Clinical and Physiological Correlates of Caffeine and Caffeine Metabolites in Primary Insomnia

Insomnia is one of the most commonly encountered complaints in medical practice. Insomnia is characterized by sleep disturbances such as long sleep onset latency, or frequent awakenings, and daytime consequences such as mood disturbance, cognitive impairment, fatigue, and an overall reduction in perceived quality of life.1,2 Epidemiological evidence indicates that 33% of the general population experience at least one symptom of insomnia, and about 6% have a specific insomnia diagnosis.3 Nearly 90% of the American population regularly consumes caffeine, a methylated xanthine which may both disrupt sleep and increase alertness in the setting of poor or insufficient sleep.4 Despite this, the degree to which regular daily doses of caffeine, individual differences in metabolism, and individual variations in pharmacodynamic sensitivity to the effects of caffeine on sleep in good sleepers or those with insomnia remains poorly defined. Caffeine is one of the most widely used drugs in the world, found most commonly in coffee and tea, but also in hundreds of sodas, energy drinks, and snacks. The ability of caffeine to enhance mood, arousal, and improve attention is widely recognized.5 For example, a recent study demonstrated that caffeine improves simple reaction time, numeric working memory, and sentence verification accuracy. These improvements occur in both habitual caffeine users as well as abstainers, strengthening the hypothesis that the effects of caffeine occur independently of habitual use by the individual.6 Caffeine is frequently self-administered to attenuate the effects of mental fatigue and daytime sleepiness through interactions with physiological sleep regulatory processes. For example, caffeine's ability to suppress somnolence is directly related to the time of administration and the status of the subject's concomitant homeostatic sleep drive.7 Caffeine exerts a greater effect during periods of prolonged sleep deprivation than during a period of rested wakefulness. BRIEF SUMMARY Current Knowledge/Study Rationale: Caffeine disrupts objective measures of sleep in controlled laboratory studies of adults, but less is known about caffeine-sleep relationships with habitual use in the home environment. The aim of this study was to examine the relationships between plasma caffeine levels and objective sleep measures in adults with chronic insomnia or good sleep. Study Impact: Caffeine and xanthine plasma levels in the evening were significantly related to reported caffeine intake, but were not related to sleep measures in insomnia or good sleeper groups. Low to moderate amounts of caffeine may not be a major source of sleep disruption among individuals with chronic insomnia. The biochemical basis of caffeine's effects lies in its ability to antagonize adenosine A1 and A2A receptors in the cholinergic basal forebrain and ventrolateral pre-optic nucleus of the hypothalamus, respectively.8,9 In this manner, caffeine functions to block the brain's recognition of a key chemical indicator of prolonged wakefulness and mental fatigue, adenosine, in areas of the brain involved with sleep-wake regulation. Caffeine administration also alters physiologic markers of sleep in a variety of experimental paradigms. Acute administration of caffeine mimics the symptoms and polysomnographic (PSG) correlates of insomnia, including increased sleep onset latency and reduced sleep efficiency.10–12 Caffeine administration attenuates the increase in delta density and decrease in spindle activity typically observed during recovery sleep following total sleep deprivation.13,14 These effects can be long lasting. Early morning caffeine intake in experimental studies is sufficient to induce these EEG changes during night sleep many hours later, even as plasma caffeine concentrations approach zero.15 Paradoxically, high levels of caffeine intake are also positively correlated with indicators of daytime sleepiness. Increased levels of caffeine intake have been associated with reduced time in bed,16 and high levels of daytime sleepiness are associated with high levels of caffeine intake.17 Other studies have found similar findings even among children.18,19 However, these cross-sectional data cannot determine whether caffeine is inducing sleep disturbance or whether subjects are self-administering caffeine to counteract daytime sleepiness due to other types of sleep disturbance. Caffeine appears to have differential effects upon insomniacs and good sleepers. Individuals with situational insomnia and those with elevated scores on a test of predisposition to insomnia greater sleep disturbance from a caffeine challenge than good sleepers.20;21 Genetic variations may also influence physiologic responses to caffeine. For example, a genome-wide search for chromosomal regions associated with resistance to caffeine-induced insomnia in adult twin pairs demonstrated significant linkage to an area on the long arm of chromosome 2.22 Another study found a specific adenosine A2A receptor polymorphism was associated with increased beta (16-20 Hz) activity in the NREM EEG. Epidemiologic evidence suggests that individuals with this genotype are at increased risk for sleep disturbance following a caffeine challenge.23 This body of evidence indicates that primary insomniacs may differ from good sleepers at the level of their adenosine receptor avidity to, ability to metabolize, and/or perceived sensitivity to methylxanthines such as caffeine. Insomnia treatment strategies frequently utilize behavioral modification techniques including reduction of caffeine intake. Specifically, many experts recommend improving sleep hygiene by abstaining from caffeine, particularly in the afternoon hours.24 Reducing caffeine is a plausible intervention, given the above evidence that caffeine may have a more robust effect on sleep disturbance in insomnia sufferers versus good sleepers. However, the extent to which insomniacs versus good sleepers self-administer caffeine, and the degree to which regular, low-level caffeine consumption affects sleep measures in these populations, remain poorly defined. In summary, the role of caffeine in promoting sleep disturbance and symptoms of insomnia is well-established in experimental studies. Less attention, however, has been paid to factors which modulate physiological effects of caffeine during routine self-administration. The goal of the present study was to investigate the relationship between caffeine, caffeine metabolites, and sleep in individuals with and without insomnia. Our first aim was to compare caffeine use and plasma concentrations of its primary active metabolite, paraxanthine, in good sleeper controls (GSC) and individuals with primary insomnia (PI). Our second aim was to determine whether caffeine consumption was related to increased caffeine and metabolite plasma concentrations in PI versus GSC. Finally, we examined whether caffeine consumption or plasma concentrations of caffeine and paraxanthine were related to self-report and PSG measures of sleep, and whether these relationships differed in PI versus GSC.