Pregabalin

Indications

• FDA-approved for neuropathic pain associated with diabetic peripheral neuropathy, for postherpetic neuralgia and for neuropathic pain after spinal cord injury.
• FDA-approved for management of fibromyalgia in adults, where it was the first agent to carry that specific indication.
• FDA-approved as adjunctive therapy for partial-onset seizures in patients aged 1 month and older, dosed by weight in children.
• The controlled-release formulation covers diabetic neuropathy and postherpetic neuralgia once daily but is not approved for fibromyalgia.
• Off-label for generalized anxiety disorder, an indication approved in Europe, with effect sizes comparable to SSRIs and onset within a week.
• Off-label use in alcohol withdrawal, restless legs and social anxiety is common but is tempered by real misuse and diversion potential.

Mechanism of action

• Binds the alpha-2-delta auxiliary subunit of voltage-gated calcium channels, reducing calcium influx into hyperexcited presynaptic terminals.
• That reduction dampens release of glutamate, norepinephrine and substance P, quieting central sensitization in neuropathic pain states.
• Despite the name it has no direct action at GABA receptors, is not converted to GABA and does not alter GABA reuptake.
• Binding affinity is higher and absorption far more predictable than gabapentin, giving a linear and more reliable dose-response relationship.
• Rapid anxiolysis and dose-dependent euphoria explain both its off-label popularity and its schedule C-V misuse liability.

Pharmacokinetics

• Oral bioavailability exceeds 90% and is dose-independent, unlike gabapentin whose saturable transporter caps absorption at higher doses.
• Elimination half-life is about 6.3 h, supporting two or three daily doses, or once-daily controlled release after the evening meal.
• Metabolism is negligible: more than 90% of a dose is excreted unchanged in the urine, so renal function dictates every dose decision.
• It is not protein bound, does not inhibit or induce CYP enzymes, and therefore has essentially no pharmacokinetic drug interactions.
• Hemodialysis removes roughly half of circulating drug in 4 h, so a supplemental dose is required after each session.

Dosing

• Diabetic peripheral neuropathy: start 50 mg three times daily and increase to 300 mg/day within one week; the maximum for this indication is 300 mg/day.
• Postherpetic neuralgia: start 75 mg twice daily, move to 300 mg/day within a week, and increase to a maximum of 600 mg/day if needed.
• Fibromyalgia: start 75 mg twice daily, increase to 150 mg twice daily within a week, with a maximum of 450 mg/day in divided doses.
• Adjunctive partial-onset seizures in adults: 150 mg/day divided two or three times daily, titrated to a maximum of 600 mg/day.
• Reduce by roughly half at creatinine clearance 30-60 mL/min, to a quarter at 15-30, and further below 15, with a supplemental dose after dialysis.
• Taper over at least 1 week when stopping; abrupt withdrawal causes insomnia, nausea, headache, diarrhea and seizures in epilepsy patients.

Adverse effects

• Dizziness in up to 45% and somnolence in up to 28% are dose-related, appear early and are the commonest reasons for discontinuation.
• Peripheral edema affects about 16% and weight gain of 7% or more occurs in a similar proportion, both worse with thiazolidinediones.
• Blurred vision, dry mouth, ataxia, euphoria and difficulty with attention or word finding occur and matter in older or working patients.
• Respiratory depression can occur with opioids, benzodiazepines or in respiratory disease, a risk the FDA formally warned about in 2019.
• Angioedema, hypersensitivity reactions, thrombocytopenia and rare rhabdomyolysis are uncommon but require prompt discontinuation.
• Suicidal ideation carries the antiepileptic class warning at roughly one additional case per 500 treated, and misuse or dependence does occur.

Monitoring

• Creatinine clearance at baseline and periodically, because dosing is determined almost entirely by renal elimination.
• Weight and lower-extremity edema at each visit, particularly in heart failure or with concurrent thiazolidinedione therapy.
• Sedation, gait and fall risk in older adults, ideally with a formal gait assessment after any dose increase.
• Mood and suicidal ideation, and creatine kinase whenever unexplained muscle pain, tenderness or weakness appears.
• Prescription drug monitoring program review and a misuse assessment when the patient also uses opioids or has a substance use history.

Interactions

• Opioids and other CNS depressants produce additive sedation and respiratory depression, a combination implicated in many overdose deaths.
• Alcohol, benzodiazepines and sedating antihistamines compound cognitive and psychomotor impairment in a dose-dependent way.
• Thiazolidinediones such as pioglitazone add to fluid retention and weight gain and may precipitate heart failure decompensation.
• ACE inhibitors combined with pregabalin appear to raise the risk of angioedema above either agent alone.
• There are no cytochrome P450 or protein-binding interactions, so no adjustment is needed for other psychotropics.

Special populations

• Pregnancy: registry data raise the possibility of a small increase in major congenital malformations, so reserve use for clear indications.
• Lactation: pregabalin is excreted into human milk and breastfeeding during treatment is generally not recommended.
• Pediatric: approved as adjunctive seizure therapy from 1 month of age with weight-based dosing, generally 2.5-14 mg/kg/day.
• Geriatric: reduce the dose for renal decline and weigh sedation, edema and fall risk; Beers criteria caution against pairing it with opioids.
• Renal impairment governs dosing at every level and requires a supplemental dose after each hemodialysis session; no hepatic adjustment is needed.

Clinical pearls

• Dose it by creatinine clearance; over 90% leaves the body unchanged in urine.
• Adding an opioid raises overdose death risk, the subject of a 2019 FDA warning.
• It is anxiolytic within a week off-label, but it is C-V and genuinely misused.