Medication and Substance Abuse Timothy Roehrs; Thomas Roth

Home , Alcohol use and sleep, REM rebound, Wakefulness

Chapter 140 Medication and Substance Abuse Timothy Roehrs; Thomas Roth

Chapter Highlights • Most psychoactive drugs with abuse • Some of the drugs of abuse are legal and widely liability have effects on sleep and used socially and may be the cause of patients’ wakefulness. sleep or alertness complaints. • The mechanisms underlying substance abuse • Other drugs with abuse liability are drugs are known, but the role of the drug’s sleep-wake indicated in the treatment of sleep disorders. state–altering effects in substance abuse is • This chapter provides guidelines for sleep not fully known, although it is likely to be disorders clinicians to differentiate drug-seeking important. behavior from therapy-seeking behavior.

Various legal medications and all illegal central nervous system criteria is important for referral decisions. Substance abuse (CNS)–acting drugs have a high abuse liability, that is, the and dependence are common, as 18% of the U.S. population likelihood for development of physiologic or behavioral will experience a substance abuse disorder during their life- dependence on these substances is heightened. The various time, and about 20% of patients in general medical practice terms often used in discussing substance abuse are confusing, and 35% of psychiatric patients present with substance abuse are controversial, and need clarification. Physiologic depen- disorders. dence is a state induced by repeated drug use that results in a Virtually all drugs with a high abuse liability have pro- withdrawal syndrome when the drug is discontinued or an found effects on sleep and wake. For this reason, sleep disor- antagonist is administered. Many legal medications and illegal ders clinicians should assess all the drug-taking behavior of drugs can produce physiologic dependence, although the syn- their patients, including prescribed and over-the-counter drome intensity, relation to dose, and necessary duration of drugs, recreational drugs, tobacco and caffeine, health foods, use vary among different drugs. The fact that a drug produces steroids, botanicals, and natural substances. This chapter physiologic dependence, meaning that a withdrawal syndrome reviews the sleep-wake alterations produced by administration appears when the drug is discontinued, does not necessarily and discontinuation of various drug classes associated with imply substance abuse. abuse. Also discussed is the way that the state-altering char- In the sleep field, a phenomenon suggestive of the presence acteristics (i.e., their disruptive effects on sleep or daytime of physiologic dependence on a drug is rapid eye movement alertness) of these drugs contribute to their dependence liabil- (REM) sleep rebound. When drugs that suppress REM sleep ity. Finally, what is known about the neurobiologic and behav- are discontinued, a REM rebound (i.e., increased REM pres- ioral mechanisms that underlie these drugs’ abuse liability and sure) is seen, which is manifested by reduced REM sleep their state-altering effects is discussed. latency, by increased REM sleep time and REM density, and Some drugs of abuse have no legal therapeutic indications subjectively with reports of nightmares. Most of the antide- (i.e., various inhalants, LSD); others have narrowly defined pressant medications at therapeutic doses suppress REM therapeutic indications (i.e., amphetamine, methylphenidate), sleep, and a REM sleep rebound occurs when the drug is and some have broader therapeutic indications (i.e., benzodi- discontinued. However, a REM sleep rebound after antide- azepine receptor agonists). Other drugs of abuse have wide pressant use does not lead to resumption of antidepressant use. use as social drugs (i.e., alcohol and caffeine). Marijuana occu- On the other hand, a reduced REM latency (e.g., one sign of pies a unique position as it remains illegal federally but as of REM pressure and an underlying REM sleep disturbance) in 2014 is legal in 20-plus states for specific therapeutic indica- abstinent alcoholics is predictive of alcoholic relapse. tions and in a few states for recreational and social use. For Physiologic dependence may be a component of but is these various reasons, guidelines are provided for sleep disor- neither a necessary nor a sufficient condition for behavioral ders clinicians that will help them differentiate drug-seeking dependence. Behavioral dependence is a pattern of behavior behavior from therapy-seeking behavior. In drug-seeking characterized by repetitive and compulsive drug seeking and behavior, the drug and its effects are the focus of the drug use, consumption, despite considerable substance-related prob- whereas in therapy-seeking behavior, the medications’ ability lems. The formal diagnostic criteria according to theDiagnos - to reverse the signs and symptoms of the disease is the focus tic and Statistical Manual of Mental Disorders, fifth edition of the drug use. This distinction is important because many of (DSM-5) are discussed later. Whereas the sleep disorders the drugs used by sleep disorders clinicians are used chroni- clinician will not make formal diagnoses, awareness of the cally, and hence it is important to differentiate long-term use 1380 Downloaded for Rohul Amin ([email protected]) at Uniformed Services Univ of the Health Sciences from ClinicalKey.com by Elsevier on September 29, 2018. For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved. Chapter 140 Medication and Substance Abuse 1381

from abuse. Many of these medications also have scientifically state, such as a withdrawal syndrome, insomnia, or excessive documented efficacy and are hence indicated for specific sleep sleepiness-fatigue. The two processes, positive and negative disorders; some of these drugs also are abused and, impor- drug reinforcement, are not necessarily mutually exclusive and tantly, may be the cause of a sleep disorder. may operate concurrently or at the different stages in a drug abuse cycle (i.e., its initiation, maintenance, or relapse). These DIAGNOSIS OF SUBSTANCE-RELATED two reinforcement processes lead to the initiation and main- DISORDERS tenance of excessive and hazardous drug use. How the sleep- wake state–altering consequences of the drugs addressed in The generally accepted diagnostic classification system for this chapter may function as positive or negative reinforcers substance-related disorders is DSM-5. DSM-5 reflects a can be illustrated. major departure from DSM-IV and DSM-IV-TR. Substance- The alerting effects of stimulants are reinforcing for indi- related disorders are divided into two major classes: (1) sub- viduals who are sleepy, fatigued, and having difficulty in stance use and (2) substance-induced disorders. Substance use functioning to their desired level. Healthy normals will self- disorders, formerly termed substance abuse and substance administer a stimulant when they are sleepy but not when dependence (DSM-IV-TR), are characterized by behaviors alert.1 That self-administration does not necessarily imply and consequences (a total of 11 criteria are listed) in groupings abuse. In substance abuse, however, the sleepiness may be that show impaired control, social impairment, risky use, and present as part of a withdrawal syndrome due to abstinence pharmacologic consequences (i.e., tolerance, withdrawal) associ- following chronic nonmedical use of a stimulant. It has been ated with use of 10 classes of substances. Rather than distin- hypothesized that continued substance use, difficulty in reduc- guishing abuse and dependence as in DSM-IV-TR, DSM-5 ing use, or relapse may reflect “self-medication” to reverse the rates the severity of the disorder by the number of symptoms excessive sleepiness of the abstinence. For example, in chronic present: mild, two or three; moderate, four or five; and severe, caffeine or nicotine dependence, the 8-hour sleep period is six or more. Substance-induced disorders are characterized by functionally an enforced abstinence, and given the pharmaco- symptoms reflecting the presence of intoxication, withdrawal, kinetics of these drugs, the 8-hour abstinence during the sleep or a mental disorder. As this category name implies, the dis- period is followed by enhanced sleepiness in the morning and, order has to be associated with current or very recent use of in extreme cases, smoking during the night. Caffeine or nico- the substance. tine taken immediately on arising reverses the sleepy state. Whereas most of the drugs of abuse are disruptive of sleep “When do you have your first morning cigarette?” is a question or daytime alertness, such disturbances are not major criteria clinicians can use to gauge the severity of nicotine addiction. for substance abuse in DSM-5. They are mentioned as pos- In amphetamine or cocaine abuse, excessive sleepiness during sible symptoms in a withdrawal syndrome, which is one of the the initial drug abstinence has been consistently reported. 11 criteria for a substance use disorder. DSM-5 emphasizes Again, use of these stimulants will reverse the sleepiness. that symptoms of tolerance development and withdrawal, only During a period of chronic drug use, daytime sleepiness occurring in the context of medical treatment with prescribed may also result from a drug-induced disturbance of nocturnal medications, should not receive a diagnosis of substance- sleep. All the stimulants as reviewed later disrupt nocturnal related disorder (distinguishing drug seeking from therapy sleep to some degree, depending on dose and proximity of seeking in clinical practice is discussed later). Also as discussed their use to the sleep period. Disrupted and fragmented sleep in this chapter later, the role of disruptions of sleep and produces daytime sleepiness. One could hypothesize that a daytime alertness in substance use disorders is not elaborated drug-induced sleep disturbance at night leads to daytime in DSM-5. sleepiness, which then enhances the likelihood of the self- The attempt to understand substance abuse scientifically administration of a stimulant. This is the common vicious has proceeded at two levels of analyses, behavioral and neuro- circle seen in heavy coffee drinkers. biologic. Interestingly, the scientific evidence at these two The state of sleepiness may not necessarily be drug induced. levels of analysis has converged. For sleep scientists and clini- It may also be due to chronic insufficient sleep in healthy cians, an obvious question is, “How does a drug’s effect on sleep normals or to disturbed sleep efficiency and circadian dys- and daytime alertness relate to the behavioral and neurobio- rhythmia seen in altered work schedules. We have already logic changes that occur in a person abusing the substance?” noted that healthy normals will self-administer a stimulant Behavioral Mechanisms when experiencing sleepiness. Night workers and rotating shift workers have shortened and disturbed sleep when sleep- Substance use, whether in a therapeutic and socially accepted ing during the day as well as increased sleepiness when awake recreational form or in an excessive, socially unacceptable, and at night. Rotating shift workers and night workers report a physically hazardous form, is a behavior that can be analyzed disproportionate use of sedating drugs, especially alcohol, to to determine factors important to the initiation and mainte- improve sleep and stimulants, especially caffeine, to improve nance of substance abuse. Drugs are viewed as reinforcers alertness.2,3 This substance use may increase risks of substance when they promote and maintain drug seeking and drug self- abuse. administration as a function of the effects the drug produces. The sedative-hypnotics, tetrahydrocannabinol (THC), and Those effects may include the drug’s pharmacologic effects as alcohol may become reinforcers and lead to substance depen- well as various nonpharmacologic consequences. Two mecha- dence or abuse through their capacity to induce sleep in nisms of drug reinforcement are hypothesized. First, the drug persons with insomnia or to reverse a waking “hyperaroused” produces an inferred “mood-elevating” or “euphorigenic” effect state. People with insomnia and no history of alcoholism or and thus acts as a positive reinforcer. In the second, the drug drug abuse, given an opportunity to choose between previ- acts as a negative reinforcer by reversing an inferred “aversive” ously experienced color-coded ethanol and placebo beverages

