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Gabapentin users may face 85% higher cognitive impairment risk

Gabapentin users may face 85% higher cognitive impairment risk

Gabapentin is a medication that, in the United States, is approved to treat seizures and shingles-related neuralgia. It is also used off-label to treat other health issues, including low back pain. Past studies have also found that using gabapentin may increase a person's risk of developing cognitive impairment and dementia. A new study reports that people who receive six or more prescriptions of gabapentin for lower back pain are at a higher risk of developing dementia and mild cognitive impairment.Scientists found these risks were more than doubled in adults between the ages of 35 to 49 years.Gabapentin is a medication that is approved by the Food and Drug Administration (FDA) for the treatment of some epileptic seizures, moderate-to-severe restless legs syndrome, and postherpetic neuralgia, which is a nerve pain associated with shingles. Additionally, gabapentin is sometimes prescribed off-label for anxiety disorders, insomnia, hot flashes, alcohol use disorder, akathisia, diabetic peripheral neuropathy, and lower back pain. Like all medications, gabapentin has some potential side effects, including dizziness, tiredness, water retention, and dry mouth. Past studies have also found that using gabapentin may cause breathing difficulties, and may increase a person's risk of developing cognitive impairment and dementia. Now, a new study published in the journal Regional Anesthesia & Pain Medicine reports that people who receive six or more prescriptions of gabapentin for lower back pain are at a higher risk of developing dementia and mild cognitive impairment (MCI). Scientists also discovered these risks were more than doubled in adults between the ages of 35 to 49 years.Gabapentin: How does it affect dementia, MCI risk?For this study, researchers analyzed data from more than 26,000 adults through the federated health research network TriNetX.Scientists selected participants who had a diagnosis of chronic pain, chronic pain syndrome, lumbar radiculopathy, and chronic low back pain. They also categorized study participants into different age groups: 18–64, 18–34, 35–49, 50–64, and 65 or older. Researchers assess 10-year outcomes on study participants to see what percentage developed dementia, generally, or specifically Alzheimer's disease, vascular dementia, or MCI. 'Currently, there is a discrepancy on whether taking gabapentin increases a patient's risk for developing dementia,' Nafis B. Eghrari, a 4th-year medical student at Case Western Reserve University School of Medicine in Cleveland, OH, and first author of this study, told Medical News Today.'Moreover, there lacks a strong understanding of how gabapentin impacts cognitive function and whether it contributes to neurodegenerative processes. Previous studies have shown mixed findings on this topic. Thus, we decided to explore this gap in the field,' explained Eghrari.6 or more gabapentin prescriptions linked to 85% higher MCI riskUpon analysis, researchers found that study participants who received six or more gabapentin prescriptions had a 29% higher risk of developing dementia, and an 85% greater chance of being diagnosed with MCI.'The significance of this finding is an association between gabapentin prescription and dementia on a nationwide level,' Eghrari explained. 'Though this does not imply causation, this warrants further investigation on the drug's long-term effects.''In terms of clinical significance, I recommend that physicians prescribing gabapentin for chronic pain perform cognitive exams on a regular basis when seeing patients,' he continued.'I'd also advise patients who are taking this drug to alert their physician if they notice any cognitive deficits, including confusion, poor memory, or slowed thinking,' said the researcher.Risks doubled in 35–49-year-oldsEghrari and his team also discovered that when looking at participants by age groups, the risks for dementia more than doubled and more than tripled for MCI in people who were 35 to 49 years old. 'We were surprised to find this relatively higher risk in the non-elderly population,' Eghrari said.'These results indicate that gabapentin may have a greater cognitive impact on non-elderly individuals, as elderly individuals are already at risk for neurodegeneration due to their older age. This finding warrants further investigation into the underlying mechanism of how gabapentin may impact cognition.' – Nafis B. Eghrari'The key takeaway of this study is that patients prescribed gabapentin for chronic back pain should be closely monitored by their physician for cognitive decline,' he continued. 'Moreover, gabapentin should be prescribed with caution due to the associated risk of dementia/cognitive impairment.''We hope to carry this research forward and explore whether there is a true causative relationship between gabapentin and cognitive impairment,' Eghrari added. 