Medication and Substance Abuse

Chapter 132 Medication and Substance Abuse




Abstract


Nearly all of the psychoactive drugs with a known abuse liability have profound effects on sleep and wakefulness. Substance abuse is characterized by physiologic dependence (e.g., withdrawal syndrome on drug discontinuation) and behavioral dependence (e.g., repetitive and compulsive drug seeking and consumption), both of which can vary depending on the drug and its duration of use. The neurobiological mechanisms underlying physiologic and behavioral dependence are known, but the effects of abused drugs on sleep–wake state are not fully known, although they are likely important. Legal and socially acceptable drugs can also be subject to abuse and may be the cause of patients’ sleep or alertness complaints. Some drugs indicated in the treatment of sleep disorders also have abuse liability. For that reason, guidelines are provided for sleep disorders clinicians to help in differentiating drug-seeking behavior from therapy-seeking behavior.


Substance abuse and dependence is common: 18% of the United States population will experience a substance abuse disorder during their lifetime, and about 20% of patients in general medical practice and 35% of psychiatric patients present with substance abuse disorders. Although the sleep-disorders clinician does not make formal diagnoses, awareness of the criteria for abuse are important for referral decisions. Various legal medications and all illegal drugs acting on the central nervous system (CNS) have a high abuse liability; that is, the likelihood of developing physiologic or behavioral dependence to these substances is heightened. Virtually all drugs with a high abuse liability also have profound effects on sleep and waking; therefore, sleep clinicians should be aware of the potential effects of drug dependence on treatment.


This chapter reviews the sleep–wake alterations produced by administration and discontinuation of various drug classes associated with abuse. Also discussed is the way that the state-altering characteristics (i.e., their disruptive effects on sleep or daytime alertness) of these drugs contribute to their dependence liability. Finally, what is known about the neurobiological and behavioral mechanisms that underlie these drugs’ abuse liability and their state-altering effects is discussed.



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 132-2


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


Substance dependence is a maladaptive pattern of substance use, leading to clinically significant impairment or distress, as manifested by at least three of the following, occurring at any time in the same 12-month period:









Specify physiologic dependence: Evidence of tolerance or withdrawal is present.


Course specifiers:








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


Substance-induced sleep disorder is a prominent disturbance in sleep that is sufficiently severe to warrant independent clinical attention.


There is evidence from the history, physical examination, or laboratory findings of either:




The disturbance is not better accounted for by a sleep disorder that is not substance induced. Evidence that the symptoms are better accounted for by a sleep disorder that is not substance induced might include the following:





The disturbance does not occur exclusively during the course of a delirium.


The sleep disturbance causes clinically significant distress or impairment in social, occupational, or other important areas of functioning.


Specify subtype: alcohol, amphetamine, caffeine, cocaine, opioids, sedative, hypnotic, anxiolytics, or other.


Specify type:






Specify if onset is during intoxication or during withdrawal.


DSM-IV, Diagnostic and statistical manual of mental disorders, 4th edition.


There are two kinds of drug dependence: physiologic and behavioral. Physiologic dependence is a state induced by repeated drug use that results in a withdrawal syndrome when the drug is discontinued or an antagonist is administered. Many legal medications and illegal drugs can produce physiologic dependence, although the syndrome intensity, relation to dose, and necessary duration of use vary among different drugs. The fact that a drug produces physiologic dependence, meaning a withdrawal syndrome appears when the drug is discontinued, does not necessarily imply substance abuse. Physiologic dependence may be a component of behavioral dependence, but it is not a necessary or sufficient condition for it. Behavioral dependence is a pattern of behavior characterized by repetitive and compulsive drug seeking and consumption, despite considerable substance-related problems.



Drug Dependence and Sleep Medicine


In the sleep field, rapid eye movement (REM) sleep rebound can indicate a patient’s physiologic dependence on a drug. REM sleep rebound manifests physiologically as reduced REM sleep latency, increased REM sleep time, increased REM density, and subjective reports of nightmares. Most antidepressant medications at therapeutic doses suppress REM sleep, and a REM sleep rebound occurs when the drug is discontinued. Although REM sleep rebound does not lead to resumption of antidepressant use, a reduced REM sleep latency (e.g., one sign of REM sleep pressure and an underlying REM sleep disturbance) in abstinent alcoholics predicts alcoholic relapse. This is an example of physiologic dependence that does not necessarily lead to drug dependence or abuse in one case, but does in another.


Because virtually all drugs with a high abuse potential have profound effects on sleep and wake, sleep disorders clinicians should assess all the drug-taking behavior of their patients, including: prescribed and over-the-counter drugs, recreational drugs, tobacco and caffeine, health foods, steroids, botanicals, and natural substances. Some drugs of abuse have no legal therapeutic indications (e.g., marijuana, except in several states); others have very narrowly defined therapeutic indications (e.g., amphetamine, methylphenidate), and some have broader therapeutic indications (e.g., benzodiazepine receptor agonists). Some drugs of abuse also have wide use as social drugs (e.g., alcohol and caffeine).


The following guidelines are provided for sleep disorders clinicians to help them differentiate drug-seeking behavior from therapy-seeking behavior. In drug-seeking behavior the drug and its effects are the focus of the drug use, and in therapy-seeking the medication’s ability to reverse the signs and symptoms of the disease is the focus of the drug use. This distinction is important because many of the drugs used by sleep disorders clinicians are used chronically, and hence long-term use should be differentiated from abuse. Also, many of these medications have scientifically documented efficacy and are therefore indicated for specific sleep disorders; some of these drugs also are abused and importantly may be the cause of a sleep disorder.



Understanding Substance Abuse


Scientific attempts to understand substance abuse have proceeded at two levels of analysis: behavioral and neurobiological. Interestingly, the scientific evidence at these two levels of analysis has converged. For sleep scientists and clinicians, an obvious question is: How does a drug’s effect on sleep and daytime alertness relate to the behavioral and neurobiological changes that occur in the substance-dependent person?



Behavioral Mechanisms


Substance use behavior, whether in therapeutic, socially accepted recreational forms or in excessive, socially unacceptable, physically hazardous forms, can be analyzed to determine factors important to the initiation and maintenance of substance abuse. Drug reinforcement is a major factor to be considered in substance-use behavior. Drugs are viewed as reinforcers when they promote and maintain drug-seeking and drug self-administration as a function of the effects the drug produces, which can include the drug’s pharmacologic and nonpharmacologic effects. Two mechanisms of drug reinforcement are hypothesized. In the first hypothesis, the drug produces an inferred mood-elevating or euphorogenic effect and thus acts as a positive reinforcer. In the second, the drug acts as a negative reinforcer by reversing an inferred aversive state, such as a withdrawal syndrome or excessive sleepiness or fatigue. The two processes, positive and negative drug reinforcement, are not necessarily mutually exclusive and can operate concurrently or at the different stages in a drug-abuse cycle (initiation, maintenance, or relapse). These two reinforcement processes lead to the initiation and maintenance of excessive and hazardous drug use.


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.


During a period of chronic drug use, daytime sleepiness can also result from a drug-induced disturbance of nocturnal sleep. All the stimulants reviewed later disrupt nocturnal sleep, and the degree of disruption depends on dose and proximity of their use to the sleep period. Disrupted and fragmented sleep produces daytime sleepiness. Similar to the reinforcement cycle described earlier, a drug-induced sleep disturbance at night could lead to daytime sleepiness, which then enhances the likelihood of self-administration of the stimulant. This is a common vicious circle seen in heavy coffee drinkers.


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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Mar 13, 2017 | Posted by in NEUROLOGY | Comments Off on Medication and Substance Abuse
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