Downloaded for Rohul Amin ([email protected]) at Uniformed Services Univ of the Health Sciences from ClinicalKey.com by Elsevier on September 29, 2018. For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved. 1382 PART II • Section 17 Psychiatric Disorders

at night before sleep, chose ethanol, whereas healthy normals medical or psychiatric clinics, with 20% to 50% of men and with a similar level of self-reported social drinking chose 6% to 10% of women suffering from alcoholism. 4 placebo. Interestingly, people with insomnia not only showed Alcohol in Healthy Adults nighttime self-administration of benzodiazepine receptor agonists but also self-administered them during the daytime. Alcohol in large doses is mildly stimulating on the rising However, only those who showed evidence of daytime phase of the plasma concentration curve and sedating on the physiologic hyperarousal self-administered during the day.5 declining side of the curve.7 In lower doses, it has little stimu- Whether these drug self-administration patterns reflect drug latory effects on the rising phase and is mildly sedating on the seeking or therapy seeking needs to be considered, and the declining phase. Studies of alcohol effects on sleep typically issue is further discussed later. administer alcohol 30 to 60 minutes before sleep, which results Neurobiologic Mechanisms in peak concentrations occurring before or at bedtime. The studies have used doses ranging from 0.16 to 1.0 g/kg, the The positive-reinforcement neurobiology of drug self- rough equivalent of one to six standard drinks, producing administration is generally accepted to involve mesocortico- breath ethanol concentration (BrEC) up to 0.105% at limbic projections originating in the ventral tegmental area of bedtime.8 Sleep latency is reduced over this dose range, and the rostral reticular activation system and terminating in the one study reported increased sleep time at a low 0.16 g/kg nucleus accumbens. It is a dopaminergic system.6 Most drugs dose but not at the higher 0.32 and 0.64 g/kg doses of that of abuse interact in some way with this system. This reinforce- study. Improved sleep only at low doses is likely due to a ment system is part of a broader dopaminergic system that second half of the night sleep disruptive rebound wakefulness projects into several forebrain regions and as a whole is con- that occurs with the higher doses. The typical BrEC at lights sidered to have executive and integrative functions.6 The dopa- out for higher dose studies is between 0.05% and 0.09%, and minergic neurons of the ventral tegmental area are modulated given that ethanol is metabolized at a rate of 0.01% to 0.02% by a number of other neurotransmitter systems. It is through BrEC per hour, within the first 4 to 5 hours of the sleep this modulation that sleep-wake state and level of sleepiness- period, ethanol has been completely metabolized. This leads alertness during wake could have an impact on a drug’s rein- to rebound wakefulness during the last hours of the sleep forcing properties. period.9 Thus, for the whole night, sleep time is not increased In chronic use, it is hypothesized by Koob that the neuro- at high doses and often is actually decreased. biologic systems involved in acute positive reinforcement In addition to these effects on sleep induction and main- adapt by establishing “opponent” processes.6 These opponent tenance, ethanol affects the normal progression of sleep processes neutralize the acute reinforcing effects of the drug stages.10 A dose-dependent suppression of REM sleep, at the and during abstinence are left unopposed. Consequently, they least in the first half of the night (i.e., when ethanol blood produce the abstinence syndrome, an inverse state to the drug levels are present), and in some studies increased slow wave state, which becomes a basis of negative reinforcement (i.e., sleep in the first half of the night are reported. Slow wave reversal of abstinence symptoms). For example, stimulant sleep enhancement occurs in subjects with less than age- abstinence produces sleepiness, which in turn leads to self- corrected amounts of slow wave sleep at baseline. When first- administration of stimulant drugs. Koob hypothesized that half REM sleep suppression is observed, a second-half REM the opponent processes do not necessarily develop through sleep rebound is reported as well. As with rebound wakeful- the same neurobiologic system that produces positive rein- ness, the second-half REM sleep rebound likely relates to the forcement. Other neurobiologic systems and, for the purposes timing of complete ethanol elimination from the body. of this chapter, possibly sleep-wake systems could be one basis Repeated nightly administration of ethanol leads to tolerance of the opponent processes. Two important sleep-wake find- development to both the sleep induction and sleep stage ings are consistent with this model. They are the REM sup- effects but interestingly not to the rebound effects. Finally, pression and REM rebound associated with administration discontinuation of ethanol is followed by a REM sleep and discontinuation of most all of the drugs with an abuse rebound, although the appearance of a REM sleep rebound is liability. Second, the persisting disturbance of sleep that is likely related to dose, duration of use, basal level of REM found after weeks and months of abstinence suggests that sleep, and extent of prior REM sleep suppression and toler- some type of neurobiologic adaptation within sleep-wake ance development. systems to the chronic drug exposure has occurred. 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 SLEEP-WAKE ALTERATIONS AND heavy drinking, hangover, and next-day cognitive and psycho- SPECIFIC SUBSTANCES motor performance have demonstrated impairment in the Alcohol and Alcoholism morning with BrEC zero 14 hours after ethanol ingestion the previous night and approximately 4 hours before going to Epidemiology and Risk Factors 12 bed. Some studies have related the next-day impairment to The U.S. prevalence of alcohol dependence by age, sex, and the degree of ethanol-related sleep loss and fragmentation race-ethnicity is available at www.niaaa.nih.gov. For 2012, the during the previous night.13 Even with low alcohol doses and past-month prevalence of alcohol dependence among those in the absence of hangover symptoms, the sleep-disruptive 21 years and older was estimated to be 6.9%, with the rate and performance-impairing effects may continue after alcohol being 10.8% for men and 3.4% for women. The rates for those is completely metabolized and BrEC is zero. Late afternoon aged 12 to 20 years were 4.3% for heavy drinking and 15% drinking with BrEC zero at bedtime disrupted sleep in the for binge drinking. These rates can be much higher in general second half of the night, and morning or midday drinking

