GABAPENTIN

1. Drug Name

• Generic Name: Gabapentin

• Brand Names: Neurontin, Gralise, Horizant, Gabarone

2. Drug Classification

• Class: Anticonvulsant, Neuropathic Pain Agent

• Subclass: Gamma-aminobutyric acid (GABA) analogue

3. Mechanism of Action

• Primary Action: Gabapentin is a structural analogue of GABA (gamma-aminobutyric acid), but it does not act on GABA receptors. Instead, it binds to the α2δ subunit of voltage-gated calcium channels in the central nervous system. This binding inhibits excitatory neurotransmitter release, especially glutamate, norepinephrine, and substance P, which play roles in pain transmission and seizure activity.

• Additional Effects: Gabapentin’s primary clinical uses are in treating neuropathic pain and preventing seizures. Its ability to reduce neuronal excitability and suppress the release of excitatory neurotransmitters underlies its effectiveness in conditions involving nerve dysfunction, such as neuropathic pain, postherpetic neuralgia, and epilepsy.

4. Pharmacokinetics

• Absorption: Gabapentin is rapidly absorbed after oral administration, with a bioavailability of approximately 60%, which may decrease with higher doses. Peak plasma concentrations are typically reached within 2 to 3 hours.

• Distribution: The volume of distribution (Vd) is about 57 L. Gabapentin is not significantly protein-bound, which facilitates its distribution into tissues, including the brain.

• Metabolism: Gabapentin does not undergo significant metabolism in the liver. It is not metabolized by the cytochrome P450 enzyme system, making it less likely to interact with drugs metabolized by these enzymes.

• Excretion: Gabapentin is primarily excreted unchanged in the urine. The half-life (t½) is around 5 to 7 hours in individuals with normal renal function. In patients with renal impairment, the half-life is prolonged, and dosage adjustments are necessary.

• Special Considerations: Dosing adjustments are required in patients with renal dysfunction. Gabapentin does not undergo significant hepatic metabolism, which can make it a useful option in patients with liver disease.

5. Indications

• Primary Indications:

  • Neuropathic pain (e.g., postherpetic neuralgia, diabetic neuropathy)

  • Epilepsy (as adjunctive therapy for partial seizures)

  • Restless leg syndrome (RLS) (extended-release formulation)

• Off-label Uses:

  • Generalized anxiety disorder (GAD)

  • Fibromyalgia

  • Chronic pain syndromes (e.g., complex regional pain syndrome)

  • Alcohol withdrawal symptoms

• Specific Populations: Gabapentin is beneficial in patients with neuropathic pain, seizures, or restless leg syndrome, particularly in those who have contraindications to other therapies such as opioids or benzodiazepines.

6. Dosage and Administration

• Adult Dosing:

  • Neuropathic Pain: 300 mg orally once daily, increasing gradually up to 900-1,800 mg/day in divided doses.

  • Seizures: 300 mg orally three times daily, with potential increases up to 3,600 mg/day.

  • Restless Leg Syndrome: 600 mg orally once daily at bedtime.

• Pediatric Dosing (for seizures):

  • Children 3-12 years: Start with 10-15 mg/kg/day, divided into 3 doses, and titrate up as needed.

  • Children 12 years and older: Dosing similar to adults.

• Renal/Hepatic Adjustments: Gabapentin should be dose-adjusted for patients with renal insufficiency. For mild to moderate renal impairment, the dose is generally reduced by 25% to 50%. No adjustment is required for patients with normal liver function, as gabapentin is not significantly metabolized in the liver.

• Maximal Dose: Up to 3,600 mg/day in divided doses, depending on the condition and individual tolerance.

7. Contraindications

• Absolute Contraindications:

  • Hypersensitivity to gabapentin or any of its components.

• Relative Contraindications:

  • Caution is required in patients with renal impairment or those with a history of substance abuse (as gabapentin has been associated with misuse in some individuals).

  • Pregnancy and lactation (should only be used if the potential benefit outweighs the risk).

8. Warnings and Precautions

• Black Box Warnings: None

• Warnings for Specific Conditions:

  • Suicidal Behavior and Ideation: Anticonvulsants, including gabapentin, have been associated with an increased risk of suicidal thoughts and behavior. Patients should be monitored for changes in mood or behavior.

  • Drowsiness and Sedation: Gabapentin can cause drowsiness, dizziness, and sedation, particularly at higher doses. Patients should avoid operating heavy machinery until they know how the drug affects them.

  • Renal Dysfunction: Dosage adjustment is required in patients with renal impairment, as gabapentin is primarily eliminated by the kidneys.

• Monitoring Parameters: Renal function (creatinine clearance, serum creatinine), signs of sedation or drowsiness, mental status changes, and suicidal ideation.

