A large study has linked gabapentin use to increased dementia risk in adults under 65, but experts say the findings may reflect confounding and reverse causality rather than a direct drug effect.
Researchers analysing more than a decade of patient data found that receiving six or more prescriptions of gabapentin for chronic low back pain was associated with a 29% increased risk of developing dementia, and an 85% higher risk of mild cognitive impairment, compared to matched patients who were never prescribed the drug.
Most strikingly, the risks were more than doubled in younger adults aged 18 to 64, a group “normally considered too young to develop either condition”, the study authors said in Regional Anesthesia & Pain Medicine [link here].
They noted gabapentin, originally approved in the 1990s to treat partial seizures, was now commonly prescribed for chronic and neuropathic pain including sciatica, fibromyalgia and spinal conditions. Its popularity stemmed in part from its low abuse potential compared to opioids, and its perceived neuroprotective benefits.
However, evidence around its long-term neurological safety had been mixed, prompting researchers to take a closer look, said the team led by Nafis Eghrari, a medical student at Case Western Reserve University, Cleveland in the US.
“The findings of this study support the need for close monitoring in adult patients prescribed gabapentin to assess for potential cognitive decline,” they wrote.
“Moreover, this provides a foundation to further research whether gabapentin plays a causal role in the development of dementia and cognitive decline,” the researchers added.
The observational cohort study drew on anonymised records from 68 healthcare organisations across the US, using real-time electronic health data via the TriNetX research network. After applying exclusion criteria and propensity score matching to account for comorbidities and concurrent medications, researchers analysed 26,416 patients in both the gabapentin and no-gabapentin cohorts.
The findings suggested a dose-response relationship: patients with 12 or more prescriptions had a 40% greater risk of developing dementia and a 65% higher risk of mild cognitive impairment than those prescribed the drug between three and 11 times.
Age stratification revealed the clearest signals in middle-aged adults. In the 35–49 age group, gabapentin use was associated with 2.4 times the risk of dementia and 3.5 times the risk of mild cognitive impairment. Among those aged 50–64, the risk of both conditions more than doubled. No statistically significant difference was observed in patients aged 18–34.
Although the study did not prove causation, the authors stressed that the strength and consistency of the associations warranted concern and further investigation.
“Our results support the need for close monitoring of adult patients prescribed gabapentin to assess for potential cognitive decline,” they wrote.
Experts urge caution
Experts reviewing the findings welcomed the study’s scale but urged caution in interpreting the results.
“This study found an association between gabapentin and dementia,” said Professor Ian Maidment, Professor in Clinical Pharmacy at Aston University in England. “It was an observational study and therefore conclusions about causality cannot be drawn … The jury is out on whether gabapentin causes dementia.”
Others noted the possibility of reverse causality – that is, patients experiencing early, undiagnosed signs of dementia may have presented with pain or cognitive symptoms that led to gabapentin being prescribed in the first place.
“Reverse causality must always be considered in dementia cohort studies, given the 20 years or more interval between the earliest detectable signs of Alzheimer’s disease and clinical onset,” said Professor Martin Prince, Professor of Epidemiological Psychiatry at King’s College London.
“It is possible that the CNS effects of Alzheimer’s disease modulate pain processing and appreciation, leading to more complaints of more severe pain – and ultimately the gabapentin prescription, not vice versa.”
Professor Prince also flagged potential issues with the study’s use of diagnostic codes, noting that the inclusion of patients with mild cognitive impairment, frontotemporal dementia or dementia with Lewy bodies at baseline was not clearly explained, and may have influenced the findings.
Additionally, he said the inclusion criteria extended beyond chronic low back pain to encompass other forms of chronic pain, including post-herpetic neuralgia and diabetic neuropathy – conditions that may themselves be linked to increased dementia risk. “Confounding by indication remains a distinct possibility,” he added.
Other experts raised concerns about unmeasured variables that could have influenced the results.
“One very important factor not examined in this study is levels of physical activity,” said Professor Tara Spires-Jones, Director of the Centre for Discovery Brain Sciences at the University of Edinburgh. “People with chronic pain requiring gabapentin may have been less physically active, which is a known risk factor for developing dementia.”
The researchers acknowledged the limitations of their retrospective design, including the inability to adjust for dosage or treatment duration. However, they noted the study’s strengths included its large sample size, decade-long follow-up, and robust adjustment for key confounders using propensity score matching.
Mechanistically, the drug’s modulation of voltage-gated calcium channels, which influence neurotransmitter release, may underlie its potential cognitive effects. Experimental data have also pointed to possible roles in glial signalling, neuroinflammation and synaptic plasticity, all of which are implicated in dementia pathogenesis, the researchers note.
While the clinical implications remain uncertain, the study adds to growing international scrutiny over the cognitive safety profile of gabapentinoids, particularly in younger and middle-aged adults prescribed the drug long-term.
“Research shows that nearly half of dementia cases could be prevented or delayed if modifiable risk factors are addressed,” said Dr Leah Mursaleen, Head of Clinical Research at Alzheimer’s Research UK.
“Because this study only used health records of people with chronic pain, we cannot rule out other factors that might be influencing the findings. At the moment, there’s not enough evidence to suggest pain medications are linked to higher dementia risk, but this research gives us interesting insights.”