2019 Volume 42 Issue 5 Pages 680-684
Daiokanzoto (DKT) and lubiprostone (LPS) are drugs used for constipation, but few studies have compared them. This study examined the effectiveness, adverse events, and medical economic efficiency of DKT and LPS for constipation. Patients who received DKT (DKT group) and those who received LPS (LPS group) during admission to Ogaki Municipal Hospital between November 2012 and May 2016 were enrolled. Drug efficacy was evaluated based on the median value of bowel movement frequency over 1 week before and after drug administration, and their safety was evaluated by the presence or absence of diarrhea, abdominal pain, nausea, and vomiting. To assess medical economic efficiency, drug costs for constipation per week were calculated. The median values (quartile ranges) of bowel movement frequency at 1 week after drug administration were 8.5 (6.0–12.0) in the DKT group and 5 (3.0–7.0) in the LPS group, which was significantly different (p < 0.01). Diarrhea occurred significantly less often in the DKT group (4 cases) than in the LPS group (17 cases) (p < 0.01). The median cost of drugs administered for constipation for 1 week was significantly lower in the DKT group (631 [quartile range, 513–653] yen) than in the LPS group (1431 [1135–2344] yen) (p < 0.01). DKT had a higher immediate effect on constipation and was associated with more frequent bowel movement and fewer adverse events of diarrhea than LPS, suggesting that it may be effective and safe for treating constipation, and DKT is inexpensive.
In a randomized, cohort study in the United States, the prevalence of chronic constipation in adults was 16%.1) Tamura et al. reported that 28% of adults in Japan are diagnosed with constipation according to the Rome III standard, which conceptualizes the diagnosis and treatment of functional digestive disorders.2) The prevalence of chronic constipation has been reported to increase in those age 65 years and older, and this condition has a large effect on QOL, both physically and mentally.3) Many medications for constipation are available in Japan, and many patients regularly use drugs for constipation. In Japan, where elderly people aged 65 years and older account for more than 25% of the total population, medical expenses are a serious fiscal burden.4–6) Daiokanzoto (DKT) is a drug used in Japan for constipation, and it is a Kampo medicine consisting of rhubarb and licorice. The mechanism of DKT on constipation is that after sennoside A, which is a component contained in rhubarb, is orally administered, it migrates to the large intestine without being absorbed in the stomach and small intestine; then, rheinanthrone produced by metabolism via intestinal bacteria stimulates the colon wall, increases peristalsis, and improves constipation.7,8) Liquiritin and liquiritin apioside in licorice also enhance the metabolism of sennoside A; hence, combining rhubarb and licorice has been reported to effectively improve bowel movement.9,10) Furthermore, Takayama et al. reported that rhein in rhubarb promotes metabolic activation of sennoside A.11) However, lubiprostone (LPS) is a chloride channel activator that increases the intestinal fluid of the small intestine, softens the feces, and promotes bowel movement, and it is a novel constipation therapeutic agent.12) The World Gastroenterology Organisation global guideline of Lindberg et al. recommends LPS, but not DKT.13) In Japan, guidelines for chronic constipation clinical practice 2017 have been published, but as with the World Gastroenterology Organization global guideline, LPS is highly recommended and there is no significant difference.
To our knowledge, no study has compared the treatment effect of DKT with other constipation drugs. Therefore, this study aimed to examine and compare the effectiveness, safety, and medical economic efficiency of DKT and LPS in Japan.
The study period was from November 2012 to May 2016. Patients who were hospitalized in Ogaki Municipal Hospital and receiving Tsumura DKT extract granule (medical use) or LPS for the first time were included. However, the following exclusion criteria were established: patients lacking data on bowel movement frequency in the electronic medical record, patients with organic disease of the gastrointestinal tract, patients who received DKT or LPS before hospital admission, patients who were hospitalized less than 5 d after DKT or LPS administration, patients with a bowel movement frequency of 5 or over within 1 week before DKT or LPS administration, patients who used DKT or LPS only as needed, and patients who were also prescribed other therapeutic drugs for constipation after DKT or LPS administration.
The following data were retrospectively extracted from the electronic medical record: clinical characteristics (age, sex, height, and weight), blood laboratory findings (aspartate aminotransferase [AST], alanine aminotransferase [ALT], total bilirubin [T-Bil], creatinine [Cre], blood urea nitrogen [BUN], sodium [Na], potassium [K], and chloride [Cl] levels), dosage of DKT or LPS, diagnosis, concomitant medications, medical history, bowel movement frequency, presence of diarrhea, abdominal pain, nausea, and vomiting.
Comparison of the Effects between DKT and LPSThe median value of bowel movement frequency per week before drug administration and 4 weeks after drug administration was compared between the patients who received DKT (DKT group) and those who received LPS (LPS group).
