Why I am concerned about Omeprazole use!
By Professor Rob Foale
VVS Small Animal Internal Medicine Specialist
You may read the title of this blog and immediately think that I need to get out more! Whilst you may actually be correct in this assumption, the clearly increasing use of omeprazole in practices and hospitals across the UK is something that is causing me concern, because it appears to be a trend without a sound evidence base to support it, and one that has increased since ranitidine became unavailable. Although the use of omeprazole may not have the public health issues that the use of say, antimicrobials currently has, as has also been well documented in human medicine, there is increasing evidence that omeprazole has become a markedly overused and unnecessarily prescribed medication in veterinary practice. Why do I say this? Please read on to find out!
What is omeprazole?
Omeprazole is a type of medication called a “proton pump inhibitor” and it acts to markedly reduce gastric acid secretion in the patients who receive it. Omeprazole and related proton pump inhibitors (PPI) are weak bases that are uncharged at the physiological pH of blood. However, once trapped in the acidic environment of a parietal cell, they become charged and form disulphide bonds with cysteine residues on the alpha subunit of the H+K-ATPase pump. The activation of this enzyme being the final step in the process of gastric acid secretion. The enzyme antagonism is marked, and the data in humans and experimental animals shows it can lead to an almost complete cessation of gastric acid secretion within approximately five days of starting treatment, when given at recommended doses. The antagonism for the affected parietal cells is also permanent, due to the covalent bonding, with new parietal cell formation required to overcome the blockade.
What is omeprazole used for?
Omeprazole was designed for use in human medicine to treat and help manage gastroduodenal ulceration and gastro-oesophageal reflux. Because PPI’s are more efficacious than H2-anatgonists like ranitidine (“Zantac”) and famotidine (“Pepcid”), their use has increased markedly over the past twenty years. However, it is important to note that gastric ulceration in humans is not the same as gastric ulceration in cats and dogs because of the significant effect of helicobacter pylori in human medicine, an infection that our patients do not develop. Therefore, whilst H.pylori-induced gastritis and ulceration is a common and well-recognised problem in human medicine, our patients do not develop this and the incidence of gastric ulceration in cats and dogs is almost certainly much lower than that encountered in human medicine
Is omeprazole safe?
It has been estimated that there are at least 113 million human prescriptions of omeprazole each year in the US alone1, so if there was a significant safety problem with the drug, I think we would have identified it by now. That being said, it is known to have side-effects in humans and although we do not yet have sufficient data to support these findings in our patients, the potential complications we need to consider include intestinal microbiome disruption/dysbiosis2, increased enteric infections3, diarrhoea, vitamin B12 and other micronutrient deficiency4 and an increased risk of pathological bone fracture, due to calcium deficiency with long-term use5. Omeprazole is also metabolised through the hepatic cytochrome P450 system, and it may therefore affect the metabolism of other medications inactivated through this pathway. More importantly, there are some medications that require the acidic environment of the stomach to mediate their systemic absorption and the removal of this environment may significantly and deleteriously affect their efficacy. Medications that may be affected in this manner include the azole anti-fungals, mycophenolate, clopidogrel and iron
What evidence is there it is being over-prescribed?
There have been a number of studies in human medicine raising concerns that omeprazole is being over-prescribed in both the US and Europe, with estimates that up to 60% of prescriptions are inappropriate or unnecessary6,7. There is also now a veterinary publication from a major UK veterinary teaching hospital, published in 20208, which also suggests omeprazole is being used inappropriately in small animal patients, and I strongly suspect that the pattern of usage described in this paper is replicated across the UK. The study found that omeprazole (along with maropitant) was prescribed to a large proportion of the dogs admitted to the hospital, including many without any signs suggestive of gastrointestinal disease. The study also found that it was frequently prescribed outside of current dosing recommendations and that the aims of its use were unlikely to be achieved when considering its biological action in dogs. In short, we all seem to think it is a safe medication that might, or will, benefit our patients, but this doesn’t mean that we should use it without careful thought. Ideally we should only use it when there is clinical evidence to indicate the presence of, or there is a high risk of, gastroduodenal ulceration and/or gastrooesophageal reflux and not in patients who have a short-term GI upset or pancreatitis.
So, do dogs and cats develop gastric ulceration?
Although we do not have firm statistics, the absence of H. pylori infection means that spontaneous gastric ulceration is not the problem in cats and dogs that it is in human medicine, and it is highly unlikely that our patients develop anywhere near as many gastroduodenal ulcers as humans do. However, our patients do develop gastroduodenal ulceration in certain situations, such as those associated with NSAID use and glucocorticoid use (see later), in patients with gastroduodenal neoplasia and in working sled dogs; these patients certainly require appropriate treatment. However, what we do not have any evidence for is that patients with simple inappetence, vomiting, uncomplicated gastritis, pancreatitis or enteritis have any gastrointestinal ulceration at all. Nor do we have evidence that there is any benefit to be derived by the use of PPI’s in patients with any of these conditions; this is the patient type in which I am particularly concerned we are over-using and possibly unnecessarily prescribing omeprazole for.
