What are the effects of Gabapentin, Pregabalin, and Metoclopramide, particularly in elderly patients or those with impaired renal function, a history of seizures, or psychiatric disorders?

Effects of Gabapentin, Pregabalin, and Metoclopramide

Gabapentin Effects

Gabapentin is a GABA analogue that binds to the α2δ subunit of voltage-activated calcium channels, reducing neurotransmitter release, with primary effects including anticonvulsant and analgesic properties for neuropathic pain, but carries significant risks of dizziness (19%), somnolence (14%), peripheral edema (7%), and gait disturbance (9%), particularly in elderly patients and those with renal impairment. 1, 2

Mechanism and Pharmacology

• Gabapentin binds with high affinity to the α2δ subunit of voltage-activated calcium channels, though the precise relationship to therapeutic effects remains unknown 1
• The drug is structurally related to GABA but has no effect on GABA binding, uptake, or degradation 1
• Gabapentin is not metabolized and is eliminated unchanged by renal excretion, with a half-life of 5-7 hours 1
• Bioavailability is non-linear and decreases with higher doses: 60% at 900 mg/day, 47% at 1200 mg/day, 34% at 2400 mg/day, and 27% at 4800 mg/day 1

Therapeutic Effects

• Effective for partial epilepsy as adjunctive therapy, with approximately 50% of patients experiencing at least 50% reduction in seizure frequency at 600 mg/day 3
• For neuropathic pain (postherpetic neuralgia, diabetic neuropathy), 32-38% of patients achieve at least 50% pain reduction at therapeutic doses of 1800-3600 mg/day 4, 5
• Therapeutic doses range from 900-3600 mg/day in three divided doses, with efficacy developing gradually over several weeks 4, 5

Adverse Effects Profile

• Common neurological effects: Dizziness (19%), somnolence (14%), peripheral edema (7%), gait disturbance (9%) 4
• These effects are typically mild to moderate, dose-dependent, and often transient, usually subsiding within approximately 10 days 4
• Adverse event withdrawals occur in 11% of patients versus 8.2% with placebo 4
• Weight gain and peripheral edema occur particularly in elderly patients 3

Special Population Considerations

• Elderly patients: Apparent oral clearance decreases from 225 mL/min in those under 30 years to 125 mL/min in those over 70 years 1
• Renal impairment: Gabapentin plasma clearance is reduced proportionally to creatinine clearance, requiring mandatory dose adjustment 1
• Pediatric patients: Higher oral clearance normalized per body weight in children <5 years compared to older children 1

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Pregabalin Effects

Pregabalin shares an identical mechanism and adverse effect profile with gabapentin but offers more predictable linear pharmacokinetics with 90% bioavailability, requiring lower maximum doses (600 mg/day vs 3600 mg/day for gabapentin), though it carries the same risks of dizziness (23-46%), somnolence (15-25%), peripheral edema (10%), and weight gain, with particular caution needed in elderly patients and those with renal impairment. 6, 7, 3

Mechanism and Pharmacology

• Pregabalin is a GABA analogue that binds to the α2δ subunit of voltage-activated calcium channels, reducing calcium influx and neurotransmitter release 8
• Exhibits linear pharmacokinetics with 90% oral bioavailability, making dosing more predictable than gabapentin 6
• Eliminated primarily unchanged by renal excretion (85% renally excreted), requiring dose adjustment in renal impairment 6, 7
• Terminal half-life doubles to 28 hours in severe renal impairment 6

Therapeutic Effects

• Neuropathic pain: Between one-third and one-half of patients achieve at least 50% pain reduction at 600 mg/day 3
• Postherpetic neuralgia: Number needed to treat (NNT) of 3.9-5.3 for substantial benefit at 300-600 mg/day 6
• Diabetic peripheral neuropathy: NNT of 7.8-22 for substantial benefit at 300-600 mg/day 6
• Fibromyalgia: Patients more likely to report improvement (NNT 4.8) at 300-450 mg/day 6
• Pain relief occurs within 1.5-3.5 days, faster than gabapentin which requires 2+ months 6

Adverse Effects Profile

• Common dose-dependent effects: Dizziness (23-46%), somnolence (15-25%), peripheral edema (10%), weight gain, dry mouth, constipation 6, 7
• Nearly identical adverse effect profile to gabapentin, with primary side effects occurring at similar rates 6
• Visual field restriction has been reported in clinical trials 3
• Serious breathing problems can occur when combined with opioids, benzodiazepines, or other CNS depressants 6

