PPI-Refractory Acid Reflux: What's Next?

PPI therapy fails either partially or completely in up to 30% of patients. Pharmacists can help identify a cause and choose a course of action.

Proton pump inhibitors (PPIs) have become our go-to drugs for acid reflux patients. Pharmacists—and patients, too—expect that PPIs will resolve the burning, sour reflux quickly. PPI therapy fails either partially or completely, however, for up to 30% of patients.^1,2 Patients routinely return to their pharmacist complaining of “heartburn” or other symptoms.

Gastroenterologists have yet to establish a consistent definition of PPI-refractory acid reflux, but common elements include less than 50% improvement in the patient’ s chief complaint after at least 12 weeks of twice-daily PPI therapy. (This is a larger dose than the FDA currently approves; see below.) PPI-refractory acid reflux symptoms must impair quality of life. These symptoms must also be reflux-related, which is difficult to determine without further testing since symptoms can be related to acid reflux, gas reflux, or functional complications. Clinicians must ask about specific symptoms (Table 1) because patients often complain of continuing or residual “heartburn,” which is a vague term that can indicate multiple conditions.^3-5

What’s Happening?

Researchers have identified many mechanisms for PPI-refractory reflux (Table 2). Patients who have dyspepsia or regurgitation are more likely to be PPI-refractory,^8,9 as are those who have anxiety disorders or depression. Patients who have psychosocial comorbidities are also more likely to be nonresponsive to PPIs, and conversely, patients who respond incompletely to PPI treatment are more likely to experience psychological distress.^10-13

Patients who report PPI-nonresponsiveness are often nonadherent.¹⁹ When a standard once-daily PPI dose is unsuccessful despite patient adherence, physicians often double the dose, prescribing the approved dose before breakfast and then again at dinner. No large studies support this approach, but some smaller studies suggest it is a rational choice. Experts estimate that about 30% of patients refractory to a once-daily dose will respond to a doubled dose. After 8 to 12 weeks of treatment, prescribers can begin to reduce the dose to once-daily therapy. Most patients will then be controlled on once-daily therapy, and a few may discontinue the PPI completely.²⁰

Some research suggests that switching to a different PPI can increase the chance of a response.²¹ At some point, either before or while making these changes, the clinician will probably use additional testing (Table 3) to determine if something else is causing continuing symptoms.

Next Steps

Depending on test results and the patient’s response to a PPI dose increase or a PPI switch, prescribers have several ways to proceed. If the patient’s problem is documented as real acid reflux disease (and not a different condition requiring different interventions), inevitably the prescriber and health care team review and reinforce the need for lifestyle modifications. Patients who are PPI-refractory often have not made lifestyle modifications and need to be reminded. Helpful lifestyle modifications include losing weight, elevating the head of the bed during sleep, and avoiding late-night meals.^19,26,27

Augmenting PPI therapy can help, and many patients do this spontaneously by adding an OTC antacid without a doctor’s recommendation. Alginates seem to be particularly effective.²⁸ Adding a histamine receptor antagonist (H₂RA) at bedtime can also reduce breakthrough acid reflux. Resistance to H₂RA is now well documented, and some prescribers advise patients to take H₂RA as needed or intermittently.²⁹

If transient lower esophageal sphincter relaxation is suspected, baclofen is sometimes used at doses of 5 to 20 mg 3 times a day.³⁰ Side effects such as dizziness, sedation, nausea, and vomiting often limit baclofen’s use.

If hypersensitivity to normal levels of acid is suspected, tricyclic antidepressants, trazodone, and selective serotonin reuptake inhibitors have been used to reduce esophageal pain.⁵

Some patients may need anti-reflux surgery (laparoscopic fundoplication), but it may be more effective in PPI-responsive patients than in PPI-refractory patients.³¹

Concerns and Conclusion

As off-label and long-term PPI use grows and changes, many clinicians have expressed concern about side effects. Numerous studies are under way that examine new dosing schedules, treatment duration, and potential therapy complications. Pharmacists will need to stay abreast of changes.

Ms. Wick is a visiting professor at the University of Connecticut School of Pharmacy and a freelance writer from Virginia.

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