Chronic Indigestion for Over a Year That Won’t Go Away: What Research Says About Functional Dyspepsia, Why Acid Pills Didn’t Work, and the Next Treatment Steps

A question from a health group: over a year of indigestion, nothing works — is there research?

A member of a health group asked whether there is any research on treating chronic indigestion, because it has lasted more than a year and nothing has worked.
This is a very common question, and most people in this position have taken acid pills for a year without anyone sorting out which symptom pattern they have.

Direct answer: there is plenty of research, and what works depends on the symptom subtype — not on stacking more acid suppression.
The first steps are confirming there are no warning signs and testing for H. pylori. Then work out whether post-meal fullness or epigastric pain dominates, so drugs and therapies can match the mechanism.
This article does not know the person’s test results, so it explains general principles to discuss with their own doctor.

1. What functional dyspepsia is, and how common it is

Direct answer: it is ongoing post-meal fullness, early satiety, or epigastric pain or burning, with an endoscopy that shows no disease explaining it.
Rome IV requires symptoms during the last 3 months with onset at least 6 months earlier, and classes it as a disorder of gut-brain interaction
(Rome IV 2016,
Ford 2020).

2. Two subtypes that are treated differently

Direct answer: first work out whether post-meal fullness or epigastric pain dominates, because the drugs that work differ between subtypes, and many people have both.

Table: postprandial distress syndrome (PDS) vs epigastric pain syndrome (EPS)

Based on Rome IV — for discussion with your doctor, not self-diagnosis

3. Why the stomach misbehaves when endoscopy is normal

Direct answer: the problem is in function and perception, not a visible lesion. Endoscopy looks normal, but the symptoms are real and measurable in research.

The upper stomach does not relax enough

Normally, when you start eating, the upper stomach (fundus) relaxes to receive food without a rise in pressure. In some patients it relaxes too little, so they fill up early and feel bloated after small amounts.
In a crossover trial of 17 patients, buspirone raised the volume the stomach could accommodate to 229 mL versus 141 mL on placebo, and reduced fullness and early satiety
(Tack 2012).

Oversensitive stomach nerves

Many patients feel pain or fullness when the stomach is stretched to levels most people do not notice, and the brain processes gut pain signals more intensely. Stress, poor sleep, and worry about symptoms amplify this loop
(Ford 2020).
Read more about gastric and esophageal hypersensitivity.

Low-grade duodenal inflammation and leakiness

A random Swedish population endoscopy study found that people with high duodenal eosinophil counts had 11.7 times the odds of functional dyspepsia, linked with early satiety
(Talley 2007).
Later work showed increased duodenal mucosal permeability in patients, and that proton pump inhibitors reduced both the immune cells and the leakiness
(Wauters 2021).
This is one reason acid pills help some people even though excess acid is not the core problem.

4. Why acid pills did not make it go away

Direct answer: acid pills help, but modestly, and not at all when another mechanism drives the symptoms.

A Cochrane review of 25 trials with 8,453 participants found that proton pump inhibitors slightly lowered the chance of persistent symptoms (RR 0.88) — 11 people treated for one extra responder versus placebo.
Low doses worked as well as standard doses, and results did not differ by H. pylori status or subtype
(Cochrane 2017).

• Are you taking it 30–60 minutes before food? Proton pump inhibitors work best before the first meal.
• A higher dose adds little: low doses match standard doses; after 8 weeks without benefit, change the treatment class.
• Fullness and early satiety dominate: usually an accommodation or motility problem that acid suppression does not fix.
• Long-term use without a clear reason: review it with your doctor; see long-term acid pills that haven’t worked.

5. A year without improvement: causes to recheck first

Direct answer: before calling it refractory functional dyspepsia, make sure no treatable condition has been missed.
American and Canadian guidelines recommend H. pylori test-and-treat before other drug classes
(ACG/CAG 2017).

Table: causes to recheck, clues, and tests

Your doctor will choose tests based on symptoms — not everyone needs all of them

6. Next treatment steps backed by research

Direct answer: when acid pills fail, the BSG 2022 guideline recommends a low-dose tricyclic antidepressant as second-line treatment, with other drugs or therapies chosen by subtype.
Drug names below are generic and educational; they must be prescribed and monitored by a doctor
(BSG 2022).

