Functional Dyspepsia: How to Manage the Burn and the Bloat (Part II)

Note: This article is reprinted from the Cleveland Clinic Journal of Medicine (2024;91[5]:301-307). The first portion of the published journal article reviewed the pathophysiology and symptoms of functional dyspepsia along with diagnostic tips. Part II focuses on the treatment of functional dyspepsia.

Written by Scott Gabbard, MD, and Nina Vijayvargiya, BS

Functional dyspepsia is defined as persistent symptoms of postprandial bloating, early satiety or pain in the center of the upper abdomen, without findings on upper endoscopy such as peptic ulcer disease to explain these symptoms. It is common, affecting up to 30% of the global population, but it often goes undiagnosed for years. There are two subtypes: epigastric pain syndrome (burning and pain) and postprandial distress syndrome (bloating and satiety). The authors discuss how to diagnose and treat both subtypes.

Case vignette

A 41-year-old woman reported having epigastric fullness and bloating with meals for more than 10 years, but denied having heartburn, regurgitation, dysphagia or weight loss. She underwent upper endoscopy five years before, and her esophagus, stomach and duodenum appeared normal. Biopsies of the gastric antrum and gastric corpus were negative for Helicobacter pylori, and biopsies of the duodenum were normal. She had tried two different proton pump inhibitors without success.

Treatments are all off-label

Currently, no therapy for functional dyspepsia has U.S. Food and Drug Administration approval. All the agents listed below are used off-label for treating this condition.

Antisecretory agents

Famotidine is a histamine-2 receptor antagonist used to decrease the production of stomach acid in patients with duodenal and gastric ulcers, gastro-esophageal reflux disease and erosive esophagitis. Famotidine twice daily was found to be more effective than the prokinetic medication mosapride and the antianxiety medication tandospirone in a study in patients with functional dyspepsia.¹ No specific subtype of functional dyspepsia was reported to respond better to famotidine.¹

Tachyphylaxis develops rapidly in response to histamine-2 receptor antagonists, which may limit their long-term use in functional dyspepsia.²

Proton pump inhibitors are often used to treat symptoms of acid reflux and gastroesophageal reflux disease. They work by irreversibly inhibiting the hydrogen-potassium adenosine triphosphatase proton pump in the parietal cell membrane on the luminal surface of the stomach.³

Clinical guidelines recommend starting proton pump inhibitor therapy in patients with functional dyspepsia who test negative for H pylori or who continue to have dyspeptic symptoms after H pylori eradication.⁴ Meta-analyses have found proton pump inhibitors to be better than placebo and possibly slightly better than histamine-2 receptor agonists and prokinetics.^4,5 Subgroup analysis suggested that more patients responded to proton pump inhibitors if their symptoms were related to heartburn.⁴ On the other hand, there was no difference in efficacy according to functional dyspepsia subtype, i.e., whether patients had epigastric pain syndrome or postprandial distress syndrome, and therefore experts do not recommend using the type of symptom to guide treatment choice.⁶

Possible long-term adverse effects of proton pump inhibitors include hip fracture, electrolyte imbalances, dementia, pneumonia and Clostridioides difficile infection. However, experts have concluded that these associations are probably not causal and that even if they were, the number needed to harm would be more than 1,000 in most cases.⁴ A 3-year randomized double-blind trial found pantoprazole was not associated with any adverse event, with the possible exception of an increased risk of enteric infection.⁷ Patients should stop the drug if there is no response after taking the standard dose for eight weeks, and should try to withdraw from the drug within six to 12 months, regardless of the response.

Neuromodulators

Antidepressant and antianxiety medications are often used to treat irritable bowel syndrome, but their efficacy in treating functional dyspepsia is less well known. These medications may improve central analgesic function, improve sleep, normalize orocecal transit and augment gastric accommodation, all of which are hypothesized to help alleviate functional dyspepsia symptoms.^8–11

Buspirone is a serotonin 5-HT1A receptor agonist. In a study of 17 patients with functional dyspepsia, buspirone 10 mg before meals was found to augment fundic accommodation and improve postprandial fullness, bloating and early satiety.⁸

Buspirone may also have a role in treating functional dyspepsia in patients with rapid gastric emptying. In one reported case, early satiety, nausea, vomiting and diarrhea all improved within one week of starting buspirone 10 mg three times a day before meals.⁹

