What are the potential drug interactions and adverse effects of gabapentin (Neurontin), particularly in patients with impaired renal function or those taking central nervous system (CNS) depressants?

Gabapentin Drug Interactions and Adverse Effects

Critical Drug Interactions

Gabapentin has minimal traditional drug-drug interactions but poses serious risks when combined with CNS depressants, particularly opioids, benzodiazepines, and other gabapentinoids. 1, 2

CNS Depressant Combinations (Most Important)

• Concurrent use of gabapentin with high-dose opioids (≥50 morphine milligram equivalents daily) significantly increases all-cause mortality risk (adjusted hazard ratio 2.03,95% CI 1.19-3.46) compared to duloxetine users on similar opioid doses. 3

• Gabapentin combined with opioids, benzodiazepines, or other CNS depressants causes synergistic respiratory depression and should be avoided outside highly monitored clinical settings. 1

• The combination increases risk of excessive sedation, dizziness, visual disturbances, falls, confusion, and respiratory failure—particularly dangerous in elderly patients. 1, 4

• If combination with CNS depressants is unavoidable, use the lowest effective gabapentin dose (single preoperative dose ≤75-150 mg) and implement close monitoring for respiratory depression. 1

Gabapentinoid Combinations

• Never combine gabapentin with pregabalin—this creates unacceptable additive sedative burden without established efficacy benefits, as both medications have identical mechanisms of action and adverse effect profiles. 2, 5

• No randomized controlled trials demonstrate superiority of combining two gabapentinoids over optimizing the dose of either medication alone. 2

Metabolic Drug Interactions

• Gabapentin has no clinically significant CYP450 interactions—it is not metabolized and does not inhibit or induce hepatic enzymes. 6

• Phenytoin, carbamazepine, and valproic acid do not affect gabapentin pharmacokinetics, and gabapentin does not alter their plasma concentrations. 6

• Food increases gabapentin absorption by only 14%, which is not clinically significant. 6

Adverse Effects Profile

Common Dose-Dependent Effects

• Dizziness (most common): occurs in patients receiving therapeutic doses, managed by gradual titration and dose reduction if intolerable. 2, 5

• Somnolence: reported by 80% of patients at 2400 mg/day in HIV neuropathy trials, typically mild to moderate and often transient. 5

• Peripheral edema and ataxia increase in incidence with age, particularly in patients ≥75 years. 6

• Weight gain, dry mouth, constipation, and gait disturbance occur at similar rates across age groups. 2

Serious Adverse Effects in Vulnerable Populations

• Respiratory depression risk increases dramatically when gabapentin is combined with opioids or other CNS depressants, especially in patients with underlying respiratory disease. 1, 3, 4

• Elderly patients experience increased susceptibility to falls, confusion, sedation, balance disorders, tremor, and coordination abnormalities. 2, 5

• Altered mental status, myoclonus, and severe neurologic toxicity occur with drug accumulation in renal impairment—symptoms include excessive sedation, dizziness, somnolence, gait disturbance, and confusion. 7, 8, 9

Withdrawal Symptoms

• Abrupt discontinuation causes withdrawal symptoms—taper gradually over minimum of 1 week (extend to 2 weeks if symptoms occur during taper). 2, 5

Critical Considerations in Renal Impairment

Gabapentin is almost exclusively eliminated by renal excretion as unchanged drug, making dose adjustment mandatory in patients with compromised renal function. 7, 6

Pharmacokinetic Changes

• Elimination half-life increases from 5-7 hours in normal renal function to 52 hours in severe impairment (CrCl <30 mL/min) and 132 hours in anuric patients. 6, 8

• Plasma clearance decreases from approximately 190 mL/min in normal function to 20 mL/min in severe impairment. 6

• Gabapentin renal clearance is directly proportional to creatinine clearance—calculate CrCl using Cockcroft-Gault equation before initiating therapy. 7, 6

Mandatory Dose Adjustments

• For CrCl 30-60 mL/min: reduce total daily dose by approximately 50%. 2

• For CrCl 15-29 mL/min: start at 100-200 mg once daily with maximum dose of 200-700 mg/day as single daily dose. 7

• For CrCl <15 mL/min: reduce total daily dose by 85-90%. 2

• Approximately 25.9% of gabapentin users have glomerular filtration requiring dose adjustment, yet 5.9% receive doses higher than authorized. 4

Hemodialysis Considerations

• Hemodialysis significantly removes gabapentin—elimination half-life reduces from 132 hours on non-dialysis days to 3.8 hours during dialysis. 6

• Supplemental dosing after each dialysis session is necessary. 6

Critical Pitfall in Elderly Patients

• Never assume normal renal function in elderly patients based on serum creatinine alone—age-related decline in renal function is often masked by reduced muscle mass, and creatinine-based equations can misclassify kidney disease by one stage in >30% of elderly participants. 2

• Apparent oral clearance of gabapentin decreases from 225 mL/min in patients <30 years to 125 mL/min in patients >70 years, largely explained by declining renal function. 6

High-Risk Patient Populations

Polypharmacy and Chronic Disease

• Gabapentin combined with opioids and/or anxiolytics/hypnotics is significantly associated with polypharmacy (5-9 drugs: OR 3.42; ≥10 drugs: OR 8.72), increased chronic diseases (OR 1.14), and augmented consultations/year (OR 1.01). 4

• Polypharmacy was present in 41.7% of gabapentin users (5-9 drugs) and extreme polypharmacy in 39.3% (≥10 drugs). 4

Elderly Patients

• Gabapentin use increases 2.6-fold in ages 65-74,3.8-fold in ages 75-84, and 4.0-fold in ages ≥85 compared to younger patients. 4

• Start elderly patients at lower doses (100-200 mg/day) with slower titration (increases every 3-7 days) due to decreased renal function and increased vulnerability to side effects. 5

• Treatment effect is larger in patients ≥75 years, likely due to increased gabapentin exposure from age-related decline in renal function. 6

Pregnancy and Nursing

• Gabapentin causes embryo-fetal toxicity in animal studies at doses equivalent to or less than maximum recommended human dose—increased skeletal variations in mice, hydroureter/hydronephrosis in rats, and embryo-fetal mortality in rabbits. 6

• Gabapentin interferes with neuronal synapse formation in neonatal mice during synaptogenesis period (corresponding to last trimester in humans). 6

• Gabapentin is secreted into human milk—nursed infants could be exposed to approximately 1 mg/kg/day, with unknown effects. 6

• Pregnant patients should enroll in North American Antiepileptic Drug Pregnancy Registry (1-888-233-2334). 6

Monitoring Recommendations

• Calculate creatinine clearance before initiating therapy and monitor regularly during treatment, especially in elderly patients. 2, 7

• Monitor for dizziness, somnolence, gait disturbance, confusion, and other neurological side effects, particularly during dose titration. 2, 5

• In patients receiving concurrent high-dose opioids (≥50 MME/day), closely monitor for respiratory depression and consider alternative analgesic strategies. 3

• Be particularly cautious in elderly patients who may be more susceptible to falls due to dizziness and ataxia. 2, 6

• Consider therapeutic drug monitoring in dialysis patients to avoid unintended overdose—indication and dose should be tightly controlled. 8