Why is my PPI not working?

Optimising proton pump inhibitor therapy in pharmacy

Proton pump inhibitors (PPIs) are a widely used pharmacological treatment option for management of gastro-oesophageal reflux.¹

While data on PPIs highlighted concerns about long-term use and the need for appropriate prescribing, an analysis of Pharmaceutical Benefits Scheme (PBS) data following the introduction of prescribing restrictions in 2019 suggests that a reliance on PPIs for management of reflux symptoms remains.²

Indeed, PPIs are an effective and well-tolerated pharmacotherapy for reflux and can be used confidently in the correct indications: first-line as a regular therapy for frequent/severe symptoms of gastro-oesophageal reflux disease (GORD), and second-line as an ‘on-demand’ therapy for mild/intermittent gastro-oesophageal reflux symptoms (see Therapeutic Guidelines for further information).¹ 

However, for a variety of reasons, up to 40% of patients taking daily PPI for reflux symptoms are considered to have ‘PPI treatment failure’ or refractory GORD.³ Understanding the possible causes of persistent symptoms is important for pharmacists to efficiently troubleshoot next steps in management and/or recommend the appropriate course of action for the patient and their doctor to further investigate the issue. This article will provide an overview of 6 reasons why patients may find their PPIs failing — and courses of action to manage their concerns.

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Optimising standard-dose PPI therapy

First, consider potential causes of ongoing symptoms that may typically (but not exclusively) occur when starting standard-dose PPI therapy.

1. PPIs may take 2–3 days before maximal stomach acid suppression. 

PPIs have a covalent (irreversible) binding to the proton pump, but their relatively short half-life (approximately 90 minutes) means that PPIs can’t inhibit all active proton pumps with the first dose.⁴ In fact, it can take up to 2–3 days for PPIs to reach steady state inhibition of acid secretion.⁵ Patients may not be aware of this delay and believe ongoing symptoms during the initial days of treatment mean that the PPI isn’t working. 

Antacids or alginate-antacids may sometimes be recommended to help manage breakthrough symptoms.^6-8 Alginate-antacids may provide a complementary mechanism of action by forming a ‘raft’ at the gastro-oesophageal junction, creating a mechanical barrier to help block reflux from entering the oesophagus and potentially buffering the acid pocket.³ 

Where regular treatment is indicated, if symptoms persist or recur after an initial 2-week trial for over-the-counter (OTC) PPIs (or 4–8 weeks for prescription PPIs), the patient should be referred to their medical practitioner for review.^1,4,8

2. Patients don’t take their PPI as directed in conjunction with diet and lifestyle adjustment. 

One of the causes of inadequate suppression of stomach acid is poor PPI patient adherence.³ One particularly important factor that patients may not follow is the timing of dosing. For patients who experience their strongest symptoms during the day, PPI kinetics mean that they should take their treatment ideally 30–60 minutes before eating breakfast.¹ For patients who experience their strongest symptoms at night, kinetics mean that they should take their PPI 30–60 minutes before their evening meal.^1,3,7 When initiating a PPI, it is important for patients to be counselled about the significance for optimal dose timing.¹ For patients experiencing breakthrough symptoms on longer term PPI therapy, investigate adherence (particularly with regards to timing of dose) and whether the patient may be having trouble taking the PPI as directed.¹

Diet and lifestyle adjustments are also an important part of management, such as avoiding foods or drinks that trigger symptoms; avoiding eating or drinking 2–3 hours before bedtime or vigorous exercise; and stopping smoking.^1,3 Patients may not be aware of these recommendations or may find them difficult to achieve, so it is recommended to discuss them, including potential referral for expert consultation (e.g. with a dietitian) if necessary or indicated.^1,9 It is important to note that not all restrictions and modifications will be applicable to every patient.

