New strategy of therapy for functional dyspepsia using famotidine, mosapride and amitriptyline

Authors


Dr M. Otaka, Department of Internal Medicine, Akita University School of Medicine, 1-1-1 Hondo, Akita 010-8543, Japan.
E-mail: otaka@med.akita-u.ac.jp

Summary

Background : In functional gastrointestinal (GI) disorders including functional dyspepsia (FD) and irritable bowel syndrome (IBS), there might be no small extent of contributions of psychosomatic factors. As a therapy for IBS patients, the effectiveness of antidepressants has been reported.

Aim : In this study, we evaluated the efficacy of H2-receptor antagonist (famotidine) and 5-HT4 receptor agonist (mosapride citrate). In addition, the effect of antidepressants was assessed as the second-step therapy.

Methods : Patients complaining upper GI symptoms were diagnosed as FD excluding organic diseases. Randomized patients received 20 mg/day of famotidine or 15 mg/day of mosapride citrate for 4 weeks and the efficacy was compared between the two groups based on a 10-point visual analogue scale. When symptoms were not relieved (score improvement 0–2 points), patients received amitriptyline (30 mg/day) or no medication for 4 weeks randomly. Patients who had depression in psychological test (SDS) were omitted.

Results : As the first-step therapy, both famotidine and mosapride showed beneficial effects regardless of FD subtypes, age and gender. The efficacy of these two drugs in relieving FD symptoms was not significantly different. In patients who failed in the first-step therapy, amitriptyline showed beneficial effects.

Conclusions : These findings might be clinically important in view of the efficient relief of symptoms in FD patients.

Introduction

Functional dyspepsia (FD) is characterized by a variety of upper abdominal symptoms in the absence of organic disease.1–3 FD is a very common clinical condition affecting one-third of the population.4 Therefore, the most appropriate therapeutic management or strategy is a matter of importance. FD is classified into three types: (i) ulcer-like, (ii) dysmotility-like and (iii) non-specific type based on the symptoms. Many studies have been performed to study the effect of acid-suppressive substances such as histamine H2-receptor antagonist (H2RA) or proton pump inhibitor (PPI), and prokinetics such as 5-HT3 receptor agonist cisapride or domperidone.5, 6 Recently, the 5-HT4 receptor agonist, mosapride citrate, has been reported as a prokinetic to improve gastro-oesophageal reflux disease.7

However, the most appropriate standard medication for FD has not been established, although it is also true that the effect of these drugs could give a certain satisfaction. As no studies have established the therapy for FD patients failed in the first-line therapy, the establishment of the second-line therapy with other type of medication is rather required to reduce upper abdominal symptoms more quickly in view of the quality of life.

Neuropeptide and neurotransmitters produced in the gastrointestinal (GI) tract regulate GI motility, blood flow, secretion and absorption.8, 9 The enteric nervous system and central nervous system have direct effects on each other. For example, stress is known to aggravate the GI tract by stimulating the release of neuropeptides and neurotransmitters, triggering various GI responses. This brain–gut connection (axis) seems to be a mechanism that links the psychoemotional state with GI dysfunction.8

In a therapy for irritable bowel syndrome (IBS), which is also categorized into functional intestinal disorder, the efficacy of antidepressant has been reported.10–12 However, only few studies have reported the effect of antidepressants for FD patients.13–15

Previously, we reported the possible efficacy of antidepressants for FD patients. In this study, we elucidate the efficacy of antidepressants as the second-line therapy in case the first-line therapy with H2RA or 5-HT4 agonist was not effective.

Patients and methods

This study was approved by the Ethical Committee of Akita University Hospital.

Patients with upper abdominal symptoms persisting for more than 4 weeks were included in this study according to Rome II criteria.1 Patients who had organic disorder were excluded by laboratory tests (blood cell counting, liver chemistry, serum amylase level and urinalysis), upper GI endoscopy and ultrasonography. Moreover, patients with depression (SDS score >40) were excluded from this study using the Sheehan Disability Scale.16, 17 After informed consent, FD patients were randomly divided into two groups. After a washout phase of 7 days, H2RA (famotidine, 20 mg/day: twice a day) or 5-HT4 agonist (mosapride, 15 mg/day: three times a day after each meal) were administered for 4 weeks. Patients completed diary cards everyday detailing their abdominal symptoms using 10-point visual analogue scale (no symptom: 0; maximum symptom: 10; symptom before medication).

The efficacy of treatment was defined as follows. Improvement of symptom score at 4 weeks was compared with that of the pretreatment. Improvement of score was assessed as 0–2: no effect, 3–6: responded, <7: effective.

Patients who did not respond to the first-step therapy (score 0–2) were randomly divided into two groups after informed consent was obtained. In one group, antidepressants (amitriptyline, 30 mg/day: three times a day after each meal) were administered for the next 4 weeks. In another group, patients received no medication for 4 weeks. Patients completed the same diary cards everyday detailing their abdominal symptoms.

Statistical analysis

The Mann–Whitney U-test was used as appropriate for comparison between groups. P < 0.05 was regarded as statistically significant.

Results

As shown in Figure 1, 81 patients with FD were enrolled. After randomization, 40 and 41 patients were assigned to the famotidine and mosapride groups, respectively, without statistical differences in age, sex and FD subtypes (Table 1). During this study, four cases dropped out in the second-step therapy forgetting to take medication.

