Evaluating short-term efficacy of proton pump inhibitors in GERD management

Abstract

Gastroesophageal reflux disease (GERD) is a prevalent gastrointestinal condition characterized by symptoms, such as heartburn and acid regurgitation. Proton pump inhibitors (PPIs) have long been the cornerstone of GERD treatment due to their superior acid-suppressive properties. However, variations in the short-term efficacy of different PPIs remain a clinical challenge. The recent study by Liao et al.¹ explored the comparative short-term effects of lansoprazole and rabeprazole in patients with erosive esophagitis (EE) over a one-week period, offering new insights into the pharmacodynamic responses of these drugs. This editorial aims to highlight key points of the study, discuss the implications of GERD in diagnosis and treatment, and emphasize the role of psychological factors in mild GERD cases.

Lansoprazole and rabeprazole share a common mechanism of action by covalently binding to the gastric H⁺/K⁺-ATPase enzyme, thereby inhibiting gastric acid secretion. However, their pharmacokinetic profiles diverge, significantly impacting their onset and consistency of acid suppression. Lansoprazole has a time to peak plasma concentration (T_max) of approximately 1.2–2.1 h, with a half-life (t½) of 0.9–2.1 h. It is primarily metabolized by the CYP2C19 and CYP3A4 enzymes, making its efficacy susceptible to genetic polymorphisms in CYP2C19.^{2, 3} Individuals with rapid metabolism (extensive metabolizers) may experience reduced acid suppression due to faster drug clearance, whereas poor metabolizers benefit from prolonged drug exposure. Rabeprazole exhibits a slightly delayed T_max of 3–5 h and a shorter half-life of 0.6–1.4 h.^{2, 3} Unlike lansoprazole, rabeprazole undergoes mainly non-enzymatic metabolism and has minimal dependence on CYP2C19 metabolism. This property ensures more consistent acid suppression across different genetic profiles, offering a pharmacokinetic advantage, particularly in populations with high CYP2C19 variability.⁴ PPIs are prodrugs activated in the acidic environment of the parietal cell's secretory canaliculus. Rabeprazole, with a higher pKa (~5.0) compared to lansoprazole (~4.0), undergoes faster acid activation. This rapid activation facilitates more immediate binding to the gastric proton pump, potentially leading to quicker symptom relief. Studies indicate that rabeprazole achieves more consistent intragastric pH control due to its stable metabolism and rapid activation.⁵ The study by Liang et al. evaluated the short-term efficacy of dexlansoprazole (60 mg) and esomeprazole (40 mg) in 175 GERD patients with LA Grades A/B erosive esophagitis.⁶ The complete symptom resolution (CSR) rates were similar between the two drugs: Day 1: 25.9% vs. 28.4%, Day 3: 33.3% vs. 32.1%, and Day 7: 51.9% vs. 48.1%. Similarly, Liao et al. compared lansoprazole (30 mg) and rabeprazole (20 mg) in 44 patients with erosive esophagitis and reported comparable CSR rates: Day 1: 21.7% vs. 26.3%, Day 3: 34.8% vs. 31.6%, and Day 7: 47.8% vs. 47.4%. Both studies concluded that there were no significant overall differences in efficacy between the PPIs evaluated.

GERD is traditionally classified based on the Los Angeles (LA) classification system, grading mucosal damage from A to D. The distinction between Grades A/B and C/D is essential for diagnosis and treatment planning. The Lyon Consensus 1.0 (2018) initially considered LA Grades C and D as conclusive evidence for GERD, with Grades A and B requiring further confirmation through additional diagnostic tools like pH monitoring or impedance testing.⁷ However, the Lyon Consensus 2.0 (2024) updated these criteria by recognizing LA Grade B esophagitis as conclusive evidence of GERD, aligning it with Grades C and D.⁸ Conversely, LA Grade A remains borderline and necessitates adjunctive testing for definitive diagnosis. Diagnostic tools such as: ambulatory pH monitoring (AET >6% conclusive for GERD), reflux episode counts (>80/day suggest GERD), mean nocturnal baseline impedance (MNBI) (<1500 ohms support GERD), and endoscopic findings (Barrett's esophagus, strictures) remain critical in distinguishing true GERD from functional disorders.

Liao et al.'s findings reinforce that more severe erosive disease (Grades C/D) correlates with higher symptom relief than (Grades A/B). However, the distinction of true reflux disease is pivotal in patients with Grade A esophagitis, that they did not receive adjunctive testing for definitive diagnosis according to Lyon Consensus 2.0.⁸

The psychological component of GERD is a critical but often underrecognized factor, especially in patients with mild disease (LA Grades A and B). According to Liao et al.,¹ patients with mild erosive esophagitis had significantly lower CSR rates compared to those with more severe disease (LA Grades C and D). This suggests that factors beyond acid suppression contribute to persistent symptoms, including psychological distress. Functional heartburn, a condition often driven by psychosomatic factors, accounts for approximately 21% of untreated heartburn cases, further emphasizing the role of non-acid-related mechanisms in symptom persistence.⁹

Previous studies have highlighted the association between psychological distress, including anxiety and depression, and refractory GERD. Patients with higher GERDQ score (≥10) and somatic symptom scale-8 (SSS-8) (≥12) scores were more likely to exhibit refractory symptoms (p = .004 and p = .009, respectively).¹⁰ Additionally, in the study by Kao et al.,¹¹ multivariate analysis identified specific psychological factors as independent risk predictors of incomplete symptom response in mild GERD: Globus sensation (odds ratio [OR]: 2.4, 95% confidence interval [CI]: 1.185–4.897, p = .015) and insomnia (OR: 2.0, 95% CI: 1.289–3.018, p = .002).

Esophageal hypervigilance and anxiety scale (EHAS) has been introduced as a validated cognitive-affective tool to assess centrally mediated esophageal symptom perception.¹² Studies have linked EHAS scores with symptom severity and psychological stress in GERD patients, albeit without correlations to acid reflux burden or mucosal integrity.¹³

Patients with mild GERD often present with overlapping functional gastrointestinal disorders, where acid suppression alone may be insufficient. Therefore, comprehensive management should include psychological assessment and, when necessary, adjunctive therapies such as, cognitive-behavioral therapy (CBT), neuromodulators, including tricyclic antidepressants, selective serotonin reuptake inhibitors, tegaserod, histamine-2 receptor antagonists, and stress management techniques.^{14, 15} Incorporating psychological evaluation, particularly in refractory GERD cases, may improve treatment outcomes and reduce the overuse of PPIs.

The authors declare no conflicts of interest.