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Chapter 1 AN OVERVIEW OF SLEEP AND MEDICATION The purpose of "sedatives" is to induce a calming and drowsy effect. "Hypnotics" are intended to induce a satisfying sensation of going to sleep promptly and sleeping soundly for some minimum duration. "Anxiolytics" (minor tranquilizers or anti-anxiety drugs) are intended to induce a calming effect similar to that of sedatives but without the sensation of drowsiness. In actual practice, clinical intent determines dosage and instructions for use, including time of day to be administered. Some authorities regard these drugs as parts of a single entity, emphasizing their pharmacological similarities rather than their differences. 1/ Other authors refer to "sedative- hypnotics" as one entity and "anxiolytics" as another. 2/ Unless otherwise specified, in this report medication for sleep means the hypnotics prescribed by physicians to induce sleep rather than for daytime sedation or relief of tension. All drugs in these three categories have anti-convulsant effects. They are cross-tolerant with each other and with alcohol, which means that an individual taking repeated high doses of one agent might need high doses of another agent in this group in order to obtain the desired therapeutic effect. Drugs of other types -- opiates, for example -- are not cross-tolerant with this group. Hypnotics, sedatives, and anxiolytics also have additive toxic effects -- with each other and with alcohol -- that can result in over- dose fatalities, or in impaired mental states in which driving or operating machinery can be quite hazardous. Sedatives, hypnotics, and anxiolytics all have the potential to be addicting drugs. The World Health Organization (WHO) currently includes various forms of dependence on benzodiazepines and other minor tranquilizers under the heading of "drug dependence of the the barbiturate type." 3/ When an addicted individual suddenly re- duces or discontinues his or her dose of one of these drugs, seizures may result as part of the withdrawal syndrome. The term addiction usually carries the connotation of a physical dependence on an agent, with the liability for withdrawal symptoms. A psychological drug dependence (or, in older terminology, habituation) may exist in the absence of full blown physical dependence. Within the definitions -17-

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of dependence set forth by the World Health Organization, the felt necessity for a nightly sleeping pill constitutes a form of drug dependence. However, in this report, "nightly reliance" generally will be used to describe habitual use of medication for sleep, as long as there is no accompanying patter- of escalation of dose or daytime use. Varying pharmacological pathways can lead to drowsiness and sleep. However, the precise mechanism of sedation or hypnosis by any of these drugs (or alcohol, or other drugs such as antihistamines) is unknown. This is a different situation from the opiates, the antidepressants, or the neuroleptics (antipsychotic drugs), for which there is broad scientific consensus about some of the neurochemical mechanisms associated with their psychological effects. A. The Anatomy of Sleep Sleep consists of two distinct states: Rapid Eye Movement sleep (also known as REM sleep, D-sleep, paradoxical sleep, dreaming sleep), and Non-REM or NRF.M sleep (also known as S-sleep, orthodox sleep, or slow wave sleep). 4/ REM sleep is characterized on a psychological level by dreaming and on a physiological level by cortical activation (a mixed frequency, low voltage EEG pattern), bursts of extra ocular and middle ear muscle activity, variability of heart and respiratory rates, actively induced atonia of major anti-gravity and locomotor muscles, increased cerebral blood flow, and, in most instances, increased activity of individual neurons. In short, REM sleep is a very active brain in a paralyzed body. In the normal adult, 20-25 percent of the total night's sleep is spent in REM, about 90-120 minutes per night. REM sleep occurs in approximately three to five regularly spaced periods, which begin about 70 to 100 minutes after sleep onset and occur at intervals of about 90 minutes from the onset of one period to the next. NREM sleep is usually subdivided into four stages on the basis of relatively distinguishable electroencephalographic brain wave patterns: Stage 1, a brief transitional stage between wakefulness and sleep, is about 5 percent of the total night's sleep, and has a low voltage, mixed frequency EEG pattern. Stage 2, defined on the basis of sleep spindles and K complexes, usually constitutes 40-60 percent of total sleep in the young adult. Stages 3 and 4 are often referred to as delta sleep because they are characterized by moderate and large numbers of delta waves respectively. Most Stage 3 and 4 sleep occurs during the first 1-3 hours of the night in young adults. -18-

