Chapter 132 Medication and Substance Abuse
Substance Abuse and Dependence
The generally accepted diagnostic classification system for substance-related disorders is the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV). Substance-related disorders are divided into two major classes, substance abuse and substance dependence (Boxes 132-1 and 132-2). Substance abuse is a milder expression of maladaptive substance use and typically occurs earlier in a patient’s substance use history. Substance dependence is characterized by compulsive and repeated substance use despite aversive psychosocial, legal, and medical consequences. An important feature is difficulty controlling and reducing the substance use and repeated relapse episodes after periods of abstinence.
Box 132-1
Adapted from American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 4th ed, text revision. Washington, DC: American Psychiatric Press; 2000.
DSM-IV Criteria for Substance Abuse



The symptoms have never met the criteria for substance dependence for this class of substance.
DSM-IV, Diagnostic and statistical manual of mental disorders, 4th edition.
Box 132-2
Adapted from American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 4th ed, text revision. Washington, DC: American Psychiatric Press; 2000.
DSM-IV Criteria for Substance Dependence



Specify physiologic dependence: Evidence of tolerance or withdrawal is present.
DSM-IV, Diagnostic and statistical manual of mental disorders, 4th edition.
Although most of the drugs of abuse disrupt sleep or daytime alertness (or both), such disturbances are not major criteria for substance dependence in DSM-IV. They are only mentioned as possible symptoms in a withdrawal syndrome, which is one of the seven major criteria for substance dependence. DSM-IV provides the option of using a diagnosis of substance-induced sleep disorder when the sleep or daytime alertness disturbance has an intensity or duration beyond that normally expressed during substance intoxication or withdrawal (Box 132-3). As discussed later, the role of disruptions of sleep and daytime alertness in substance dependence is not fully elaborated in DSM-IV.
Box 132-3
Adapted from American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 4th ed, text revision. Washington, DC: American Psychiatric Press; 2000.
DSM-IV Diagnostic Criteria for Substance-Induced Sleep Disorder
There is evidence from the history, physical examination, or laboratory findings of either:


