The Paradox of Caffeine-Zolpidem Interaction: A Network Analysis

Abstract

A widely prescribed and potent short-acting hypnotic, zolpidem has become the mainstay for the treatment of middle-of-the-night sleeplessness. It is expected to be antagonized by caffeine. Paradoxically, in some cases caffeine appears to slightly enhance zolpidem sedation. The pharmacokinetic and pharmacodynamic nature of this odd effect remains unexplored. The purpose of this study is to reproduce a hypothetical molecular network recruited by caffeine when co-administered with zolpidem using Ingenuity Pathway Analysis. Thus generated, network drew attention to several possible contributors to caffeine sedation, such as tachykinin precursor 1, cannabinoid, and GABA receptors. The present overview is centered on the possibility that caffeine potentiation of zolpidem sedation does not involve a centralized interaction of specific neurotransmitters, but rather is contributed by its antioxidant capacity. It is proposed that by modifying the cellular redox state, caffeine ultimately reduces the pool of reactive oxygen species, thereby increasing the bioavailability of endogenous melatonin for interaction with zolpidem. This side effect of caffeine encourages further studies of multiple antioxidants as an attractive way to potentially increasing somnolence.

Winning a Won Game: Caffeine Panacea for Obesity Syndemic

“…In it, caffeine molecule appears as a hub that establishes connections by crossing the boundaries of other intrinsic modules, thereby creating a temporary ‘parasitic’ unit. Such drug hubs were termed elsewhere ‘pharmodules’ [24]. The point of this distinction is in the fleeting character of such sub-networks that gradually disappear with a half-life determined by the drug elimination or that of its metabolites.…”