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OCR for page 137
Chapter 6
CONCLUS IONS
The study committee orig inally intended to examine the use of
hypnotics in medical practice' and compare the barbiturate hypnotics
with newer pharmacologic agents. As the inquiry proceeded, it became
clear that this approach required first addressing fundamental issues
of the physiology of sleep and the meaning of subj ective complaints
of sleep disturbance. Thus, this study has explored medical issues --
scientific knowledge and research relating to sleep, clinical practice,
and phys ic fan educe t tori; and it has exam ined soc ie tal i s sue s incl ud ing
public health risks associated with the availability of hypnotic medica-
tion and ways of enhancing consumer information.
The observations contained in this chapter are the committee' s
best judgment as to steps that might be taken to improve the physician's
therapeutic response to the complaint of unsatisfactory sleep, and to
enhance the public' s understanding of the hazards associated with the
casual, unnecessary, or excessive use of hypnotic medication.
A. Clinical Practice, Patient Information, and Public Health
To relate the scientific study of sleep, insomnia, and hypnotic
medication to contemporary health care, the committee offers the follow-
ing suggestions for prudent clinical practice, patient education and
preventive medicine, and improvement of public health.
Diagnostic Appraisal
A thorough medical and psychosocial appraisal of the insomniac
patient should precede any decision to prescribe drugs for relief of
the sleep complaint. Recent developments in sleep disorders research
permit a more detailed diagnostic classification of insomnia complaints
than was previously possible. Diagnostic possibilities include a wide
range of syndromes from the more common medical or psychiatric
illnesses ~ such as arthritis or depression) which lead to sleeplessness,
to the much less common disorders of sleep-induced ventilatory impair-
ment ~ sleep apnea) causing numerous life-saving arousals each night.
Psychosocial aspects of daytime living often play a role in the nocturnal
problems of patients in various age groups.
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Choosing the most appropriate and least hazardous approach to
providing relief depends upon interpreting the best possible diagnostic
information about the particular patient. For example, in the three
specific syndromes cited above (arthritis, depression, sleep apnea),
prescribing a hypnotic drug would be inappropriate as the primary
response to the patients' complaints of insomnia. For some patients
under certain forms of psychosocial stress, hypnotics may be useful
as temporary adjuncts to other measures, but their long-term clinical
benefit in chronic use is not established.
Prudent Prescribing
As a class of drugs, hypnotics should have only a limited place in
contemporary medical practice; it is difficult to justify much of the
current prescribing of sleeping medication. As a standard of prudent
ambulatory medical care, the committee favors the prescription of only
very limited numbers of sleeping pills for use for a few nights at a
time, to aid in specific situations such as travel or transient psycho-
social stress. Hypnotic drugs should be avoided for patients with
respiratory impairment, mental depression, or substance abuse problems
such as alcoholism. Hypnotic drugs should be selected carefully and
prescribed cautiously, if at all, for patients who are or may become
pregnant, who operate machinery, who have kidney or liver disease, or
who are old.
Data are lacking with which to judge the efficacy and safety of
long-term nightly use of hypnotics; currently, the consensus of sleep
disorders specialists seems to be that hypnotic drugs should not be
the primary form of treatment for most patients with persistent
insomnia. The committee urges physicians to closely monitor patients
receiving these medications, and generally refrain from providing auto-
matic or "as needed" refills. Long-term users of sleeping pills
should be re-appraised frequently for changes in health status,
alcohol consumption and drug use in order to prevent untoward
effects.
Patient Information
Patients should receive clear directions and warnings about the
use of hypnotic drugs. Important examples are as follows:
-- Patients receiving the benzodiazepine, flurazepam (Dalmane~ R)),
should be warned about the lingering presence of an active drug in
their bloodstream all day long and be told to avoid driving if they are
even slightly drowsy; if they do drive (or operate machinery) they
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should abstain from alcoholic beverages during the entire period --
day and night -- of treatment with this drug. Patients receiving
flurazepam should also be informed that the drug has a cumulative
action due to its active metabolite, so that nightly (or alternate
nightly) use may lead to side effects such as drowsiness or ataxia
appearing after the initial few days of drug treatment; these should
be reported to the physician promptly.
-- Patients receiving barbiturates (or most other nonbenzodiazepine
hypnotics) should be advised of possible hangover effects during the
first few mornings after treatment has begun. Patients should be told
to inform all health care personnel in the future if they continue
to take the drugs, so as to forestall complications should the need
arise for them to receive anticoagulant medication.