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Normal nocturnal sleep invariably begins with NREM sleep. As a person falls asleep, he enters Stage 1, then Stage 2, and finally Stages 3 and 4. After sleeping for about 1 1/2 hours, he enters the first period of REM sleep, which is usually brief (5-15 minutes). The NREM/REM cycle then begins again, and is repeated throughout the night. As noted, most Stage 3 and 4 occur during the first one or two cycles. Until the age of about 45, growth hormone secretion occurs during the first or second NREM phase, usually in association with delta sleep. Sleep patterns typically change with age. In the newborn, for example, total sleep time averages about 14-16 hours per 24 hours and occurs during both dark and light periods of the 24-hour day, with little circadian organization. The sleep states and stages are not yet well-defined by adult standards, and 50 percent of total sleep time may be spent in REM sleep. As adults enter middle age and old age, Stage 3 and 4 decrease markedly and sleep tends to become progressively more fragmented with brief arousals and longer periods of wakefulness. In typical non-clinical laboratory studies, the subject sleeps with an all-night polygraphic recording of brain waves (EEG), eye movements (electro-oculogram or EGG), and muscle tone (electromyogram or EMG, typically recorded from the chin muscles). The records are usually scored visually by deciding whether the subject is awake or asleep (and, if so, in what state or stage of sleep) during each successive epoch (usually 20 to 30 seconds in length). From this analysis, various sleep measures are calculated, such as latency (how long it takes to fall asleep), or total time spent awake and in each of the sleep stages. In clinical studies of sleep disorder patients, other physio- logical measures are included, such as electrocardiogram, nasal and oral air flow, chest movements, EMG on leg muscles (i.e., anterior tibial muscles), intraesophageal pressure, respiratory sounds, and oxygen saturation measured in the ear lobe. When indicated, even more sophisticated measurements can be taken without disturbing sleep, such as pulmonary arterial pressure, esophageal pH, systemic arterial pressure, and hormone secretory patterns. Some of the most important aspects of sleep are the least well known. The neurological mechanisms that underlie the different sleep states may alter control of vital regulatory functions. This is particularly true in the case of breathing where many important physio- logical differences have been described, as if, 5/ during REM sleep, the respiratory machinery that operates during wakefulness is shut down and an entirely different machine is operating. Similar differ- ences have been described concerning temperature regulation, 6/ regulation of heart rate, 7/ and endocrine function. 8/ These altera- -19-

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Lions during sleep mean that some individuals who are entirely normal while awake can, while asleep, develop potentially fatal respiratory problems 9/ or potentially fatal cardiac arrhythmias. 10/-12/ It is also possible that, because of the different physiological regulation during sleep, there could be one response of breathing and heart rate to hypnotics in the awake individual and a qualitatively or quantitatively different response of breathing and heart rate to hypnotics during sleep. Table 1 shows characteristics associated with each of the stages of sleep. Following that is a glossary of terms that will be encountered throughout the remainder of this report. B. Prescription Drugs Marketed as Hypnotics In addition to the hypnotic drugs marketed specifically for the induction of sleep, a variety of medicines marketed for other uses, such as the antihistamines and antidepressants, are sometimes given to aid sleep because they possess sedating qualities. There also are a large number of non-prescription drugs sold to promote sleep. This section is primarily a description of the pharmacology of the prescription hypnotics, which may be categorized as 1) barbiturates, 2) benzodiaze- pines, 3) non-barbiturate, non-benzodiazepine drugs. The pharmaco- logical effects of combining each of these drugs with alcohol are discussed, as these combinations contribute to their public health risks described in Chapter 3. Barbiturates The first clinically-used barbiturate was diethyl barbituric acid or barbital, developed by Fischer and van Mering in 1903. Barbital remained the principal barbiturate until the introduction of pheno- barbital shortly before World War I. After the war a variety of other barbiturates were synthesized. About 2,500 different forms have been made, and approximately 50 marketed for medical use. Today approxi- mately a dozen are in common use, primarily as hypnotics, anxiolytics (daytime sedatives), anesthetics, and anticonvulsants. 13/ The barbiturates are often classified by their duration of action, although the relationship of this to the clearance of the drug from the body by metabolism or elimination is not clear. 14/-16/ The barbi- turates often used as hypnotics, which include secobarbital (Seconal(R)), amobarbital (Amytal(R)), and pent obarbital (Nembutal(R)), are considered short-to-intermediate acting. Another popular hypnotic combines amobar- -20-

