Long-term use of proton pump inhibitors (PPIs) more than doubles the risk of gastric cancers, according to research published this week in Gut.
The Hong Kong-based study included over 63,000 people who had undergone successful eradication of Helicobacter pylori infections. H. pylori infections are linked to stomach cancer and their eradication reduces risk. But a significant number of those who have had the infection eradicated will still go on to develop stomach cancer.
In this cohort, 153 study participants went on to develop gastric cancer, with a median follow-up of 7.5 years. Those who did develop cancer were 2.4 times more likely to have been long-term users of PPIs. The cancer risk rose with higher dosages and longer-term use of PPIs: those who used PPIs daily more than quadrupled their risk of gastric cancer, while more than a year of regular use resulted in a fivefold increase in risk.
However, users of histamine H2 receptor antagonists (H2RAs), another common acid reflux therapy, did not see their risk of gastric cancer rise.
The study authors say that the association is likely to be related to the profound acid suppression of PPIs that worsens atrophic gastritis, a known risk factor in gastric cancer. They say the lack of an association with H2RAs and gastric cancer further supports a specific role for PPIs in gastric cancer development.
“Physicians should therefore exercise caution when prescribing long-term PPIs to these patients even after successful eradication of H. pylori,” the authors conclude.
Commenting on the study, Associate Professor Richard Ferrero, who heads up a GI infection and inflammation research group at the Hudson Institute of Medical Research in Melbourne, said a study published in 1996 first raised alarm over possible deleterious effects of PPIs, showing that people with a H. pylori infection increased their risk of cancer if they were on PPI therapy. Since then, H. pylori eradication has been recommended before long-term PPI treatment.
“This new study now shows that even a prior H. pylori infection increases the risk of gastric cancer in subjects receiving long-term PPI therapy,” Dr Ferrero said. “The work has important implications as PPIs, which are among the top 10 selling generic drugs, are commonly prescribed to treat heartburn.”
He said the study’s design eliminated a number of important confounding factors, although the authors were unable to obtain detailed histological findings on gastric biopsies from participants.
“This may have helped explain why stomachs that have previously been infected with H. pylori are more likely to develop cancer in response to long-term PPI treatment,” Dr Ferrero commented.
Recent studies have linked PPIs to a string of unwanted effects, including pneumonia, dementia, cardiovascular problems and bone fracture.
It’s widely recognised that emotions can directly affect stomach function. As early as 1915, influential physiologist Walter Cannon noted that stomach functions are changed in animals when frightened. The same is true for humans. Those who stress a lot often report diarrhoea or stomach pain.
We now know this is because the brain communicates with the gastrointestinal system. A whole ecosystem comprising 100 trillion bacteria living in our bowels is an active participant in this brain-gut chat.
Recent discoveries around this relationship have made us consider using talk therapy and antidepressants as possible treatments for symptoms of chronic gut problems. The aim is to interfere with the conversation between the two organs by telling the brain to repair the faulty bowel.
Gastrointestinal conditions are incredibly common. About 20% of adults and adolescents suffer from irritable bowel syndrome (IBS), a disorder where abdominal discomfort or pain go hand-in-hand with changes in bowel habits. These could involve chronic diarrhoea and constipation, or a mixture of the two.
IBS is a so-called functional disorder, because while its symptoms are debilitating, there are no visible pathological changes in the bowel. So it is diagnosed based on symptoms rather than specific diagnostic tests or procedures.
This is contrary to inflammatory bowel disease (IBD), a condition where the immune system reacts in an exaggerated manner to normal gut bacteria. Inflammatory bowel disease is associated with bleeding, diarrhoea, weight loss and anaemia (iron deficiency) and can be a cause of death. It’s called an organic bowel disease because we can see clear pathological changes caused by inflammation to the bowel lining.
People with bowel conditions may need to use the toilet 20 to 30 times a day. They also suffer pain that can affect their family and social lives, education, careers and ability to travel. Many experience anxiety and depression in response to the way the illness changes their life. But studies also suggest those with anxiety and depression are more likely to develop bowel disorders. This is important evidence of brain-gut interactions.
How the brain speaks with the gut
The brain and gut speak to each other constantly through a network of neural, hormonal and immunological messages. But this healthy communication can be disturbed when we stress or develop chronic inflammation in our guts.
Chronic intestinal inflammation may lower our sensitivity to positive emotions. When we become sick with conditions like inflammatory bowel disease, our brains become rewired through a process called neuroplasticity, which changes the connections between the nerve signals.