continues to impair performance for 2 to 3 hours after BrEC The risk of periodic limb movements (PLMs) during sleep is zero.14,15 was increased in association with self-reported alcohol con- Several clinical implications of these alcohol effects in sumption in a sample of sleep disorders clinic patients.23 healthy people might be discussed. Regular heavy drinking However, in a sample of patients abstinent of alcohol, the rate and chronic insomnia complaints, particularly sleep mainte- of PLMs was not different from the rate of a general sleep nance insomnia, are easily identified; but occasional insomnia disorders clinic sample.24 Alcoholism is associated with defi- can be related to a patient’s occasional heavy drinking. Sleep ciencies in iron, ferritin, magnesium, and vitamin B12 and diaries that query about social drug use as well as the sleep polyneuropathy, all of which are also associated with PLMs complaints can help identify for the clinician and patient this and restless legs syndrome (RLS). To the extent that the relation of the alcohol use and sleep problems. Inquiry as to patient with alcoholism has any of these deficiencies, RLS and the quantity and timing of the patient’s alcohol consumption PLMs may be precipitated or exacerbated. and attempt to sleep may reveal the sleep-disruptive potential Sleep and Alcohol Effects in Alcoholism of the alcohol. Just as important are the potential next-day impairing effects of evening alcohol consumption as discussed Patients with alcoholism commonly complain of sleep prob- earlier. Recognition that sleep-disruptive alcohol consump- lems, daytime sleepiness, and parasomnias. During drinking tion combined with sleepiness due to other causes can have binges, people with alcoholism report polyphasic sleep pat- additive daytime impairing effects is also important. terns, with short sleep periods followed by short wake periods Alcohol Effects in Primary Sleep Disorders that are distributed across the 24-hour day. This type of sleep pattern is seen in organisms without a circadian pacemaker Approximately 30% of individuals with insomnia in the (i.e., lesioned suprachiasmatic nuclei). It is possible that during general population use alcohol to help them sleep, and 67% these binges, the sleep-wake cycles of people with alcoholism of those people have reported that the alcohol was effective are so chaotic that they are arrhythmic. It would be of interest in inducing sleep.16 The laboratory studies of healthy normals to see the circadian pattern of temperature, dim light melato- showing sleep-disruptive ethanol effects used higher doses nin onset, and other phase markers in this population. Labora- (e.g., BrEC >0.05% at bedtime, about five or six drinks) than tory studies of patients with alcoholism show that sleep the doses (e.g., one or two drinks) reportedly used by insom- latency and total sleep time are disturbed on both drinking niacs. In laboratory studies of people with primary insomnia, and discontinuation nights.25 The prolonged sleep latency in ethanol administered 30 minutes before sleep, which raised alcoholism when drinking contrasts with the reduced sleep BrEC to only 0.04% at bedtime, improved sleep without latency that alcohol produces in people without alcoholism producing a second-half wakefulness rebound.17 Compared and suggests tolerance development and possible neurobio- with age-matched people without insomnia and with a similar logic changes as discussed before. In addition, as in insomnia social drinking history, those with insomnia chose to self- and some healthy normals with basally low amounts of slow administer alcohol before sleep more frequently. The risk asso- wave sleep, drinking in people with alcoholism is associated ciated with using alcohol as a sleep aid is that tolerance to its with increased slow wave sleep and REM sleep suppression, initial beneficial effect develops within three to five nights, with rapid tolerance development to these effects.25 and people with insomnia increase their self-administered The acute alcohol abstinence phase lasts 1 to 2 weeks, dose to compensate.18 Later in the chapter, guidelines are although some of the withdrawal symptoms, such as mood offered for determining when what could be initially consid- instability, disturbed sleep, and craving, remain beyond this ered therapy seeking (e.g., use of alcohol as a sleep aid) has period. During the acute abstinence phase, slow wave sleep is shifted to drug seeking. reduced, sometimes to minimal levels, and REM sleep conti- Alcohol is a mild respiratory depressant in the wake state, nuity is disrupted.26 There are frequent REM episodes and and during sleep it exacerbates obstructive sleep apnea syn- shortened non-REM (NREM)–REM cycles during the acute drome and may precipitate sleep disordered breathing in abstinence. at-risk persons. In one study, patients with moderate obstruc- Recovery and Long-term Abstinence tive sleep apnea, defined as an average respiratory disturbance index (RDI; number of apneas and hypopneas per hour of Some of these abnormal sleep patterns can persist for up to 3 sleep) of 22, received 300 mL of bourbon 2 hours before years in some patients with alcoholism. Sleep remains short- bedtime.19 That dose of ethanol increased the RDI to 28. In ened and REM sleep pressure elevated, as evident in elevated another study, patients with a range of sleep-related breathing levels with shortened latencies to REM sleep.27 Figure 140-1 disorders were studied.20 An unspecified dose and BrEC illustrates the abnormally short sleep and elevated REM sleep increased the RDIs of every patient with baseline RDI percentage in abstinent primary alcoholism. Whereas it is between 14 and 54. The effects of ethanol are also found in tempting to attribute these sleep abnormalities to the exces- other sleep-related respiratory disorders. For example, in sive alcohol drinking of the patients, the sleep problems could several patients with chronic obstructive pulmonary disease, have preceded the development of the alcoholism or they ethanol worsened the degree of hypoxemia, and in several could be secondary to the development of other medical and patients with only a snoring history, it induced apnea.20 That psychiatric disorders during the alcoholic drinking of the an asymptomatic snorer with no apnea will develop apnea patient. after ethanol was convincingly shown in a later study.21 In one Regardless of the cause of the sleep disturbance evident in study, ethanol (BrEC = 0.08%) in snoring men increased their alcoholism, both objective and subjective measures of sleep RDIs to a pathologic level (i.e., RDI >10).22 On the other taken after the immediate acute abstinence predict the likeli- hand, the findings in asymptomatic individuals without risk hood of relapse during the long-term abstinence. Early labo- factors have been inconsistent. ratory studies suggested that low levels of slow wave sleep are

Sedating antidepressant medications, such as trazodone ONE YEAR FOLLOW-UP IN SOBER ALCOHOLICS and doxepin, are often used in the United States to treat 30 primary insomnia and insomnia comorbid with depression. Trazodone has been used to treat sleep disturbance in alcoholism patients in open-label, noncontrolled studies.30 In doses 25 of 50 to 300 mg, it improved self-reported measures of insom- Normal mean ± 90% Cl nia. Currently, the three Food and Drug Administration– approved alcoholism treatments are disulfiram, naltrexone, 20 and acamprosate. Unfortunately, sleep problems have not been major outcome measures in those studies testing the efficacy REM sleep time (%) Sober nondepressed patients (n = 9) of these agents used as alcoholism treatments. One exception 15 is a recently completed large trial of the anticonvulsant gaba- 0 10 20 30 40 50 60 pentin, in which both sleep and drinking outcomes were improved.31 400 Cognitive-behavioral therapy for insomnia (CBT-I) is an alternative to medications, and several trials in alcoholism 375 Normal mean ± 90% Cl with sleep disturbance have been conducted. A randomized 350 controlled trial of brief CBT-I associated with alcoholism was done in 60 patients without comorbid depression.32 The 325 CBT-I treatment, compared with wait-list controls, improved sleep diary measures of sleep quality, sleep efficiency, awaken- 300 ings, and time to fall asleep. However, CBT-I had no impact Total sleep time (min) Sober nondepressed patients (n = 9) on drinking relapse rates during the 6-month follow-up 275 period. An open trial of CBT-I in patients with alcoholism 0 10 20 30 40 50 60 similarly found improved sleep but not improved drinking 33 Weeks of abstinence outcomes. It is tempting to assume that the excessive alcohol intake Figure 140-1 Polygraphic sleep recordings for rapid eye movement (REM) is the sole or primary cause of insomnia in alcoholism. Earlier sleep percentage and total sleep time in nine male, sober, recovering, primary it was noted that other primary sleep disorders and possibly nondepressed, alcoholic patients for more than 1 year. Note that both measures differ from those of age-matched healthy control subjects for most of circadian disorders are present in patients with alcoholism at the recovery period. Values for the patients are mean ± dstandar error of the a higher rate than in those without alcoholism. Furthermore, mean; values for healthy control subjects are mean + 90% confidence interval depression is often present in alcoholism, and the sleep dis- (CI). (Modified from Drummond SP, Gillin JC, Smith TL, Demodena A. The sleep turbances of depression have been well documented. Appro- of abstinent pure primary alcoholic patients: natural course and relationship priate treatment of the comorbid sleep or psychiatric disorder to relapse. Alcohol Clin Exp Res 1998;22:1796–802.) should be pursued. Insomnia treatment in patients with alcoholism must begin with referral to addiction treatment spe- cialists. Treating the insomnia alone will not initiate abstinence. Patients with alcoholism often deny their drinking problems predictive of alcoholism relapse.28 More recent studies have and may focus on their sleep problems to avoid confronting identified REM sleep disturbances, either elevated REM sleep their drinking problems. percentage or shortened REM sleep latency, as predictive of 29 Epidemiology and Risk Factors for Drugs of Abuse relapse. Interestingly, that risk was greater than that associated with other variables, such as age, marital status, employ- Prevalence data on abuse of specific drugs other than alcohol ment, duration and severity of alcoholism, hepatic enzymes, are highly variable across years and regions of the country. and depression ratings. U.S. prevalence estimates on use and dependence are col- Treatment of the Sleep Disturbance of Alcoholism lected annually by the U.S. government Office of Applied Studies in the Substance Abuse and Mental Health Services Treatment of sleep disturbance in patients with alcoholism is Administration. Prevalence tables by drug, age, sex, and challenging as there are few placebo-controlled studies to region of the country for lifetime, past year, and past month guide the clinician. The benzodiazepine receptor agonists are use and for dependence or abuse are available at www.oas the drug class of choice for insomnia treatment in patients .samhsa.gov. In the 2013 National Survey on Drug Use and without alcoholism. However, whereas these drugs have a Health, 9.4% of Americans 12 years and older were current relatively low abuse liability in those without alcoholism, illicit drug users, which includes marijuana, cocaine, heroin, their risk in outpatients with alcoholism after acute inpatient hallucinogens, inhalants, and the nonmedical use of prescrip- withdrawal is unknown.30 These drugs are effective for the tion medications. immediate inpatient withdrawal syndrome because they Stimulants share the same mechanism of action as that of alcohol itself, Caffeine promotion of γ-aminobutyric acid inhibition. A further caution to their outpatient use is that they have a high Caffeine often is not considered a drug of abuse by society, potential for toxicity and overdose when combined with and even within the medical community, its potential for alcohol, thereby being dangerous for the people with alcohol- abuse is not fully appreciated. Laboratory data indicate ism who relapse. there are conditions under which caffeine is persistently