-- Women of childbearing age who receive prescriptions for either
benzodiazepine or barbiturate hypnotics should be told they may use
them in future episodes of insomnia only if they are certain that they
are not pregnant at that time, or if instructed to do so by a physi-
cian .
-- With any hypnotic, patients should be advised of the potential
for the development of habituation in the form of nightly reliance on
sleeping pills.
In addition to oral instructions from health care personnel, many
patients could be assisted by informational brochures, available in the
medical office, which would provide guidance on proper use of the medica-
tion (and, perhaps, other sleep-related information of a non-pharmaco-
logical nature).
Suicide Prevention
The reduction in the ready availability of barbiturates since
1970 because of changes in prescribing patterns has reduced the number
of deaths, particularly suicides, from barbiturate overdose. Only a
relatively small decline can be detected, however, in the overall
drug suicide rate. The use of multiple drugs, including alcohol, is
the increasingly predominant mode in suicides and accidental deaths
due to drugs. It would thus appear that efforts to control the avail-
ability of drugs should not be based solely upon the toxicity of a
drug used by itself in overdose, but should take into account the dangers
of combining different kinds of medication with each other and with
alcohol.
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Implusive pill-taking in suicide attempts conceivably could be
discouraged by (a) larger pills; (b) individually wrapped pills; or
(c) inclusion of an emetic compound in small amounts in each pill so
that vomiting would occur in case of overdose. The last proposal may
not be clinically feasible, requires further pharmacological research,
and may have medico-legal drawbacks; but the first two could be explored
and tested for those drugs which are perennially attractive to suicidal
individuals (analgesics, hypnotics, tranquilizers and anti-depressants).
Drawbacks to be considered include greater difficulty for those with
dexterity problems (e.g., the elderly) and increased costs passed on
to all consumers.
Clearly, an alert health care team can be the first line of attack
on a suicide problem. A great many suicidal drug-ingesting episodes
have been preceded by visits to physicians; often it is recently pre-
scribed medication that is used self-destructively.
Toxicology
In studies of drug deaths and traffic accident victims, modern
toxicological analyses for the commonly prescribed benzodiazepines
and their metabolites should be performed, in addition to traditional
tests for alcohol, opiates and barbiturates. Nationally, there is a
need for adequate toxicological analyses to provide more reliable data
with which to assess the role played by psychotropic drugs in suicide
and various kinds of accidental death or injury.
Epidemiology
Current national mortality and morbidity statistics are inadequate
for determining the extent and source of drug problems in the United
States. The currently used coding manual, International Classification
of Diseases, Adapted (Ninth Revision) does not allow sufficient dis-
aggregation of data on deaths by ingestion of various types of drugs.
What is needed is a code system which would allow the coding of indi-
vidual drugs so that their patterns of use may be accurately determined.
Such a system could be an expansion of the international code.
B. Benzodiazepines vs. Barbiturates as Hypnotic Drugs
Benzodiazepines are now used as hypnotics or bedtime sedatives
far more often than barbiturates or other types of drugs in this
group. In fact, one benzodiazepine, flurazepam, is prescribed more
often than all other hypnotics combined. In Europe, nitrazepam
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is similarly popular. Other benzodiazepines used primarily as anxiolytics
or daytime sedatives are also often taken at bedtime for sleep. This
represents a significant change from the state of affairs a decade ago,
when barbiturate hypnotics and glutethimide were overwhelmingly predomi-
nant; this in part reflects the medical profession's response to some
well-known advantages of the benzodiazepines -- especially their relative
safety when taken alone in attempted suicidal overdose and the absence
of interference with actions of certain other drugs, especially anti-
coagulants. From anecdotal and clinical reports, the committee noted
that physicians have found patient satisfaction with benzodiazepines
generally to be about equal to that obtained from barbiturate hypnotics;
and physicians have preferred to continue prescribing benzodiazepines
because of their reputation for safety.
There is a lack of standardized criteria for defining insomnia
and a lack of clear documentation of efficacy in alleviating the
patients' actual complaints. These problems are compounded by the
diverse methods by which efficacy studies are performed and data are
presented. Little can be reliably said about the comparative benefits
of various hypnotics. Until such knowledge is available, the committee
concludes that relative risks of individual hypnotics for particular
patients should be the dominant factor in choosing which to prescribe.
