What are the alternative treatments to proton‑pump inhibitors for gastro‑oesophageal reflux disease, peptic ulcer disease, or other acid‑peptic disorders?

Alternatives to Proton Pump Inhibitors for Acid-Peptic Disorders

H2-receptor antagonists (H2RAs) such as famotidine or ranitidine are the primary pharmacologic alternative to PPIs for patients with mild-to-moderate acid-peptic disorders or those at lower risk for complications. 1, 2

Primary Pharmacologic Alternative: H2-Receptor Antagonists

H2RAs are less potent than PPIs but represent a reasonable alternative in specific clinical contexts:

• H2RAs suppress gastric acid by only 37-68% over 24 hours compared to PPIs, making them most effective for duodenal ulcer healing rather than gastric ulcers or severe GERD 2
• Famotidine 40 mg daily reduced gastroduodenal ulcers to 3.8% versus 23.5% with placebo in aspirin users 2
• H2RAs are less effective than PPIs for preventing NSAID-related gastric ulcers and should be reserved for lower-risk patients 1, 2
• Avoid cimetidine in patients taking clopidogrel due to CYP2C19 inhibition; use famotidine or other H2RAs instead 1, 2

Emerging Alternative: Potassium-Competitive Acid Blockers (P-CABs)

P-CABs such as vonoprazan represent a newer class with more potent acid suppression than PPIs:

• Vonoprazan achieves maximal acid suppression by Day 1 (versus 3-5 days for PPIs) and maintains target intragastric pH for longer periods throughout the 24-hour cycle 1, 3
• P-CABs are acid-stable, do not require premeal dosing, and are not metabolized by CYP2C19, eliminating genetic variability in response 1, 3
• P-CABs should be used in patients with LA Grade C/D erosive esophagitis who have failed standard PPI therapy 1
• P-CABs are recommended for H. pylori eradication therapy and high-risk peptic ulcer disease prophylaxis 1
• P-CABs are NOT recommended as first-line therapy for non-erosive GERD or on-demand heartburn treatment 1

Non-Pharmacologic and Adjunctive Therapies

For patients with refractory symptoms or extraesophageal manifestations, consider non-acid suppressive alternatives:

• Alginate-containing antacids provide a physical barrier and can be added to existing acid suppression 1, 2
• Pain modulators (tricyclic antidepressants, SSRIs) are effective for functional heartburn and esophageal hypersensitivity when acid suppression fails 1
• Cognitive-behavioral therapy and relaxation training may benefit patients with psychosomatic components 1
• Weight reduction in overweight/obese patients improves symptom control 1

Antacids and Mucosal Protectants

These agents have limited roles as PPI alternatives:

• Antacids provide direct acid buffering but require frequent dosing and are suitable only for on-demand symptom relief, not healing 2
• Sucralfate is effective for duodenal ulcers but NOT for gastric ulcers or NSAID-related injury 2

Clinical Decision Algorithm

When selecting alternatives to PPIs, stratify by risk and indication:

High-Risk Patients (age >60-65, prior GI bleeding, concurrent anticoagulants/NSAIDs):

• PPIs remain the preferred treatment with superior protection against GI bleeding (OR 0.04) compared to H2RAs (OR 0.43) 2
• If PPI intolerance or drug interactions exist, consider P-CABs rather than H2RAs 1

Moderate-Risk Patients:

• H2RAs are reasonable alternatives, particularly for duodenal ulcer disease 1, 2
• For erosive esophagitis that fails standard PPI therapy, escalate to P-CABs rather than switching to H2RAs 1

Low-Risk Patients:

• H2RAs provide adequate protection with less potent acid suppression 1, 2
• On-demand antacids for intermittent symptoms 2

Refractory GERD After 12 Weeks of PPI:

• Do NOT continue empirical PPI trials; pursue objective testing (endoscopy, manometry, pH monitoring) 1, 2
• Consider non-acid suppressive alternatives: pain modulators, alginates, behavioral therapy 1, 2
• If confirmed acid-related disease with normal anatomy, consider P-CABs for LA Grade C/D erosive esophagitis 1

Important Caveats and Pitfalls

Avoid these common errors when using PPI alternatives:

• Do not use H2RAs as first-line therapy for high-risk patients on antiplatelet/NSAID therapy—PPIs provide significantly superior GI bleeding protection 1, 2
• Cimetidine specifically inhibits CYP2C19 and should never be used with clopidogrel; other H2RAs do not share this interaction 1, 2
• H2RAs are ineffective for gastric ulcers and severe erosive esophagitis—do not substitute for PPIs in these conditions 2
• P-CABs raise serum gastrin levels higher than PPIs, though long-term safety data through 5 years show comparable adverse event profiles 1
• For extraesophageal symptoms (laryngitis, asthma, chronic cough) without confirmed esophageal GERD, empirical PPI or H2RA therapy is NOT recommended—pursue objective testing first 1