Mirtazapine. The antidepressant mirtazapine is an antagonist to histamine-1 receptor, serotonin receptors 5-HT2C and 5-HT3 and the A2 adrenergic receptor. Mirtazapine has been studied in patients with symptoms of functional dyspepsia and associated weight loss, as the drug is associated with weight gain and its antagonist activity on the 5-HT3 receptor specifically is associated with nausea suppression. One study reported a mean weight gain of nearly 4 kg in patients with functional dyspepsia after eight weeks of treatment with mirtazapine 15 mg daily, along with improvements in early satiety, nausea, quality of life, meal volume tolerance and gastrointestinal-specific anxiety.¹⁰

Tricyclic antidepressants. Amitriptyline is a tricyclic antidepressant used most commonly to treat major depressive disorder, pain disorders, migraine, headaches and fibromyalgia.

The Antidepressant Therapy for Functional Dyspepsia trial¹¹ measured the benefits of amitriptyline and the selective serotonin reuptake inhibitor escitalopram in patients with functional dyspepsia who were not on antidepressants and did not present with depression. Patients were given amitriptyline 50 mg, escitalopram 10 mg, or placebo for 10 weeks. The patients on amitriptyline had a higher response rate (53%) than those on escitalopram (38%) or placebo (40%, P = .05), leading to the conclusion that amitriptyline has therapeutic benefit in functional dyspepsia while escitalopram does not. In the subset of patients with ulcer-like symptoms, the response rate for those receiving amitriptyline was 67%, compared with 39% with placebo and 27% with escitalopram. In patients who had normal gastric emptying, amitriptyline significantly improved abdominal pain, suggesting that tricyclic antidepressants could be used for patients with pain-leading symptoms. Amitriptyline and citalopram did not improve the symptom of satiety compared with placebo, and patients with delayed gastric emptying were less likely to benefit.¹¹

Gabapentin is a gamma-aminobutyric acid analog anticonvulsant medication used to treat neuropathic pain and seizures.¹² There is also evidence that it has therapeutic effects on visceral hypersensitivity. An open-label trial indicated that gabapentin could help in treating functional dyspepsia.¹² Patients were started on gabapentin 25 to 100 mg at bedtime, which was increased at two-week intervals to 300 mg three times per day. They reported significant improvement in postprandial fullness, upper and lower abdominal pain, heartburn, nausea and vomiting, while no change in bloating was noted.¹²

Although gabapentin significantly reduced functional dyspepsia symptoms, more studies are needed to establish it as a treatment.

Pregabalin is a gabapentinoid neuromodulator currently used to manage partial-onset seizures, postherpetic neuralgia, pain induced by impairment to the nerves due to spinal cord injury or diabetes, and fibromyalgia. It works within the central nervous system, acting on voltage-gated calcium channels.

Pregabalin has been studied to determine its potential benefit on reducing visceral hypersensitivity in patients with functional dyspepsia who did not respond to proton pump inhibitors.¹³ Patients reported significant improvement in some symptoms, particularly epigastric burning and pain and the feeling of regurgitating acid. However, postprandial fullness, nausea, bloating and early satiety did not improve with pregabalin.¹³

Prokinetic therapy

Prokinetic drugs have shown success in treating functional dyspepsia. The prokinetic drug metoclopramide has antidopaminergic and cholinergic actions. Its anti-dopaminergic properties are primarily responsible for its antiemetic effect.

In a randomized, double-blind trial, metoclopramide improved symptoms in 83% of patients in the subgroup with regurgitation or heartburn compared with 89% with cisapride, the comparator treatment.¹⁴ In patients with epigastric symptoms, the response rates were 72% with metoclopramide vs 86% with cisapride. However, two weeks after treatment stopped, the response rates dropped to 39% in the metoclopramide group vs 71% in the cisapride group.¹⁴

Use of metoclopramide is limited by adverse effects including tardive dyskinesia, and expert recommendations advise caution when using it for functional dyspepsia.⁴

Antibiotics

Rifaximin, an antibiotic commonly used to treat diarrhea associated with irritable bowel syndrome, has been shown to reduce global dyspeptic symptoms, postprandial bloating and satiety, and belching in patients with functional dyspepsia.¹⁵