Insufficien;t recognition has been given to undesirable or possibly
hazardous features of the benzodiazepines. Some potentially hazardous
attributes of the longer-acting benzodiazepines which are not found
qualitatively in barbiturate hypnotic use are:
· the accumulation of long-lived active metabolites when used on
consecutive or alternate nights, especially with flurazepam and nitraze-
pam.
o an increasing likelihood of adverse drug reactions with advanc-
ing age of the patient.
· a greater likelihood of adverse drug reactions in patients
with diminished kidney function.
Benzodiazepines also share the following potentially hazardous attri-
butes with barbiturate hypnotics:
~ In combined overdose (either suicidal or accidental) with other
depressant drugs, including alcohol, benzodiazepines act additively
to increase the risk of death. The level of each of the substances
may be distinctly sub-lethal, but the end result may still be fatal.
(On a dose-for-dose basis, this appears to be less of a hazard than
it is with barbiturates.)
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· During the day after nocturnal drug use, long-acting benzodiaze-
pine hypnotics -- flurazepam and nitrazepam -- produce deficits on tests
of visual-motor coordination which may be related to automobile driving
skills. (Following seven nights' drug use, the impairment caused by
these drugs is distinctly greater than that resulting from such use of
a barbiturate hypnotic.)
o When alcohol is ingested the day after a benzodiazepine hypnotic
has been used, driving-related skills are very much impaired. (This
potential problem is greater with flurazepam and nitrazepam than with
with barbiturate hypnotics, especially following seven nights of drug use.)
o Some benzodiazepines (diazepam but not, as yet, flurazepam) have
been used in serious drug dependence of the barbiturate type. The extent
of addiction to benzodiazepines is difficult to ascertain, but it is a
source of growing concern in the medical community. (The potential for
fatality from established barbiturate addiction is greater than that
resulting from addiction to benzodiazepines.)
0 Nightly reliance on drugs for sleep is equally likely to arise
with either benzodiazepines or barbiturates.
e The benzodiazepines are respiratory depressants (quantitatively
less potent than barbiturates on a dose-for-dose basis).
O The teratogenic effects of either class of drug have not been
fully explored, but -- if confirmed by future studies -- are likely
to be of very low frequency. On the the basis of limited evidence, the
benzodiazepi-nes would seem to increase the risk of a baby being born
with cleft lip. This finding warrants further research, as does the very
recent finding of increased risk of brain tumor in children whose mothers
took barbiturates during pregnancy.
· Like the barbiturates, most benzodiazepines are tolerated poorly
by patients with liver disease.
The committee believes that benzodiazepines are not innocuous
drugs. They pose hazards that have been insufficiently appreciated,
while the narrow margin of overdose safety of barbiturate hypnotics
appears to be well-known to the medical profession. As for efficacy,
the committee concludes that both types of drugs are probably equally
effective in short-term use. In long-term use, the side effects
and risks of benzodiazepine hypnotics are likely to increase, and
tolerance is likely to develop to sleep-promoting properties of
barbiturates. A number of older patients have become reliant on
barbiturates for nightly use; it is likely that a number of younger
patients will become reliant upon nonbarbiturate hypnotics. The
safety and efficacy of nightly use of any type of hypnotic for
prolonged periods is not established at this time. The committee
believes that, until long-term safety and efficacy of regular
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hypnotic use is established, physicians should rarely, if ever, prescribe
hypnotic drugs for periods beyond two to four weeks for patients who have
not yet become reliant upon regular use of hypnotics. In the case of
patients who are already reliant, the committee recommends frequent re-
appraisal of diagnosis, risks and benefits of hypnotic use, and main-
tenance of vigilance for development of either toxic side effects or risk
factors which would make continuation of the drug hazardous (e.g., preg-
nancy, renal disease, alcoholism, depression).
In light of its review of safety, efficacy and public health
problems associated with various hypnotic drugs, the committee finds
no justification for more restrictive scheduling of barbiturate
hypnotics under the Controlled Substances Act; this removal of barbi-
turates from general availability in ambulatory medical care would be
unwarranted at the present time.
The "ideal hypnotic" has not been found. Drugs that might more
safely relieve various types of sleep complaints should be investigated.*
For example, the reality of chronic drug use emphasizes the need to
find and evaluate drugs that do not accumulate in the body with repeated
doses and do not result in adverse daytime effects; and the reality of
overdose deaths dramatizes the need for drugs with the widest possible
margin of safety, even when combined with other drugs and alcohol.
