What are the risks of long-term gabapentin (Neurontin) use?

Risks of Long-Term Gabapentin Use

Long-term gabapentin use carries significant risks including physical dependence with withdrawal symptoms, increased falls and fractures (especially at doses ≥600 mg/day), cognitive impairment, sedation, dizziness, peripheral edema, and potential for misuse—risks that accumulate with prolonged exposure beyond 12 months. 1, 2, 3

Physical Dependence and Withdrawal

• Abrupt discontinuation of gabapentin after long-term use can precipitate serious withdrawal problems, including withdrawal-precipitated seizures and status epilepticus in patients with epilepsy. 2
• In England, approximately 50% of patients prescribed gabapentinoids had been treated continuously for at least 12 months, a practice of doubtful efficacy in many cases and associated with physical and psychological withdrawal symptoms upon cessation. 1
• Physical dependence develops through neuroadaptive changes that require time to establish, typically requiring more than 5 days of continuous administration based on pediatric intensive care data. 4
• Gabapentin should never be stopped abruptly; gradual tapering with medical supervision is mandatory to avoid withdrawal complications. 2

Falls, Fractures, and Neurologic Adverse Effects

• Gabapentin significantly increases the risk of falls or fractures with a clear dose-response relationship—the highest risk occurs at doses ≥2,400 mg/day (RR 1.90). 3
• In a large cohort of 571,718 US Veterans, gabapentin exposure was associated with an incidence of falls or fractures of 1.81 per 100 person-years compared to 1.34 per 100 person-years in unexposed patients (RR 1.35). 3
• Altered mental status occurs at an increased rate with gabapentin exposure (RR 1.12), particularly at doses between 600-2,399 mg/day. 3
• Common CNS adverse effects reported in long-term studies (up to 2 years) include nystagmus, somnolence, diplopia, tremor, ataxia, and dizziness. 5
• Somnolence and dizziness are dose-dependent, occurring in 19-21% and 17-28% of patients respectively in controlled trials, compared to 5-9% with placebo. 2

Cognitive and Behavioral Effects

• Long-term gabapentin use can cause decreased cognition, particularly affecting concentration and memory. 1
• In children aged 3-12 years, gabapentin causes emotional changes, aggressive behavior, problems with concentration, restlessness, changes in school performance, and hyperactivity. 2
• These cognitive impairments may be particularly problematic in elderly patients and those with baseline cognitive dysfunction. 1

Metabolic and Physical Effects

• Peripheral edema and weight gain are common with prolonged gabapentin use, especially in elderly patients. 6
• Visual disturbances including acute myopia, ocular pain, and potential visual field restriction have been reported. 1, 6
• Gabapentin does not cause consistent changes in clinical laboratory values during long-term treatment. 5

Suicidal Ideation and Psychiatric Risks

• Gabapentin, like all antiepileptic drugs, approximately doubles the risk of suicidal thoughts or behavior (adjusted RR 1.8), with an estimated incidence of 0.43% versus 0.24% with placebo. 2
• This increased risk appears as early as one week after starting treatment and persists throughout treatment duration. 2
• Four suicides occurred in drug-treated patients across pooled AED trials, though numbers were too small for definitive conclusions. 2
• Patients require monitoring for emergence or worsening of depression, unusual mood changes, or suicidal thoughts. 2

Drug Interactions and Synergistic Risks

• When combined with opioids, benzodiazepines, or other CNS depressants, gabapentin causes dangerous synergistic respiratory depression and enhanced sedation. 1
• Concomitant morphine treatment increases gabapentin concentrations, requiring dose adjustment. 2
• The 2019 AGS Beers Criteria recommends using gabapentinoids with caution when combined with other CNS-active drugs due to increased fall risk and cognitive impairment. 1
• Abrupt discontinuation is particularly problematic when gabapentin is used concurrently with benzodiazepines or opioids. 4

Special Population Considerations

• Elderly patients and those with renal dysfunction require dose adjustments and heightened caution due to drug accumulation and increased adverse effects. 1
• Patients with hepatitis C, HIV, or alcohol use disorder have elevated baseline incidence of falls, fractures, and altered mental status regardless of gabapentin exposure, though gabapentin adds additional risk. 3
• Gabapentin is eliminated unchanged in urine, requiring dose reduction even in moderate renal failure (creatinine clearance <60 mL/min). 6

Efficacy Concerns with Long-Term Use

• For perioperative pain management, gabapentinoids should be limited to a single lowest preoperative dose to avoid sedative side effects, as repeated dosing shows no additional benefit. 1
• Long-term efficacy beyond initial treatment periods remains uncertain, with 30% of patients in long-term studies withdrawing due to lack of efficacy. 5
• For chronic non-cancer pain, opioids (and by extension gabapentinoids used with opioids) have little effectiveness beyond short-term use. 1

Rare but Serious Adverse Reactions

• Gabapentin can cause serious or life-threatening allergic reactions affecting skin, liver, or blood cells, requiring immediate discontinuation. 2
• Symptoms include skin rash, hives, difficulty breathing, fever, swollen glands, facial swelling, jaundice, unusual bruising or bleeding, severe fatigue, unexpected muscle pain, and frequent infections. 2
• Animal studies with pregabalin (closely related to gabapentin) suggest possible risk of hemangiosarcoma, though no human cases have been described. 6

Monitoring and Risk Mitigation

• Clinicians should monitor gabapentin safety especially at doses ≥600 mg/day in all patients, with or without comorbid conditions. 3
• For neuropathic pain management, gabapentin is recommended as second-line after tricyclic antidepressants, not for routine first-line use. 1
• When long-term treatment exceeds 12 months, the risk-benefit ratio should be reassessed given evidence that approximately half of long-term prescriptions may be of doubtful efficacy. 1