self-administered and that it does have abuse liability, albeit a Psychomotor Stimulants relatively low liability compared with other recognized drugs of abuse.34 As might be expected, caffeine in doses of 150 Cocaine. Cocaine is the CNS stimulant with the greatest to 400 mg administered immediately before sleep prolongs abuse liability. Some laboratory studies have examined the the onset of sleep and reduces total sleep time in healthy effects of cocaine and its discontinuation on sleep and daytime normals.34-39 To compare the disruptive effects of caffeine with alertness. Clinical assessments have described continued and the psychomotor stimulants, in one study 300 mg of caffeine prolonged wakefulness during “cocaine runs,” days of pro- reduced sleep efficiency from 89% to 74%, whereas 40 mg of tracted cocaine use. The cocaine runs are then followed by pemoline reduced it to 80%, and 20 mg of methylphenidate “crashes,” which are characterized by excessive sleep and sleep- reduced it to 61%.36 As to sleep stage effects, some studies iness.46 Several polysomnography (PSG) studies of cocaine report reductions of stage 3–4 sleep,35,36 but unlike with the discontinuation in cocaine-dependent persons have reported psychomotor stimulants, stage REM sleep is not affected. elevated sleep time and a REM sleep rebound during the Discontinuation of the chronic use of caffeine is associated initial abstinence. That disturbance was then followed bya with mood and performance disturbance. A withdrawal syn- persisting insomnia and REM sleep disturbance for the drome was observed after a double-blind, placebo-controlled 3-week study duration.47 A laboratory study of cocaine admin- cessation of chronic but moderate (235 mg daily on average) istration and discontinuation found that 600 mg/day intrana- caffeine consumption.37 Putting the dose in context, an sal cocaine (insufflated from 1900 to 2100 hours) severely 8-ounce cup of coffee contains 100 mg of caffeine. On the disrupted sleep, delaying its onset at the 2300 hours bedtime second day of caffeine cessation (20 hours after caffeine use), for up to 3 to 4 hours and suppressing REM sleep.48 During in addition to the ubiquitous headache, reduced vigor and the first two discontinuation days, average daily sleep latency increases in sleepiness, fatigue, and drowsiness were experi- on the Multiple Sleep Latency Test (MSLT) was less than 5 enced. For moderate to heavy caffeine users, the morning cup minutes (i.e., a pathologic level of sleepiness), most probably of coffee immediately after arising probably restores caffeine because of the severe sleep disturbance of the prior 5 days of levels and alertness as the 8-hour sleep period is essentially a cocaine self-administration. The MSLT also showed multiple caffeine discontinuation. sleep-onset REM periods, probably due to the prior REM Nicotine sleep suppression during the cocaine administration nights. Then, even after 14 days of abstinence, a nocturnal sleep and That nicotine is a drug of abuse is undisputed, and some have REM sleep disturbance remained, although the MSLTs were argued that it rivals the abuse liability of cocaine. The study free of sleep-onset REM periods and the sleep latencies of nicotine’s effects on sleep has been facilitated with the returned to normal levels. Later, we discuss how these state- development of nicotine delivery systems (i.e., nicotine gum altering effects may serve to maintain cocaine dependence. and patches) for use in clinical smoking cessation programs. Some PSG studies have now shown that slow wave sleep and In healthy normals, transdermal nicotine (7 to 14 mg) pro- REM sleep disturbances are predictive of relapse during duced a dose-dependent increase in wakefulness and a reduc- short-term abstinence.49 tion in percentage REM sleep relative to a placebo patch.40 A second study of nonsmoking normals also found that 17.5 mg Amphetamine. Amphetamine is also a drug of abuse. During transdermal nicotine increased wake time and decreased the 1950s, before its manufacture and distribution became REM sleep percentage.41 In obese, nonsmoking patients with tightly controlled, an epidemic of amphetamine abuse occurred sleep disordered breathing, 15 mg transdermal nicotine in the United States. Although it is not the drug of choice, it reduced both total sleep time and percentage REM sleep; it has therapeutic indications for the treatment of narcolepsy did not improve the sleep disordered breathing of these and attention deficit/hyperactivity disorder (ADHD). Few patients, which was the study’s primary purpose.42 PSG studies of amphetamine administration and discontinu- The discontinuation of nicotine in nicotine-dependent ation have been done. In one of the earliest PSG drug studies, individuals is associated with a disturbance of sleep and alert- 10 or 15 mg of d-amphetamine doubled sleep latency and ness. In an uncontrolled study that compared the sleep of suppressed REM sleep in healthy young adults.50 Another smokers during the week before and after cessation of chronic study of healthy adults and patients with narcolepsy reported smoking, the number of arousals, awakenings, and sleep stage that a 7 to 8 am administration of methamphetamine (10 mg) changes were all increased during the cessation week.43 In a reduced sleep efficiency that night (11pm bedtime) in control double-blind study using a placebo versus nicotine patch subjects and at 40- to 60-mg doses in the narcoleptics.51 No during the discontinuation of the average daily use of 30 ciga- REM sleep effects were observed in the normals. However, rettes, the number of arousals was increased relative to the the patients received higher doses, and their REM sleep smoking baseline in the placebo group, whereas in the nicotine latency was increased and REM sleep time was reduced. A (22 mg) patch group, arousals were reduced and stage 3–4 study of amphetamine-dependent subjects assessed sleep sleep was increased relative to the smoking baseline.44 However, during the drug’s discontinuation.52 On the second night after given the pharmacokinetics of nicotine, any smoking baseline the last amphetamine dose, REM sleep time rebounded and is a partial discontinuation during the usual 8-hour sleep remained elevated for three to five nights. This REM sleep period of nonsmoking. Because the nicotine patch was worn rebound was delayed relative to that associated with cocaine continuously, it is probable that sleep was improved relative discontinuation, which may be due to the pharmacokinetic to a partial discontinuation (i.e., a smoking baseline). Such is differences between the drugs (i.e., the longer half-life of consistent with the several questionnaire studies that find amphetamine). The rebound also was longer lasting, which smokers are more likely than nonsmokers to report problems may be due to differences in the duration or amount of prior falling asleep and staying asleep.45 use or in the level of REM sleep suppression caused by the