A study by Tan et al¹⁵ in 2017 postulated a relationship between gut dysbiosis and functional dyspepsia symptoms. Rifaximin has been shown to improve bloating and pain symptoms in patients with irritable bowel syndrome, two symptoms common in patients with functional dyspepsia. It has also been shown to decrease gut inflammation and visceral hyperalgesia (contributors to functional dyspepsia), and to act as an antibiotic. After eight weeks, 78% of patients who had received rifaximin 400 mg three times a day for two weeks had global dyspepsia symptom relief, compared with 52% with placebo (P = .02), and this trend was more apparent in female patients.¹⁵

Complementary and alternative medicine

STW 5 is a preparation consisting of extracts of nine herbs: chamomile flower, celandine herb, caraway fruit, milk thistle fruit, licorice root, balm leaf, peppermint herb, angelica root and bitter candytuft. It has demonstrated effects on hypertension and gastric motility and has antioxidative, anti-inflammatory, antacid and gastroprotective properties. Particularly, the extract from bitter candytuft (Iberis amara) has shown promising effects on intestinal motility.¹⁶ In a randomized, double-blind trial, patients receiving STW 5 (20 drops before meals) improved by 6.9 points on the 40-point Gastrointestinal Symptom Score after eight weeks, compared with 5.9 points with placebo (P < .05).¹⁶

Caraway oil and L-menthol (COLM-SST) is a preparation of caraway oil 25 mg and L-menthol 20.75 mg. In a randomized trial, two capsules of COLM-SST twice daily provided relief of functional dyspepsia symptoms within 24 hours compared with placebo.¹⁷ Patients experiencing more extreme symptoms had a stronger response. At 24 hours after the start of treatment, patients who received COLM-SST had a statistically significant decrease in postprandial distress symptoms of heaviness, pressure sensations and fullness. Epigastric pain symptoms also improved, but the difference was not statistically significant. After 28 days of treatment, however, none of these reductions were statistically significant.¹⁷

Capsaicin, an active component of red peppers, can be a treatment for functional dyspepsia symptoms, as it desensitizes visceral nociceptive C-type fibers. Bortolotti et al¹⁸ found that symptoms decreased by 60% in patients taking red pepper powder daily, compared with 30% with placebo. Symptoms actually increased the first day patients took red pepper powder, but subsequently there were statistically significant reductions in general symptom score, epigastric pain, nausea, and epigastric fullness, and a borderline significant reduction in early satiety. There were no statistically significant differences in bloating, epigastric burning, or burping or belching.¹⁸ The dosage used in the study was 500 mg before breakfast and 1,000 mg before lunch and dinner.¹⁸

Acupuncture. In a study in patients with functional dyspepsia, acupuncture in four specific areas (stomach meridian-specific acupoints, stomach meridian-nonspecific acupoints, transport and alarm acupoints, and gallbladder meridian-specific acupoints) five times a week for 1 month resulted in significant symptom improvement compared with sham acupuncture.¹⁹ Patients with postprandial distress syndrome had a stronger response to acupuncture, particularly stomach meridian-specific acupoints, than patients with epigastric pain syndrome. There were statistically significant decreases in postprandial fullness, early satiety and quality of life, but no statistically significant decreases in epigastric burning and epigastric pain.¹⁹

Hypnotherapy. Hypnosis induces a conscious state with focused attention, decreased awareness peripherally and increased susceptibility to external suggestion. Neuroimaging studies show changes in brain activity in networks of the prefrontal cortices, thalamus, anterior cingulate and basal ganglia associated with hypnosis.²⁰

Popa et al²⁰ performed a systematic review of four studies of hypnotherapy for functional dyspepsia. One study found that one session of hypnosis was more effective than cisapride in alleviating epigastric pain, abdominal discomfort, epigastric fullness and gastric emptying. Another study showed hypnotherapy was more effective than ranitidine 300 mg/day. A third study reported that 80% of patients had improvements in pain frequency and severity with hypnotherapy, compared with 23% of control patients.²⁰ Further randomized controlled trials are needed to definitively determine the efficacy of hypnotherapy in treating functional dyspepsia.

