Recognizing the presence of functional heartburn is vital to prevent unnecessary acid-suppressive therapy and invasive antireflux treatments, which are ineffective and “might even lead to harm,” cautions a new clinical practice update from the American Gastroenterological Association.

Dr. Ronnie Fass

Dr. Ronnie Fass

Proton pump inhibitors (PPIs) “have no therapeutic value in functional heartburn,” unless patients also have gastroesophageal reflux disease (GERD), Ronnie Fass, MD, of MetroHealth System in Cleveland, and coauthors wrote in Gastroenterology. If clinical work-up finds no clear evidence of GERD, “an attempt to discontinue PPI therapy is warranted,” they added. Likewise, antireflux surgery and endoscopic treatments for GERD “have no therapeutic benefit in functional heartburn and should not be recommended.” However, histamine2 receptor antagonists (H2RAs) “may have an independent benefit in functional heartburn from an esophageal pain modulatory effect.”

Heartburn consists of burning or discomfort that radiates retrosternally from the epigastrium. Patients may report reflux, regurgitation, chest pain or discomfort, fullness, water brash, belching, or a sour and bitter taste in the mouth. Functional heartburn is heartburn that persists after at least 3 months of maximal (double-dose) PPIs taken before meals. Confirming functional heartburn requires high-resolution manometry to rule out major esophageal motor disorders, esophageal endoscopy with biopsy to rule out structural abnormalities and mucosal disorders (e.g., erosive esophagitis, Barrett’s esophagus, and eosinophilic esophagitis), and either pH monitoring while off PPI therapy or pH-impedance monitoring on therapy if patients have proven GERD. According to the clinical practice update, pH studies should document physiological acid exposure in the distal esophagus that is unlinked to symptoms (i.e., both a negative symptom index and a negative symptom association probability).

Functional heartburn resembles GERD, but symptoms are unrelated to acid exposure. Balloon distension studies indicate that patients with functional heartburn experience both esophageal and rectal hypersensitivity. Anxiety and mood disorders also are highly prevalent, and patients “will likely not improve unless esophageal perception and underlying affective disorders are adequately managed,” Dr. Fass and coauthors emphasized.

In keeping with this approach, limited evidence from clinical trials supports the first-line use of neuromodulator therapies, including selective serotonin reuptake inhibitors, tricyclic antidepressants, the serotonin 4 receptor antagonist tegaserod, and H2RAs (e.g., cimetidine, famotidine, nizatidine). The only SSRI studied thus far in functional heartburn is fluoxetine. In a placebo-controlled trial of patients with normal endoscopy and heartburn that had not responded to once-daily PPI therapy, 6 weeks of fluoxetine (20 mg daily) significantly outperformed double-dose omeprazole (P < .001) for the primary endpoint of heartburn-free days. “This superior therapeutic effect of fluoxetine was seen only in the subset of patients with a normal pH test,” the experts noted.

In another placebo-controlled trial, the neuromodulator tegaserod (a serotonin 5-HT4 receptor partial agonist) significantly improved tolerance of esophageal pressure during balloon distension and significantly decreased heartburn, regurgitation, and associated distress among patients with functional heartburn. Melatonin, which “also has a pain modulatory effect in the gastrointestinal tract,” significantly improved symptom-related quality of life, compared with nortriptyline and placebo in a randomized, three-arm trial. The patients on melatonin received a 6-mg dose at bedtime for 3 months.

Acupuncture and hypnotherapy also have shown benefit in small studies of functional heartburn patients and may be appropriate as monotherapy or adjunctive treatment, according to the clinical practice update. In a small randomized study, 10 acupuncture sessions delivered over 4 weeks significantly improved daytime and nighttime heartburn and acid regurgitation scores, compared with double-dose PPI. “Mean general health score was significantly improved only in those receiving acupuncture,” the experts noted. Hypnotherapy, the only psychological intervention to have been studied in functional heartburn, was associated with significant improvements in symptoms, visceral anxiety, and quality of life in an uncontrolled study of nine patients.

Although the overall prevalence of functional heartburn is unclear, it has been detected in 21%-39% of PPI-refractory patients evaluated with pH-impedance monitoring, Dr. Fass and associates wrote. Because functional heartburn and GERD can co-occur, some patients with functional heartburn may develop long-term complications of GERD, such as Barrett’s esophagus or peptic stricture. However, the experts noted, “this is anticipated to be rare, and the vast majority of patients with functional heartburn will have compromised quality of life, rather than organic complications over time.

Dr. Fass reported receiving consulting, research, and speaking fees from Ironwood, Takeda, and Salix, among other pharmaceutical companies; Dr. Zerbib received consulting fees from Reckitt Benckiser; and Dr. Gyawali received teaching and consulting fees from Medtronic, Diversatek, and Ironwood.

SOURCE: Fass R et al. Gastroenterology. 2020 Feb 1. doi: 10.1053/j.gastro.2020.01.034.

This story was updated on 6/11/2020.