9. Adverse Effects

• Common Adverse Effects (≥10%):

  • Drowsiness

  • Dizziness

  • Ataxia

  • Fatigue

  • Peripheral edema

• Less Common but Clinically Significant:

  • Weight gain

  • Memory problems

  • Tremors

  • Nausea and vomiting

• Serious Adverse Reactions:

  • Respiratory depression (especially when combined with CNS depressants)

  • Severe allergic reactions (e.g., angioedema, anaphylaxis)

  • Suicidal thoughts or behavior

  • Multiorgan hypersensitivity reactions (e.g., fever, rash, eosinophilia, and liver function abnormalities)

10. Drug Interactions

• Major Drug Interactions:

  • CNS Depressants (e.g., opioids, benzodiazepines, alcohol): The sedative effects of gabapentin may be enhanced when taken with other CNS depressants, increasing the risk of respiratory depression and sedation.

  • Antacids (containing aluminum or magnesium): These can reduce the absorption of gabapentin, and it should be taken at least 2 hours apart from antacids.

  • Morphine: Co-administration with morphine may increase gabapentin's serum concentration, increasing the risk of adverse effects such as sedation and respiratory depression.

• Food-Drug Interactions: Food does not significantly alter the bioavailability of gabapentin, but it may reduce the peak plasma concentration.

• Lab Test Interference: Gabapentin may interfere with certain lab tests, such as the measurement of urinary protein levels, resulting in false-positive results.

11. Clinical Pharmacology

• Pharmacodynamics: Gabapentin’s action is thought to be related to its modulation of calcium channel activity, particularly through binding to the α2δ subunit, which reduces excitatory neurotransmitter release. This results in its ability to control seizures and alleviate neuropathic pain by inhibiting abnormal neural firing.

• Additional Effects: Gabapentin’s ability to reduce neuronal excitability also makes it effective in treating conditions such as generalized anxiety disorder and fibromyalgia, although these uses are off-label.

12. Special Populations

• Pregnancy: Gabapentin is classified as Pregnancy Category C, which means it should only be used if the benefits outweigh the risks. Animal studies have shown reproductive toxicity.

• Lactation: Gabapentin is excreted in breast milk, but the effects on a nursing infant are unknown. It should be used with caution in lactating women.

• Pediatric Use: Gabapentin is approved for use in children for seizure disorders, but pediatric dosing should be carefully monitored, especially in younger children.

• Geriatric Use: In the elderly, dose adjustments are often needed, particularly due to potential renal impairment and the increased sensitivity to CNS effects.

13. Therapeutic Uses

• First-Line Use: Gabapentin is commonly used as adjunctive therapy in the management of partial seizures and for the treatment of neuropathic pain, particularly in postherpetic neuralgia and diabetic neuropathy.

• Combination Therapy: Often combined with other anticonvulsants or pain medications to enhance therapeutic efficacy, especially in cases of mixed pain syndromes or refractory seizures.

• Clinical Trials and Efficacy: Numerous studies have demonstrated gabapentin’s effectiveness in reducing neuropathic pain and controlling seizures. It has been particularly useful in conditions where other analgesics or anticonvulsants are ineffective or poorly tolerated.

14. Monitoring and Follow-Up

• Recommended Lab Tests: Kidney function tests (serum creatinine, creatinine clearance), and monitoring for signs of sedation or drowsiness.

• Patient Symptom Checklists: Monitoring for signs of depression or suicidal ideation, cognitive effects (e.g., memory problems), and potential allergic reactions.

• Therapeutic and Toxic Levels: Gabapentin has a wide therapeutic index, but overdose may lead to severe CNS depression and respiratory issues.

15. Overdose Management

• Symptoms of Overdose: Drowsiness, double vision, slurred speech, lethargy, respiratory depression, and coma.

• Treatment Protocols: Overdose management involves symptomatic and supportive care. There is no specific antidote for gabapentin overdose. Activated charcoal may be used if the overdose is recent. Hemodialysis can enhance the clearance of gabapentin in severe overdose.

• Supportive Measures: Ensure adequate airway management, ventilation, and fluid resuscitation as necessary.

16. Patient Counseling Information

• Key Points to Discuss with Patients:

  • Take gabapentin as prescribed and avoid sudden discontinuation to prevent withdrawal seizures.

  • Inform the healthcare provider of any existing kidney problems or changes in health status.

  • Gabapentin may cause dizziness or drowsiness, so avoid activities requiring mental alertness until the patient knows how the drug affects them.

  • Alcohol can exacerbate CNS depression; limit or avoid its consumption while on gabapentin.

• Signs/Symptoms to Watch For:

  • Signs of allergic reactions such as rash, swelling of the face, or difficulty breathing.

  • Suicidal thoughts or changes in mood.

  • Severe dizziness, uncoordinated movements, or significant fatigue.