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Dr Yoshikazu Kinoshita, Department of Gastroenterology and Hepatology, Shimane University School of Medicine, 89-1 Enya-cho, Izumo-shi, Shimane 693-8501, Japan. E-mail: email@example.com
Background : An effective therapeutic strategy for functional dyspepsia (FD) has not been well-established.
Aim : We investigated and compared the therapeutic effects of famotidine, mosapride and tandospirone for the control of dyspeptic symptoms.
Methods : Fully examined FD patients of outpatient clinics at seven different medical centres were enrolled in the study. They were randomly assigned to three groups based on the type of drug administered: famotidine, mosapride and tandospirone. The effects of treatment over 4 weeks were assessed by visual analogue scales.
Results : All of the drugs showed beneficial effects, although famotidine was the most effective for symptom relief, which was significantly greater than tandospirone, while the effect of mosapride was similar to that of famotidine. No subtype of FD showed a better response to a particular type of drug.
Conclusions : For the treatment of FD, famotidine demonstrated the best therapeutic effect, followed by mosapride, while that of tandospirone was significantly lower.
Functional dyspepsia (FD) is characterized by the presence of chronic or intermittent pain, fullness, and other unpleasant symptoms in the epigastric area, without demonstrable gastrointestinal or hepatobiliary organic disease.1 The pathogenesis of FD may be multifactorial, with hypersensitivity to gastric acid, motor dysfunction of the gastrointestinal tract, and psychosomatic disorders considered to be major causes.2 As it is difficult to identify the pathogenesis in individual cases, drugs that inhibit gastric acid secretion and stimulate the motor activity of the gastrointestinal tract, as well as anti-depressants have been administered in clinical practice.2 As for the therapeutic effects of these drugs, several investigators have reported the efficacy of individual drugs over a placebo and suggested their value in the treatment of FD.3–6 However, few studies have made direct comparisons of the efficacy of these three types of medications for symptomatic control of FD.
In the present study, we enrolled patients with FD who had been thoroughly examined and gave them famotidine, mosapride or tandospirone, representing the three kinds of drugs, in a prospective randomized fashion and then evaluated the symptomatic resolution in each group. Famotidine and mosapride were selected in this study as they were the most widely used histamine H2-receptor antagonist (H2RA) and prokinetic drugs in Japan. Tandospirone was selected as an anti-depressant, as it has anti-anxiety as well as anti-depressing effects. From those results, we compared the therapeutic value of these drugs for treatment of FD.
Materials and methods
Patients with FD and being treated in the period from April 2003 to December 2004 in seven medical centres located in western Japan (Shimane University Hospital, Unnan General Hospital, Ono Municipal Hospital, Hirata Municipal Hospital, Masuda Red Cross Hospital, Ohda Municipal Hospital and Kasai Municipal Hospital) were invited to participate in the study. The diagnosis of FD was made according to the Rome II criteria.1 Patients with chronic or intermittent epigastralgia, epigastric fullness, or other epigastric discomfort for over 3 months in the previous 1-year period were given upper gastrointestinal endoscopy and abdominal ultrasonographic examinations, and blood and urine samples were submitted to laboratory tests, which included complete blood cell counting, liver function tests and serum amylase analysis. Only those patients without organic diseases that may cause epigastric symptoms were enrolled.
The enrolled patients were randomly divided into three groups according to pre-fixed random division sheets. They were administered mosapride at 5 mg three times per day after each meal (mosapride group), famotidine at 20 mg twice a day after breakfast and dinner (famotidine group), or tandospirone at 10 mg three times per day after each meal (tandospirone group). Each patient was requested to record the severity of their symptoms on a 100-mm visual analogue scale (VAS) before, and 2 and 4 weeks after the start of administration. Symptom severity of <5 mm on the VAS at any time during treatment was regarded as a reasonably acceptable level of symptom resolution. The subtypes of FD, dysmotility-like, ulcer-like and non-specific, were determined according to the Rome II criteria when the patients were enrolled in the study.1
The ethical committees of Shimane University School of Medicine and the other participating hospitals approved the study protocol, which was performed according to the Declaration of Helsinki, and written informed consent was obtained from the enrolled patients.
Mann-Whitney U and chi-square tests were used as appropriate for statistical comparisons between groups. Statistical data are presented as mean ± S.E., with P < 0.05 regarded as statistically significant.
Seventy-nine patients with FD were enrolled, with 25, 27 and 27 assigned to the mosapride, famotidine and tandospirone groups respectively. There were no statistically significant differences between the three groups in regard to age, gender and type of FD. Prior to treatment, the VAS score value of all patients was 50 ± 2 mm and no significant differences were found among the groups (Table 1). For many of the patients, daily activities were remarkably influenced by their dyspeptic symptoms.