The disturbance does not occur exclusively during the course of a delirium.
Specify if onset is during intoxication or during withdrawal.
DSM-IV, Diagnostic and statistical manual of mental disorders, 4th edition.
Understanding Substance Abuse
Behavioral Mechanisms
The state-altering consequences in negative and positive reinforcement can be relevant to the treatment of sleep disorders. The alerting effects of stimulants, for instance, are reinforcing for persons who are sleepy, fatigued, and having difficulty functioning at their desired level. Healthy normal subjects self-administer a stimulant when they are sleepy but not when alert.1 That self-administration does not imply dependence or abuse. However, in substance abuse, sleepiness may be present as part of a withdrawal syndrome due to abstinence following chronic use of a stimulant. It has been hypothesized that continued substance use, difficulty reducing use, or relapse might reflect self-medication to reverse excessive sleepiness caused by abstinence. For example, in amphetamine or cocaine abuse, excessive sleepiness during initial drug abstinence has been consistently reported, and use of the stimulants reverses the sleepiness. More commonly, in chronic caffeine or nicotine dependence, the 8-hour sleep period is functionally an enforced abstinence. The pharmacokinetics of these drugs and the enforced abstinence of the sleep period can result in enhanced sleepiness in the morning, and, in extreme cases, smoking during the night. Caffeine or nicotine taken immediately when arising reverses the sleepy state, which reinforces use of these stimulants. Clinicians can gauge the severity of a nicotine addiction by asking patients when they have their first morning cigarette.
Daytime sleepiness is not necessarily drug induced. Chronic insufficient sleep in healthy normal persons or disturbed sleep efficiency and circadian dysrhythmia seen in altered work schedules can also cause daytime sleepiness. Night workers and rotating-shift workers have shortened and disturbed sleep when sleeping during the day as well as increased sleepiness when awake at night. Rotating-shift workers and night workers report a disproportionate use of sedating drugs, especially alcohol, to improve sleep and stimulants, especially caffeine, to improve alertness.2,3 Although healthy normal persons might self-administer a stimulant when experiencing sleepiness, this kind of substance use can increase risks of substance dependence and abuse.
Sedative-hypnotics, tetrahydrocannabinol (THC), and alcohol can become reinforcers and lead to substance dependence or abuse through their capacity to induce sleep in persons with insomnia or to reverse a waking hyperaroused state. In one study, persons who had insomnia but no history of alcoholism or drug abuse and healthy normal subjects were given an opportunity to choose between previously experienced color-coded ethanol and placebo beverages at night before sleep. The insomniac subjects chose ethanol, but healthy normal subjects with a similar level of self-reported social drinking chose placebo.4 Interestingly, insomniac subjects showed not only nighttime but also daytime self-administration of benzodiazepine-receptor agonists. However, only insomniac subjects who showed evidence of daytime physiologic hyperarousal self-administered benzodiazepines during the day.5 Whether these drug self-administration patterns reflect drug-seeking or therapy-seeking is considered later.
Neurobiological Mechanisms
The positive-reinforcement neurobiology of drug self-administration is generally accepted to involve mesocorticolimbic projections originating in the ventral tegmental area of the rostral reticular activation system and terminating in the nucleus accumbens. Most drugs of abuse interact in some way with this system. This dopamine system is part of a broader dopaminergic system that projects into several forebrain regions and as a whole is considered to have executive and integrative functions.6 The dopaminergic neurons of the ventral tegmental area are modulated by a number of other neurotransmitter systems. It is through this modulation that sleep–wake state and level of sleepiness or alertness during wake could have an impact on a drug’s reinforcing properties.
In chronic use, Koob hypothesized that the neurobiological systems involved in acute positive reinforcement adapt by establishing opponent processes.6 These opponent processes neutralize the acute reinforcing effects of the drug and during abstinence are left unopposed. Consequently, they produce the abstinence syndrome, an inverse state to the drug state, which becomes a basis of negative reinforcement (reversal of abstinence symptoms). For example, stimulant abstinence produces sleepiness, which in turn leads to self-administration of stimulant drugs. Koob hypothesized that the opponent processes do not necessarily develop through the same neurobiological system that produces positive reinforcement. Other neurobiological systems, and possibly sleep−wake systems, could be one basis of the opponent processes. Consistent with this model are two important sleep–wake findings: One is the REM sleep suppression and REM sleep rebound associated with administration and discontinuation of most of the drugs with an abuse liability. The other, the persisting disturbance of sleep that is found after weeks of abstinence, suggests that some type of neurobiological adaptation to the chronic drug exposure has occurred within sleep–wake systems.
Sleep–Wake Alterations and Specific Substances
Alcohol and Alcoholism
Alcohol in Healthy Adults
Alcohol in large doses is mildly stimulating on the rising phase of the plasma concentration curve and is sedating on the declining side of the curve.7 In lower doses it has few stimulatory effects on the rising phase and is mildly sedating on the declining phase. Studies of alcohol effects on sleep typically administer alcohol 30 to 60 minutes before sleep, which results in peak concentrations occurring before or at bedtime. Doses used in these studies range from 0.16 to 1.0 g/kg, the rough equivalent of one to six standard drinks, producing breath ethanol concentrations (BrEC) up to 0.105% at bedtime.8 One study reported increased sleep time at a low 0.16 g/kg dose but not at higher 0.32 and 0.64 g/kg doses. The sleep-disruptive rebound wakefulness that occurs in the second half of the night with the higher doses of alcohol is likely why improved sleep is seen only at low doses. The typical BrEC at lights out for higher doses is between 0.05% and 0.09%; because ethanol is metabolized at a rate of 0.01% to 0.02% BrEC per hour, it has been completely metabolized within the first 4 to 5 hours of the sleep period. This leads to a rebound wakefulness during the last hours of the sleep period.9 Thus, sleep time for the whole night is not increased at high doses and instead is often decreased.
In addition to these effects on sleep induction and maintenance, ethanol affects the normal progression of sleep stages.10 Studies report a dose-dependent suppression of REM sleep and, in some cases, increased slow-wave sleep in the first half of the night (i.e., when ethanol blood levels are present). When first-half REM sleep suppression is observed, a second-half REM sleep rebound is reported as well. As with rebound wakefulness, the second-half REM sleep rebound likely relates to the timing of complete ethanol elimination from the body. Repeated nightly administration of ethanol leads to tolerance to both the sleep induction and sleep stage effects, but interestingly not in the rebound effects. Finally, discontinuation of ethanol is followed by a REM sleep rebound, although the appearance of a REM sleep rebound is likely related to dose, duration of use, basal level of REM sleep, and the extent of prior REM sleep suppression and development of tolerance.
The aftereffects of heavy alcohol consumption, commonly referred to as hangover, are typically experienced after peak BrECs of 0.100% and greater.11 Some laboratory studies of heavy drinking, hangover, and next-day cognitive and psychomotor performance have demonstrated impairment in the morning with BrEC zero 14 hours after ethanol ingestion the previous night and approximately 4 hours before going to bed.12 Some studies have related the next-day impairment to the degree of ethanol-related sleep loss and fragmentation during the previous night.13 Even with low alcohol doses and an absence of hangover symptoms, the sleep-disruptive and performance-impairing effects can continue after alcohol is completely metabolized and BrEC is zero. Late-afternoon drinking with BrEC zero at bedtime disrupted sleep in the second half of the night, and morning or midday drinking continues to impair performance for 2 to 3 hours after BrEC is zero.14,15

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