Anxiety and depression are common in people suffering chronic bowel problems. Approximately 20% of those living with inflammatory bowel disease report feeling anxious or blue for extended periods of time. When their disease flares, this rate may exceed 60%.
Interestingly, in a recent large study where we observed 2,007 people living with inflammatory bowel disease over nine years, we found a strong association between symptoms of depression or anxiety and disease activity over time. So, anxiety and depression are likely to make the symptoms of inflammatory bowel disease worse long-term.
It makes sense then to offer psychological treatment to those with chronic gut problems. But would such a treatment also benefit their gut health?
Our recent study combined data from 14 trials and 1,196 participants to examine the effects of talk therapy for inflammatory bowel disease. We showed that talk therapy – particularly cognitive behavioural therapy (CBT), which is focused on teaching people to identify and modify unhelpful thinking styles and problematic behaviours – might have short-term beneficial effects on depression and quality of life in people with inflammatory bowel disease.
But we did not observe any improvements in the bowel disease activity. This could be for several reasons. Inflammatory bowel disease is hard to treat even with strong anti-inflammatory drugs such as steroids, so talk therapy may not be strong enough.
Talk therapy may only help when it’s offered to people experiencing a flare up in their disease. The majority of the included studies in our review were of people in remission, so we don’t know if talk therapy could help those who flare.
On the other hand, in our latest review of 15 studies, we showed antidepressants had a positive impact on inflammatory bowel disease as well as anxiety and depression. It’s important to note the studies in this review were few and largely observational, which means they showed associations between symptoms and antidepressant use rather than proving antidepressants caused a decrease in symptoms.
The studies showed symptoms such as diarrhoea and constipation improved in 56% of those who took antidepressants, compared to 35% in the group who received a placebo. Abdominal pain significantly improved in around 52% of those who took antidepressants, compared to 27% of those in the placebo group.
Symptoms also improved in around 48% of patients receiving psychological therapies, compared with nearly 24% in the control group, who received another intervention such as usual management. IBS symptoms improved in 59% of people who had cognitive behavioural therapy, compared to 36% in the control group.
Stress management and relaxation were found to be ineffective. Interestingly, hypnotherapy was also found effective for bowel symptoms in 45%, compared to 23% of control therapy participants.
Better studies exploring the role of talk therapy and antidepressants for symptoms of inflammatory bowel disease need to be conducted. We should know in a few years which patients are likely to benefit.
In the meantime, there is enough evidence for doctors to consider referring patients with irritable bowel syndrome for talk therapy and antidepressants.
The Taiwanese study looked at the stroke risks of 200,000 people on a PPI treatment course compared with a similar number of matched controls. There was a 36% higher risk of stroke during a 120 day follow-up after PPI medication.
Gender, history of myocardial infarction, diabetes, hypertension, NSAID use or type of PPI taken had no effect on the risk.
The researchers cautioned that their study was retrospective and therefore couldn’t prove cause and effect. But they speculated PPIs could increase plasma levels of asymmetric dimethylarginine, which is a risk factor for cardiovascular events.
Here are some other recent studies which have placed a serious question mark over the prescribing of PPIs:
A meta-analysis published in JAMA earlier this year found that PPI use increased the risk of recurrent Clostridium difficile infection by more than half.
Regular users of PPIs have a 44% greater risk of dementia, according to a German study of 74,000 people aged 75 or older.
The Sax Institute’s 45 and Up study showed a 70% increased risk of hospitalisation for infectious gastroenteritis in people using PPIs.
PPI use has been linked to chronic kidney damage even in the absence of acute disease. A study compared 125,000 people on PPIs with 18,000 users of H2 blockers, which are generally prescribed for the same conditions. Those on PPIs were much more likely to develop kidney disease.
A large Australian study confirmed a link between PPIs and fracture risk. It found 35% of elderly women on PPIs were subsequently diagnosed with osteoporosis, compared with 24% not on PPI therapy.
And finally, an Italian study found that people discharged from hospital with a PPI prescription had a 50% higher risk of dying within the year compared with those discharged without PPIs.
PPIs are one of the most commonly prescribed gastric acid suppressants, with over 19 million scripts written annually in Australia.
But the dangers of long-term PPI use is becoming increasingly recognised, with some Australian hospitals insisting on a deprescribing plan for all patients discharged with a PPI script.