What is pregabalin?

What is Pregabalin?

Pregabalin is a prescription medication that binds to the alpha-2-delta subunit of voltage-gated calcium channels in the central nervous system, approved for treating neuropathic pain conditions (diabetic neuropathy, postherpetic neuralgia, fibromyalgia, spinal cord injury pain) and as adjunctive therapy for partial-onset seizures. 1

Mechanism of Action

Pregabalin works by binding with high affinity to the alpha-2-delta site on voltage-gated calcium channels in the brain and spinal cord 1. This binding reduces calcium-dependent release of excitatory neurotransmitters, which explains its effectiveness in treating pain and seizures 1, 2.

Important distinction: Despite being structurally related to the neurotransmitter GABA (gamma-aminobutyric acid), pregabalin does not directly interact with GABA receptors, does not bind to benzodiazepine receptors, and does not affect opioid receptors 1, 2.

FDA-Approved Indications

Pregabalin is approved for adults (18 years and older) to treat 1:

• Neuropathic pain from diabetes (diabetic peripheral neuropathy)
• Postherpetic neuralgia (nerve pain following shingles)
• Fibromyalgia (widespread body pain)
• Spinal cord injury-related neuropathic pain
• Partial-onset seizures (as adjunctive therapy with other seizure medications, approved for patients 1 month and older)

Pharmacokinetic Profile

Pregabalin has highly predictable and linear pharmacokinetics that make dosing straightforward 1, 2:

• Absorption: Greater than 90% bioavailability, with peak plasma concentrations reached within 1.5 hours 1, 2
• Food effects: Taking with food decreases peak concentration by 25-30% but does not affect total absorption, so it can be taken with or without food 1
• Protein binding: Does not bind to plasma proteins 1
• Metabolism: Undergoes negligible metabolism—approximately 90% is excreted unchanged in urine 1, 2
• Half-life: Approximately 6.3 hours, allowing twice or three times daily dosing 1, 2
• Steady state: Achieved within 24-48 hours 1, 2
• Drug interactions: Does not interact with cytochrome P450 enzymes, resulting in minimal drug-drug interactions 1, 2

Dosing Framework

Standard dosing ranges from 150-600 mg/day in divided doses 3, 4, 5:

• Starting dose: 50 mg three times daily or 75 mg twice daily 4, 1
• Titration: Can increase to 300 mg/day after 3-7 days based on response 4, 5
• Maximum dose: 600 mg/day in 2-3 divided doses 4, 1
• Therapeutic assessment: Full efficacy can be evaluated after 4 weeks of treatment 5

Critical caveat: Dose adjustment is mandatory in patients with renal impairment since pregabalin is eliminated unchanged by the kidneys 4, 1. Elderly patients should start with lower doses and slower titration due to increased risk of adverse effects 4.

Common Adverse Effects

The most frequently reported side effects are dose-dependent 3, 1:

• Dizziness: 23-46% of patients 4
• Somnolence (sleepiness): 15-25% of patients 4
• Peripheral edema (swelling): 10% of patients 4
• Weight gain: Particularly at higher doses 6, 7
• Dry mouth and constipation 4

Serious Safety Concerns

Life-threatening risks require immediate medical attention 1:

• Severe allergic reactions: Swelling of face, mouth, throat, or difficulty breathing
• Respiratory depression: Especially when combined with opioids or other CNS depressants 1
• Suicidal thoughts: Like other antiepileptic drugs, pregabalin carries a risk of suicidal ideation (approximately 1 in 500 patients) 1
• Angioedema: Risk increases when combined with ACE inhibitors 1

Controlled Substance Status

Pregabalin is classified as a Schedule V controlled substance due to potential for abuse and dependence 3, 8. The medication should not be discontinued abruptly—gradual tapering is necessary to avoid withdrawal symptoms 1. Approximately 50% of patients prescribed pregabalin in England had been on continuous treatment for at least 12 months, highlighting concerns about long-term prescribing practices 3.

Clinical Context for Specific Conditions

For neuropathic pain management, pregabalin is considered a first-line treatment alongside gabapentin and duloxetine 3. The American Diabetes Association recommends pregabalin at 150-600 mg/day in divided doses for diabetic peripheral neuropathy 3, 5. For postherpetic neuralgia, 300 mg/day is the standard moderate dose, with higher doses reserved only for patients with ongoing pain who tolerate the lower dose 3, 4.

Important exception: In frail older adults with limited life expectancy (less than 1 year), continuation of pregabalin for neuropathic pain management is often considered appropriate, but initiation requires careful consideration 3.

Comparison to Gabapentin

Pregabalin offers several advantages over its related compound gabapentin 4:

• More predictable absorption and linear pharmacokinetics 4
• Lower maximum daily dose: 600 mg/day for pregabalin versus 3600 mg/day for gabapentin 4
• Simpler dosing schedule due to predictable kinetics 4

When switching from gabapentin to pregabalin, start with 50 mg three times daily or 75 mg twice daily while gradually tapering gabapentin over several days to weeks 4.