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TABLE 1. GElARACTERI STICS OF THE STAGES OF SLEEP EEG Patterns Other Physiological Characteristics Psychological Characteristics Proportion of Total Sleep REM Low voltage, mixed Generalized Dreaming 20-25% frequency, "sawtooth" motor inhibition Conflict waves Autonomic resolution (?) variability Creative juxta- Increased position of cerebral experiences (?) neuronal ac- Memory consolida- tivity Lion (?) Increased brain temperature Increased cerebral blood flow Poikil.othermia Penile tume- scence Diminished or absent C02 chemoreceptor sensitivity Diminished or absent pulmonary stretch reflexes NREM - Stage 1 Low voltage, mixed Increased airway Hypnagogic 1-5Z of total frequency resistance hallucinations sleep (snoring) Slow eye movements Stage 2 Sleep spindles Abstract thoughts 40-60% of K complexes total sleep Stage 3 Delta waves:20-507 of given epoch Secretion of growth Abstract thoughts 10-207 of hormone Memory consolida- total sleep Lion (?) Stage 4 Delta waves: greater than 507 of given epoch 21

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Glossary of Sleep Research Terms Delta Sleep Stages 3 and 4 Delta Wave EEG pattern defined by amplitude of 75 uv or more and duration of 0.5 sec. or longer. Defines Stages 3 and 4. Depth of Sleep More a term of art than science, presumably referring to how difficult it is to arouse a sleep subject The term is infrequently used by sleep scientists owing to difficulty of defining and measuring it. Drug Withdrawal Transient reduction in total sleep time in comparison Insomnia with pre-drug levels observed upon abruptly discon- tinuing certain hypnotic medication; also called rebound insomnia. Early Morning Time awake spent in bed after final period asleep and Awake before arising; also called wake after final arousal or WAFA. Intermittent Time awake after sleep onset and before final arousal Awake of sleep period; also known as wake after sleep onset or WASO. NREM Sleep Non-Rapid-Eye-Movement Sleep; known also as orthodox sleep, S-sleep, slow-wave sleep. Consists of Stages 1 to 4. K-complex An EEG pattern composed of low amplitude negative wave followed by a high amplitude positive wave lasting at least 0.5 sec. Helps define Stage 2. REM Sleep Rapid Eye Movement Sleep, also known as D-sleep, dreaming sleep, or paradoxical sleep. Sleep stage during which most, but not all, dreaming occurs. Defined on basis of low voltage, mixed frequency EEG pattern, bursts of rapid eye movements, and atonia of submental (chin) muscles. REM Rebound An increase in total amount of REM sleep or of REM per cent (proportion of total sleep spent in REM) as compared with normal baseline levels which follows a period of REM deprivation. May be associated with increased subjective awareness of dreaming or night- mares. May last for several nights or weeks depending upon duration of REM deprivation and method to achieve it. -22-

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REM Deprivation REM suppression, or reduction in amount of REM sleep. Sleep Spindle An EEG pattern composed of rhythmic burst of 12-14 cycles per second wave lasting at least 0.5 sec. Helps define Stage 2. REM Latency Duration of non-REM sleep between onset of sleep and first REM period. In normal young adults, averages about 90 minutes. Tends to be short in narcolepsy, primary depression, and following REM deprivation. Tends to be increased by certain drugs which suppress REM sleep. Sleep Latency Duration of time required to fall asleep, usually measured from "lights out" to first sleep spindle or K-complex as the sleep onset criterion. Sleep Efficiency Usually defined as percentage of time spent asleep while in bed. In normal young and middle-aged adults, sleep efficiency is usually about 90 percent or above. Stage 1 A stage of non-REM sleep, defined by low voltage, mixed frequency EEG pattern in absence of rapid eye movements and EMG atonia. Usually seen as brief transition phase lasting 1-3 minutes between wake- fulness and other stages of sleep. Stage 2 A stage of NREM sleep, characterized by sleep spindles and K complexes in EEG patterns. Usually comprises 40-60 percent of sleep of normal young adults. Stage 3 ~ stage of NREM sleep, characterized by delta waves for 20-50 percent of each scoring epoch. Stage 4 A stage of NREM sleep, characterized by delta waves for 50 percent or more of a scoring epoch. Total Sleep Time Total time spent in NREM and REM sleep. 23