drug. Total sleep times were elevated during the same 3- to 3–4 sleep, and REM sleep in abstinent opioid-dependent 5-day period, probably reflecting recovery sleep due to the people.59 All these drugs also produced increased brief arous- prior drug-induced sleep loss, but subsequently sleep times als and frequent sleep stage changes (i.e., sleep fragmentation). became shorter than normal, suggesting continuing insomnia. Several studies have indicated that tolerance to the sleep- As in abstinence from cocaine dependence, the continued disruptive effects develops within weeks.60 With tolerance insomnia in amphetamine abstinence raises questions about a development, the sleep fragmentation is lessened, and the stimulant-induced persisting alteration of CNS sleep-wake REM sleep–suppressive effects tend to diminish. mechanisms. The discontinuation of chronic opioid use is associated No studies of the effects of amphetamine discontinuation with sleep disturbance. Heroin-dependent people being on daytime levels of sleepiness-alertness have been done in maintained on methadone in an outpatient research treatment amphetamine-dependent persons. One would predict that program were discontinued from their treatment and sleep amphetamine discontinuation is associated with increased was recorded in the laboratory.61 Sleep latency and latency to daytime sleepiness and multiple sleep-onset REM periods on REM sleep were prolonged and percentage stage 3–4 sleep the MSLT similar to what is reported for the discontinuation was reduced compared with normals. Interestingly, after a of cocaine. week of buprenorphine 4 mg, a partial µ opioid agonist, the sleep patterns normalized. Methylphenidate. Methylphenidate is generally considered a Opioids also have an impact on other sleep disorders. safer drug as regards its abuse liability, although case reports Although not the first line of treatment, opioids improve RLS of its abuse have appeared over the years. Its indications are and are often used in patients who do not respond to dopa- for ADHD and narcolepsy. It is the drug of choice for ADHD mine agonists. In contrast, given negative effects on respira- and a second-choice drug for narcolepsy. In healthy normals, tory drive, they are contraindicated in sleep apnea. 20 mg reduced total sleep time, increased the latency to REM Sedative-Hypnotics sleep, and reduced the minutes of REM sleep, whereas 10 mg increased only REM sleep latency.53 In an earlier study, 5 mg Within society and the medical community, sedative- was reported to increase the latency to REM sleep and to hypnotics are considered to have a relatively high abuse liabil- reduce the percentage of REM sleep without affecting other ity. The scientific evidence from epidemiologic and laboratory sleep measures.54 In children with ADHD, studies of the studies indicates that the abuse liability of modern sedative- effects of methylphenidate taken during the day on subse- hypnotics is relatively low. The distinction “modern” is critical quent sleep are inconclusive. Sleep time was shortened in one in that the early sedative-hypnotics, barbiturates and ethanol- study55 and increased in another,56 and in one study REM based drugs (i.e., ethchlorvynol, choral hydrate), clearly sleep was fragmented.56 However, these studies can be ques- produce both physical and behavioral dependence, but the tioned for a variety of methodologic and control issues. modern benzodiazepine receptor agonists are not as likely We are unaware of studies that have documented the dis- to do so. continuation effects of methylphenidate in dependent indi- In the 1980s, daytime self-administration studies were viduals. Increased daytime sleepiness with multiple sleep-onset done in normals, persons with substance abuse histories, and REM periods would be predicted. The role that the excessive patients with anxiety disorders; the results showed a generally sleepiness following discontinuation of any of these stimulant low behavioral dependence liability. The benzodiazepine drugs may have in their continued use and abuse is illustrated receptor agonists were self-administered by people with a by self-administration studies done in healthy normals. When substance abuse history at low and declining rates over time62 given an opportunity to self-administer methylphenidate and were not differentially self-administered relative to (20 mg), healthy normals, with no current or previous sub- placebo by the normals or patients with anxiety disorders.63,64 stance abuse history, choose active drug on only 20% of the Research has found that some patients with anxiety disorders opportunities after 8 hours of time in bed the previous night self-administered alprazolam relative to placebo.65 Our but on 80% of the opportunities (i.e., 20% placebo choice) short-term studies of pre-sleep zolpidem or placebo self- after 4 hours of time in bed.1 These data are consistent with administration in patients with insomnia have found that and extend the cocaine data, showing that stimulants have triazolam and placebo are self-administered at similar rates performance-enhancing effects in sleep-deprived healthy (67% to 88%) in a single-choice paradigm (i.e., choice of normals and profoundly reinforcing effects for sleepy indi- taking the available capsule or not).66-68 However, when sub- viduals or normal individuals experiencing sleep loss. jects were forced to choose on a given night between triazolam 68 Opioids and placebo, triazolam was preferred 80% of the time. Most important, when subjects were given an opportunity, in a The opioids are drugs with a high abuse liability. They have single-choice paradigm, to self-administer multiple capsules disruptive effects on sleep continuity and sleep staging. Heroin on the same night, a 0.27-mg average nightly triazolam dose (3, 6, and 12 mg/70 kg) administered intramuscularly in a was self-administered (i.e., one capsule), whereas the placebo double-blind placebo-controlled design to abstinent opioid- dose was escalated to the three-capsule maximum. Long-term dependent people produced dose-related decreases in total studies of nightly use of zolpidem or placebo for 1 year showed sleep time, stage 3–4 sleep, and REM sleep.57 Heroin is that (1) zolpidem was preferred to placebo by people with metabolized to morphine, and as would be expected, mor- insomnia, but its overall rate of self-administration did not phine (7.5, 15, and 30 mg/70 kg) also produced a dose-related increase during 12 months of nightly use (i.e., a stable average decrease in sleep time, stage 3–4 sleep, and REM sleep in the nightly dose of 9.5 mg was self-administered), whereas abstinent opioid-dependent people.58 Finally, methadone (7.5, placebo self-administration did increase during the 12 months, 15, and 30 mg/70 kg) also decreased total sleep time, stage again to the three maximum capsules69; (2) 12 months of

nightly zolpidem use did not produce rebound insomnia or 500 withdrawal signs and symptoms after chronic use70; and (3) relative to placebo, zolpidem increased total sleep time, and 400 this hypnotic efficacy did not diminish during 8 months of * nightly use.71 300 Hallucinogens THC ** 200 THC is one of the principal active ingredients in marijuana. In the United States, marijuana still remains the most fre-

Total sleep time (min) 100 quently abused illicit drug, although its popularity appears to cycle, trending up and down over decades. THC is clas- sified as a mild sedative at low doses and a hallucinogen at 0 high doses. Treatment Recovery Study of THC’s effects on sleep and wakefulness occurred *P < .05 Night predominantly during the 1970s. Low doses of THC (4 to **P < .01 20 mg), in either experienced marijuana users or nonusers, had 18 72-74 mildly REM sleep–suppressive effects. In several of the 16 72,74 studies, total sleep time or stage 3–4 sleep was increased, 14 which then decreased after a week of repeated nightly use.74 At high doses (50 to 210 mg) in naive or experienced marijuana 12 users, THC again suppressed REM sleep, but effects on total 10 75 sleep time were not observed, and stage 3–4 sleep was reduced 8 ** in one report.76 Some of the studies reported a REM sleep 6 rebound on the THC discontinuation nights,72,75 and some reported a reduction in sleep time or an increase in sleep 4 73,75 latency. All of these studies have involved pre-sleep labora- 2 MSLT mean sleep latency (min) tory administration of THC. Several studies in situ or in 0 semicontrolled laboratory situations with moderate and heavy Treatment Recovery marijuana users smoking their usual marijuana cigarettes during the day or early evening have also been done. Self- Day reported or rater-observed sleep time was increased in two such Placebo studies.77,78 In a PSG study, little or no effects on sleep measures 79 MDMA 2 mg/kg were observed. These mild sedative effects have also been Sleep restrict observed during daytime studies using performance assessments. In situ assessment of daily activity levels also showed 78 Figure 140-2 Polygraphic sleep recordings for total sleep time and mean reduced activity during moderate or heavy marijuana use. sleep latency on the Multiple Sleep Latency Test (MSLT) were less than MDMA 5 minutes (i.e., a pathologic level of sleepiness), most probably because of the severe sleep disturbance the following day in moderate MDMA users An amphetamine derivative that has become increasingly (n = 7) after placebo, MDMA 2 mg/kg, or a 4-hour restricted bedtime. Drug ± or placebo was administered at 1800 hours, and bedtime was 2300 to popular as a recreational drug and drug of abuse is ( )3,4-met 0700 hours on drug or placebo nights and 0300 to 0700 hours on sleep- hylenedioxymethamphetamine (MDMA) or “ecstasy.” This restricted nights. Note the unusually high MSLT times after placebo and drug has hallucinogenic properties and acts indirectly by again after MDMA despite the MDMA-shortened sleep time the previous stimulating the release of brain monoamines.80 Exposure to night. After sleep restriction, the MSLT time did decline. (Modified from Randall S, Johanson CE, Tancer M, Roehrs T. Effects of acute 3,4-met MDMA decreases total sleep time with a decrease in NREM hylenedioxymethamphetamine on sleep and daytime sleepiness in MDMA sleep but no significant effects on REM sleep. Among NREM users: a preliminary study. Sleep 2009;32:1513–9.) sleep stages, individuals who use MDMA have less stage 2 sleep, but there are no apparent differences in stage 1 or slow wave sleep (stages 3 and 4).81 In a placebo-controlled study, acute MDMA shortened sleep primarily by increasing sleep are provocative. A trial of CBT-I and daytime sleepiness in latency and reducing stage 3–4 sleep and suppressing REM adolescents improved the sleep of those completing more than sleep.82 The MDMA-reduced sleep time was not associated four sessions.83 The improved sleep showed a trend toward with increased daytime sleepiness the following day as seen in reducing substance abuse problems at the 1-year follow-up. A a 4-hour sleep restriction condition (Figure 140-2). Average treatment trial of nicotine-dependent adults compared a daily sleep latency on the MSLT the day after nighttime 16-hour versus 24-hour nicotine patch during smoking absti- placebo was increased in MDMA users compared with age- nence.84 The patches reduced smoking urges, with the 24-hour matched controls, and MDMA users had an elevated number patch having a greater effect than the 16-hour patch. The of sleep-onset REM periods compared with controls. 24-hour patch improved sleep, specifically the amount of slow Treatment of the Sleep Disturbance in Drug Abuse wave sleep. This result in nicotine-dependent adults is in contrast to the sleep-disruptive effects of a nicotine patch on the The literature on treating sleep disturbance in drug abuse is sleep of nonsmokers. In the drug abuse treatment literature, even more limited than that for alcoholism, but the few studies sleep is rarely included as an outcome measure. The need for

