What is somnolence, particularly in patients with a history of cognitive impairment or substance abuse taking pregabalin?

What is Somnolence

Somnolence is a state of excessive daytime sleepiness or drowsiness that impairs alertness and the ability to perform daily tasks, and when it occurs as a medication side effect—particularly with pregabalin—it represents a dose-dependent adverse reaction that requires careful monitoring, especially in patients with cognitive impairment or substance abuse history.

Clinical Definition and Presentation

Somnolence refers to a pathological state of drowsiness characterized by:

• Excessive daytime sedation that interferes with normal functioning and alertness 1
• Impaired consciousness ranging from mild drowsiness to more severe sedation 2
• Reduced ability to perform tasks such as driving or operating machinery 3
• Unexplained daytime drowsiness that may indicate underlying sleep disorders or medication effects 1

Somnolence as a Pregabalin Side Effect

Incidence and Characteristics

In pregabalin-treated patients, somnolence is one of the two most common adverse reactions, occurring in 15-25% of adult patients compared to 8% of placebo-treated patients. 4, 3

• Somnolence generally begins shortly after initiation of pregabalin therapy and occurs more frequently at higher doses 3
• In 42% of affected patients, somnolence persisted until the last dose in short-term controlled studies 3
• Somnolence was one of the adverse reactions most frequently leading to withdrawal (4%) from controlled studies 3
• Dose-related sedation is reported in approximately 10-30% of patients, depending on the dose used and speed of titration, typically occurring in the first 2 weeks of treatment 5

Pediatric Populations

• In pediatric patients 4 to less than 17 years of age, somnolence was reported in 21% of pregabalin-treated patients compared to 14% of placebo-treated patients 3
• In patients 1 month to less than 4 years of age, somnolence (including related terms lethargy, sluggishness, and hypersomnia) occurred in 15% compared to 9% of placebo-treated patients 3

Critical Safety Concerns in High-Risk Populations

Patients with Cognitive Impairment

Benzodiazepines and sedating medications like pregabalin should be avoided in older patients and in patients with cognitive impairment, because they have been shown to cause decreased cognitive performance. 1

• Elderly patients are at increased risk of dizziness, somnolence, confusion, balance disorder, tremor, and coordination abnormalities with pregabalin 4
• Lower starting doses and slower titration are recommended for elderly patients due to these heightened risks 4, 6

Patients with Substance Abuse History

Pregabalin possesses significant abuse potential, particularly among patients with a history of substance abuse, and can cause euphoric and dissociative effects when taken in doses exceeding therapeutic dosages. 7

• 88% of intoxicated patients with pregabalin abuse had moderate to severe symptoms including impaired consciousness (74%), respiratory distress (40%), agitation/aggressiveness (28%), restlessness (14%), hallucinations (8%), or seizures (8%) 2
• Pregabalin users consumed more additional substances than other patients (median 4 vs. 2 substances, p < 0.001) and were more often in opioid substitution treatment (41.2% vs. 21.7%, p < 0.001) 2
• The most co-abused drugs with pregabalin were benzodiazepines (66.3%), methadone (48.8%), buprenorphine (32.5%), and heroin (22.5%) 2

Respiratory Depression Risk

There is evidence from case reports, human studies, and animal studies associating pregabalin with serious, life-threatening, or fatal respiratory depression when co-administered with CNS depressants, including opioids, or in the setting of underlying respiratory impairment. 3

• When co-prescribing pregabalin with another CNS depressant, particularly an opioid, monitor patients for symptoms of respiratory depression and sedation 3
• Consider initiating pregabalin at a low dose in patients receiving concurrent CNS depressants or those with underlying respiratory impairment 3

Management of Pregabalin-Related Somnolence

Dose Optimization Strategy

• Start pregabalin at 75 mg at bedtime or 50 mg three times daily (150 mg/day total), with gradual increase weekly to effective dose 4
• The optimal benefit-to-risk ratio is achieved at 300 mg/day for most patients, as higher doses are not consistently more effective but cause significantly more adverse effects 4
• Tolerance to somnolence typically develops within a few weeks of treatment 8

Monitoring Requirements

• Monitor patients for symptoms of respiratory depression and sedation, especially when combining pregabalin with other CNS depressants 3
• Assess for signs of abuse, particularly in patients with a history of substance abuse, as pregabalin has Schedule V controlled substance status 9, 7
• Evaluate cognitive performance in elderly patients and those with pre-existing cognitive impairment 1

Distinguishing Somnolence from Other Sleep Disorders

Daytime Sedation vs. Hypersomnia

• Refractory daytime sedation can be treated with central nervous system stimulants like methylphenidate (starting dose 2.5-5 mg orally with breakfast) or modafinil 1
• Hypersomnia is characterized by mean sleep latency ≤8 minutes on Multiple Sleep Latency Test (MSLT), indicating objective excessive sleepiness 10
• Medication-induced somnolence should be distinguished from primary central disorders of hypersomnolence through careful medication review and consideration of polysomnography 10, 6

Critical Pitfalls to Avoid

• Do not ignore somnolence as a benign side effect in patients with cognitive impairment, as it significantly increases fall risk and further cognitive decline 1
• Do not combine pregabalin with other gabapentinoids or multiple CNS depressants without careful monitoring, as this creates an unacceptable additive sedative burden 4
• Do not abruptly discontinue pregabalin if somnolence necessitates stopping the medication—taper gradually over a minimum of 1 week to avoid withdrawal symptoms 3
• Do not prescribe standard doses in patients with renal impairment, as pregabalin is primarily excreted unchanged by the kidneys and requires mandatory dose reduction 4