'We also plan to investigate the underlying mechanisms of how the drug may impact cognition.'What are the drawbacks of large dataset studies?MNT had the opportunity to speak with Neel Anand, MD, MCh Orth, a board-certified orthopedic spine surgeon and director of the Cedars-Sinai Spine Center in Los Angeles, about this study. Anand, who was not involved in the research, commented that there are pros and cons to studies with big data sets as there are many variables and it is hard to determine the true causative factor.Additionally, little or no information was provided on any other illnesses participants may have had or other medications they were taking.'The best thing I would take from the study is […] [that] there's not a single drug without a side effect — they all have some issues,' Anand pointed out. 'So the answer is, if you're chronically going to take something, you better watch out — something's [potentially] going to go wrong somewhere.'Anand said the best way to prove anything is to take a cohort of study participants who take a specific medication and nothing else, and compare them to another cohort who does not take the medication. And researchers need to ensure that participants take the medication if it is prescribed to them.He noted that, in some cases, patients do not follow the doctor's indications regarding prescription medication. 'Sometimes they do more, sometimes they'll take less,' Anand said. 'The only way to actually study [the real-life effects of long-term drug use] would be to literally take a thousand people and give them gabapentin and nothing else, and a thousand you don't, and then follow them over 5 years or more,' he suggested.Still, he admitted that 'at least we can be cognizant' that there may be a heightened risk of dementia with prolonged gabapentin use.That is 'a possibility that [doctors] needs to be aware [of] or at least counsel our patients [on] — that's fair,' Anand added.
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To Richard Lathe, a molecular biologist at the University of Edinburgh, UK, some of the most interesting evidence for this theory comes from a handful of cases where fungal and other microbial brain infections were coincidentally discovered in people initially diagnosed with Alzheimer's disease. In several cases where doctors prescribed infection-fighting medication, "the symptoms of dementia remitted", Lathe says. "Quite remarkably, some of them went back to work". Lathe believes that microbes slip across the blood-brain barrier quite frequently but are usually suppressed or killed in people with healthy immune systems. Because our immune systems weaken with age, that could allow microbes to accumulate in the brain, perhaps triggering nerve-killing inflammation. "It's only when the immune system declines that you see damage," he says. Scientists have long linked Alzheimer's to a build-up of certain proteins in the brain, but there's now a growing debate over whether the presence of those proteins is the cause or merely a symptom of the disease. Lathe argues these proteins are actually produced as a defence mechanism against microbial intrusion, based on research suggesting the proteins have infection-fighting properties. Further evidence that brain-intruding microbes could be causing Alzheimer's comes from experiments in mice, where scientists have witnessed the fungus Candida albicans entering the brain after the rodents' immune systems were compromised. And in one pre-print study – which hasn't yet been peer-reviewed by other scientists – Lathe and his colleagues examined brain slices from deceased healthy people and Alzheimer's patients. They found large quantities of bacteria, viruses and fungi in both groups – but more in the brains from patients who had Alzheimer's. If microbes are indeed a factor in Alzheimer's, we may be able to mitigate or even prevent the disease by strengthening people's immune defences, for instance with vaccines that have been shown to boost general immunity. But this theory is young, Lathe says. "It's a new idea." And a debated one, too. Olm and others argue it's hard to rule out that the microbial genetic material may have appeared because of contamination, as fragments of microbes tend to be ubiquitous. Lathe finds that unlikely, though, pointing to reports that microbe fragments in brain tissue are just as abundant inside the samples as they are on the surface, whereas contamination from the air would mostly settle on the brain surface. Still, Olm says that finding more microbe fragments in Alzheimer's brains isn't proof that those microbes cause the disease. For instance, those people's brains might simply have had a weaker blood-brain barrier or some other issue, meaning more microbes entered their brains over time before being killed off by their immune systems. However, new evidence that microbes can invade the brains of animals like fish strengthens the