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bital with secobarbital in equal proportions (Tuinal(R)~. The plasma half-lives of these drugs (a measure of duration of a drug's presence in the body, defined as the time required for the body to remove half of the drug present) are not clearly separable. The half-life of an initial dose of secobarbital is 20 to 28 hours, of pentobarbital is 21 to 42 hours and of amobarbital is 14 to 42 hours. These half-lives are shorter with consecutive or repeated doses because barbiturates stimulate the liver enzymes that initiate metabolism of the drug. Another drug in the short-to-intermediate group is butabarbital (Butisol(R)) which is used mostly as an anxiolytic. Phenobarbital, which is used primarily as an anticonvulsant and anxiolytic, and much less often as a hypnotic, is considered a long-acting agent, with a half-life of 24-96 hours. The ultra-short acting agents, such as metho- hexital and thiopental which have half-lives of 3-8 hours are used primarily as intravenous anesthetics in the United States. Half-life is not the only characteristic that determines a drug's length of action. The lipid solubility of the drug determines its movement between blood and brain and between blood and other tissues where the drugs are not active. For example, the "ultra-short-acting" agents have a rapid onset and short time of action after intravenous administration, because they are carried rapidly to brain. They are then rapidly removed from the brain and gradually accumulate in tissues such as fat where they have no important biological activity. Thus, the effect of these drugs is governed by their distribution and redistribution within the body as well as by their half-life, the half- life reflecting only the amount of drug in the body, not necessarily that at the active site. As a sodium salt, the barbiturates are rapidly absorbed from the gastrointestinal tract. The short-to-intermediate-acting agents are metabolized into relatively inactive substances in the liver and excreted by the kidneys. The longer acting phenobarbital is excreted partially unchanged in the urine. The long use of barbiturates has brought recognition of their benefits and problems. Probably most important among the latter is their toxicity (deleterious effects) in acute overdose. Ingestion of approximately 10 times the hypnotic dose produces dangerous toxicity, and 15-20 times the hypnotic dose is often lethal. The short-acting hypnotic barbiturates often produce death at lower blood levels than longer acting barbiturates, and may do so more rapidly. Toxicity is worsened by concomitant ingestion of alcohol. The major conse- quences of barbiturate toxicity are respiratory depression, circula- tory collapse, renal failure and coma. There is no specific antidote to the toxicity of barbiturates or any of the other prescription -24-