Table 140-1 Characteristics of Drug-Seeking behavior. For example, one is concerned about the use of versus Therapy-Seeking Behavior ethanol as a hypnotic by an insomniac. Whereas pre-sleep ethanol use may initially be effective in improving sleep, rapid Drug-Seeking Behavior tolerance development is likely, which may lead to dose escala- • Drug chosen over other commodities or activities tion. Further, other reinforcing effects of ethanol (i.e., its • Drug taken in excessive, nontherapeutic amounts euphorigenic effects) may be discovered by the person, espe- • Drug taken on chronic basis, leading to tolerance and physical dependence cially as dose is escalated, and its use may then extend beyond • Drug taken in nontherapeutic context the therapeutic context (i.e., before sleep as a hypnotic). A similar shifting pattern can be described for stimulant or Therapy-Seeking Behavior opiate use. On the other hand, drug seeking may be main- • Drug has demonstrated efficacy tained because the drug, in addition to its mood-altering and • Duration and dose of self-administration are limited to euphorigenic effects, also has therapeutic effects (i.e., the therapeutic effects stimulant effects of cocaine or amphetamine do reverse the • Patient has signs and symptoms for which drug is excessive sleepiness that is experienced during drug discon- indicated tinuation). Thus, the dependence is maintained by both its • Drug is believed to be and is experienced as being mood-altering effects and its therapeutic effects, what others efficacious have termed self-medication (i.e., both positive and negative reinforcing effects). Sleep-Wake Disturbance in Alcoholism and Drug Abuse clinical trials that focus on treatment of sleep complaints in substance abuse is clearly evident. The role of sleep-wake disturbance in alcoholism and substance abuse is not well understood. It is known that insomnia CONTROVERSIES AND PITFALLS is a risk factor for substance abuse. Yet, earlier in discussing Drug Seeking versus Therapy Seeking diagnoses, the point was made that sleep-wake disturbances are not major criteria in making DSM-5 abuse diagnoses. The It is often difficult to differentiate drug seeking from therapy extent to which insomnia or daytime sleepiness leads to new seeking in clinical practice. In drug seeking, the drug and its cases of alcoholism or drug abuse is not known. Furthermore, effects, typically its euphorigenic effect, are the focus of the the degree to which treatment of insomnia or daytime sleepi- drug use, whereas in therapy seeking, the alleviation of disease- ness in abstinent alcoholism and drug abuse reduces risk of related symptoms is the focus of the drug use. However, in relapse is not known. To date, the few alcoholism treatment the clinic, drug seeking and therapy seeking can become trials have failed to clearly demonstrate that improved sleep closely intertwined, and what was once therapy seeking can reduces relapse, and the only drug abuse treatment trial, shift to drug seeking. The clinical challenge to sleep disorders although encouraging, is not conclusive. There is the inherent clinicians is to differentiate the two phenomena in making assumption in this discussion that sleep disturbance is causally diagnoses and appropriately treating patients. Some of the related to alcoholism or drug abuse, as either the precipitant potentially differentiating and defining characteristics of drug or consequent, but it may be comorbid and independent or seeking versus therapy seeking are presented in Table 140-1. related to a third common factor. The defining characteristic of drug seeking is evidence that the drug is taken in excessive amounts and in nontherapeutic contexts and is preferred to other commodities (e.g., money) and various social and occupational activities. The degree to CLINICAL PEARL which the drug is chosen over other commodities or social The sleep clinician, in assessing patients with sleep complaints, activities is evidence for the extent of its risk for abuse. Sup- must query about substance use, including prescribed and portive of its reinforcing capacity is evidence in the scientific over-the-counter drugs, legal recreational drugs, and illegal literature that the drug is readily discriminated from placebo recreational drugs. Attention to the quantity and pattern of use by behavioral and subjective assessment. These assessments is important. When substance abuse is suspected, referral to a typically rate the drug for it euphorigenic and drug-liking substance abuse specialist is desirable. When drugs with a effects, that is, the drug’s subjective effects are the focus of its known abuse liability are prescribed, patients should be use. Then, to the degree that the dose is escalated over time, observed closely to monitor their appropriate therapeutic use. one has evidence of the development of tolerance and possible Use of alcohol as a sleep aid should be discouraged as toler- physical dependence. ance develops rapidly to its low-dose beneficial effects. In contrast, therapy seeking is evident if the drug has demonstrated efficacy for the disorder or condition being treated. As well, the patient has the signs and symptoms and the appropriate diagnosis for the indicated use of the drug. SUMMARY The pattern of drug taking, its dose and duration of use, is consistent with its therapeutic effects. Finally, the patient Almost all of the psychoactive drugs with a known abuse believes that the drug is effective and readily experiences its liability have profound effects on sleep and wakefulness. Sub- therapeutic effects. However, the distinction between drug stance abuse is characterized by physiologic (e.g., withdrawal seeking and therapy seeking becomes difficult in situations syndrome on drug discontinuation) and behavioral (e.g., in which therapy-seeking behavior shifts to drug-seeking repetitive, compulsive drug seeking and consumption and

relapse) dependence, in which the relative contribution of Johanson CE, Roehrs T, Schuh K, Warbasse L. The effects of cocaine on each can vary according to the drug and its duration of use. mood and sleep in cocaine-dependent males. Exp Clin Psychopharmacol 1999;4:338–46. The neurobiologic mechanisms underlying both physiologic Johnson EO, Roehrs T, Roth T, Breslau N. Epidemiology of alcohol and and behavioral dependence are known, but the role of the medication as aids to sleep in early adulthood. Sleep 1998;21:178–86. abused drug’s sleep-wake state–altering effects in substance Koob GF, Stinus L, LeMoal M, Bloom FE. Opponent theory of motivation: abuse is not fully known, although it is likely to be important. neurobiological evidence from studies of opiate dependence. Neurosci Biobehav Rev 1989;13:135–50. Some of the drugs of abuse are legal and widely used socially Ogeil RP, Phillips JG, Rajaratnam SM, Broadbear JH. Risky drug use and and may be the cause of patients’ sleep or alertness complaints. effects on sleep quality and daytime sleepiness. Hum Psychopharmacol Other drugs with abuse liability are drugs indicated in the 2015;30(5):356–63. treatment of sleep disorders. For that reason, guidelines Randall S, Roehrs TA, Roth T. Efficacy of eight months of nightly zolpidem: have been provided for sleep disorders clinicians to help in a placebo controlled study. Sleep 2012;35:1551–7. Roehrs T, Papineau K, Rosenthal L, Roth T. Ethanol as a hypnotic in insom- differentiating drug-seeking behavior from therapy-seeking niacs: self administration and effects on sleep and mood.Neuropsychophar - behavior. macology 1999;20:279–86. Troxel WM, Ewing B, D’Amico EJ. Examining racial/ethnic disparities in the association between adolescent sleep and alcohol or marijuana use. Selected Readings Sleep Health 2015;1(2):104–8. Bonnet MH, Arand DL. Caffeine use as a model of acute and chronic Wetter DW, Fiore MC, Baker TB, Young TB. Tobacco withdrawal and nico- insomnia. Sleep 1992;15:526–36. tine replacement influence objective measures of sleep. J Consult Clin Brower KJ. Insomnia, alcoholism and relapse. Sleep Med Rev Psychol 1995;63:658–67. 2003;7:523–39. Willoughby A, de Zambotti M, Baker F, Colrain I. Partial K-conplex recovery Garcia AN, Salloum IM. Polysomnographic sleep disturbances in nicotine, following short-term abstinence in individuals with alcohol use disorder. caffeine, alcohol, cocaine, opioid, and cannabis use: a focused review. Am Alcohol Clin Exp Res 2015;39:1417–24. J Addict 2015;24(7):590–8. A complete reference list can be found online at Griffiths RR, Weerts EM. Benzodiazepine self-administration in humans ExpertConsult.com. and laboratory animals. Implications for problems of long-term use and abuse. Psychopharmacology (Berl) 1997;134:1–37.

