Pregabalin - Drug Monograph

Introduction

Pregabalin is a centrally-acting analgesic and anticonvulsant medication belonging to the gabapentinoid class. Originally developed as a successor to gabapentin, pregabalin was approved by the FDA in 2004 and has since become widely prescribed for various neurological and psychiatric conditions. It is classified as a Schedule V controlled substance in the United States due to its potential for abuse and dependence.

Mechanism of Action

Pregabalin exerts its therapeutic effects by binding to the alpha-2-delta subunit of voltage-gated calcium channels in the central nervous system. This binding reduces the release of several neurotransmitters, including glutamate, norepinephrine, substance P, and calcitonin gene-related peptide. By modulating calcium influx into nerve terminals, pregabalin reduces neuronal excitability and synaptic transmission, resulting in its anticonvulsant, analgesic, and anxiolytic properties. Unlike traditional GABAergic agents, pregabalin does not directly interact with GABA receptors.

Indications

FDA-approved indications include:

• Neuropathic pain associated with diabetic peripheral neuropathy
• Postherpetic neuralgia
• Adjunctive therapy for adult patients with partial-onset seizures
• Fibromyalgia
• Neuropathic pain associated with spinal cord injury

Off-label uses include:

• Generalized anxiety disorder
• Social anxiety disorder
• Restless legs syndrome
• Prevention of postoperative pain
• Various other neuropathic pain conditions

Dosage and Administration

• Neuropathic pain: Initial dose 150 mg/day in 2-3 divided doses, may increase to 300 mg/day within 1 week, maximum 600 mg/day
• Fibromyalgia: Initial dose 150 mg/day in 2 divided doses, may increase to 300-450 mg/day
• Epilepsy: Initial dose 150 mg/day in 2-3 divided doses, may increase to maximum 600 mg/day

• Renal impairment: Dose reduction required based on creatinine clearance

- CrCl 30-60 mL/min: 75-300 mg/day in divided doses - CrCl 15-30 mL/min: 25-150 mg/day in divided doses - CrCl <15 mL/min: 25-75 mg/day in single daily dose

• Hepatic impairment: No dose adjustment needed
• Elderly: Consider reduced doses due to decreased renal function
• Pediatrics: Safety and efficacy not established under age 18

• Oral administration with or without food
• Available as capsules, oral solution, and extended-release tablets
• Should be tapered gradually when discontinuing (reduce by 25-50% per week)

Pharmacokinetics

• Absorption: Rapidly absorbed with bioavailability >90%; Tmax 1-1.5 hours; food delays absorption but does not affect extent
• Distribution: Volume of distribution 0.5 L/kg; minimally protein bound (<1%)
• Metabolism: Negligible hepatic metabolism; no cytochrome P450 interactions
• Elimination: Primarily excreted unchanged in urine; elimination half-life 6-7 hours; clearance proportional to creatinine clearance

Contraindications

• Hypersensitivity to pregabalin or any component of the formulation
• Concomitant use with thiazolidinedione antidiabetic agents due to risk of fluid retention

Warnings and Precautions

• Angioedema: Serious allergic reactions including life-threatening angioedema reported
• Dizziness and somnolence: May impair ability to drive or operate machinery
• Peripheral edema: May occur, particularly in elderly and those with cardiac conditions
• Weight gain: Significant weight gain and increased appetite reported
• Suicidal ideation: Antiepileptic drugs increase risk of suicidal thoughts/behavior
• Respiratory depression: Risk increased with concomitant CNS depressants
• Withdrawal symptoms: Abrupt discontinuation may cause insomnia, nausea, headache, anxiety
• Vision-related effects: Blurred vision, diplopia, visual field changes reported
• Creatine kinase elevation: Rhabdomyolysis and muscle damage reported
• Tumorigenic potential: Pancreatic acinar cell tumors observed in animal studies

Drug Interactions

• CNS depressants: Additive effects with alcohol, opioids, benzodiazepines, barbiturates
• Thiazolidinediones: Contraindicated due to increased risk of fluid retention
• Angiotensin-converting enzyme inhibitors: Increased risk of angioedema
• Oral contraceptives: No significant interaction
• Other antiepileptic drugs: No clinically significant pharmacokinetic interactions

Adverse Effects

• Dizziness (29%)
• Somnolence (22%)
• Dry mouth (13%)
• Peripheral edema (12%)
• Blurred vision (8%)
• Weight gain (8%)
• Constipation (7%)
• Euphoria (5%)

• Angioedema
• Suicidal ideation and behavior
• Respiratory depression
• Rhabdomyolysis
• Severe dizziness and syncope
• Stevens-Johnson syndrome
• Thrombocytopenia

Monitoring Parameters

• Efficacy assessment based on indication (pain scales, seizure frequency, anxiety scales)
• Renal function at baseline and periodically
• Weight and body mass index regularly
• Signs of edema, particularly in patients with cardiac risk factors
• Mental status and mood changes, including suicidal ideation
• Visual changes and ophthalmologic exams if symptoms develop
• Signs of misuse or abuse in at-risk patients
• Withdrawal symptoms during dose reduction

Patient Education

• Take medication exactly as prescribed; do not suddenly stop taking
• May cause dizziness, drowsiness, or blurred vision—avoid driving until effects known
• Report any swelling, breathing difficulties, or allergic reactions immediately
• Avoid alcohol and other CNS depressants
• Monitor weight regularly and report significant changes
• Use caution when rising quickly from sitting or lying position
• Inform all healthcare providers about pregabalin use
• Store securely and do not share medication
• Report mood changes, depression, or suicidal thoughts
• Use effective contraception if of reproductive potential

References

1. Bockbrader HN, et al. Clin Pharmacokinet. 2010;49(10):661-669. 2. Toth C. Drugs. 2014;74(9):971-1000. 3. FDA prescribing information: Lyrica (pregabalin). Revised 2022. 4. Moore RA, et al. Cochrane Database Syst Rev. 2009;(3):CD007076. 5. Baldwin DS, et al. Int Clin Psychopharmacol. 2013;28(4):167-178. 6. Semel D, et al. Pain Med. 2016;17(5):970-983. 7. Zaccara G, et al. Seizure. 2011;20(1):15-25. 8. Schifano F. CNS Drugs. 2014;28(6):491-496. 9. Cross AL, et al. Pain Ther. 2022;11(3):741-763. 10. National Institute for Health and Care Excellence (NICE). Neuropathic pain in adults: pharmacological management. 2013.