Figure 1.

Study protocol and number of patients (responded: score improvement of 3–6, effective: score improvement >7).

Table 1.  Clinical characteristics of FD patients
 Groups (first-step therapy)
FamotidineMosapride
Number4041
Age72 ± 671 ± 8
Sex (m:f)18:2215:26
Subgroup of FD (ulcer-like: dysmotility-like: non-specific)15:17:813:18:10

Famotidine vs. mosapride (the first-step therapy)

No patient dropped out during the first-step therapy using famotidine or mosapride. No severe adverse reaction and exacerbation of symptoms were observed. As shown in Figure 2a,b, the famotidine-treated group showed 65.0% (26/40) of efficacy (more than 3 points improvement). The mosapride-treated group showed 58.5% (24/41) of efficacy with no significant difference compared with the famotidine-treated group.

Figure 2.

(a) Efficacy of therapy and number of patients (responded: score improvement of 3–6, effective: score improvement >7). (b) Effect of the first-step (famotidine or mosapride) therapy. Both famotidine and mosapride showed approximately 60% of efficacy rates. (c) Effect of the second-step therapy by amitriptyline. In the famotidine-failed group, amitriptyline had 66.7% (4/6) of efficacy and 75.0% (6/8) of efficacy was observed in the mosapride-failed group.

Effect of the tricyclic antidepressant amitriptyline (the second-step therapy)

Fourteen and 17 patients did not respond to famotidine or mosapride, respectively, in the first-step therapy (Figure 1). These FD patients were randomly divided into two groups and administered amitriptyline or followed up without medication. In the famotidine-failed group, six patients were treated with amitriptyline. In the mosapride-failed group, eight patients were treated with amitriptyline. The efficacy is shown in Figure 2A,C. In the famotidine-failed group, amitriptyline had 66.7% (4/6) of efficacy and 75.0% (6/8) of efficacy was observed in the mosapride-failed group. Therefore, FD symptoms were relieved in 93.8% (88.2%; per protocol) of patients when no treatment groups in the second-step therapy were omitted.

In both the first-step and the second-step therapy, age, gender and FD subtypes did not affect therapeutic effects of any drugs (data not shown). No severe adverse reactions were observed in patients enrolled in this study.

Discussion

Functional dyspepsia is characterized by a variety of upper abdominal symptoms including epigastric pain, fullness and discomfort in the absence of organic disease.1–3 In order to establish the therapy, many clinical studies have been performed. The efficacy of antisecretory (H2RA, PPI) and prokinetic (5-HT3 agonist, 5-HT4 agonist) therapies have been reported with a certain satisfaction, although the most appropriate therapy has not been well established.5–7 Actually, 65.0 or 58.5% (per protocol) of efficacy was observed in the famotidine-treated group or the mosapride-treated group, respectively, in the present study. These efficacies, especially in famotidine, are thought to be satisfactory as organic disorders have been almost completely excluded by endoscopy and ultrasonography in our study. Furthermore, our results and many other clinical studies indicate that as a mechanism of upper abdominal symptom in FD, acid secretion and/or GI motility might play an important role in more than half of FD patients.

The problem on hand in the therapy of FD is to establish therapy for FD patients whose symptoms are not resolved by antisecretory or prokinetic therapy.

In a therapy for IBS, which is also categorized as functional intestinal disorder, the efficacy of antidepressants has been reported. However, only few studies have reported the effect of antidepressants for FD patients. It would be possible that antidepressants, especially tricyclic antidepressants, which also show anti-cholinergic and analgesic properties, could be effective for FD patients.

Previously, we reported the possible efficacy of antidepressants for FD patients. In this study, we elucidate the efficacy of a tricyclic antidepressant FD agonist as the second-line therapy after the first-step therapy with H2RA or 5-HT4 agonist.

Our results show that in the famotidine-failed group, amitriptyline showed 66.7% (4/6) of efficacy and 75.0% (6/8) of efficacy was observed in the mosapride-failed group. Upper abdominal symptoms disappeared in 93.8% (88.2%; per protocol) of FD patients by the two-step therapy using H2RA or 5-HT4 agonist followed by a tricyclic antidepressant within 8 weeks. At the second-step therapy, patients who took no medication (non-treated group) showed a lower efficacy rate compared with placebo effects reported in other studies. Although the reason is not clear, one possibility is that we did not use placebo medication.

The efficacy of amitriptyline might be explained by its anticholinergic properties.10 This action might reduce the pressure inside of the stomach and motility. Moreover, analgesic action of this drug could be beneficial for FD patients whose threshold level of visceral sensitivity is lower (visceral hypersensitivity) compared with healthy subjects.10

Another possibility is that although patients with depression (SDS score >40) have been excluded from this study, patients with sub-clinical mild depressive state might be included in FD patients.

In conclusion, our study indicates that both famotidine and mosapride are beneficial for FD patients with >60% efficacy in the first-step therapy.

When the tricyclic antidepressant amitriptyline was applied for non-responded cases in the first-step therapy, symptoms were reduced in more than 90% of FD patients within 8 weeks without any adverse reaction or dropout.

These findings might be clinically important in view of the quality of life in FD patients because it should be the goal of FD therapy to reduce symptoms more quickly.

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