Gut-brain neuromodulators

In a randomized trial of 292 patients without depression treated for 10 weeks, adequate relief was reported by 53% on amitriptyline, 40% on placebo, and 38% on escitalopram.
In pain-predominant patients, amitriptyline raised the odds of relief 3.1-fold, but patients with delayed gastric emptying responded less
(Talley 2015).

A meta-analysis of 13 trials with 1,241 patients found that psychotropic drugs lowered the chance of no improvement (RR 0.78, NNT 6),
but the benefit was limited to tricyclics and low-dose antipsychotics, and side effects leading to withdrawal were more common (NNH 21)
(Ford 2017).

Early satiety and weight loss: mirtazapine and buspirone

A pilot trial in 34 patients who had lost more than 10% of their weight found that mirtazapine 15 mg improved early satiety, food tolerance, quality of life, and weight more than placebo
(Tack 2016).
Buspirone increased upper-stomach accommodation in a trial of 17 patients. Both studies are small, so use depends on the doctor’s judgment
(Tack 2012).

Prokinetics

Used for fullness-dominant symptoms — for example domperidone, itopride, and acotiamide, whose availability differs by country. The BSG guideline says they may help but the evidence is weak.
Domperidone carries a heart-rhythm risk in older adults or people on QT-prolonging drugs, so it is used at low doses for short periods under medical supervision
(BSG 2022).

Gut-brain therapy: hypnotherapy and cognitive behavioral therapy

In a randomized trial of 126 patients, gut-directed hypnotherapy improved symptoms by 73% at 56 weeks, versus 34% with supportive therapy plus placebo and 43% with medical treatment.
During follow-up, 82–90% of the comparison groups started new medication, while no one in the hypnotherapy group did
(Calvert 2002).
Gut-focused cognitive behavioral therapy (CBT) is another option when drugs have not worked.

Diet: what helps and where evidence is thin

• Small, frequent meals with less fat and no large meals: reduces gastric stretch and suits fullness-dominant symptoms, but do not cut food so much that weight falls.
• Low-FODMAP diet: most evidence comes from IBS, and data in functional dyspepsia are limited. It suits people with prominent bloating or overlapping IBS, ideally short term with a dietitian.
• Ginger plus artichoke-leaf extract: one randomized trial in 126 patients over 4 weeks reduced nausea, epigastric fullness, epigastric pain, and bloating more than placebo, but did not measure motility, and some investigators were from the manufacturer
  (Giacosa 2015).
  People with gallstones should avoid artichoke; people on blood thinners should ask before taking high-dose ginger.

7. Myths to correct about chronic indigestion

Direct answer: many shared claims are partly true, but overstating them can lead people to stop a drug that is helping or expect more than research shows.

“Indigestion has nothing to do with acid, so acid pills are useless” — not quite

Most patients do not have excess acid, but acid pills genuinely help a subset (NNT 11), possibly by calming duodenal inflammation rather than only lowering acid
(Cochrane 2017,
Wauters 2021).

“Low-dose antidepressants work very well for everyone” — overstated

Amitriptyline raised relief from 40% to 53%, mainly in pain-predominant symptoms, while escitalopram, an SSRI, was no better than placebo.
Nerve-acting drugs need to be matched to the subtype
(Talley 2015).

“Ginger and artichoke strongly stimulate stomach motility” — not shown

There is one 4-week trial that measured symptoms, not motility. It can be an add-on, but should not replace testing or core treatment.

“There is a special term for a polluted or badly inflamed gut lining” — not a medical term

What research actually shows is low-grade inflammation from eosinophils and mast cells, and a more permeable duodenal lining in some patients,
seen on biopsy. It does not mean the gut is dirty or needs a detox
(Talley 2007).

“More than a year means it can’t be treated” — not true

Many people have not tried second-line treatment, been tested for H. pylori, or had their subtype identified. Symptoms often wax and wane with life circumstances.
A realistic goal is fewer, milder episodes so normal life is possible.

Table: comparing treatment options for functional dyspepsia

Drugs, natural options, and lifestyle measures compared by fit, evidence, and cautions — generic drug names only

Frequently asked questions (FAQ)

What is functional dyspepsia, and how is it different from an ordinary stomach problem?

It is bothersome post-meal fullness, early satiety, or epigastric pain or burning during the last 3 months, with symptoms that started at least 6 months earlier, when endoscopy shows no ulcer, mass, or other disease that explains them. Rome IV splits it into postprandial distress syndrome (PDS) and epigastric pain syndrome (EPS), which are treated differently. It affects about 7 percent of people and is classed as a disorder of gut-brain interaction, not something imagined.

