Part X: Pharmacology Harold R. Smith Department of Neurology, University of California, Irvine School of Medicine, Irvine, California, ULS.A. INTRODUCTION The use of stimulant and hypnotic medications in Neurology, Sleep Medicine, and general Medicine and Surgery settings has become ubiquitous. Published data (Table 1) for pharmacological treatment of insomnia in 2002, based on estimates of 3400 physicians representing 29 medical specialties across the U.S.A,, reporting data for all patient visits in a 24-hour period once per month, projected estimates of more than 11,000,000 “drug occurrences” for “hypnotic/sedative/ promote sleep” actions (1). If taking into account the additional non-prescribed use of stimulants and/or hypnotics by the general population, the magnitude of stimulant and hypnotic use is potentially staggering. The impact of the use or misuse of stimulants or hypnotics results in a myriad of medical symptoms and disorders. The constella- tion of these problems when “things go wrong” with stimulants or hypnotics is encompassed in stimulant- dependent sleep disorder and hypnotic-dependent sleep disorder. STIMULANT-DEPENDENT SLEEP DISORDER Definition and Background Stimulant-dependent sleep disorder involves disruption of sleep or insomnia as a consequence of using central nervous stimulants and excessive somnolence or disrupted wakefulness following withdrawal of stimulants. The second edition of the International Classification of Sleep Disorders classifies stimulant-dependent sleep disorder under two categories: Insomnia due to drugs or substances and Hypersomnolence due to drugs or substances (2). Stimulant- dependent sleep disorder has been codified as a “reduction of sleepiness or suppression of sleep by central stimulants, and resultant alterations in wakefulness following drug abstinence” (3). Both medicinally prescribed stimulants and nonprescribed stimu- lant abuse may result in the features of stimulant-dependent sleep disorder. The earliest medical reports of sleep disruptions due to stimulants were published in the 1930s, even though medicinal stimulant use has been present for centuries (4,5). More detailed reports of the negative impacts of stimulants were elucidated in what was labeled “Amphetamine Psychosis” in the 1950s and 1960s. These reviews touched upon the impacts of stimulants on sleep and wakeful- ness, and emphasized the overall clinical and psychiatric sequelae (6,7) Amphetamine stimulants result in increased wakefulness and also reduce total sleep time as well as reduce the time spent in rapid eye movement (REM) sleep (Table 2). In addition, amphetamines were found electrophysiologically to increase the time to the first REM period while asleep, that is, increased REM 405406 Smith TABLE 1 The 16 Drugs with the Most "Drug Occurrences” with a Desired Action of "Hypnotic," “Promote Sleep.” or "Sedate Night, in 2002 from the Verispan Physician Drug and Diagnosis Audit ‘Occurrences Rank Drug (millions) 1 Trazodone 2.730 2 Zolpidem 2.074 3 Amitriptyline 0.774 4 Mirtazapine 0.682. 5 Temazepam 0.588 6 Quetiapine 0.459, 7 Zaleplon 0.405, 8 Clonazepam 0.994 9 Hydroxyzine 0.293 10 Alprazolam 0.287 n Lorazepam 0.277 2 Olanzapine 0.216 3 Flurazepam 0.205, “ Doxepin 0.199 15 Cyclobenzaprine 0.195, 16 Diphenhydramine 0.192, ‘Source: Republished with permission of AASM/CCC from: Walsh JK, Sleep 2004, 27:8, latency. Stimulant withdrawal results in notable increase in total sleep times—in some individuals, up to 18 to 48 hours of continuous sleeping. During the withdra- wal period, REM sleep often increases substantially (“REM sleep rebound”) and the latency to REM sleep is often much shorter—the opposite of the effects seen during stimulant use (8,9). The uncharacteristically high percentage of REM sleep relative to total sleep time and the very short latency to REM sleep in the stimulant withdrawal state have been described as not occurring until one or two nights after the last dose of stimulant (10). More sophisticated electrophysiological studies of sleep revealed that differ- ent categories of stimulants resulted in dissimilar impacts on wakefulness and sleep. Derivatives of amphetamines used for weight loss, such as the anorexiants fenfluramine and mazindol, do not result in any substantial sleep-wake or REM TABLE 2 Amphetamine Effects on Sleep Amphetamine use Increased wakefulness Reduced total sleep time Reduced time in REM sloop Increased time to first REM sleep period ‘Amphetamine withdrawal Reduced wakefulness Increased total sleep times (up to 48 hrs) Increased time in REM sleep Reduced time to first REM sleep period ‘Abbreviation: REM, rapid eye movement‘Stimulant-Dependent and Hypnotic-Dependent Sleep Disorders 407 sleep disruptions (11,12). Caffeine, a xanthine, does not affect sleep, wakefulness, or REM sleep when compared with the amphetamines, until doses of 300 mg of caffeine are reached. When caffeine intake is at or above 300 mg, total sleep time is reduced and REM periods later in the night are delayed (13,14), Methylphenidate, a heterocyclic derivative of amphetamine, results in very similar sleep, wake, and REM sleep effects as the parent compound. Cocaine use reduces REM sleep and increases latency to REM sleep; conversely, cocaine withdrawal results in REM sleep rebound and shortens latency to REM sleep (15,16) Modafinil withdrawal has not resulted in excessive somnolence in animal studies (17,18). The unique mechanisms of action of modafinil appear to minimize the adverse effects on sleep, rebound wakefulness, and REM sleep seen with amphetamines. Identifying and Pharmacological Features ‘Though the precise etiology of stimulant-dependent sleep disorder is not yet clearly defined, stimulant use may result in euphoria or self-perception of improved performance and aptitude, which prompts continued use or abuse of the stimulant (19), Amphetamine-like stimulants’ release of norepinephrine results in the subjec- tive “high,” and mesolimbic dopamine pathways mediate repetitive stimulant use behavior (20). During the period of stimulant abuse, repetitive behaviors such as sorting, cleaning, assembling, and disassembling may occur, which has been described as “punding” (21). Molecular mechanisms of sensitization via dopamin- ergic pathways result in stimulant-induced changes and relapses in the stimulant use or abuse (22,23). Pre-existent psychiatric illness may predispose individuals to stimulant- dependent sleep disorder (3). In addition, those who abuse stimulants may develop periods of complete sleep deprivation followed by hypersomnolence in the withdrawal phase. This may result in psychiatric symptomatology, particularly in chronic abusers. The clinical features may be subtle, such as restlessness, akathisia, or nervousness. More obvious manifestations could include hypomania or euphoria, and, on occasion, a toxic psychosis similar to paranoid schizophrenia ‘When stimulant abuse is interrupted by abstention or withdrawal, hypersom- nolence occurs. Uninterrupted sleep lasting up to several days may result, and depression may be seen in the abstinent period. Stimulant-dependent sleep disorder withdrawal effects may persist for several months (11). Polysomnographic studies for sustained periods during stimulant withdrawal reveal a pattern of acute hypersomnolence and REM sleep rebound for the first seven to ten days. This pattern then reverses with reduced REM sleep and disrupted nocturnal sleep and reduced total sleep time for two to three weeks following stimulant abstinence (24,25). The indirect sympathomimetic type of stimulants are those most likely to cause stimulant-dependent sleep disorder. Amphetamines, cocaine, and methyl- phenidate block the reuptake and enhance the release of central nervous system. norepinephrine, dopamine, and serotonin. The dopaminergic system effects are those with the most prominent neuropharmacological activity for indirect sympathomimetics (20,26). Tolerance to this category of stimulants and rebound hypersomnolence seen with these agents are the most pronounced of all stimulants and are major contributing factors to stimulant-dependent sleep disorder.