As long as flurazepam continues to be the most widely prescribed
hypnotic in North America, a suggestion regarding its use is in order:
o The usual dose should be 15 ma. Studies of flurazepam generally
describe only modest differences between a 15 mg and 30 mg dose in terms
of the effect on objective (EEG) sleep measures or subjective satis-
faction. Yet there are strong dose-related correlations when it comes
to toxic side effects. The drug manufacturer (with FDA approval)
continues to propose the 30 mg dose as the customary one for adults,
except for "elderly" or "debilitated'' individuals, for whom 15 mg is
suggested. The recommendations of clinical investigators that the
15 mg dose be used more frequently 1/-3/ have not been heeded.
Occasional trials of doses less than 15 mg in some patients is currently
impossible because the manufacturer does not make a capsule contain-
ing less than 15 ma, and flurazepam is not marketed in scored tablets.
C. Professional Education
The findings of current and future research into sleep disorders
and medication for their treatment must be translated for possible
clinical use by practicing physicians. The committee finds that
.
*See Section E., below, on research needs
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although hypnotics are prescribed widely, most physicians receive
little training in their use. Medical school curricula should include
training in the diagnosis and management of sleep disorders. (In 1977,
42 out of 91 responding medical schools indicated that they did not
offer even one lecture on sleep problems or sleep-related physiology
within their required curriculum 4/~.
The committee believes that major professional education efforts
should be developed in the diagnosis and therapy of insomnia, and
that these efforts should not be underwritten primarily by the pharma-
ceutical industry. Programs on insomnia should become part of the
continuing medical education that has become mandatory in many
jurisdictions and in several specialty societies. The incentive to
become proficient in this area would be increased if licensing and
specialty board examinations would give sleep disorders a prominence
commensurate with their occurrence in clinical practice and if research
in this area were encouraged by appropriate federal support.
However, before such professional education campaigns are launched,
it would seem appropriate to convene a "consensus development exer-
cise" -- in 1979, to be re-convened every two or three years there-
after -- on the therapeutic and clinical research issues posed in this
study. Modeled on recent NIH conferences on therapeutics (such as
radical vs. simple mastectomy, surgical treatment of extreme obesity,
treatable dementia in the elderly), such a meeting would bring together
experts in several relevant disciplines to explore areas of consensus
on diagnosis and management of various kinds of insomnia and the
appropriate use of various therapeutic approaches, including drugs.
Opportunity for input from consumers should also be provided. The
consensual viewpoint could then be published and disseminated through
specialty societies and continuing medical education courses. The
need for such periodic "therapeutic reviews" is suggested by the rapid
pace of developments in the sleep research field.
A vigorous program of continuing medical education based on
current consensual therapeutic reviews and sponsored by specialty
societies, medical associations and the federal government would help
diminish casual or inappropriate prescribing of hypnotic drugs. In
addition, the committee recognizes that computer data files of ambulatory
prescribing patterns exist in several states, including those in which
PSROs are monitoring Medicaid practice, or law enforcement or medical
disciplinary boards are checking on potentially unprofessional or illegal
prescribing patterns.* With proper safeguards of patient privacy, each
prescribing physician in those states could be sent a print-out showing
his or her prescribing patterns compared with state norms or with
standards generated by peers or professional organizations. The committee
believes that this should be explored and would be a method of self-
education to which many Physicians are likely to respond.
*Described further in a Technical Supplement to this report.
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D. Advertising and Labeling
"Detail men," sales representatives of pharmaceutical companies,
have been found to constitute the most influential single source of
information for physicians during the period when a drug is first being
prescribed. 5/ Advertising in medical journals and material in the
Physician's Desk Reference (PDR) have been shown to be frequently relied
upon by physicians in matters such as dosage and adverse reactions for
drugs. 5/ It is essential that the information conveyed by these promo-
tional materials be accurate and complete.