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hypnotics. In spite of these difficulties, advances in supportive care have lowered mortality of those overdose patients who reach the hospital alive to about one percent. 17/-19/ When barbiturates stimulate liver enzymes, the enzymes increase the rate of the metabolism not only of the barbiturates, but also of a wide range of other drugs, including oral anticoagulants and antidepressants. This may result in decreased effectiveness of these drugs when they are given to a patient who is also receiving barbiturates. Barbiturates may also stimulate the activity of the enzyme ALA synthetase, thereby precipitating attacks of acute intermittent porphyria in genetically susceptible persons. Barbiturates taken in large quantities for prolonged periods of time may produce physical dependence. It has been estimated that if 0.4 to 0.8 g of pentobarbital (4-8 times the hypnotic dose) is taken for 2 to 6 months, it is likely that a physical withdrawal syndrome will occur upon cessation of the drug. 17/,20/ Withdrawal symptoms may vary from tremulousness, anxiety and insomnia to severe states which include delirium and seizures. Interaction with ethanol Both human and animal studies have consistently described the toxic interaction of ethanol with acutely ingested barbiturates. Fatal doses of secobarbital, for instance, are usually associated with blood levels of 1.1-6.0 mg/100 ml; for ethanol, fatal blood levels are generally thought to be about 400 mg/100 ml. Fatalities have occurred, however, with a combination of respective levels of 0.5 and 100 mg/100 ml. 18/ Thus, the ingestion of 6 to 10 100 mg secobarbital tablets and the rapid consumption of about 5 ounces of whiskey by a 150 lb. person would constitute the lower limit of well-recognized lethality. _ /,19/ In rats, the dose of barbiturates that will kill half the animals (the LD 50) decreases as progressively higher doses of ethanol are given. 21/ In humans this lethality is well described 22/-24/ and in lower combined doses the resultant impairment of driving skills has been documented. 25/ The mechanism of this interaction is not entirely clear, but probably includes such factors as inhibition of barbiturate metabolism, 26/ changes in drug distribution in tissues and direct effects in the nervous system. 27/ Cross tolerance between ethanol and barbiturates may develop in chronic use: unusually large doses of barbiturates may be needed to produce sleep in alcoholics, 28/ and barbiturate addicts may be relatively insensitive to the sedative qualities of moderate amounts of ethanol. 29/ But when alcoholism leads to severe liver damage, the alcoholic may become unusually sensitive to relatively small amounts of ethanol and barbiturates. -25-

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"Barbiturate Automatism" For some years it was believed in medical circles that one pathway to barbiturate intoxication and death was "automatism." A user of hypnotics, it was said, would "forget" that he had already taken his sleeping pill and would continue to ingest several doses in the course of a restless night. Blood levels of barbiturates could thereby become quite dangerous especially if the victim was also intoxicated with alcohol. In two intensive investi- gations of over 900 cases, however, only two cases of barbiturate overdose associated with genuine amnesia for ingesting the pills were found (and one case was rather dubious); all other cases of alleged "automatism" were discovered to be based on retrospective denial of suicidal intent by disturbed individuals who had indeed attempted suicide. 30/,31/ According to these researchers, the concept of "automatism" or "amnesia" is used by patients, their families and even their physicians to avoid the pain of either public revelation or personal scrutiny of suicidal tendencies. Benzodiazepines The first widely used benzodiazepine, chlordiazepoxide (Librium (R)), was synthesized by Sternbach and Reeder in the mid-1950s and marketed in 1961. At that time the most widely used psychoactive drugs had been the anxiolytic meprobamate and the anti-psychotic medication, ("major tranquilizer") chlorpromazine. Chlordiazepoxide, which had sedative, muscle-relaxing and anti-convulsant properties, was followed a few years later by the more potent diazepam (Valium(R)), which now is the most commonly prescribed medication in the Western World. Some 2,000 benzodiazepine compounds have been synthesized, and a large number are used clinically. Only one, flurazepam (Dalmane(R)), is specifically marketed as a hypnotic in the United States and Canada; another, nitrazepam, is marketed for this purpose In Great Britain, Scandinavia, and Israel. The use of flurazepam has increased greatly since its introduction in 1970, and it is now by far the single most commonly prescribed hypnotic. It appears likely that other benzodiazepines not marketed as hypnotics (e.g., diazepam, chlordiazepoxide, oxazepam) are often used at bedtime for this purpose. The benzodiazepines, like the short-to-intermediate-acting barbi- turates, are primarily metabolized by the liver, and the metabolites are excreted by the kidneys. Unlike the barbiturates, however, the most frequently prescribed benzodiazepines produce clinically important psychoactive metabolites with half-lives of one to eight days. 32/ These long-acting drugs include flurazepam, diazepam, nitrazepam, c-hlordiazepoxide and clorazepate (Tranxene(R)~. Two shorter-acting benzodiazepines -- oxazepam (Serax(R)) and lorazepam (Ativan (R)) -- do not produce active metabolites and have half-lives in the five to twenty hour range. -26-

