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Tuesday, July 29, 2025

Pregabalin


Generic Name: Pregabalin
Brand Names: Lyrica, Lyrica CR, Lecaent, Rewisca, Alzain, among others


Drug Class: Anticonvulsant, Analgesic, Anxiolytic (GABA analogue)
Pharmaceutical Category: Central Nervous System (CNS) agent
Formulations: Oral capsules, oral solution, extended-release tablets (Lyrica CR)
Routes of Administration: Oral

1. Pharmacological Classification

Pregabalin is a structural analogue of gamma-aminobutyric acid (GABA) but does not bind directly to GABA or benzodiazepine receptors. It is classified as an anticonvulsant and neuropathic pain agent, with anxiolytic and anti-seizure properties. It is considered a Schedule V controlled substance in the United States due to its potential for abuse and dependence.

2. Mechanism of Action

Pregabalin binds with high affinity to the alpha-2-delta subunit of voltage-gated calcium channels in the central nervous system. This action:

  • Reduces calcium influx into presynaptic neurons.

  • Inhibits release of excitatory neurotransmitters: glutamate, norepinephrine, substance P, and calcitonin gene-related peptide.

  • Stabilizes neuronal firing and decreases nerve excitability, which leads to reduced seizure activity, pain perception, and anxiety.

It does not act directly on GABA receptors, nor does it alter GABA uptake or degradation.

3. Therapeutic Uses

A. FDA-Approved Indications

  1. Neuropathic pain associated with diabetic peripheral neuropathy

  2. Postherpetic neuralgia

  3. Adjunctive therapy for partial-onset seizures (in patients ≥1 month of age)

  4. Fibromyalgia

  5. **Neuropathic pain associated with spinal cord injury

  6. Generalized anxiety disorder (GAD) – Approved in the EU and other countries, but not FDA-approved in the US

B. Off-label Uses

  • Social anxiety disorder

  • Chronic lower back pain

  • Chemotherapy-induced peripheral neuropathy

  • Restless legs syndrome (RLS)

  • Bipolar disorder (adjunctive therapy)

  • Migraine prophylaxis (limited evidence)

4. Dosage and Administration

Initial Dosing (Adults)

  • Neuropathic pain (DPN/PHN/SCI):
    150 mg/day in 2–3 divided doses, titrated up to 300–600 mg/day based on response and tolerability.

  • Fibromyalgia:
    Start with 75 mg twice daily; may increase to 150 mg twice daily. Maximum: 450 mg/day.

  • Seizures (adjunct):
    Start 75 mg twice daily; usual range: 150–600 mg/day in divided doses.

  • Generalized anxiety disorder (non-US):
    Starting dose: 150 mg/day in 2–3 divided doses; max: 600 mg/day.

Extended-Release (Lyrica CR)

  • Once-daily formulation taken after an evening meal

  • Indicated for postherpetic neuralgia and diabetic peripheral neuropathy

  • Not approved for epilepsy or fibromyalgia

Pediatric Use

  • For epilepsy (≥1 month): weight-based dosing; use oral solution or capsule

  • Not approved for pain or anxiety in pediatric populations

5. Pharmacokinetics

  • Absorption: Rapid, linear; peak plasma concentration ~1 hour post-dose

  • Bioavailability: ≥90% (independent of dose)

  • Protein Binding: <1%

  • Metabolism: Negligible hepatic metabolism

  • Elimination: Renal excretion of unchanged drug

  • Half-life: ~6.3 hours

  • Dose Adjustment: Required in renal impairment (based on creatinine clearance)

6. Contraindications

  • Hypersensitivity to pregabalin or any excipients

  • Lactose intolerance (formulations contain lactose)

  • Severe renal impairment without dose adjustment

  • Caution in pregnancy, breastfeeding, and patients with substance abuse history

7. Warnings and Precautions

  • Angioedema: Risk of facial, lip, tongue, and throat swelling—can be life-threatening.

  • Suicidal thoughts and behavior: As with all antiepileptic drugs.