The PDR, distributed annually without charge to most practicing
physicians, is essentially a collection of professional package inserts
containing the "complete labeling" (also called "complete prescribing
information") which has met with FDA approval. Drug manufacturers list
their products by paying the publishing company a fee. The information
on each drug usually includes data on chemistry, animal pharmacology
and toxicity, indications, dosages, contraindications, precautions,
side effects, and special warnings, if any. This approved prescribing
information is a product of negotiation between the manufacturer
and the FDA. On some occasions, the FDA insists that a specific
warning be added to the professional information for a given product
or group of drugs. Such is the case, for example, with all benzodiaze-
pines, which carry the warning against usage during the first tri-
mester of pregnancy because of an increased risk of teratogenicity.
Recently, the FDA has required the drug manufacturers to submit
for its approval a clinical (human) pharmacology section to be added to
the prescribing information contained in the professional package
insert and the PDR, although it need not be in the advertising. This
requirement has resulted in disclosure of the existence of flurazepam's
long-lived metabolite in the new labeling, which first reached physicians
in a supplement to the PDR in late 1978 -- five years after publication
of the research article that first described flurazepam's pharmaco-
kinetics in man. Even in the new labeling, however, the half-life
of the metabolite is stated without indicating the implications of its
accumulation. Instead of stating that blood levels on the eighth
morning after a week of consecutive nightly use are likely to be four
to six times that found on the first morning, with concomitant potential
for adverse daytime effects, the new prescribing information places
the clinical implications of the drug's "pharmacokinetic profile"
in a wholly favorable light.*
*This pharmacokinetic profile may be responsible for the clinical
observation that flurazepam is increasingly effective on the second or
third night of consecutive use and that one or two nights after the
drug is discontinued both sleep latency and total wake time may still
be decreased." 7/
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The "warning" that physicians are encouraged to give their fluraze-
pam patients about driving or operating machinery is deficient in that
it specifies that the patient be told to avoid such activities "shortly
after ingesting the drug" (presumably on the way to bed). It fails to
mention that the drug can produce adverse effects on coordination the
next day or can interact adversely with alcohol the next day as well.
In advertisements aimed at health professionals, manufacturers of
prescription drugs are not required to include the "complete prescribing
information," but must offer a "summary" which includes the special warn-
ings such as avoiding use during pregnancy. The advertising claims for a
drug are supposed to be consistent with the indications and other infor-
mation originally approved by the FDA when the drug was first allowed
on the market. Unlike the approved labeling, advertising copy is not
submitted to FDA for pre-clearance. If, after the fact, an advertisment
is found to be misleading, the FDA may step in and order corrective
action.
Only three hypnotic drugs -- none of them a barbiturate -- are
currently advertised to the medical profession in the United States.
Examination of current advertisements raises doubts about whether they
present balanced, clinically relevant information to aid the con-
scientious physician in prescribing.
Advertisements for flurazepam for example, demonstrate the
limitations of advertising as an information source. A typical
artistically attractive, three-page full color spread will emphasize
the laboratory procedures showing the drug's "effectiveness" lasting
up to 28 nights in insomniac patients. An implication of these ad-
vertisements is that insomnia is a unitary disorder, appropriately
treatable for 28 nights at a time with flurazepam. Nowhere do these
advertisements reveal that the claim of effectiveness for 28 nights
is based on studies of only ten patients and that hundreds of individ-
uals with sleep complaints had to be screened to select these severe
insomniacs for research purposes. The emphasis on the sleep laboratory
technology distracts attention from the absence of data on subjective
relief and daytime measures of drug-induced improvement or impairment.
Finally, the "summary" of prescribing information in current advertise-
ments does not include even the limited information about flurazepam's
long-acting metabolite which now appears in the PDR.
The flow of information about drugs provided to the practicing
physician is dominated by printed advertising in medical journals,
manufacturers' sales representatives and the Physician's Desk Reference.
In the case of hypnotic drugs the committee finds much of this informa-
tion is apt to be incomplete and of questionable relevance to physicians.
At present, responsibility is left to the professional journals whose
vigilance in holding advertisers to high standards of accuracy and
balance is unknown. Except in rare instances, the Food and Drug
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Administration is not legally authorized to screen advertising prior
to its appearance, but it could be more vigilant and timely in insisting
on "complete labeling" (prescribing information) which is maximally
useful in format and content to the physician. Consideration should
be given to requiring that such complete information should appear
in advertisements, rather than being limited to the PDR and professional
package inserts. Pharmaceutical sales representatives should be required
to leave copies of this information with the physician whenever a product
is discussed.