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N-desalkylf lurazepam, the major psychoactive metabolite of f lurazepam, has a plasma half-life of 50-100 hours. The cumulative effect of flurazepam's active metabolite is a cause of some concern. By the seventh to; tenth morning after consecutive nightly administra- tion, the accumulation will level off at four to six times the concen- tration in the blood stream that had been present on the first morning. 34/ By comparison, most other hypnotics Meg., amobarbital, glutethimide, chloral hydrate) do not accumulate significantly in healthy subjects after consecutive nightly administration. 25/ Benzodiazepines do not stimulate hepatic drug-metabolizing enzymes to any appreciable degree in humans, and thus do not interfere with concomitant drug therapy in the way barbiturates and some other hypnotics do. The disposition and elimination of the longer acting benzodiazepine drugs are greatly impaired in the elderly and in patients with liver disease; the pharmacokinetics of oxazepam and lorazepam seem to be unaffected by these factors. 33/ Although the benzodiaz~pines are regarded as much less potent respiratory depressants than the barbiturates, they are not entirely safe in this regard. Nitrazepam administration may result in carbon dioxide narcosis when given to patients with compromised broncho- pulmonary function. 35/ Similarly, diazepam administration during childbirth may cause respiratory difficulties in the neonate. In some animal studies, benzodiazepines may cause more respiratory depres- sion than the barbiturate thiopental. 13/ Diazepam in doses used to prepare a patient for endoscopy has been reported to produce respiratory depression. 36/ When benzodiazepines have been taken alone in overdose - without any other drugs or alcohol -- the outcome usually has been benign, even when the dose has been rather large. 37/ However, Finkle and associates have reported two cases of drug overdose death due solely to ingestion of diazepam in their 1976 survey of American and Canadian deaths in which this drug had been toxicologically confirmed as present in post-mortem examination. 38/ The diazepam blood levels in the two decedents were 5.0 micrograms/ml and 19.0 micrograms/ml -- about five and 19 times the therapeutic range, respectively. In 912 combined drug deaths, diazepam was present along with various amounts of other drugs, including alcohol. (In 325 additional cases, death was not attributed to the direct toxic action of the agents ingested, and the presence of diazepam was determined to be incidental.) In un- published studies, 39/-40/ the Los Angeles Medical Examiner has also presented recent evidence of accidental or suicidal fatalities re- sulting from combinations of diazepam with sub-lethal amounts of other drugs (antidepressants, hypnotics, analgesics) and alcohol. Unfor- tunately, this area of toxic effects of prescription drugs with each other and with alcohol is one that heretofore has received little atten- tion with adequate toxicological and behavioral research methods. 41/ -27-

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TABLE 2. SCHEDULES OF CONTROLLED SUBSTANCES SCHEDULE I Placement A. The substance has a high potential for abuse. B. The substance has no currently accepted medical use in treatment in the United States. C. There is a lack of accepted safety for use of the substance under medical supervision. Requirements Dispensing limits: Security: Manufacturing quotas: S CHEDULE II Placement Requirements Research use only Vault/safe Yes A. The substance has a high potential for abuse. B. The substance has a currently accepted medical use in treatment in the United States or a currently accepted medical use with severe restrictions. Abuse of the substance may lead to severe psychological or physical dependence. Dispensing limits: Security: Manufacturing quotas: S CHEDULE I II Placement Prescription: written, no refills Vault/safe Yes A. The substance has a potential for abuse less than the drugs or other substances in Schedules I and II. B. The substance has a currently accepted medical use in treatment in the United States. Abuse of the substance may lead to moderate or low physical dependence or high psychological dependence. 36

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SCHEDULE III (continued) Requirements Dispensing limits: Prescription: written or oral, with medical authorization; refills up to 5 times in 6 months Security: Manufacturing Quotas: SCHEDULE IV Placement Secure storage area No, but some drugs limited by Schedule II quotas. A. The substance has a low potential for abuse relative to the substances in Schedule III. B. The substance has a currently accepted medical use in treatment in the United States. C. Abuse of the substance may lead to limited physical dependence or psycho- logical dependence relative to the substances in Schedule III. Requirements Dispensing limits: Prescription: written or oral, with medical authorization, refills up to 5 times in 6 months Security: Secure storage area Manufacturing Quotas: No SCHEDULE V Placement C. A. The substance has a low potential for abuse relative to the substances in Schedule IV. B. The substance has a currently accepted medical use in treatment in the United States. Abuse of the substance may lead to limited physical dependence or psycho- logical dependence relative to the substances in Schedule IV. Requirements Dispensing limits: Security: Manufacturing quotas: OTC or Prescription drugs limited to M.D order Secure storage area No, but some drugs limited by Schedule II quotas Source: U.S. Department of Justice, Drug Enforcement Administration Office of Compliance and REgulatory Affairs, Washington, D.C. ~37~