Comparison of Adverse Events between DKT and LPSFour weeks after drug administration, the presence or absence of the main adverse events (diarrhea, abdominal pain, nausea, and vomiting) was compared between the DKT group and LPS group. Clinical laboratory values before drug administration and 1 week after drug administration were evaluated using Common Terminology Criteria for Adverse Events, version 4.0 (Japan Clinical Oncology Group, 2016) and compared between the two groups.
Comparison of Medical Economic Efficiency of DKT and LPSBy multiplying the median dose of the therapeutic agent for constipation including concomitant medication by the medicinal price for 1 week after the start of administration, the drug cost of constipation was calculated and compared between the two groups. For drug prices, the drug price standard (2016) recommended by the Ministry of Health, Labor, and Welfare of Japan was used. The drug prices were 5.3 yen per gram of DKT extract granule, 161.1 yen per capsule of LPS, 12.6 yen per 1 g of magnesium oxide fine grain, 5.8 yen per 330-mg magnesium oxide tablet, 5.8 yen per senna extract tablet, 9.8 yen per 1 mL of picosulfate sodium internal solution 0.75%, and 5.8 yen per 2.5-mg picosulfate sodium tablet.
Statistical AnalysisEZR (version 1.26, Saitama Medical Center) was used for statistical analysis. Statistical analysis was performed to compare bowel movement frequency, laboratory test values, and drug costs between the DKT group and LPS group using Mann–Whitney’s U test. To compare the presence or absence of adverse events, Fisher’s exact probability test was used. The significance level was set to 5%.
Ethical ConsiderationThis study was conducted with approval from the Ethics Committee of the Ogaki Municipal Hospital (20170126-2) and in accordance with the ethical principles for medical research outlined in the Declaration of Helsinki 1964 as modified by subsequent revisions.
Of the 138 patients administered with DKT during the study period, the following patients were excluded: 38 in whom the number of days before and after DKT administration was less than 5 d, 54 in whom the value of bowel movement frequency within 1 week before DKT administration was more than 4, and 2 in whom DKT was used only as needed. Moreover, of the 74 patients administered with LPS during the study period, the following patients were excluded: 5 in whom the number of days before and after LPS administration was less than 5 d and 16 in whom the value of bowel movement frequency within 1 week before LPS administration was more than 4. Ultimately, 44 patients administered with DKT (DKT group) and 53 patients administered with LPS (LPS group) were included.
Patients’ Baseline CharacteristicsThere was no significant difference between the DKT group and LPS group in terms of age, sex, height, weight, and BMI (Table 1). The median daily dose (quartile range) of DKT was 7.5 (7.5–7.5) g. The median daily dose of LPS (quartile range) was 24 (24–48) µg. Previous cerebrovascular events occurred in 3 and 13 patients in the DKT group and LPS group, respectively, which was significantly different (p < 0.01). There was no significant difference between the groups in terms of diabetes, a history of Parkinson’s disease, or opioid administration. Concomitant administration of a drug for treating constipation was significantly more frequent in the DKT group than in the LPS group (p < 0.01). There were no significant differences between the groups in terms of periodical oral dosing of senna extract, picosulfate sodium, and Kampo medicines (daikenchuto, junchoto, and mashiningan) used for the treatment of constipation.
| DKT group (n = 44) | LPS group (n = 52) | p-Value | ||
|---|---|---|---|---|
| Age | ≥ 65 years | 47 | 5 | 0.16 |
| < 65 years | 35 | 9 | ||
| Sex (M/F) | 27/25 | 27/17 | 0.41 | |
| Height (cm) | 158.9 (152.4–166.5) | 156.0 (150.0–163.7) | 0.23 | |
| Body weight (kg) | 53.4 (44.6–63.2) | 52.0 (47.1–60.0) | 0.89 | |
| BMI (kg/m2) | 21.4 (18.7–24.1) | 21.9 (19.5–24.6) | 0.52 | |
| Final bowel movement (days before admission) | 4 (2–6) | 3 (2–5) | 0.18 | |
| Constipation risk factors | ||||
| Cerebrovascular events | 3 (6.8%) | 15 (28.8%) | < 0.01 | |
| Diabetes | 7 (15.9%) | 11 (21.2%) | 0.6 | |
| Opioid use | 3 (6.8%) | 4 (7.7%) | > 0.99 | |
| Parkinson’s disease | 0 (0.0%) | 2 (3.8%) | 0.5 | |
| Concomitant drug | ||||
| Regular use of magnesium oxide | 38 (86.3%) | 13 (25%) | < 0.01 | |
| Regular use of Kampo medicine | 0 (0.0%) | 5 (9.6%) | 0.06 | |
| Regular use of senna extract | 4 (9.1%) | 9 (17.3%) | 0.37 | |
| As needed use of senna extract | 3 (6.8%) | 11 (21.1%) | 0.07 | |
| As needed use of sodium picosulfate | 6 (13.6%) | 5 (9.6%) | 0.75 | |
Data for height, weight, BMI, and final bowel movement are expressed as median (quartile range). BMI, body mass index; DKT, daiokanzoto; F, female; LPS, lubiprostone; M, male.
