Drug Interactions Between Pregabalin and Melatonin
Pregabalin and melatonin can be safely co-administered without clinically significant pharmacokinetic interactions, though additive sedation and dizziness may occur and should be monitored. 1
Pharmacokinetic Interaction Profile
No direct drug-drug interaction exists between pregabalin and melatonin at the metabolic level. This favorable interaction profile stems from their distinct pharmacokinetic pathways:
Pregabalin is not metabolized by cytochrome P450 enzymes and does not induce or inhibit the CYP450 system, making pharmacokinetic drug interactions extremely unlikely. 1
Pregabalin is excreted virtually unchanged (<2% metabolism) by the kidneys and does not bind to plasma proteins, eliminating the potential for displacement interactions. 1
Melatonin is primarily metabolized by CYP1A2, but since pregabalin has no effect on hepatic enzymes, it cannot alter melatonin metabolism. 1, 2
Pharmacodynamic Considerations
The primary concern when combining these agents is additive central nervous system depression, not a true drug-drug interaction:
Both pregabalin and melatonin can cause dose-dependent sedation and dizziness, which may be enhanced when used together. 3
Pregabalin produces sedation through modulation of excitatory neurotransmitter release at voltage-gated calcium channels, while melatonin acts via M1 and M2 receptor binding. 3, 4, 1
When CNS depressants are combined with melatonin, additive sedation and impaired psychomotor performance can occur, warranting caution and monitoring. 4
Clinical Management Algorithm
Start with conservative dosing and titrate based on tolerability:
Initiate melatonin at 3 mg taken 1.5-2 hours before bedtime if adding to an established pregabalin regimen. 4
Monitor for excessive daytime sedation, dizziness, and impaired motor function during the first 1-2 weeks of combined therapy. 3, 4
Adjust pregabalin dosing if renal insufficiency is present, as this is the only clinically relevant factor affecting pregabalin pharmacokinetics. 3, 1
Avoid increasing melatonin above 5 mg initially, as higher doses increase adverse effects without improving efficacy and may cause receptor desensitization. 4
Evidence from Combined Use
A prospective comparative trial demonstrated that melatonin and pregabalin can be used together safely in the perioperative setting:
Both agents provided anxiolytic and analgesic effects when administered preoperatively, with pregabalin showing superior anxiolysis but comparable analgesia to melatonin. 5
No adverse drug interactions were reported when these medications were given in combination, supporting their safety profile together. 5
Sedation levels were comparable across groups, suggesting that the combination does not produce excessive sedation beyond what would be expected from either agent alone at therapeutic doses. 5
Important Caveats
Several factors require special attention when combining these medications:
Elderly patients may be more sensitive to the sedative effects of both agents and should start at the lowest effective doses. 3
Melatonin product quality varies significantly because it is regulated as a dietary supplement; choose United States Pharmacopeial Convention Verified formulations for reliable dosing. 4
Dose adjustment of pregabalin is mandatory in renal insufficiency (creatinine clearance-based), but melatonin dosing remains unchanged. 3, 1
Avoid benzodiazepines when using this combination, as the triple combination significantly increases fall risk and cognitive impairment, especially in older adults. 3
Morning grogginess with melatonin indicates the dose is too high and should be reduced, particularly when combined with pregabalin. 4