Why didn’t acid pills make it go away?

Because acid is only one part of the mechanism. A Cochrane review of 25 trials with 8,453 participants found that proton pump inhibitors do help, but modestly: about 11 people must be treated for one extra person to improve compared with placebo. People whose symptoms come mainly from poor stomach relaxation, oversensitive nerves, or stress usually do not improve with acid suppression alone. If symptoms persist after 8 weeks of correctly timed doses, the diagnosis should be reviewed and the treatment class changed rather than raising the acid-pill dose again and again.

Do low-dose antidepressants really help indigestion if I am not depressed?

They help some people, not everyone. A randomized trial in 292 patients without depression found adequate relief in 53 percent with low-dose amitriptyline versus 40 percent with placebo, with the clearest benefit in pain-predominant symptoms. Escitalopram was no better than placebo. These drugs are used at doses far below those used for depression, to calm oversensitive gut-brain nerve signaling. A doctor needs to weigh side effects such as drowsiness, dry mouth, and constipation.

What helps if I feel full after a few bites and am losing weight?

Unintentional weight loss is a warning sign that needs endoscopy and a search for other causes first. Once a doctor confirms functional dyspepsia, a small trial in 34 patients who had lost more than 10 percent of their weight found that low-dose mirtazapine improved early satiety, food tolerance, quality of life, and body weight. Buspirone increased how much the upper stomach could relax to receive food in a trial of 17 patients. Both work best alongside small, frequent, lower-fat meals.

How is H. pylori related to chronic indigestion?

American and Canadian gastroenterology guidelines recommend testing for H. pylori and treating it if found in people with dyspepsia, because eradication relieves symptoms in a subset and lowers ulcer risk. If you have been treated for a year without ever being tested, or were treated for the infection without a follow-up test to confirm it is gone, raise this with your doctor before moving to other drug classes.

Do ginger and artichoke really improve stomach motility?

The evidence is limited. A single randomized trial in 126 patients over 4 weeks found that ginger plus artichoke-leaf extract reduced nausea, epigastric fullness, epigastric pain, and bloating more than placebo, but it did not measure stomach motility directly, and some investigators were from the extract manufacturer. Product quality varies widely. People with gallstones should avoid artichoke, and people on blood thinners should ask their doctor before taking high-dose ginger.

Can hypnotherapy or cognitive behavioral therapy really help stomach symptoms?

There is supporting evidence. A randomized trial in 126 patients found that gut-directed hypnotherapy improved symptoms by 73 percent at 56 weeks, compared with 34 and 43 percent in the comparison groups, and no one in the hypnotherapy group needed to start new medication during follow-up. The 2022 British Society of Gastroenterology guideline also supports gut-brain psychological therapies when drugs have not worked. This does not mean the symptoms are in your head; it retrains signaling between the gut and the brain.

Which symptoms need an endoscopy even after a functional dyspepsia diagnosis?

See your doctor again if symptoms change or warning signs appear: unintentional weight loss, difficult or painful swallowing, repeated vomiting, vomiting blood, black stools, pallor or anemia, a lump in the abdomen, or a close relative with stomach or esophageal cancer. American and Canadian guidelines advise endoscopy for people with symptoms aged 60 or older, while in Asian countries where stomach cancer is more common, doctors often consider endoscopy at a younger age.

Scientific mechanism

Two parts of the stomach do different jobs: the upper stomach is a reservoir that relaxes through vagal nerve signals as soon as eating starts, while the lower stomach grinds food and pushes it into the small intestine.
If the upper part does not relax enough, food moves to the lower part too quickly and stretches the wall, causing early satiety and fullness
(Tack 2012).

The duodenum is where signals start: a more permeable lining activates eosinophils and mast cells, which release substances that sensitize nerve endings
and send feedback that reduces stomach relaxation. Acid pills reduce both the immune cells and the leakiness in some patients
(Wauters 2021,
Talley 2007).

The brain sets the volume: the brain acts like a volume knob, and stress and worry turn up gut pain signals.
Low-dose tricyclics and gut-brain therapy turn the volume down, buspirone stimulates 5-HT1A serotonin receptors that relax the upper stomach, and mirtazapine helps early satiety and appetite through serotonin and histamine receptors
(Rome IV 2016,
Ford 2017).

Compiled and reviewed by Asst. Prof. Dr. Norawit Raatpiboon

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