Can pregabalin be given once daily as a morning dose instead of divided doses?

Pregabalin Once-Daily Morning Dosing Is Not Recommended

Pregabalin should not be given as a once-daily morning dose; it must be administered in divided doses (2-3 times daily) to maintain therapeutic drug levels throughout the day. 1

Why Divided Dosing Is Mandatory

• Pregabalin has a mean elimination half-life of only 6.3 hours, which is too short to maintain therapeutic concentrations over a 24-hour period with once-daily dosing 2, 3
• The FDA-approved dosing regimen explicitly requires administration in 2 or 3 divided doses for all approved indications, including neuropathic pain, postherpetic neuralgia, fibromyalgia, and adjunctive seizure therapy 1
• Steady-state plasma concentrations are achieved within 24-48 hours with divided dosing, but once-daily administration would result in subtherapeutic troughs and excessive peaks 2

Standard Dosing Schedules by Indication

For Neuropathic Pain (Diabetic Peripheral Neuropathy)

• Start at 50 mg three times daily (150 mg/day total) 1
• May increase to 100 mg three times daily (300 mg/day) within 1 week based on efficacy and tolerability 1
• Maximum recommended dose is 300 mg/day; doses above this are not recommended due to dose-dependent adverse effects without additional benefit 1

For Postherpetic Neuralgia

• Start at 75 mg twice daily OR 50 mg three times daily (150 mg/day total) 1
• May increase to 150 mg twice daily OR 100 mg three times daily (300 mg/day) within 1 week 1
• If insufficient relief after 2-4 weeks at 300 mg/day, may increase to 300 mg twice daily or 200 mg three times daily (600 mg/day maximum) 1

For Fibromyalgia

• Start at 75 mg twice daily (150 mg/day) 1
• Increase to 150 mg twice daily (300 mg/day) within 1 week 1
• May further increase to 225 mg twice daily (450 mg/day) if needed 1

Pharmacokinetic Rationale

• Pregabalin demonstrates linear, dose-proportional pharmacokinetics with rapid absorption (time to peak concentration approximately 1 hour) 2
• High bioavailability is maintained regardless of food intake, but the short half-life necessitates multiple daily doses 2
• Pregabalin is excreted virtually unchanged (<2% metabolism) by the kidneys, with no hepatic metabolism or cytochrome P450 involvement 2
• The predictable pharmacokinetics allow for effective starting doses without titration, but only when given in divided doses as prescribed 2

Critical Pitfalls to Avoid

• Never attempt once-daily dosing with immediate-release pregabalin—this will result in treatment failure due to inadequate drug exposure during trough periods 1, 2
• Do not confuse pregabalin with extended-release gabapentin formulations (gabapentin enacarbil), which have different pharmacokinetics 4
• Always adjust doses in renal impairment (creatinine clearance <60 mL/min requires dose reduction) since pregabalin is renally eliminated 1, 2
• Taper gradually over minimum 1 week when discontinuing to avoid withdrawal symptoms 1

Comparison with Gabapentin

• Unlike gabapentin, pregabalin has linear pharmacokinetics and does not have saturable absorption, making dose escalation more predictable 5, 2
• Gabapentin requires three-times-daily dosing due to saturable absorption, while pregabalin can be given twice daily for some indications 4, 1
• Both medications require divided dosing—neither should be given once daily 4, 1

Expected Onset and Efficacy

• Onset of pain relief can occur as early as day 2 with proper divided dosing, with median time to onset of 1.5-3.5 days versus >4 weeks with placebo 6
• Full efficacy assessment requires 4 weeks of treatment at therapeutic doses 5
• At 600 mg/day in divided doses, approximately one-third to one-half of patients achieve ≥50% pain reduction in neuropathic pain conditions 7, 6, 8

Adverse Effects with Divided Dosing

• Somnolence occurs in 15-25% and dizziness in 27-46% at 600 mg/day 8
• Treatment discontinuation due to adverse events occurs in 18-28% of patients 8
• Tolerance to dizziness and somnolence typically develops within a few weeks of continued therapy 3
• Weight gain and peripheral edema may occur, especially in elderly patients 7