References 29. Gillin JC, Smith TL, Irwin M, et al. Increased pressure for rapid eye movement sleep at time of hospital admission predicts relapse in nonde- 1. Roehrs T, Papineau K, Rosenthal L, Roth T. Sleepiness and the reinforc- pressed patients with primary alcoholism at 3-month follow-up. Arch Gen ing and subjective effects of methylphenidate. Exp Clin Psychopharmacol Psychiatry 1994;51:189–97. 1999;7:145–50. 30. Brower KJ. Insomnia, alcoholism and relapse. Sleep Med Rev 2. Johnson EO, Roehrs T, Roth T, Breslau N. Epidemiology of alcohol and 2003;7:523–39. medication as aids to sleep in early adulthood. Sleep 1998;21:178–86. 31. Mason BJ, Quello S, Goodell V, et al. Gabapentin treatment for 3. Johnson E, Roehrs T, Roth T, Breslau N. Epidemiology of medication as alcohol dependence. A randomized clinical trial. JAMA Intern Med aids to alertness in early adulthood. Sleep 1999;22:485–8. 2014;174:70–7. 4. Roehrs T, Papineau K, Rosenthal L, Roth T. Ethanol as a hypnotic in 32. Currie SR, Clark S, Hodgins DC, el-Guebaly N. Randomized controlled insomniacs: self administration and effects on sleep and mood.Neuropsy - trial of brief cognitive-behavioural interventions for insomnia in recover- chopharmacology 1999;20:279–86. ing alcoholics. Addiction 2004;99:1121–32. 5. Roehrs T, Bonahoom A, Pedrosi B, et al. Nighttime versus daytime hyp- 33. Arnedt JT, Conroy D, Rutt J, et al. An open trial of cognitive-behavioral notic self-administration. Psychopharmacology (Berl) 2002;2161:137–42. treatment for insomnia comorbid with alcohol dependence. Sleep Med 6. Koob GF, Stinus L, LeMoal M, Bloom FE. Opponent theory of 2007;8:176–80. motivation: neurobiological evidence from studies of opiate dependence. 34. Griffiths RR, Mumford GF. Caffeine—a drug of abuse? In: Bloom FE, Neurosci Biobehav Rev 1989;13:135–50. Kupfer DJ, editors. Psychopharmacology: the fourth generation of progress. 7. Papineau K, Roehrs T, Petrucelli N, et al. Electrophysiological assessment New York: Raven Press; 1995. p. 1699–713. (The Multiple Sleep Latency Test) of the biphasic effects of ethanol in 35. Brezinova V. Effect of caffeine on sleep: EEG study in late middle age humans. Alcohol Clin Exp Res 1998;22:231–5. people. Br J Clin Pharmacol 1974;1:203–8. 8. Stone BM. Sleep and low doses of alcohol. Electroencephalogr Clin 36. Karacan I, Thornby JI, Anch M, et al. Dose-related sleep disturbances Neurophysiol 1980;48:706–9. induced by coffee and caffeine. Clin Pharmacol Ther 1977;20:682–9. 9. Roehrs T, Roth T. Sleep, sleepiness, sleep disorders and alcohol use and 37. Nicholson AN, Stone BM. Heterocyclic amphetamine derivatives and abuse. Sleep Med Rev 2001;5:287–97. caffeine on sleep. Br J Clin Pharmacol 1980;9:195–203. 10. Hyde M, Roehrs T, Roth T. Alcohol, alcoholism, and sleep. In: 38. Okuma T, Matsuoka H, Matuse Y, Toyomura K. Model insomnia by Lee-Chiong T, editor. Sleep: a comprehensive handbook. Philadelphia: John methylphenidate and caffeine and use in the evaluation of temazepam. Wiley & Sons; 2006. p. 867–71. Psychopharmacology (Berl) 1982;76:201–13. 11. Roehrs T, Roth T. Alcohol, sleep, sleep disorders, and consequent daytime 39. Bonnet MH, Arand DL. Caffeine use as a model of acute and chronic impairment. In: Pandi-Perumal SR, Verster JC, Monti JM, et al., editors. insomnia. Sleep 1992;15:526–36. Sleep disorders: diagnosis and therapeutics. Oxford, UK: Taylor and Francis; 40. Gillin LC, Lardon M, Ruiz C, et al. Dose-dependent effects of transder- 2008. p. 480–6. mal nicotine on early morning awakening and rapid eye movement 12. Yesavage JA, Leirer VA. Hangover effects on aircraft pilots 14 hours sleep time in non-smoking normal volunteers. J Clin Psychopharmacol after alcohol ingestion: a preliminary report. Am J Psychiatry 1994;14:264–7. 1986;143:1546–50. 41. Salin-Pascual RJ, de la Fuente JR, Galicia-Polo L, Drucker-Colin R. 13. Roehrs T, Yoon J, Roth T. Nocturnal and next-day effects of ethanol and Effects of transdermal nicotine on mood and sleep in nonsmoking major basal level of sleepiness. Hum Psychopharmacol 1991;6:307–11. depressed patients. Psychopharmacology (Berl) 1995;121:476–9. 14. Landolt HP, Roth C, Dijk DJ, Borbely AA. Late-afternoon ethanol 42. Davila DG, Hurt RD, Offord KP, et al. Acute effects of transdermal intake affects nocturnal sleep and sleep EEG in middle-aged men.J Clin nicotine on sleep architecture, snoring, and sleep-disordered breathing in Psychopharmacol 1996;16:428–36. nonsmokers. Am J Respir Crit Care Med 1994;150:469–74. 15. Roehrs T, Roth T. Sleep, sleepiness, and alcohol use. Alcohol Res Health 43. Prosise Gl, Bonnet MH, Berry RB, Dickel ML. Effects of 2001;25:101–9. abstinence from smoking on sleep and daytime sleepiness. Chest 16. Ancoli-Israel S, Roth T. Characteristics of insomnia in the United 1994;105:1136–41. States: results of the 1991 National Sleep Foundation Survey. I. Sleep 44. Wetter DW, Fiore MC, Baker TB, Young TB. Tobacco withdrawal and 2000;22:S347–53. nicotine replacement influence objective measures of sleep.J Consult Clin 17. Roehrs T, Roth T. Sleep, sleepiness, sleep disorders and alcohol use and Psychol 1995;63:658–67. abuse. Sleep Med Rev 2001;5:287–97. 45. Phillips BA, Danner FJ. Cigarette smoking and sleep disturbance. Arch 18. Roehrs T, Blaisdell B, Cruz N, Roth T. Tolerance to hypnotic effects of Intern Med 1995;155:734–7. ethanol in insomnias [abstract]. Sleep 2004;27:352. 46. Gawin FH, Kleber HD. Abstinence symptomatology and psychiatric 19. Guilleminault C. Sleep apnea syndromes: impact of sleep and sleep states. diagnosis in cocaine abusers. Gen Psychiatry 1986;43:107–13. Sleep 1980;3:227–34. 47. Kowatch RA, Schnoll SS, Knisely JS, et al. Electroencephalographic 20. Issa FG, Sullivan CE. Alcohol, snoring and sleep apneas. J Neurol Neu- sleep and mood during cocaine withdrawal. J Addict Dis 1992;11: rosurg Psychiatry 1982;45:353–9. 21–45. 21. Mitler MM, Dawson A, Henriksen SJ, et al. Bedtime ethanol increases 48. Johanson CE, Roehrs T, Schuh K, Warbasse L. The effects of cocaine on resistance of upper airways and produces sleep apneas in asymptomatic mood and sleep in cocaine-dependent males. Exp Clin Psychopharmacol snorers. Alcohol Clin Exp Res 1988;12:801–5. 1999;4:338–46. 22. Herzog M, Riemann R. Alcohol ingestion influences the nocturnal 49. Angarita GA, Canavan SV, Forselious E, et al. Correlates of polysomno- cardio-respiratory activity in snoring and non-snoring males. Eur Arch graphic sleep changes in cocaine dependence: self-administration and Otorhinolaryngol 2004;261:459–62. clinical outcomes. Drug Alcohol Depend 2014;143:173–80. 23. Aldrich MS, Shipley JE. Alcohol use and periodic limb movements of 50. Rechtschaffen A, Maron L. The effect of amphetamine on the sleep cycle. sleep. Alcohol Clin Exp Res 1993;17:192–6. Electroencephalogr Clin Neurophysiol 1964;16:438–45. 24. Le Bon O, Verbanck P, Hoffmann G, et al. Sleep in detoxified alcoholics: 51. Mitler MM, Hajdukovic R, Erman MK. Treatment of narcolepsy with impairment of most standard sleep parameters and increased risk for methamphetamine. Sleep 1993;16:306–17. sleep apnea, but not for myoclonias—a controlled study. J Stud Alcohol 52. Watson R, Hartmann E, Schildkraut JJ. Amphetamine withdrawal: 1997;58:30–6. affective state, sleep patterns and MHPG excretion. Am J Psychiatry 25. Brower KJ. Alcohol’s effects on sleep in alcoholics. Alcohol Res Health 1972;129:262–9. 2001;25:110–25. 53. Nicholson AN, Stone BM. Stimulants and sleep in man. Agressologie 26. Hyde M, Roehrs T, Roth T. Alcohol, alcoholism and sleep. In: Lee- 1981;22:73–8. Chiong T, editor. Sleep: a comprehensive handbook. Hoboken, NJ: John 54. Braekeland F. The effect of methylphenidate on the sleep cycle in man. Wiley & Sons; 2006. p. 867–71. Psychopharmacologia 1966;10:179–83. 27. Drummond SPA, Gillin JC, Smith TL, Demondena A. The sleep of 55. Tirosh E, Sadeh A, Munvez R, Lavie P. Effects of methylphenidate on abstinent pure primary alcoholic patients: natural course and relation to sleep in children with attention-deficit hyperactivity disorder. Am J Dis relapse. Alcohol Clin Exp Res 1998;22:1796–802. Child 1993;147:1313–15. 28. Allen RP, Wagman AM, Funderburk FR, Well DT. Slow wave sleep: a 56. Greenhill L, Puig-Antich J, Goetz R, et al. Sleep architecture and REM predictor of individuals differences in response to drinking? Biol Psychia- sleep measures in prepubertal children with attention deficit disorder try 1980;15:345–8. with hyperactivity. Sleep 1983;6:91–101.