3. Other medicines the patient is taking can cause or worsen reflux. 

Assessing if medicines contribute to reflux symptoms is an important role of the pharmacist in reflux management.¹⁰ Several mechanisms are involved, such as reduction of lower oesophageal sphincter (LOS) pressure, direct irritant effect of the medicine on the oesophageal mucosa and delayed gastric emptying leading to increased pressure on the LOS.¹⁰ Medicines commonly implicated in causing or worsening reflux symptoms are listed in Table 1. 

Table 1: Medicines commonly implicated in causing or worsening reflux symptoms

Whether initiating an OTC PPI or dispensing a prescription PPI, it’s important to assess what other OTC, prescription, and complementary medicines the patient may be taking to determine possible causes of reflux symptoms. If a medicine is found to be contributing to reflux symptoms, appropriateness should be reviewed in consultation with the patient’s medical practitioner.¹ If symptoms persist, it is worth repeating this assessment – some patients may commence an implicated medicine after initiating their PPI, while others may simply forget to mention all their other medicines when first asked.

Beyond standard-dose PPI therapy

If symptoms persist despite attempting multimodal therapy and adjusting patient variables, more complex conditions – and thus management approaches – may be required. Consider the following potential causes of refractory symptoms.

4. Standard dose PPI may be insufficient for some patients. 

A high-dose PPI or combination therapy may need to be trialled for some patients, such as those with frequent or severe symptoms experiencing inadequate symptom control.¹

If the patient is showing inadequate response to long-term daily low or standard dose PPI therapy, the pharmacist can refer the patient back to their GP for gastroenterologist referral and consideration of high-dose PPI (e.g. standard PPI dose taken twice daily). While awaiting specialist review, the GP may alternatively consider combination therapy, such as standard-dose PPI therapy in the morning, and a H₂-receptor antagonist in the evening.¹

The American Gastroenterological Association Clinical Practice Update, released in 2022, also recommends adjunctive pharmacologic therapy with an on-demand alginate-antacid in some patients with refractory heartburn to help control breakthrough symptoms.^3,7 Further studies are needed to confirm the efficacy of sodium alginate in patients with refractory GORD.³ 

Once adequate symptom control is achieved, the need for PPI therapy should be regularly reviewed and step-down therapy regularly attempted, in consultation with the patient’s medical practitioner or gastroenterologist.¹ To reduce risks associated with long-term PPI use, maintenance therapy (if required), should be taken at the lowest possible dose and frequency that controls symptoms, or eventually ceased.¹

5. Metabolic enzyme polymorphism. 

PPIs are metabolised by cytochrome P450 2C19 (CYP2C19), and genetic polymorphism causes some patients to be classified as either poor, intermediate, or rapid metabolisers of PPIs. Patients categorised as rapid metabolisers develop comparatively lower PPI plasma levels, developing undetectable plasma levels 3 hours after PPI dosing and experiencing lower effectiveness of PPIs.^3,11 

If a patient requires long-term PPI therapy and is showing an inadequate response to treatment, this is a possible consideration. In an analysis of more than 2 million direct-to-consumer genetics research participants in the United States, researchers found that 26% had a CYP2C19 genotype that predicted they would be rapid metabolisers.¹² A GP can refer the patient for pharmacogenomic testing to assess the patient’s cytochrome status and adviser next steps accordingly.¹³ 

6. The diagnosis may need to be reassessed.

For refractory patients, consider the possibility of other diagnoses – particularly if symptoms do not respond following multimodal therapy and/or high-dose PPI trial.¹ For example, PPIs are less effective for non-erosive reflux disease (NERD; a distinct phenotype of GORD defined by the presence of typical GORD symptoms in the absence of visible oesophageal mucosal injury at endoscopy), functional dyspepsia, and laryngopharyngeal reflux (LPR).^3,14 Treatment needs to be altered accordingly if alternate diagnoses are identified. If this is suspected in the patient, suggest a discussion with the GP for further diagnostic testing and potential referral to a specialist.