E. Research Needs
Insomnia and Appropriate Therapeutic Responses
Clinical Investigations As in many other fields, critical links
between basic science research and clinical practice are forged in
the research arena of clinical investigation. No research effort
consonant with the prevalence of the complaint of insomnia has been
undertaken. Because insomnia complaints are in great part subjective
complaints but also lend themselves to objective measurement, intensive
clinical investigation of patients offers promise for greater clarifica-
tion of these problems in the future.
Clinical investigations are needed on two levels: analyses of
fundamental issues regarding human sleep, and studies of series of
patients. Development of normative data is required for respiratory,
cardiac, and endocrine function during sleep; it has become clear that
the physiology of these functions differs greatly in the sleeping and
waking states. Further work on experimentally induced sleep disturbance
could shed light on the sequelae of interrupted or short sleep for
later comparison with the daytime results of insomniacs' sleep patterns
(with and without therapeutic intervention).
Clinical studies should be conducted (1) of patients with sleep
complaints, but whose findings on objective sleep measures are well
within "normal" limits; (2) of individuals of various ages whose sleep
is not a source of distress, in order to extend the normative data
base; (3) of individuals who only use sleeping medications intermit-
tently (several times a year for a few days); (4) of individuals who
are nightly users of sleeping medication, who appear to be satisfied,
and whose insomnia complaints are "remedied"' by such nightly use. Their
daytime functioning as well as nighttime sleep measurements need to be
studied; (5) of the actual mechanisms whereby hypnotic drugs promote
sleep. In the latter, there is a need for fundamental neurochemical
research as well as sophisticated psychological investigations of
satisfied users of hypnotic medications.
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Epidemiological research is needed to distinguish the potential
. ~
from the actual hazards to drivers, pedestrians, and industrial workers
of residual daytime effects from nocturnal hypnotic medication. All
such studies must include the psychiatric condition of the subjects
as a variable. Studies are also needed to discern what hazards, if any,
accompany a poor night's sleep that has not been treated with drugs.
Further studies should be undertaken of the industrial accident rate
by shift workers, both on and off hypnotic medication. Further studies
on teratogenicity and carcinogencity of hypnotic drugs are essential.
Longitudinal studies are required to develop knowledge about the
duration of various kinds of insomnia complaints and the crucial
determinants of the duration in such cases. In one large follow-up
survey, a significant relationship between stated sleep time and mor-
tality was found. 7/ The less a person slept (by report) the more likely
that person was to be dead in six years. The same was true for prolonged
(by report) sleep and for those who reported taking sleeping pills
frequently. These relationships need to be explored in depth.
Health services research could help to determine how primary health
. .
care practitioners respond to patients with behavioral problems such
as insomnia. Primary care physicians do not customarily receive payment
for much of their time spent in office counseling on problems like
insomnia. Demonstrations and studies should be made of greater utili-
zation of paramedical personnel for this purpose (e.g., nurses, social
workers, physician's assistants) as well as third party payment for
physicians' time spent talking with patients.
Treatment research With the present inadequate data base, the
committee is unable to endorse the efficacy of specific therapies,
drugs or classes of drugs in the management of insomnia complaints.
The committee recommends that new, more sophisticated multidisci-
plinary research be initiated to test the efficacy of various
pharmacological, psychotherapeutic, behavioral, and psychosocial
treatment approaches to various types of insomnia.
Patients with an insomnia complaint tend to differ widely from
each other in their objective and subjective sleep abnormalities,
age, sex, primary diagnosis, psychopathology and daytime mood and
psychomotor functioning. Prior to selection for study, the patients
need to be carefully evaluated from a multidisciplinary point of
view, with special attention to objective and subjective sleep
characteristics, including appropriate tests to diagnose specific
sleep disorders such as sleep apnea and nocturnal myoclonus; the
patients also need to be evaluated from the point of view of daytime
functioning, mood, and psychopathology.
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The effect of any particular treatment must be evaluated on many dimen-
sions, including objective and subjective sleep characteristics, daytime
measures of mood, psychopathology, functioning, and cognition and memory,
with a view to establishing both the potential benefits and risks of the
treatment. The duration of effectiveness must also be established.
Someday, it may be possible to match a pharmacological (or nonpharmaco-
logical) treatment to an individual's chief sleep complaint, once adequate
diagnostic rigor has been applied and there has been more clinical
research comparing diagnoses and outcomes.
