By Sunhae Chang, PharmD Candidate c/o 2013

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When patients complain of heartburn, the blame usually shifts to gastroesophageal reflux disease (GERD).  Therefore, patients receive the “standard therapies for GERD”: antacids, histamine-2 receptor antagonists (H2RAs), proton pump inhibitors (PPIs), or prokinetics.^1,2  Luckily, most patients respond well to these agents.^1,2  Unfortunately, the not-as-lucky ones, despite PPI use, continue to suffer from the classic symptoms of GERD.²

GERD involves mucosal damage from gastric content reflux into the esophagus, causing heartburn and symptoms like burning in the throat, difficulty swallowing, or chest pain.²  The medications prescribed for GERD target acid in the stomach, including counteracting the acidity or reducing the production / release of gastric acid.²  Yet, what if the culprit is not just the acid?  Interestingly, less than 5% of all acid reflux events (pH < 4) are responsible for symptoms like heartburn.³  Upon pH testing, patients and healthy volunteers demonstrate multiple acid reflux events, but report very few complaints of heartburn episodes, if any.³  For patients not responding to conventional drugs that combat acidity, another cause for their symptoms may exist: esophageal hypersensitivity.¹  In such patients, the esophagus is hypersensitive to even normal physiological amounts of acid, inducing a feeling of heartburn.¹

The “-hydroxides, -tidines, and -prazoles” (i.e. antacids, H2RAs, and PPIs) only work for acid reduction, but not for an overly sensitive esophagus.¹  So, what is the alternate solution to GERD? Antidepressants!¹  Previously published studies described strange patterns in esophageal responses with antidepressants, such as tricyclic antidepressants (TCAs) and selective serotonin receptor inhibitors (SSRIs).¹  In a study by Peghini, imipramine, a TCA, raised the esophageal pain threshold (i.e. decreased esophageal pain perception).⁴  In this double-blind, placebo-controlled crossover study, esophageal perception for first sensation and pain was measured with intraesophageal balloon distension in 15 healthy male volunteers who received imipramine in increasing doses (25 mg on days 1–3, 50 mg on days 4–6, 75 mg on days 7–12).⁴  The results showed that the balloon inflation volume at pain threshold was higher for the imipramine group (p = 0.015) compared to the placebo group.⁴  The authors concluded that increased pain thresholds for the imipramine group in the absence of changes in esophageal tone implied the presence of a visceral analgesic effect.⁴

There is more!  In another study, citalopram, an SSRI, was shown to lower chemical stimulation (discomfort during < 15 min of esophageal acid perfusion) and mechanical hypersensitivity (discomfort during < 10 mL esophageal balloon distention) without changing esophageal motility.¹  On two separate occasions, 10 healthy volunteers with established esophageal hypersensitivity received placebo or citalopram 20 mg intravenously in a randomized, crossover, double-blind trial.²  Citalopram significantly increased the threshold inducing first perception (4.6 ± 0.3 vs. 6.7 ± 0.4 mL, P < 0.005) and discomfort (8.6 ± 0.4 vs. 9.9 ± 0.6 mL, P < 0.01) during balloon distention.¹  It also significantly prolonged the acid perfusion time to induce perception of heartburn (6.0 ± 0.9 vs. 10.7 ± 0.6 min, P < 0.005) and discomfort (12.2 ± 0.8 vs. 16.7 ± 0.7 mL, P < 0.001).¹  Seven subjects (70%) experienced a retrosternal sensation during edrophonium provocation with placebo, which was reduced to two out of ten (20%) after citalopram (P = 0.02).¹

Encouraged with such results, researchers are looking into SSRIs for the treatment of hypersensitive esophagus.⁵  In a recent study, 252 patients with normal endoscopy and typical reflux symptoms (e.g. heartburn, chest pain, and regurgitation), despite twice daily PPI therapy, underwent ambulatory 24-hour pH impedance monitoring.⁵  Through this pH monitoring, 75 out of 252 (29.8%) patients had normal distal esophageal acid exposure time, but had positive symptom indices (SI) for either acid and/or nonacid reflux.⁵  These patients had hypersensitive esophagus, and randomly received citalopram 20 mg or placebo once daily for 6 months, while PPIs were discontinued.⁵  At the end of the follow-up period, 15 of the citalopram arm (38.5%) continued to report reflux symptoms, which was significantly less than the 66.7% proportion seen in the placebo arm (p = 0.021).⁵

It is without question that more studies in this area are necessary, but SSRIs do seem promising in treating hypersensitive esophagus.  However, antidepressants will, certainly not be a “magic bullet” for everyone with heartburn.  In addition to having a more serious side effect profile than antacids, H2 antagonists, PPIs, and prokinetics, antidepressants have sociopsychological impacts.  The side effects of traditional GERD therapies are relatively limited to headaches, dizziness, constipation, and diarrhea, while the side effects of SSRIs include suicidal ideation, somnolence, and insomnia.⁵  Thorough education is required for patients to overcome the stigma associated with being on a psychiatric medication.  If we consider similar circumstances, bupropion is an antidepressant frequently used for smoking cessation, and citalopram may become the antidepressant frequently used for esophageal hypersensitivity.

SOURCES:

1. Broekaert D, Fischler B, Sifrim D, et. al. Influence of citalopram, a selective serotonin reuptake inhibitor, on oesophageal hypersensitivity: a double-blind, placebo-controlled study.  Aliment Pharmacol Ther. 2006 Feb 1;23(3):365-70.
2. Mainie I, Tutuian R, Shay S, et. al.  Acid and non-acid reflux in patients with persistent symptoms despite acid suppressive therapy: a multicentre study using combined ambulatory impedance-pH monitoring.  Gut. 2006 Oct;55(10):1398-402.
3. Mattox HE 3rd, Richter JE.  Prolonged ambulatory esophageal pH monitoring in the evaluation of gastroesophageal reflux disease.  Am J Med. 1990 Sep;89(3):345-56.
4. Peghini PL, Katz PO, Castell DO.  Imipramine decreases oesophageal pain perception in human male volunteers.  Gut. 1998 Jun;42(6):807-13.
5. Viazis N, Karamanolis G, Vienna E, et. al. Selective-serotonin reuptake inhibitors for the treatment of hypersensitive esophagus.  Therap Adv Gastroenterol. 2011 Sep;4(5):295-300.