What about eosophagitis and gastro-oesophageal reflux?
We do have evidence that BOAS patients and some patients undergoing prolonged orthopaedic surgery can experience potentially significant gastro-oesophageal reflux (GOR)9,10. The use of omeprazole in these patients has also now been shown to help prevent the change in distal oesophageal pH that accompanies GOR, but this is probably as a result of the change in gastric pH that omeprazole mediates, not because omeprazole reduces the actual frequency of GOR11. However, preventing acid damage to the distal oesophagus where there is a known risk is appropriate, so it is therefore rational to use omeprazole in some surgical patients where there is a risk of GOR, and especially in BOAS patients where GOR is a known risk
Should we use omeprazole routinely with NSAID’s?
The number of animals receiving NSAID medication in 2011 was estimated to be 26 million dogs and 6 million cats12. Without doubt, these numbers will have markedly increased today. However, the incidence of gastric ulceration arising from these prescriptions is currently unclear. It is generally thought that the incidence of gastroduodenal ulceration in cats and dogs receiving NSAID’s is low, but a recent paper in 2021 has questioned this, as it found 83% of the dogs on NSAID’s that they investigated had small gastric erosions13. However, this study only included 14 dogs, so its conclusions need to be substantiated. A much larger (albeit retrospective) study14, also published in 2021, also suggests that the presence of erosions and ulcers in small animals receiving NSAID’s is more common than previously thought. It indicated that the factors associated with the development of gastroduodenal ulceration in dogs were the use of NSAID’s, the use of glucocorticoids, gastrointestinal mechanical disease (eg: foreign bodies, GDV), neoplasia and working dog breeds. However, from a clinical point of view, the vast majority of dogs and cats who receive long-term NSAID’s do not exhibit clinical signs or evidence of significant gastric ulceration- so we have a dilemma! Without doubt, there is a risk that dogs receiving NSAID’s may develop gastric erosions or ulcers, but the incidence with which this occurs is not clear and the clinical indication is that the numbers affected are probably actually quite (if not very) small. The large study published in 2021 contained 168 affected dogs, which were gathered over a ten-year data collection period; if we compare this number with the number of dogs treated with NSAID’s in the same time period, the number of prescriptions issued will run into tens of millions. Therefore, what is needed is a detailed prospective study to establish the incidence of NSAID-induced gastroduodenal ulceration, the severity of the ulceration and the clinical significance of the ulceration, to help inform us whether we should be recommending the routine use of omeprazole or other gastroprotectants in patients we place on NSAID’s. However, until we have this data, there is little evidence available to support our routine use of omeprazole in patients for whom we prescribe NSAIDs
Should we use omeprazole routinely with glucocorticoids?
Glucocorticoids are prescribed frequently in small animal practice and over a wide dose range depending on the desired clinical effect. Glucocorticoids have been associated with gastroduodenal ulceration mainly as a result of studies published into the use of high-dose (eg: 30mg/kg methylprednisolone) glucocorticoids in patients with known spinal compression, but more recently, a prospective double-blinded study15 has indicated that prednisolone used at 2mg/kg once a day is associated with a four-times increased risk of developing endoscopically visible gastric erosions compared to dogs treated with a placebo, so the incidence of glucocorticoid-induced gastroduodenal ulceration may be underestimated. However, none of the dogs in this study developed clinical signs of gastric ulceration or of GI haemorrhage, so again, the true clinical relevance of this study raises two main questions; are we missing something in patients that we treat with immunosuppressive doses of glucocorticoids and should we be doing something about this or not? Currently there is no convincing evidence that gastroprotectant medications are beneficial in patients we treat with glucocorticoids, but further work in this area is required. Anecdotally, over more than twenty years the author has treated, or supervised the treatment of, hundreds of patients who have required high-dose glucocorticoid therapy and has not documented a single case of clinically relevant gastroduodenal ulceration in this time, but the question of whether sub-clinical ulceration was present but unrecognised is obviously unknown
If we are going to use is, how often should omeprazole be dosed?