With regard to research on pharmacologic treatment methods, every
effort must be made to standardize and upgrade hypnotic drug efficacy
studies. There must be clear definitions of the specific problems and of
the goals of treatment. Above all these goals must be related to the
actual problems. Many sleep laboratory studies have omitted significant
descriptions of the subjective complaints of the individuals whose
responses to hypnotic drugs were being measured. In fact, in a good
number of studies the subjective effects upon the individual have gone
unreported in the midst of a flurry of EEG tracings. Most surprising,
many sleep laboratory studies have presented only meager objective
data. They have not specified when the drug was taken, how long the
patient spent in bed (and whether this was at the discretion of the
patient or the experimenter), total sleep time, sleep efficiency, early
morning wake time, individual differences in treatment response, or a
host of other potentially significant measures of effectiveness. More-
over, many of the measures that were reported have remained undefined.
With regard to daytime effects, it is necessary to assess mood,
mental alertness, and visual-motor coordination. New and sophisticated
tests have been developed from aviation and traffic safety sources
which should be applied in modeled evaluations. Special attention to
the risks associated with the accumulation of long-acting metabolites
is of major concern with some drugs; these could impair driving skill,
potentiate the effects of alcohol and be involved in late-developing
adverse reactions.
Clinical experimentation with low doses of flurazepam and other
agents with long-lasting metabolites should be pursued. Shorter-acting
benzodiazepines - oxazepam (Serax(R)) and lorazepam (Ativan(R))
which are generally marketed for use as daytime tranquilizers, should be
tested in the United States specifically for their hypnotic utility and
their liabilities, such as drug abuse potential. Other promising drugs
which have been incompletely evaluated for efficacy and safety in various
types of patients include methyprylon (Noludar(R)), chloral hydrate,
diphenhydramine (Benadryl(R)), L-tryptophan, and antidepressants like
amitryptiline (Elavil(R)) and doxepin (Sinequan (R)~.
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Nonpharmacological treatments for different types of insomnia also
must be further investigated. Various forms and combinations of
behavioral techniques have shown some promise for the individual who
suffers from uncomplicated chronic insomnia, though these have not been
documented in controlled studies. The utility of psychotherapy for such
individuals, even in the absence of a specific mental disorder, could be
tested by controlled clinical research. As with all such studies, it would
be best if these were collaborative studies in which representatives from
different disciplines engaged in mutual evaluation and consultation.
Much more research is necessary on the sleep difficulties of elderly
patients, with special attention to nonpharmacological, psychosocial
therapeutic approaches. The elderly are likely to remain relatively
refractory, in many cases, to pharmacological efforts. Taking any
medication for sleep may add new hazards to their already complicated
drug regimens. Low doses of carefully selected and monitored medications
should be evaluated, but special efforts should be made to develop and
evaluate psychosocial and behavioral intervention.
Finally, for the individual who awakens with a sense of unsatisfactory
sleep and may even claim that he or she did not sleep (though objective
findings show otherwise), there is a need for a multifaceted attempt to
understand the problem. Indeed, here is an area where an intersection
of clinical psychiatry and psychoanalysis (which originated the 20th
century investigation of sleep and dreams) and the big-behavioral
disciplines of neurophysiology and sleep medicine may prove fruitful.
The need for Independent Research and Evaluation of Hypnotics
Although the problem of insomnia is widespread and the inappropriate
use of hypnotics can have serious and even life-threatening consequences,
the Federal government has supported few studies of hypnotic efficacy
and safety. Nearly all of the investigations into prescription drugs
and insomnia conducted in the United States have been sponsored by drug
manufacturers. In the United Sates, there is no independent clinical
research, supported either by the government or by philanthropic founda-
tions, with which to seek answers to legitimate public health questions
about hypnotic drugs.
Although various agencies of the Public Health Service (especially
the National Institute of Mental Health) have supported studies of
sleep physiology and sleep disturbance associated with such specific
mental disorders as depression or schizophrenia, the amount of clinical
investigation directed toward treatment methods for insomnia has
been negligible. A few studies of the efficacy of L-tryptophan, a
dietary supplement not marketed as a drug, have been supported by the
National Institute on Drug Abuse. There are three studies currently
funded by the National Institute on Mental Health of behavioral
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techniques in the therapy of insomnia. The National Institute on Aging
has begun funding investigations of the changes of sleep with age, but
these are not as yet treatment-oriented. Some studies have been funded
by the National Institutes of Health specifically on sleep apnea and
nocturnal myoclonus, and the NIH has provided support for the multi-
faceted studies of the Boston Collaborative Drug Surveillance Program,
including several clinical studies of hypnotic drugs in hospital patients.