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Key points

• Reflux symptoms may continue during PPI initiation as steady state acid suppression takes 2-3 days to achieve. Antacids or alginate-antacids may be considered as an adjunct therapy in some patients to help control symptoms during this time. 
• Lack of adherence to PPI dosing, improper diet and lifestyle adjustment, and contributions from other medicines may contribute to persisting symptoms, reinforcing the importance of comprehensive education at initiation of PPI treatment
• Patients uncontrolled on standard-dose PPI therapy require referral to a medical practitioner for further assessment, where high-dose PPI therapy or combination therapy may be considered. 
• Pharmacists should also consider alternate diagnoses in refractory patients, such as NERD, functional dyspepsia, and LPR — suggest a discussion with the GP for further diagnostic testing if this is suspected. 

References

1. Gastro-oesophageal reflux in adults [published August 2022]. In: Therapeutic Guidelines. Melbourne: Therapeutic Guidelines Limited. At: www.tg.org.au
2. Daniels B, Schaffer A, Buckley NA, et al. The impact of tightened prescribing restrictions on proton pump inhibitor use in Australia: an evaluation using interrupted time series analysis. Pharmacoepidemiol Drug Saf 2022;31(3):370–8.
3. Fass R. Approach to refractory gastroesophageal reflux disease in adults. UpToDate. Current to September 2023.
4. MacFarlane B. Management of gastroesophageal reflux disease in adults: a pharmacist’s perspective. Integr Pharm Res Pract 2018;7:41–52.
5. Shin JM, Sachs G. Pharmacology of proton pump inhibitors. Curr Gastroenterol Rep 2008;10(6):528–34.
6. Reimer C, Lødrup AB, Smith G, et al. Randomised clinical trial: alginate (Gaviscon Advance) vs. placebo as add-on therapy in reflux patients with inadequate response to a once daily proton pump inhibitor. Aliment Pharmacol Ther 2016;43(8):899–909.
7. Yadlapati R, Gyawali CP, Pandolfino JE, et al. AGA Clinical Practice Update on the Personalized Approach to the Evaluation and Management of GERD: Expert Review. Clin Gastroenterol Hepatol 2022;20(5):984–94.e1.
8. Sansom LN, ed. Australian pharmaceutical formulary and handbook. 2024. Gastro-oesophageal reflux; [updated 2023]. At: https://apf.psa.org.au/non-prescription-medicine-guides/gastro-oesophageal-reflux/gather-patient-information
9. Montoro-Huguet MA. Dietary and nutritional support in gastrointestinal diseases of the upper gastrointestinal tract (I): Esophagus. Nutrients 2022;4819(14):1–24.
10. Mungan Z, Pinarbasi Simsek B. Which drugs are risk factors for the development of gastroesophageal reflux disease? Turk J Gastroenterol 2020;28(Supp1):S38–S43.
11. Ichikawa H, Sugimoto M, Sugimoto K, et al. Rapid metabolizer genotype of CYP2C19 is a risk factor of being refractory to proton pump inhibitor therapy for reflux esophagitis. Rapid J Gastroenterol Hepatol 2016;31(4):716–26.
12. Ionova Y, Ashenhurst J, Zhan J, et al. CYP2C19 allele frequencies in over 2.2 million direct-to-consumer genetics Research participants and the potential implication for prescriptions in a large health system. Clin Transl Sci 2020;13:1298–1306.
13. RACGP. Genomics in General Practice. (Last updated 12/01/2022).
14. Spantideas N, Drosou E, Bougea A, et al. Proton pump inhibitors for the treatment of laryngopharyngeal reflux. A systematic review. J Voice 2020;34(6):918–29.

Our authors

John Bell has been a member of advisory boards for, or provided advice to: Astellas, Astra Zeneca, Bayer, GSK, Mylan, Novartis, Nutricia, Pfizer, Procter & Gamble and Reckitt Benckiser. He is currently a member of the international multidisciplinary Global Pain Faculty.