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REFERENCES 1 2 Cole, J.O. and Davis, J.M. Minor Tranquilizers, sedatives and hypnotics. In A.M. Freedman, et al (Eds.) Comprehensive Textbook of Psychiatry II, . (volume 1~. Second edition. (Baltimore: The Williams & Wilkins Co., 1975~. HEW, National Institute of Drug Abuse, Sedative-Hypnotic Drugs: Risks and Benefits, J.R. Cooper, Ed., ADAMHA, August 1977. 3 A Manual on Drug Dependence edited by Kramer, J.F. and Cameron, D (World Health Association: Geneva), 1975. 4 6 7 8 9 10 Rechtshaffen, A. and Kales, A.D. A Manual of standardized terminology, techniques and scoring system for sleep stages of human subjects. Brain Information Service/Brain Research Institute, Los Angeles, 1968. Phillipson, E. Respiratory Adaptations in Sleep. Annul Rev. Physiol. 40:133-156, 1978. Heller, H. and Glotzbach, S. Thermoregulation during sleep and hiber- nation. Int. Rev. Physiol. 15:147-188, 1977. . Baust, W. and Bohnert, B. The regulation of heart rate during sleep. Exp. Brain Res. 7:169-180, 1969. Weitzman, E.D. Circadian rhythms and episodic hormone secretion in man. Annul Rev. Med. 27:225-243, 1976. Guilleminault, C. and Dement, W. (Eds.) Sleep Apnea Syndromes, (Alan R. Liss, Inc., New York 1978~. Guilleminault, C., Malta, J., et al; Asystole and rapid eye movement sleep: a life threatening disease related to phase events? Presented at the 18th Annual Meeting of the Association for the Psychophysio- logical Study of Sleep, Palo Alto, California, April 1978. 38

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11 14 15 16 17 18 19 ~0 Nevins, D. First and second degree A-V heart block with rapid eye movement sleep. Ann. Intern. Med. 76:981-983 Shaw T., Corrall, R. and Craib, I. Cardiac and respiratory stand- still during sleep. Brit. Heart J. 40:1055-1058, 1978. Harvey, S.C. "Hypnotics and Sedatives" in The Pharmacological Basis of Therapeutics feds. Goodman, L.S. and Gilman, A.) N.Y: McMillan Pub. Co., 1975. Hinton, J.M. "A comparison of the effects of six barbiturates and mobility in psychiatric patients." Academic Dept. of Psychiatry, Middles ex Hospital, London, W.1. Brit. J. Pharmacol. 20:319-325, 1963. Lasagna, L. A study of hypnotic drugs in patients with chronic diseases, J. Chronic Dis. 3:122-133, 1956. Breimer, D.D., DeBoer, A.G., Rost-Kaiser, G., and Bracht, H. Unpublished investigations, 1977. Smith, D.E. and Wesson, D.R. Diagnosis and Treatment of Adverse Reactions to Sedative-Hypnotics. USDHEW, NIDA, ADAMHA, 1974, pp. .- 1-68. Gupta, R.C. and Kofoed, J., Toxicological statistics for barbi- turates, and other sedatives, and tranquilizers in Ontario: A 10-year survey. Can. Med. Assoc. J. 94:863-865, 1966. Parker, K.S., Elliott, H.W. et al, Blood and urine concentrations of subjects receiving barbiturates, meprobamate, glutethimide, of diphenylhydantoin, Clinical Toxicology, 3:1, 131-145, 1970. Berger, P.A. and Tinklenberg, J.R. ''Treatment of abusers of alcohol and other addictive drugs,)' in Psychopharmacology: From Theory to Practice. (Barchas, J.D., Berger, P.A., et al. eds.), : N.Y.: Oxford University Press, 1977, pp. 355-385. -39-

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