During the study, 19 patients stopped taking the assigned medication before the 4-week treatment period had ended (Figure 1), of whom two in the famotidine group stopped because their symptoms had nearly disappeared. In contrast, the other 17 patients (3, 2 and 12 in the mosapride, famotidine and tandospirone groups respectively) stopped taking their assigned drugs because of ineffectiveness. Thus, of the 25 patients in the mosapride group, 22 completed the 4-week study period and three stopped early because their symptoms were not controlled, while of the 27 patients in the famotidine group, two stopped early because of ineffectiveness and two stopped because of the disappearance of bothersome symptoms. In the tandospirone group, 12 of the 27 patients refused to continue the administration protocol because of ineffectiveness of the medication.
With VAS scores under 5 mm considered to show reasonably resolved symptoms, 9 of 25 mosapride-administered cases, 15 of 27 famotidine-administered cases and 4 of 27 tandospirone-administered cases showed reasonable symptomatic resolution within the 4-week study period (Figure 2). When the effects of the three types of drugs were compared at 4 weeks after the start of administration, famotidine was found to resolve dyspeptic symptoms more effectively than the other two types. Type of dyspepsia, age and gender did not have a significant influence on the therapeutic effect of any of the drugs (data not shown). No side effects were reported by any of the enrolled patients.
Functional dyspepsia is one of the most frequently encountered diseases by primary care doctors and gastroenterologists in outpatient clinics, and previous reports have shown that more than 20% of patient populations were cases with FD.7, 8 Although the disease is divided into three types (dysmotility-like, ulcer-like and non-specific), based on the primary symptoms, the pathogenic mechanisms have not been clarified. Proposed possible causes of FD include acid hypersensitivity of the gastroduodenal mucosa, motor dysfunction of the gastroduodenal tract, Helicobacter pylori-induced inflammation of the gastric mucosa, irritability of gastrointestinal sensory neurones and cognitive abnormality of gastroduodenal perception.2, 9 As a result, several therapeutic options have been proposed and many investigators have tested their efficacy, with gastric acid-suppressing, prokinetic and anti-depressant drugs the three major types tested.
In the present study, the efficacy of three types of drugs used for symptomatic relief was compared in patients with FD. Famotidine is a histamine H2RA and is generally used as a acid-suppressing drug. Previously, H2RAs were reported to have a small, but significant, symptom relieving effect for patients with FD.6 Mosapride is a prokinetic that does not have an adverse influence on cardiac functions and is widely used in place of cisapride in Japan. Many original studies and meta-analysis results have suggested the beneficial effect of prokinetics on dyspeptic symptoms.10, 11 Antidepressants including selective serotonin re-uptake inhibitors have also been tried for intractable dyspeptic symptoms.12, 13 However, as they have some side effects, we selected tandospirone, an agonist of serotonin type 1A receptor, as the antidepressant used in the present study. The strong point of our analysis is a comparison of these three types of drugs used clinically for the treatment of FD in Japan in a single multi-centred prospective randomized study.
Thirty-eight of the 79 enrolled patients had dysmotility-like dyspepsia, while 23 cases had ulcer-like dyspepsia, which is representative of the ratio of dyspepsia subtypes seen in Japanese patients.8 The mean VAS score of all enrolled patients was 50 ± 2 mm and the daily activities of many were decreased. Following the start of administration, many of the subjects continued to be bothered by their dyspeptic symptoms and 17 stopped taking the assigned drug before the end of the 4-week test period because of ineffectiveness.
In the present study, the number of patients whose dyspeptic symptoms were relieved increased steadily from 2 weeks after starting the administration to the end point of the study (4 weeks) in the famotidine and mosapride groups, whereas there was only a limited number of successful cases in the tandospirone group throughout the study period. Therefore, we speculated that the effectiveness of famotidine and mosapride may continue to increase after 4 weeks of administration. On the contrary, the effects of tandospirone did not increase after 4 weeks when compared with after 2 weeks, implying that the long-term therapeutic effects of famotidine and mosapride may be widely different than those of tandospirone. After 4 weeks of treatment, patients treated with famotidine had the best results, while those who received mosapride had better results that those treated with tandospirone. In addition, the number of patients who stopped treatment with tandospirone prior to the end of the study was significantly larger (P < 0.01) than those in the other groups, which suggested that tandospirone is inappropriate for the control of FD symptoms.
When the therapeutic effects of famotidine and mosapride were compared, famotidine showed a more favourable effect, although the difference was not statistically significant. We also performed an FD subgroup analysis to determine clinical characteristics that would guarantee better symptomatic relief by famotidine or mosapride. However, no specific factor was found, as ulcer-like dyspepsia did not respond better to the acid-suppressing drug, famotidine, and dysmotility-like dyspepsia did not show a good response to the prokinetic agent, mosapride. Therefore, it is difficult to select a first-line therapeutic agent based on the principal symptoms of dyspeptic patients and a standardized empirical therapy must be considered. In such empirical therapy, the reasonable first drug of choice may be famotidine and the first option mosapride, while tandospirone may be considered as the second-line choice if either of these is ineffective.
In summary, a prospective multi-centre randomized study was conducted with 79 FD patients. Among the three kinds of drugs tested, famotidine showed the best therapeutic effect followed by mosapride, while that of tandospirone was considerably lower.