General management principles

In our practice, we follow the recommendations of the Rome Committee and the American College of Gastroenterology guidelines in diagnosis and treatment of functional dyspepsia. In particular, the American College of Gastroenterology guidelines do not recommend upper endoscopy in patients under age 60, as their risk of cancer is less than 1%, even with alarm symptoms.⁴ If H pylori testing or upper endoscopy is negative, patients can be diagnosed with functional dyspepsia per the Rome IV criteria.

Our general practice is to treat with a proton pump inhibitor for two months. If symptoms respond, then we taper off the medication or reduce it to the lowest effective dose. If dyspepsia does not respond to a proton pump inhibitor, we use an individualized approach, discussing the agents listed above.^1,4,5,8–20

Educational sources

A thorough understanding of functional dyspepsia is vital for healthcare professionals and patients. Two patient sources of information about functional dyspepsia are:

• American College of Gastroenterology (https://gi.org/topics/dyspepsia/, also available in Spanish)
• Cleveland Clinic (my.clevelandclinic.org/health/diseases/22248-functional-dyspepsia).

Additionally, the American College of Gastroenterology Patient Care Committee, in conjunction with its patient-education partner Gastro Girl, has prepared a free podcast for patients and clinicians about functional dyspepsia.

Case follow-up: Improvement with buspirone

The 41-year-old patient in the introductory scenario was diagnosed with functional dyspepsia (postprandial distress subtype) and given information about the disease. She started taking buspirone 10 mg 15 to 30 minutes before meals, and her postprandial bloating improved significantly. The proton pump inhibitor she had been taking was then discontinued without worsening her symptoms. A plan was made to continue therapy for 12 months, then reassess the need for buspirone.

References

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2. Komazawa Y, Adachi K, Mihara T, et al. Tolerance to famotidine and ranitidine treatment after 14 days of administration in healthy subjects without Helicobacter pylori infection. J Gastroenterol Hepatol 2003; 18(6):678–682.
3. Wolfe MM. Proton pump inhibitors: overview of use and adverse effects in the treatment of acid related disorders. UpToDate. Updated January 25, 2024. www.uptodate.com/contents/proton-pump-inhibitors-overview-of-use-and-adverse-effects-in-the-treatment-of-acid-related-disorders. Accessed April 17, 2024.
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12. Staller K, Thurler AH, Reynolds JS, et al. Gabapentin improves symptoms of functional dyspepsia in a retrospective, open-label cohort study. J Clin Gastroenterol 2019; 53(5):379–384.
13. Kotikula I, Thinrungroj N, Pinyopornpanish K, et al. Randomised clinical trial: the effects of pregabalin vs placebo on functional dyspepsia. Aliment Pharmacol Ther 2021; 54(8):1026–1032.
14. Fumagalli I, Hammer B. Cisapride versus metoclopramide in the treatment of functional dyspepsia. A double-blind comparative trial. Scand J Gastroenterol 1994; 29(1):33–37.
15. Tan VP, Liu KS, Lam FY, Hung IF, Yuen MF, Leung WK. Randomised clinical trial: rifaximin versus placebo for the treatment of functional dyspepsia. Aliment Pharmacol Ther 2017; 45(6):767–776.
16. von Arnim U, Peitz U, Vinson B, Gundermann KJ, Malfertheiner P. STW 5, a phytopharmacon for patients with functional dyspepsia: results of a multicenter, placebo-controlled double-blind study. Am J Gastroenterol 2007; 102(6):1268–1275.
17. Chey WD, Lacy BE, Cash BD, Epstein M, Corsino PE, Shah SM. A novel, duodenal-release formulation of a combination of caraway oil and l-menthol for the treatment of functional dyspepsia: a randomized controlled trial. Clin Transl Gastroenterol 2019; 10(4):e00021.
18. Bortolotti M, Coccia G, Grossi G, Miglioli M. The treatment of functional dyspepsia with red pepper. Aliment Pharmacol Ther 2002; 16(6):1075–1082.
19. Ma T, Zeng F, Li Y, et al. Which subtype of functional dyspepsia patients responses better to acupuncture? A retrospective analysis of a randomized controlled trial. Forsch Komplementmed 2015; 22(2):94–100.
20. Popa S-L, Chiarioni G, David L, Dumitrascu DL. The efficacy of hypnotherapy in the treatment of functional dyspepsia. Am J Ther 2019; 26(6):e704–e713.