Now that many studies are raising serious concerns about the long-term use of proton pump inhibitors (PPIs), it is time to bust some myths and learn useful facts from an expert. Dr. Ajay Kumar breaks down the various controversies surrounding this class of drugs and clarifies whether PPIs are indeed safe to be prescribed for longer periods to patients.

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‘‘The first duties of the physician is to educate the masses not to take medicine’’ 

- Sir William Osler (1849-1919)

Proton pump inhibitors (PPIs) are the drugs that block the proton pump in gastric parietal cell and inhibit acid secretion effectively. They have been in clinical use for more than thirty years and have proven their efficacy in treating or preventing acid-related disorders effectively over years. Common molecules in use are Omeprazole, Lansoprazole, Pantoprazole, Rabeprazole and so on.

Over the years, this group of drugs has become one of the most frequently prescribed classes of drugs across the world because they combine a high level of efficacy with low toxicity.

1. According to one estimate in 2006, about 7 billion sterling pounds worth of drugs were prescribed across the world.
2. In 2012, 7.8% of the population in the USA were on long term PPI.
3. In India, the PPIs alone or in combination with prokinetic drugs represent a market of INR 5,122 crores. With a projected 6.3% annual growth, it may touch as high as INR 5,500 crores by next year.

This is despite the fact that over time, prices of PPIs have come down and still we see such a rise in rupee worth, showing the increasing long-term use of these drugs.

When PPIs were first introduced in the market, concerns were raised regarding the risk of infections and carcinoid tumours. Risk of infections was raised on the theoretical basis of protective gastric acid being suppressed, predisposing to enteric infections. But this fear was unfounded as long years of its use has shown no such increase, even in developing countries with poor public health infrastructure.

The other fear was achlorhydria causing hypergastrinemia which may further lead to carcinoids. This was suggested by animal studies. But this again was shown to occur, only when used in very large doses (much more than therapeutic dose). Thus both fears were considered to be of no clinical relevance and Omeprazole was released for clinical use in 1988.

Over years, this group of drugs has proven its clinical usefulness in a variety of disorders requiring acid suppression like peptic ulcer, upper GI bleeding, reflux oesophagitis, prevention of stress ulcers and NSAID-associated ulcers and treatment of H. pylori infection. There is no debate on the short term use of PPIs and its usefulness. They may cause mild GI symptoms and headaches which are quite acceptable. But over years, some indications have evolved for long term use of PPIs like:

• Barrett’s oesophagus with or without erosive esophagitis
• Erosive esophagitis – LA grade C and D
• PPI responsive non-erosive gastroesophageal reflux disease
• Prevention of GI bleeding in patients on antiplatelets and anticoagulants
• Zollinger Ellison’s syndrome

There has been recent interest in this topic because of a large number of publications regarding side effects of long term use of PPIs ranging from absorption of nutrients like iron, B12, calcium, magnesium, risk of infections, cancers and kidney and brain injury. Some of these are based on sound theoretical foundations like interaction with clopidogrel which reduces its effectiveness and thus may cause increased cardiac mortality in cardiac patients, like kidney and brain damage, give no such rational explanation. This has raised concerns among the general public, patients and the medical fraternity.

How safe it is to take PPIs for long duration?

A doctor is often asked the question. At times, the doctor finds himself at a loss for words to explain to the patient. So it is important to educate ourselves regarding the right answer so that we can convince our patients satisfactorily.

As said earlier, most of the studies reporting these side effects have been retrospective observatory studies. There have been prospective studies like Lotus and Sopran which showed that long term use of PPIs are safe and not associated with clinically relevant side effects. The most interesting and relevant study by Moyyudu et al, published in a leading American Journal, mentioned that use of PPIs over three years is safe. The strength of this is that it is a prospective controlled trial with a large number of patients (17,598) from 33 countries followed over three years. This shows that other than the increased risk of bacterial infections with Pantoprazole (the PPI used in the referenced study), there is no significant increased risk of any other complication. There may be some theoretical explanations for some side effects but in properly conducted scientifically valid prospective studies we have not been able to show any significant side effects so as to call for its stoppage in clinical use.

Promote rational use of PPIs

This means the right indication, right dosages, and duration. Quite often there is a tendency to prescribe these drugs in very high doses, which should be discouraged. The adage “If some is good, then more is better” is necessarily not true.

1. If patients are on BD dosage, it should be reduced to OD. If they are on OD dosage, an attempt should be made to gradually downgrade it to H2 blockers or make it on-demand therapy.
2. Issue of various supplements like calcium, vitamin B12, iron etc. is controversial and not recommended at present and neither is regular BMD estimation.

To sum up, PPIs are an important group of drugs and helpful in treating various acid-related disorders. Today, there is no reason to stop using them despite so much literature regarding their side effects. They are safe but nothing is perfectly safe. In the absence of measurable clinical benefit, even a minuscule risk becomes dominating. There is little concern to alter current practice unless the use is inappropriate.

This article was originally published on October 5, 2020.

Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.

The author, Dr. Ajay Kumar is the Past President Society of GI Endoscopy of India, Immediate Past President, Indian Society of Gastroenterology, Chairman of BLK Liver and Digestive Diseases Institute from Pusa Road, New Delhi.