What are the best treatments if symptoms don’t match reflux on testing?

The short version: when testing rules out reflux, the best treatments target a sensitized nervous system, not stomach acid.

The evidence points away from acid-suppressing drugs. A 2016 randomized trial of low-dose imipramine (a tricyclic neuromodulator) for functional heartburn found that the drug did not beat placebo on the primary endpoint: 37.2% of the imipramine group improved versus 37.5% of the placebo group [1]. Quality of life did improve more with imipramine (72 versus 61), but the main symptom result was a flat failure [1]. That trial tells you that neuromodulation is not a sure bet, and that the placebo response in functional heartburn is substantial.

For functional dyspepsia without heartburn, a 2023 study found that vonoprazan (a potent acid blocker) and acotiamide (a prokinetic) worked about equally well: 55% versus 59% symptom improvement, a difference that was not statistically significant [2]. That suggests that for symptoms that are not classic heartburn, acid suppression is not the answer either.

The broader picture matters. Functional heartburn overlaps heavily with functional dyspepsia and irritable bowel syndrome [3]. Patients with functional heartburn show higher somatization scores and traits of functional bowel disorder [4]. That means treatments that work for other functional gut disorders — cognitive behavioral therapy, gut-directed hypnotherapy, low-FODMAP diet, and tricyclic antidepressants at low doses — are the logical options, even though the evidence here does not include a head-to-head trial in functional heartburn specifically.

My call: stop PPIs if testing has ruled out reflux. Try a low-dose tricyclic antidepressant (starting at 10-25 mg at bedtime) or a gut-brain behavioral therapy. The evidence for any single treatment is weak, but the category of neuromodulation and brain-gut therapies is the only one that fits the mechanism. Confidence: moderate — the diagnostic framework is solid, but the treatment evidence is thin and the imipramine trial was negative on its primary endpoint.