notion that this could be happening in mammals – and perhaps even humans, Olm says. In a 2024 study, scientists labelled bacteria with tiny, fluorescent green molecules and added them to tanks housing salmon and trout. "After a week, you see these microbes making their way into the fish brain, lighting the fish brain up green," Olm says, and curiously, "[the microbes] seemingly live there without huge consequences for these fish over their lifetime." In any case, the notion of fungi and other microbes getting into the brain in old age – either due to a weakening brain immune system or a worn-out blood brain barrier – is more plausible. "I think we've now reached that threshold where there's enough smoke around this hypothesis… it's worth spending money on figuring out if that is happening," Olm says. More like this:• What your snot can reveal about your health• Why the microbes that live on your skin matter• The mystery origins of Candida auris Interestingly, fungi might not need to enter the brain in order to influence it. In a 2022 study, immunologist Iliyan Iliev of Weill Cornell Medicine in the US and colleagues found that adding Candida albicans to the guts of mice made them more resilient to damage of their gut linings caused by bacterial infections or heavy antibiotic use. Strengthening the gut wall may be a defence mechanism by the body to prevent the fungus and other microbes from escaping the gut and infecting other tissues, Iliev says. But the big surprise came when the team observed the rodents' behaviour. Remarkably, fungi-colonised mice were much more likely to sniff, communicate and engage with other mice – meaning that exposure to the fungi appeared to have some sort of behavioural effect too. Based on other experiments, the scientists theorise that certain molecules released by the mice's immune cells enter the bloodstream and somehow stimulate certain nerve cells in the brain that are involved in behaviour. "It was very surprising to us," Iliev recalls. It's a mystery why, at least in mice, this crosstalk between gut fungi and the brain exists. Is it a coincidence that fungus-triggered immune signals affect the brain, or "is that actually deliberately done by the fungus to benefit its survival?" Iliev asks. Perhaps mammalian bodies somehow benefit from changing their behaviour in response to fungi, Iliev speculates. There's no evidence yet that this crosstalk between gut fungi and the brain happens in humans, but the possibility would be worth investigating, Olm says. In recent years, evidence has mounted that gut-dwelling bacteria may be able to send signals to the brain via the immune and nervous systems, or by producing substances associated with the symptoms of depression, anxiety, and relaxation. In principle, Olm says, "there's no reason to think that fungi aren't doing this as well". (Read more about how gut bacteria could be influencing the brain). Some scientists are even investigating whether fungi could be involved in mental disorders. Several studies have found differences in the makeup of gut fungi in people who suffer from depression or bipolar disorder. In women with schizophrenia, those who showed signs of exposure to the gut-dwelling Candida albicans tended to score lower on tests of memory and other cognitive abilities, according to a 2016 study by Johns Hopkins neuroscientist Emily Severance and her colleagues. She is exploring the possibility that Candida overgrowth – caused by stress or antibiotics, for instance – provokes an imbalance of gut microbes, altering the substances they produce in ways that make susceptible people more likely to develop schizophrenia. If true, it could allow doctors to treat schizophrenia symptoms by giving people probiotics that help reverse the overabundance of Candida – which would in any case be helpful, she says. But finding an association doesn't mean that the fungi cause schizophrenia. It could simply be that these patients are somehow more prone to high levels of Candida. So far "we can only come up with associations", says Severance. 'I think that that's typical for a field of study that is very exciting – but still very early on in the timeline.' Which of our fungal inhabitants – if any at all – are really influencing our brains is something scientists hope to learn in the coming years. "[Fungi are] definitely important," Drummond says, "but exactly how they're important, I think, is still being worked out." One thing is already clear: while bacteria have long been in the limelight, it may be time we also pay serious attention to the fungi quietly shaping our health from within. -- For trusted insights into better health and wellbeing rooted in science, sign up to the Health Fix newsletter, while The Essential List delivers a handpicked selection of features and insights. For more science, technology, environment and health stories from the BBC, follow us on Facebook, X and Instagram.

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