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OCR for page 17
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.
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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.
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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.
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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/
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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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OCR for page 39
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Representative terms from entire chapter:
rem sleep
