier function of epithelial cells in esophageal mucosa. J Gastroenterol. 2010;45:478–87.PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2011

Authors and Affiliations

  • Kazunari Tominaga
    • 1
  • Ryuichi Iwakiri
    • 2
  • Kazuma Fujimoto
    • 2
  • Yasuhiro Fujiwara
    • 1
  • Mio Tanaka
    • 2
  • Yasuyuki Shimoyama
    • 3
  • Eiji Umegaki
    • 4
  • Kazuhide Higuchi
    • 4
  • Motoyasu Kusano
    • 3
  • Tetsuo Arakawa
    • 1
  • and the GERD 4 Study Group
  1. 1.Department of GastroenterologyOsaka City University Graduate School of MedicineOsakaJapan
  2. 2.Department of Internal MedicineSaga Medical SchoolSagaJapan
  3. 3.Department of Endoscopy and Endoscopic SurgeryGunma University HospitalGunmaJapan
  4. 4.Second Department of Internal MedicineOsaka Medical CollegeTakatsukiJapan

Personalised recommendations