The median values (quartile ranges) of bowel movement frequency within 1 week before drug administration were 2.0 (1.0–4.0) and 1.5 (0.75–3.0) in the DKT and LPS groups, respectively (p = 0.08). The median values (quartile ranges) of bowel movement frequency at 1 week after drug administration were 8.5 (6.0–12.0) in the DKT group and 5 (3.0–7.0) in the LPS group, which was significantly different (p < 0.01; Fig. 1). The median values of bowel movement frequencies (quartile ranges) at 2 weeks after drug administration were 8 (5.3–10.8) in the DKT group and 4 (3.0–8.5) in the LPS group, which was significantly different (p < 0.01). The median values of bowel movement frequencies (quartile ranges) at 3 and 4 weeks after drug administration were 9.5 (3.5–13.0) and 8.5 (5.5–12.5) in the DKT group and 4.5 (3.0–7.5) and 7 (3.0–9.0) in the LPS group, and there were no significant differences (p = 0.10 and 0.30, respectively). According to the exclusion criteria, there were 26 patients in the DKT group and 30 patients in the LPS group 2 weeks after drug administration. There were 12 patients in the DKT group 3 weeks after drug administration and 22 patients in the LPS group. There were 8 patients in the DKT group at 4 weeks after drug administration and 13 patients in the LPS group.
The number of bowel movements per week before drug administration and up to 4 weeks after drug administration is indicated by the median (quartile range). p-values <0.01 according to Mann–Whitney U test are indicated by **. Since the number of cases according to exclusion criteria decreased, the number of cases per week in the DKT group and the LPS group are shown. DKT, daiokanzoto; LPS, lubiprostone.
In terms of adverse events, 4 patients (9.1%) in the DKT group and 17 (32.7%) in the LPS group had Grade 1 diarrhea, which was significantly different (p < 0.01; Table 2). One patient (2.3%) in the DKT group and none (0.0%) in the LPS group had Grade 1 abdominal pain (p = 0.46). Grade 1 nausea was present in 5 patients of the DKT group (11.4%) and 5 of the LPS group (9.6%) (p > 0.99). Grade 1 vomiting was present in 1 patient of the DKT group (2.3%) and 3 of the LPS group (5.8%) (p = 0.62).
| DKT group (n = 44) | LPS group (n = 52) | p-Value | |
|---|---|---|---|
| Diarrhea | 4 (9.1%) | 17 (32.7%) | < 0.01 |
| Abdominal pain | 1 (2.3%) | 0 (0.0%) | 0.46 |
| Nausea | 5 (11.4%) | 5 (9.6%) | > 0.99 |
| Vomiting | 1 (2.3%) | 3 (5.8%) | 0.62 |
DKT, daiokanzoto; LPS, lubiprostone.
In the laboratory test values before DKT and LPS administration, the ALT level was significantly lower in the LPS group than in the DKT group, but within the reference range (p < 0.01; Table 3).
| DKT group (n = 44) | LPS group (n = 52) | p-Value | |
|---|---|---|---|
| Na level (mEq/L) | 138 (135.8–140) | 138 (136–140.3) | 0.48 |
| K level (mEq/L) | 4.1 (3.9–4.5) | 4.1 (3.7–4.4) | 0.28 |
| Cl level (mEq/L) | 102 (100–106) | 103 (100.8–107) | 0.37 |
| AST level (IU/L) | 21 (15–30.8) | 21 (15–26.3) | 0.54 |
| ALT level (IU/L) | 19.5 (12.8–27) | 13.5 (9.8–18) | < 0.01 |
| T-Bil level (mg/dL) | 0.55 (0.4–0.8) | 0.5 (0.4–0.7) | 0.84 |
| BUN level (mg/dL) | 17.8 (14.5–22.7) | 15.3 (12.2–20.9) | 0.16 |
| Cre level (mg/dL) | 0.64 (0.57–0.94) | 0.73 (0.54–0.99) | 0.63 |
Data are expressed as median (quartile range). ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; Cl, chloride; Cre, creatinine; DKT, daiokanzoto; K, potassium; LPS, lubiprostone; Na, sodium; T-Bil, total bilirubin.