Dosing Considerations

• Standard effective dose is 300 mg/day (150 mg twice daily or 100 mg three times daily), providing optimal benefit-to-risk ratio 6
• Maximum dose of 600 mg/day should be reserved only for patients with inadequate pain relief at 300 mg/day who tolerate the medication well 6
• Start at 75 mg twice daily or 50 mg three times daily (150 mg/day), increasing to 300 mg/day within 1 week 6
• Elderly patients require lower starting doses and slower titration due to increased risk of dizziness, somnolence, confusion, balance disorder, tremor, and coordination abnormalities 6, 7

Special Population Considerations

• Renal impairment: Mandatory dose reduction required - approximately 50% reduction for creatinine clearance 30-60 mL/min, 75% for 15-30 mL/min, and 85-90% for <15 mL/min 6
• Elderly patients: Age-related decline in renal function often masked by normal serum creatinine due to reduced muscle mass, requiring calculated creatinine clearance before initiating therapy 6
• Pregnancy: Contraindicated in women who are pregnant or actively trying to conceive 9

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Metoclopramide Effects

Metoclopramide is a dopamine antagonist and prokinetic agent that elevates prolactin levels and carries serious risks of extrapyramidal reactions (more common in pediatric populations), tardive dyskinesia (particularly in elderly patients and with prolonged use), and parkinsonian-like symptoms, with additional concerns about sedation, confusion, and methemoglobinemia risk in neonates and patients with specific enzyme deficiencies. 10

Mechanism and Effects

• Dopamine antagonist that elevates prolactin levels, with elevation persisting during chronic administration 10
• Prokinetic effects facilitate gastric emptying and small bowel motility 10
• Approximately one-third of human breast cancers are prolactin-dependent in vitro, though clinical significance of elevated prolactin levels is unknown for most patients 10

Serious Adverse Effects

• Extrapyramidal reactions (EPS): More common in pediatric populations than adults, including dystonias 10
• Tardive dyskinesia: Elderly patients at greater risk, particularly with prolonged use 10
• Parkinsonian-like symptoms: Risk increases with ascending dose, particularly in geriatric patients 10
• Sedation: May cause confusion and manifest as over-sedation in elderly patients 10
• Methemoglobinemia: Increased risk in neonates due to prolonged clearance and reduced NADH-cytochrome b5 reductase levels 10

Special Population Considerations

• Pediatric patients: Safety profile in adults cannot be extrapolated to pediatric patients; dystonias and extrapyramidal reactions more common 10
• Neonates: Prolonged clearance produces excessive serum concentrations; reduced NADH-cytochrome b5 reductase levels increase methemoglobinemia risk 10
• Geriatric patients: Should receive lowest effective dose; if parkinsonian-like symptoms develop, metoclopramide should generally be discontinued before initiating anti-parkinsonian agents 10
• Renal impairment: Substantially excreted by kidney; risk of toxic reactions greater in patients with impaired renal function 10
• Patients with NADH-cytochrome b5 reductase deficiency: Increased risk of methemoglobinemia and/or sulfhemoglobinemia 10
• G6PD deficiency: Methylene blue treatment not recommended if metoclopramide-induced methemoglobinemia develops 10

Pregnancy and Lactation

• Reproduction studies in animals showed no impairment of fertility or significant harm to fetus, but no adequate well-controlled studies in pregnant women exist 10
• Should be used during pregnancy only if clearly needed 10
• Excreted in human milk; caution should be exercised when administered to nursing mothers 10

Endocrine Effects

• Disturbances including galactorrhea, amenorrhea, gynecomastia, and impotence have been reported with prolactin-elevating drugs 10
• Chronic administration of prolactin-stimulating drugs increased mammary neoplasms in rodents, though no association demonstrated in human studies to date 10

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Critical Safety Warnings for Combined Use

Never combine gabapentin and pregabalin together, as they share identical mechanisms of action and adverse effect profiles, creating an unacceptable additive sedative burden without established efficacy benefits, particularly dangerous in elderly patients or those at risk for falls. 6, 11

• No randomized controlled trials demonstrate that combining gabapentin and pregabalin is superior to optimizing the dose of either medication alone 6
• Both medications cause identical adverse effects including dizziness, somnolence, peripheral edema, gait disturbance, and visual disturbances, with additive pharmacodynamic effects 6
• A case report documented a patient prescribed both medications concomitantly who developed drowsiness, dizziness, fatigue, and ataxia, with symptoms resolving after discontinuing pregabalin 11
• The combination should be avoided in routine practice, especially in elderly patients or those with fall risk 6