The current recommendation is that, if we need to use omeprazole it should be dosed twice a day for up to 3 – 4 weeks and then the dosage weaned down before stopping16, but it is frequently only used once a day which is thought to significantly reduce the clinical benefit. Stopping omeprazole suddenly may also risk a rebound gastric hyperacidity, as omeprazole increases gastrin levels and this is why a wean down is recommended. However, the clinical incidence and relevance of this in veterinary patients is unclear, and it may be that this precaution is not necessary in our patients
Conclusions:
The use of omeprazole and other gastroprotectants has been shown to have risen markedly over the past 10-20 years. In situations where there is proven gastroduodenal ulceration, gastro-oesophageal reflex or a strong reason to believe that reflux is likely to occur, omeprazole is superior to other gastroprotectant medications, and it is appropriate to use omeprazole as long as a correct dose and dosing interval are used and appropriate monitoring is undertaken. However, it should not be given concurrently with other medications that require an acid environment for their activation or absorption. Away from this however, there is currently no strong evidence to support the use of omeprazole in patients with simple non-erosive gastritis, enteritis, pancreatitis, IRIS stage 1 – 3 renal disease, thrombocytopaenia-induced haemorrhage or in critically ill patients unless definitive risk factors such as NSAID use is known and cannot be avoided. Further work is therefore required to confirm the benefit and appropriate use of omeprazole in healthy patients who receive routine treatment with NSAID’s, to assess the benefits of concurrent administration of omeprazole alongside glucocorticoids, and also to investigate the potential benefits of omeprazole in patients with the other conditions listed above. Until further work has been undertaken, the benefits of dispensing omeprazole are unclear and we should proceed with caution!
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References:
1: Katz M. H. (2010) Failing the acid test: benefits of proton pump inhibitors may not justify the risks for many users. Arch. Intern. Med. 170, 747–748
2: Jackson, M. A. et al. (2016). Proton pump inhibitors alter the composition of the gut microbiota. Gut 65, 749–756
3: Bavishi, C. & Dupont, H. L. (2011). Systematic review: the use of proton pump inhibitors and increased susceptibility to enteric infection. Aliment. Pharmacol. Ther. 34, 1269–1281
4: Lam, J. R., Schneider, J. L., Zhao, W. & Corley, D. A. (2013). Proton pump inhibitor and histamine 2 receptor antagonist use and vitamin B12 deficiency. JAMA 310, 2435–2442
5: Yang, Y. X., Lewis, J. D., Epstein, S. & Metz, D. C. (2006). Long-term proton pump inhibitor therapy and risk of hip fracture. JAMA 296, 2947–2953
6: Heidelbaugh, J. J. & Inadomi, J. M. (2006). Magnitude and economic impact of inappropriate use of stress ulcer prophylaxis in non-ICU hospitalized patients. Am. J. Gastroenterol. 101, 2200–2205
7: Reid, M. et al. (2012). Inappropriate prescribing of proton pump inhibitors in hospitalized patients. J. Hosp. Med. 7, 421–425
8: McCormack, R., Olley, L., Glanemann, B. et al. (2020). Prospective observational study of the use of omeprazole and maropitant citrate in veterinary specialist care. Sci Rep 10, 15727
9: Panti, A. et al. (2009). The effect of omeprazole on oesophageal pH in dogs during anaesthesia. J. Small Anim. Pract. 50, 540–544
10: Kaye, B. M., Rutherford, L., Perridge, D. J. & Ter Haar, G. (2018). Relationship between brachycephalic airway syndrome and gastrointestinal signs in three breeds of dog. J. Small Anim. Pract. 59, 670–673
11: Shaver, S. L. et al. (2017). Evaluation of gastroesophageal reflux in anesthetized dogs with brachycephalic syndrome. J. Am. Anim. Hosp. Assoc. 53, 24–31
12: Carmichael S. (2012). Know your NSAID’s. Proc WSAVA/FECAVA/BSAVA
13: Mabry, K., Hill T. and Tolbert M.K. (2021). Prevalence of gastrointestinal lesions in dogs chronically treated with nonsteroidal anti-inflammatory drugs. J. Vet. Intern. Med. 35, 853 – 859
14: Pavlova E., Gold R.M., Tolbert M.K. and Lidbury J.A. (2021). Medical conditions associated with gastroduodenal ulceration or erosion in 168 dogs: 2008 – 2018. J. Vet. Intern. Med., 35, 2697 – 2704
15: Whittemore, J.C., Mooney A.P., Price J.M. and Thomason J. (2019). Clinical, clinicopathological and gastrointestinal changes from administration of clopidogrel, prednisone, or a combination in healthy dogs: A double-blind retrospective trial. J. Vet. Intern. Med., 33, 2618 – 2627 16: Marks, S. L., Kook, P. H., Papich, M. G., Tolbert, M. K. & Willard, M. D. (2018). ACVIM consensus statement: support for rational administration of gastrointestinal protectants to dogs and cats. J. Vet. Intern. Med.32, 1823–1840