57. Kay DC, Pickworth WB, Neidert GL. Morphine-like insomnia 71. Randall S, Roehrs TA, Roth T. Efficacy of eight months of nightly from heroin in non-dependent human addicts. Br J Clin Pharmacol zolpidem: a placebo controlled study. Sleep 2012;35:1551–7. 1981;11:159–69. 72. Pivik RT, Zarcone V, Dement WC, Hollister LE. Delta-9-tetrahydro- 58. Kay DC, Eisenstein RB, Jasinski DR. Morphine effects on human cannabinol and synhexl: effects on human sleep patterns. Clin Pharmacol REM state, waking state, and NREM sleep. Psychopharmacologia Ther 1972;13:426–35. 1969;14:404–16. 73. Freemon FR. The effect of delta-9-tetrahydrocannabinol on sleep. 59. Pickworth WB, Neidert GL, Kay DC. Morphine-like arousal by metha- Psychopharmacologia 1974;35:39–44. done during sleep. Clin Pharmacol Ther 1981;30:796–804. 74. Barratt ES, Beaver W, White R. The effects of marijuana on human sleep 60. Kay DC. Human sleep during chronic morphine intoxication. Psycho- patterns. Biol Psychiatry 1974;8:47–53. pharmacologia 1975;44:117–24. 75. Feinberg I, Jones R, Walker JM, et al. Effects of high dosage delta-9- 61. Mello NK, Mendelson JH, Lukas SE, et al. Buprenorphine treatment tetrahydrocannabinol on sleep patterns in man. Clin Pharmacol Ther of opiate and cocaine abuse: clinical and preclinical studies. Harv Rev 1976;17:458–66. Psychiatry 1993;1:168–83. 76. Tassinari CA, Ambrosetto G, Peraita-Adrados MR, Gastaut H. The 62. Griffiths RR, Weerts EM. Benzodiazepine self-administration in humans neuropsychiatric syndrome of delta-9-tetrahydrocannabinol and cannabis and laboratory animals. Implications for problems of long-term use and intoxication in naive subjects: a clinical and polygraphic study during abuse. Psychopharmacology (Berl) 1997;134:1–37. wakefulness and sleep. In: Braude MC, Szara S, editors. The pharmacology 63. deWit H, Pierri J, Johanson CE. Reinforcing and subjective effects of marihuana. New York: Raven Press; 1976. p. 357–82. of diazepam in nondrug-abusing volunteers. Pharmacol Biochem Behav 77. Babor TF, Mendelson JH, Kuehnle J. Marihuana and human physical 1989;33:205–13. activity. Psychopharmacology (Berl) 1976;50:11–19. 64. deWit H, Uhlenhuth EH, Hedeker D, et al. Lack of preference for 78. Chait LD. Subjective and behavioral effects of marijuana the morning diazepam in anxious volunteers. Arch Gen Psychiatry 1986;43:533–41. after smoking. Psychopharmacology (Berl) 1990;100:328–33. 65. Oswald LM, Roache JD, Rhoades HM. Predictors of individual 79. Karacan I, Fernandez-Salas A, Coggins WJ, et al. Sleep differences in alprazolam self-medication. Exp Clin Psychopharmacol electroencephalographic-electrooculographic characteristics of chronic 1999;7:379–90. marijuana users: part I. Ann N Y Acad Sci 1977;103:348–74. 66. Roehrs T, Merlotti L, Zorick F, Roth T. Rebound insomnia and hypnotic 80. Schmidt CJ, Levin JA, Lovenberg W. In vitro and in vivo neurochemical self administration. Psychopharmacology (Berl) 1992;107:480–4. effects of methylenedioxymethamphetamine on striatal monoamine 67. Roehrs T, Pedrosi B, Rosenthal L, et al. Hypnotic self administration and systems in the rat brain. Biochem Pharmacol 1987;36:747–55. dose escalation. Psychopharmacology (Berl) 1996;127:150–4. 81. Allen RP, McCann UD, Ricaurte GA. Persistent effects of (±)3,4- 68. Roehrs T, Pedrosi B, Rosenthal L, et al. Hypnotic self administration: methylenedioxymethamphetamine (MDMA, “ecstasy”) on human sleep. forced-choice versus single-choice. Psychopharmacology (Berl) 1997;133: Sleep 1993;16:560–4. 121–6. 82. Randall S, Johanson CE, Tancer M, Roehrs T. Effects of acute 3,4- 69. Roehrs TA, Randall S, Harris E, et al. Twelve months of nightly zolpidem methylenedioxymethamphetamine on sleep and daytime sleepiness in does not lead to dose escalation: a prospective placebo-controlled study. MDMA users: a preliminary study. Sleep 2009;32:1513–19. Sleep 2011;34:1–6. 83. Bootzin RR, Stevens SJ. Adolescents, substance abuse, and the treatment 70. Roehrs TA, Randall S, Harris E, et al. Twelve months of nightly of insomnia and daytime sleepiness. Clin Psychol Rev 2005;25:629–44. zolpidem does not lead to rebound insomnia or withdrawal symptoms: 84. Aubin HJ, Luthringer R, Demazieres A. Comparison of the effects of a a prospective placebo-controlled study. J Psychopharmacol 2012;26: 24-hour nicotine patch and a 16-hour nicotine patch on smoking urges 1088–95. and sleep. Nicotine Tob Res 2006;8:193–201.

REVIEW QUESTIONS 3. The Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5) diagnosis of substance-related 1. Alcohol: disorders: A. Increases slow wave sleep A. Rates the severity of the disorder by the number of B. Increases slow wave sleep only in the first half of the symptoms present night B. Classifies disorders as substance use versus substance- C. Increases slow wave sleep in persons with reduced slow induced disorders wave sleep C. Characterizes substance-induced disorders as the pres- D. Reduces stage 1 sleep ence of tolerance, withdrawal, or a mental disorder E. Suppresses second-half REM sleep D. Does not consider tolerance or withdrawal in the 2. Therapy-seeking behavior is primarily differentiated from context of medical use of a substance as substance abuse drug-seeking behavior by: E. Any of the above A. Chronic use of a drug 4. Sleep and wakefulness disturbances: B. Drug is taken in a nontherapeutic context A. Are associated with most all drugs of abuse C. Drug is preferred to placebo B. Can be a consequence of drugs used to treat sleep D. Drug is taken in stable, therapeutic doses disorders E. Discontinuation of the drug is followed by a withdrawal C. Can be predictive of relapse in substance abuse syndrome D. When properly treated will prevent relapse to substance abuse E. A, B, and C

ANSWERS As DSM-5 clearly states, tolerance and withdrawal in the context of medical treatment should not be considered 1. C. The literature is equivocal regarding total and first-half substance abuse (i.e., drug seeking). slow wave sleep induction. The section on alcohol describes 3. E. The DSM-5 is discussed in the first section ofthe a study in which the same moderate alcohol dose increased chapter. slow wave sleep only in insomniacs who had reduced basal 4. E. The role of sleep and wakefulness disturbance - isdis slow wave sleep relative to their age-matched controls. cussed in the Controversies and Pitfalls section of the 2. B. Therapy seeking versus drug seeking is discussed in the chapter. As yet, studies have not clearly shown that treat- Controversies and Pitfalls section. The one clear differen- ment of the sleep-wake disturbances will prevent relapse. tial is use of the drug outside of the therapeutic context.