What are the long-term risks of pregabalin (Lyrica) or gabapentin (Neurontin)?

Long-Term Risks of Pregabalin and Gabapentin

Both pregabalin and gabapentin carry significant long-term risks including dependence and withdrawal symptoms, cardiovascular complications, cognitive impairment with potential dementia risk, weight gain, peripheral edema, and respiratory depression when combined with opioids—risks that necessitate careful monitoring and avoidance in patients with substance use disorders. 1

Dependence and Withdrawal

Approximately 50% of patients prescribed gabapentinoids continue treatment for at least 12 months, a practice often not recommended by clinical guidelines or of doubtful efficacy. 1 The evidence demonstrates:

• Sudden cessation leads to physical and psychological withdrawal symptoms, requiring careful tapering and support for patients on long-term therapy 1
• Pregabalin appears more addictive than gabapentin regarding the magnitude of behavioral dependence symptoms and transitions from prescription to self-administration 2
• The principal at-risk population consists of patients with current or past substance use disorders, particularly opioid and multi-drug users 2
• Pure gabapentinoid overdoses are relatively safe but become lethal when mixed with opioids or sedatives, with pregabalin carrying higher risk than gabapentin 2

Cardiovascular Complications

Long-term gabapentinoid use is associated with significantly increased cardiovascular risk in patients with diabetic neuropathy. 3 The 5-year risks include:

• Deep venous thrombosis: 1.58-fold increased risk with gabapentin, 1.57-fold with pregabalin 3
• Pulmonary embolism: 1.5-fold risk (gabapentin), 1.28-fold (pregabalin) 3
• Peripheral vascular disease: 1.37-fold (gabapentin), 1.35-fold (pregabalin) 3
• Stroke: 1.31-fold (gabapentin), 1.26-fold (pregabalin) 3
• Myocardial infarction: 1.25-fold (gabapentin), 1.29-fold (pregabalin) 3
• Heart failure: 1.14-fold (gabapentin), 1.2-fold (pregabalin) 3

Even short-term (3-month) use shows significant associations with heart failure, myocardial infarction, peripheral vascular disease, and venous thromboembolism. 3

Cognitive Decline and Dementia Risk

Gabapentinoid exposure is associated with a 1.45-fold increased risk of dementia, with risk increasing proportionally to cumulative defined daily doses 4. Critical findings include:

• Younger patients (age <50) face the highest risk with a 3.16-fold increased hazard ratio compared to older patients 4
• The risk is significant across all age subgroups but particularly concerning in susceptible populations 4
• These medications should be used with extreme caution given this neurocognitive risk profile 4

Respiratory Depression

When gabapentinoids are combined with opioids, dangerous respiratory depression can occur. 1 This represents a critical safety concern:

• Watch for increased sleepiness or decreased breathing when starting treatment or increasing doses 5
• The combination increases overdose risk through cumulative and synergistic effects 1
• Serious breathing problems can occur in patients with pre-existing respiratory conditions 5

Weight Gain and Peripheral Edema

Pregabalin treatment causes weight gain in 9% of patients (≥7% over baseline) compared to 2% with placebo. 5 Additional metabolic concerns include:

• Peripheral edema occurs in 6% of gabapentinoid patients versus 2% with placebo 5
• Combined use with thiazolidinedione antidiabetic agents dramatically increases risk: 19% peripheral edema rate versus 3% with thiazolidinediones alone or 8% with pregabalin alone 5
• Weight gain averages 1.6 kg in diabetic patients, with some gaining up to 16 kg 5
• In long-term cohorts (≥2 years), average weight gain reaches 5.2 kg 5
• Exercise caution in patients with NYHA Class III or IV heart failure due to fluid retention risk 5

Ophthalmologic Effects

Blurred vision occurs in 7% of pregabalin-treated patients versus 2% with placebo. 5 Long-term monitoring reveals:

• Visual acuity reduction in 7% of treated patients 5
• Visual field changes detected in 13% of patients 5
• Funduscopic changes in 2% of patients 5
• Patients should notify physicians if vision changes occur, with consideration for more frequent ophthalmologic assessment 5

Common Adverse Effects Requiring Monitoring

According to the CDC and FDA labeling, monitor for 6, 5:

• Dizziness and somnolence (most common CNS effects)
• Cognitive impairment and confusion, particularly in elderly patients 6
• Peripheral edema and weight gain 6, 5
• Blurred vision 6
• Higher doses associated with increased withdrawal rates due to adverse events 6

Special Population Considerations

In elderly patients, neurological adverse reactions occur more frequently, including dizziness, blurred vision, balance disorder, tremor, confusional state, coordination abnormalities, and lethargy 5. Additional concerns:

• Pregabalin is substantially excreted by the kidney; dose adjustment required for renal impairment 5
• Risk of toxic reactions greater in patients with impaired renal function 5
• Use with caution in perioperative settings due to sedative effects 6

Clinical Implications

Given the substantial long-term risks, gabapentinoids should be avoided in patients with substance use disorder history 2, and if indispensable, administered with strict therapeutic and prescription monitoring 2. The evidence highlights the need for improved guidance, monitoring, and effective patient care for the approximately 50% of patients receiving continuous long-term prescriptions 1.