There was no significant difference between the levels of AST, T-Bil, Cre, BUN, Na, K, and Cl before drug administration between the DKT group and LPS group. There was also no significant difference between the DKT group and LPS group in the clinical laboratory test values 1 week after drug administration (Table 4).
| DKT group (n = 44) | LPS group (n = 52) | p-Value | |
|---|---|---|---|
| Na level (mEq/L) | 138 (137–139) | 138 (136–140) | 0.83 |
| K level (mEq/L) | 4.3 (3.8–4.5) | 4.0 (3.6–4.5) | 0.41 |
| Cl level (mEq/L) | 104 (102–106) | 105 (100–106.5) | 0.69 |
| AST level (IU/L) | 18.5 (13–28.5) | 21 (17–31) | 0.2 |
| ALT level (IU/L) | 15 (11–34) | 16 (9–27) | 0.98 |
| T-Bil level (mg/dL) | 0.5 (0.3–0.6) | 0.5 (0.4–0.7) | 0.6 |
| BUN level (mg/dL) | 14.6 (11.0–18.9) | 15.8 (11.2–28.9) | 0.09 |
| Cre level (mg/dL) | 0.67 (0.56–0.87) | 0.69 (0.5–0.99) | 0.92 |
Data are expressed as median (quartile range). ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; Cl, chloride; Cre, creatinine; DKT, daiokanzoto; K, potassium; LPS, lubiprostone; Na, sodium; T-Bil, total bilirubin.
The median values (quartile ranges) of medication expenses for constipation over 1 week, including concomitant medication, were 631 (513–653) yen in the DKT group and 1431 (1135–2344) yen in the LPS group (p < 0.01).
In this study, the findings suggested that DKT was more effective than LPS, as it acted faster and increased the bowel movement frequency at 1 week and 2 weeks. There are similar reports on LPS,14) but not on DKT. Based on the results of this study, DKT possibly has an immediate effect over LPS, and further investigation is necessary.
According to a study by Nelson et al., a meta-analysis of randomized, placebo-controlled trials in adults with chronic idiopathic constipation showed that irritating laxatives, such as bisacodyl, are more effective in increasing the bowel movement frequency per week than chloride channels, such as LPS. One study reported that DKT is superior to chloride channel activator.15) DKT containing sennoside A is classified as an irritating laxative and considered to support the analysis of this study. DKT stimulates the intestinal wall with senoside A, which is the main component that increases peristaltic movement. LPS activates the type-2 chloride channel locally, promotes water secretion into the intestinal tract, softens the feces, enhances transport within the intestinal tract, and promotes bowel movement. Differences in these mechanisms of action may have affected the differences in bowel movement frequency.
The mechanisms of action had an effect for the following reason. Licorice is the main ingredient of DKT, a traditional Kampo medicine mainly used for the treatment of peptic ulcer, hepatitis C, and pulmonary and skin diseases. In licorice, many components, including triterpene saponin, flavonoid, isoflavonoid, and chalcone, have been isolated.16) Among them, glycyrrhizic acid, which is regarded as the main biologically active ingredient, suppresses diarrhea caused by Escherichia coli toxin,17) and there are reports that colitis is improved by suppressing inflammatory cytokines and increasing regulatory cytokines.18) In other words, the low result in the presence of diarrhea with DKT is considered to have been due to the intestinal protective action of glycyrrhizic acid.
In addition, the prevalence of diarrhea caused by LPS was reported at 30% in the safety assessment at the time of approval, and in this study, it was not much different at 32.7%. The prevalence of nausea caused by LPS was reported at 23% in the safety assessment at the time of approval, but in this study, it was only 9.6%. This was thought to be due to the difficulty in extracting the description of nausea from the retrospective chart review.
In this study, occurrence of diarrhea, which is a side effect of laxatives, was significantly lower with DKT administration than with LPS administration, suggesting the safety of DKT.
In this study, medication expenses per week were significantly less with DKT than with LPS and that the drug effect was equivalent or DKT was better. Therefore, active use of DKT was suggested to reduce medical costs, which have been problematic in recent years.
This study has limitations, such as patients’ background information could not be adjusted, and QOL could not be evaluated. Due to the retrospective nature of the study, bowel movement frequency was the only efficacy measure that could be evaluated. In the World Gastroenterology Organisation global guideline of Lindberg et al., probiotics has not been recommended, so it was excluded from the extraction subject in this study. In addition, as a concomitant medication for treating constipation, magnesium oxide was used significantly more in the DKT group than in the LPS group; thus, careful evaluation of the effectiveness of DKT is necessary. Moreover, further cases are necessary for in-depth evaluation.
This study’s findings suggested that compared with LPS, DKT has an immediate effect on constipation and few adverse events, and it is medically and economically efficient.
The authors declare no conflict of interest.
