Gabapentin Linked to Dementia Risk: What Pharmacists Need to Know

Gabapentin has become a go-to medication for chronic pain management, praised for its relatively favorable safety profile and lower abuse potential compared to opioids. But a recent study published in Regional Anesthesia & Pain Medicine raises important questions about its long-term cognitive effects, questions that every pharmacist, pharmacy student, and healthcare professional should be asking.

The Study at a Glance

Researchers analyzed data from over 1.4 million adult patients diagnosed with chronic low back pain between 2004 and 2014, using the TriNetX national database. After rigorous propensity score matching to control for demographics, comorbidities, and other pain medications, they compared 26,416 patients prescribed gabapentin with an equal number not receiving the drug.

The findings? Patients with six or more gabapentin prescriptions showed a 29% increased risk of dementia (RR: 1.29; 95% CI: 1.18–1.40) and an 85% increased risk of mild cognitive impairment (RR: 1.85; 95% CI: 1.63–2.10) within 10 years of their initial pain diagnosis.

The Age Factor: A Surprising Twist

While we might expect elderly patients to be most vulnerable to cognitive decline, the data tells a more nuanced story. Non-elderly adults (ages 18–64) prescribed gabapentin faced over twice the risk of developing dementia (RR: 2.10) and mild cognitive impairment (RR: 2.50) compared to those not taking the medication.

Breaking it down further:

• Ages 35–49: 2.44-fold increased dementia risk and 3.50-fold increased MCI risk
• Ages 50–64: 2.28-fold increased dementia risk and 2.22-fold increased MCI risk
• Ages 18–34: No significant difference detected (though numbers were small)
• Ages 65+: 1.28-fold increased dementia risk and 1.53-fold increased MCI risk

The stronger association in younger adults is particularly striking and warrants careful consideration when prescribing gabapentin to middle-aged chronic pain patients.

Dose Matters: The Prescription Frequency Connection

The study also examined whether prescription frequency—a proxy for cumulative exposure—influenced outcomes. Patients with 12 or more prescriptions showed significantly higher rates of dementia (RR: 1.40) and MCI (RR: 1.65) compared to those with 3–11 prescriptions.

This dose-response relationship strengthens the case for a potential causal connection, though the retrospective design prevents definitive conclusions about causality.

What's Happening in the Brain?

Gabapentin's mechanism of action provides some clues to these findings. The drug binds to the α2δ-1 subunit of voltage-gated calcium channels, reducing the release of excitatory neurotransmitters. While this effectively dampens pain signaling and seizure activity, chronic modulation of these pathways may have unintended consequences.

Several mechanisms could explain the cognitive effects:

Neuroinflammation: Gabapentin activates spinal glial cells, and chronic microglial activation plays a central role in dementia pathophysiology.

Reduced Neuroplasticity: Long-term exposure may decrease neurogenesis and synaptic plasticity in memory-related brain regions.

GABA Modulation: By increasing GABA levels and chronically suppressing neuronal excitability, gabapentin might contribute to cognitive slowing over time.

Calcium Channel Effects: Prolonged calcium channel modulation could affect long-term synaptic function and memory consolidation.

Clinical Implications for Pharmacy Practice

This research doesn't mean gabapentin should be abandoned—it remains an effective medication for specific indications like postherpetic neuralgia and diabetic neuropathy. However, it does suggest we need a more thoughtful approach:

For Pharmacists:

1. Counsel patients about potential cognitive effects, especially those under 65
2. Monitor refill patterns and discuss alternatives for patients requiring long-term therapy
3. Document baseline cognitive status when possible for patients starting gabapentin
4. Consider medication reviews for patients on chronic gabapentin therapy who report memory concerns

For Prescribers:

1. Weigh risk versus benefit more carefully in non-elderly adults
2. Use the lowest effective dose for the shortest necessary duration
3. Consider alternatives for chronic pain management when appropriate
4. Monitor cognitive function in patients on long-term therapy

Study Limitations and Context

It's important to note this study's limitations. The retrospective design means we can't establish causation—only association. The researchers couldn't control for specific dosages or duration of use, and database studies always carry risks of coding errors and lost follow-up.

Interestingly, not all research agrees. One 2024 study of over 200,000 chronic pain patients found no increased dementia risk with gabapentin use. Some studies even suggest gabapentin may be well-tolerated in elderly patients with existing dementia.

These conflicting findings highlight the need for prospective studies specifically designed to assess gabapentin's long-term cognitive effects.

The Bottom Line

This large-scale study adds important evidence to an ongoing conversation about gabapentin's cognitive safety profile. While the drug remains valuable for specific indications, healthcare professionals should:

• Exercise increased caution when prescribing to non-elderly adults for chronic conditions
• Consider cognitive monitoring for patients on long-term therapy
• Explore alternative pain management strategies when appropriate
• Stay informed as more research emerges

For pharmacists and pharmacy students, this research underscores the importance of comprehensive medication reviews and patient counseling. As medication experts, we're uniquely positioned to identify patients who might benefit from therapy adjustments and to advocate for evidence-based prescribing practices.

The goal isn't to create fear around a widely-used medication, but to ensure we're using it thoughtfully, with full awareness of potential long-term risks. After all, that's what evidence-based practice is all about—continually refining our approach as new data emerges.