Cognitive Side Effects of Pregabalin
Pregabalin causes large increases in cognitive effects including confusion, difficulty with concentration/attention, and problems with cognition and language, with these effects being dose-dependent and occurring in 2-9% of patients depending on the dose. 1
Specific Cognitive Impairments
The FDA-approved labeling and CDC guidelines clearly document the following cognitive side effects:
Primary Cognitive Effects
- "Thinking abnormal" (FDA terminology) occurs in 1-3% at 300 mg/day and up to 6% at 600 mg/day in postherpetic neuralgia trials 2
- This category primarily consists of difficulty with concentration and attention, but also includes cognition problems, language difficulties, and slowed thinking 2
- Confusion occurs in 1-3% at 300 mg/day and up to 7% at 600 mg/day 2
- Amnesia (memory problems) occurs in 1-2% at 300 mg/day and up to 4% at 600 mg/day 2
Associated Neurological Effects That Impact Cognition
- Dizziness occurs in 23-46% of patients (large increase versus placebo) 1, 3
- Somnolence/sedation occurs in 15-25% of patients (large increase versus placebo) 1, 3
- Speech disorder occurs in up to 3% at 600 mg/day 2
- Blurred vision occurs in 3-9% depending on dose (large increase versus placebo) 1
Evidence from Controlled Studies
Class I Evidence in Healthy Volunteers
A rigorous double-blind, placebo-controlled study in 32 healthy volunteers demonstrated that pregabalin 600 mg/day (300 mg twice daily) caused significant negative cognitive effects on three of six target measures after 12 weeks 4:
- Digit Symbol test (processing speed and attention): significantly impaired versus placebo
- Stroop test (executive function and cognitive flexibility): significantly impaired versus placebo
- Controlled Oral Word Association (verbal fluency): significantly impaired versus placebo
- These effects were paralleled by subjective complaints on the Portland Neurotoxicity Scale 4
This Class I evidence demonstrates that cognitive impairment occurs even in healthy individuals without underlying neurological conditions, suggesting the effects are direct pharmacological consequences rather than disease-related 4.
Dose-Dependent Relationship
The cognitive side effects show clear dose-dependency, with higher doses causing substantially more problems 1:
- At 150 mg/day: "thinking abnormal" occurs in 1-2% of patients 2
- At 300 mg/day: "thinking abnormal" occurs in 1-3% of patients 2
- At 600 mg/day: "thinking abnormal" occurs in 3-6% of patients 2
The CDC guidelines specifically note that higher dosages of pregabalin are associated with increased risk for withdrawal due to adverse events, including cognitive effects 1.
Clinical Significance and Management
Impact on Quality of Life
The cognitive effects are significant enough that they contribute to treatment discontinuation in clinical practice 5. In an audit of 96 epilepsy patients, 2 patients discontinued pregabalin specifically due to cognitive side effects 5.
Comparison to Other Medications
Pregabalin shows less cognitive and psychomotor impairment than alprazolam (a benzodiazepine), though it still causes measurable effects 6. Both pregabalin and gabapentin cause large increases in cognitive effects with similar profiles 1.
High-Risk Populations
Elderly Patients
Elderly patients face substantially higher risk for cognitive side effects 3:
- Increased susceptibility to confusion, dizziness, and somnolence 3
- Higher risk of falls secondary to cognitive impairment and dizziness 3
- Lower starting doses (50 mg three times daily or 75 mg twice daily) and slower titration are mandatory 3
Patients with Baseline Cognitive Impairment
The American Geriatrics Society specifically warns about using pregabalin in patients with existing cognitive deficits, as the additive effects can be substantial 3.
Critical Clinical Pitfalls to Avoid
Do not assume cognitive effects will resolve with continued treatment - while tolerance develops to dizziness and somnolence within a few weeks 6, the controlled study in healthy volunteers showed persistent cognitive impairment after 12 weeks 4
Do not routinely prescribe 600 mg/day - this maximum dose causes significantly more cognitive side effects without consistently providing additional pain relief compared to 300 mg/day 3
Do not combine with other CNS depressants without extreme caution - the FDA warns that serious breathing problems and enhanced sedation occur when pregabalin is combined with opioids, benzodiazepines, or other CNS depressants 2
Do not abruptly discontinue - taper gradually over at least 1 week to avoid withdrawal symptoms, which can include cognitive disturbances 3
Monitoring Recommendations
- Assess cognitive function before initiating therapy to establish baseline 4
- Monitor specifically for concentration difficulties, memory problems, confusion, and slowed thinking during dose titration 2
- Consider dose reduction if cognitive effects emerge, as these are dose-dependent and often manageable without complete discontinuation 1, 7
- In elderly patients, monitor closely for falls risk related to combined cognitive impairment and dizziness 3