  • CNS depression: Dizziness and somnolence are common; may impair ability to drive or operate machinery.

  • Weight gain and peripheral edema: Dose-dependent and more frequent in diabetic patients.

  • Withdrawal symptoms: Insomnia, nausea, headache, diarrhea, anxiety. Taper dose gradually over at least 1 week.

  • Abuse and dependence: Though less than benzodiazepines or opioids, misuse has been documented, particularly among individuals with a history of substance use disorder.

  • Visual disturbances: Blurred vision and diplopia may occur.

  • Creatine kinase elevations: Rare cases of rhabdomyolysis have been reported.

  • Hypersensitivity reactions: Rash, urticaria, pruritus reported.

8. Adverse Effects

Common (≥10%)

  • Dizziness

  • Somnolence

  • Dry mouth

  • Edema

  • Blurred vision

  • Weight gain

  • Difficulty concentrating

  • Constipation

  • Ataxia

Less Common (1–10%)

  • Euphoria

  • Confusion

  • Tremor

  • Diplopia

  • Peripheral edema

  • Fatigue

  • Mood changes

  • Increased appetite

Serious (<1%)

  • Stevens-Johnson syndrome (rare)

  • Rhabdomyolysis

  • Suicidal ideation

  • Angioedema

  • Respiratory depression (especially with co-administered CNS depressants)

9. Drug Interactions

CNS Depressants

  • Benzodiazepines, opioids, alcohol, antipsychotics – Increased risk of sedation, dizziness, respiratory depression.

Thiazolidinediones (e.g., pioglitazone)

  • Additive risk of peripheral edema and weight gain

ACE Inhibitors

  • Possible increased risk of angioedema

No significant interactions with:

  • Oral contraceptives

  • Warfarin

  • Digoxin

  • Insulin or metformin (but monitor for edema)

Pregabalin is not metabolized via cytochrome P450, thus has minimal risk of CYP-mediated interactions.

10. Pregnancy and Lactation

Pregnancy

  • Category C (old system); not recommended unless clearly necessary

  • Animal studies show fetal toxicity, including skeletal abnormalities

  • Human data are limited; registry exists for monitoring (North American Antiepileptic Drug Pregnancy Registry)

Breastfeeding

  • Pregabalin is excreted into breast milk

  • Use with caution; potential infant CNS depression not well established

11. Dependence and Abuse Potential

Although initially thought to have low abuse risk, recent data show pregabalin misuse especially in those with:

  • Opioid dependence

  • Polydrug abuse history

  • Psychiatric comorbidities

Pregabalin is now classified as a controlled substance (Schedule V in the US) and is under prescription monitoring programs in several countries.

Symptoms of misuse:

  • Euphoria

  • Sedation

  • Hallucinations

  • Disinhibition

12. Tapering and Discontinuation

Abrupt discontinuation may lead to withdrawal symptoms, even after short-term use, including:

  • Anxiety

  • Insomnia

  • Headaches

  • Sweating

  • Nausea

  • Seizures (especially in epileptic patients)

Recommended taper: Gradually reduce dose over minimum 1 week depending on dose and duration.

13. Formulations and Brand Availability

  • Lyrica (Pfizer): Most recognized global brand

  • Lyrica CR: Extended-release formulation (once daily)

  • Oral capsules: 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 225 mg, 300 mg

  • Oral solution: 20 mg/mL

  • Global generics: Available under various names (e.g., Alzain, Pregral, Lecaent)

14. Clinical Notes and Comparison

  • Pregabalin vs. Gabapentin:

    • Pregabalin has faster absorption, higher bioavailability, and more predictable kinetics than gabapentin.

    • Preferred in patients who require rapid symptom relief or have failed gabapentin.

  • Fibromyalgia: Pregabalin is one of the few FDA-approved drugs for fibromyalgia.

  • Generalized Anxiety Disorder: Although not FDA-approved for this indication, pregabalin is widely prescribed in Europe, with favorable efficacy and faster onset than SSRIs or SNRIs.

  • Diabetic patients: Monitor for weight gain, edema, and glycemic control deterioration.




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