There has been a modest amount of intramural clinical study within the
Veterans Administration hospital system.
These appear to be the entire inventory of Federally-funded
clinically-oriented investigations of sleep problems associated with
insomnia over the past decade. In contrast to the notable efforts of the
National Institute of Mental Health and the Veterans Administration to
collaboratively examine the efficacy and safety of antipsychotic drugs
and antidepressant medication, hypnotic prescription drugs have been
relatively neglected. Furthermore, relatively few investigators have
presented research proposals to the Public Health Service to study
drugs and insomnia.
Approximately 150 studies of hypnotic drug efficacy* were reviewed
in the course of preparing this report; all but a handful were sponsored
by pharmaceutical companies. The results of most of these are extremely
difficult to interpret. There has been a failure to set high standards
of interpretability, replicability, and general validity in the published
studies. In the design of the original experiments as well as in the
report of the outcomes, the manufacturer has a strong influence on
which aspects are to be emphasized. Reports of manufacturer-sponsored
research are generally presented to the Food and Drug Administration by
the manufacturer, not directly by the investigators themselves. There
is no adequate, independent peer review of protocols or healthy competi-
tion for support. Rigorous peer review depends upon the availability of
a reasonably large group of individuals knowledgeable about the discipline.
Until recently, there has been little to encourage the career development
of sleep disorders specialists and sleep pharmacologists.
It is noteworthy that nearly all the investigations of residual
adverse effects of hypnotics on daytime psychomotor performance tests,
have taken place overseas where support was provided by the respective
foreign governments. The one American preliminary study was partially
supported by the National Aeronautics and Space Administration (NASA),
not by a drug manufacturer. Federal support of research in this area
would increase the opportunity to obtain objective data concerning
these and other adverse effects of these drugs.
The committee believes that independent clinical pharmacology should
be strengthened in the United States through the creation of support
and networks of peer review, particularly for studies of hypnotic drugs.
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*Tabulated in the Technical Supplement to this report.
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Within the present authority of the Alcohol, Drug Abuse and Mental
Health Administration (ADAMHA) as well as the National Institutes of
Health (NIH) there should be increased research into the nature of various
types of sleep disturbance and appropriate measures for their relief --
including non-pharmacological methods. In funding this research, these
federal agencies must take care not to repeat errors of past research.
The committee recognizes that the drug regulatory system in this
country relies heavily upon data produced by companies that have a com-
mercial interest in the way the data are interpreted. Ways must be found
to collect data and sponsor research which will supplement the information
put forth by pharmaceutical companies in New Drug Applications and in
post-marketing reports to the FDA. One approach recommended by the
committee is to greatly expand the FDA's access to and use of qualified
outside consultants. Establishment of a new standing committee on
hypnotic drugs should be considered. If such a committee were formed
its members should include independent sleep laboratory researchers,
clinical pharmacologists, basic pharmacologists, drug addiction experts,
consumer representatives, and specialists in appropriate branches of in-
ternal medicine, primary care, psychiatry, and the behavioral sciences.
F. Initiation and Coordination of Federal Efforts
The committee recommends a search within the Public Health Service
to identify an ongoing mechanism or mechanisms to identify and fund
quality research and collect and disseminate information on the practical
questions that have been raised in this study. As a first step, the
committee suggests that an organizational entity be foraged within the
Public Health Service to review the current scientific, educational,
and administrative issues associated with sleep disorders and their
treatment. Working with specialty societies, medical associations and
academic health centers, this authority could begin the process of
improving research and education and encouraging high standards of
medical practice and clinically relevant research. It could-coordinate
the consensus development and professional and public education efforts
in the field of sleep disorders, as well as identify promising research
for grant funding or intramural programs of the Public Health Service.
The committee recognizes that many of the problems associated with
treatment of insomnia and the medical use of hypnotic drugs resemble
those encountered in the clinical management of other health care pro-
blems -- which also require evaluation and professional education
by those without a commercial stake in the results. The establishment
of this central authority and coordination effort might eventually
lead the way to a more organized focus on therapeutics and health care
evaluation, ultimately resulting in better health care for those who
suffer from a variety of widespread conditions which heretofore have
been given low priority on the health science agenda.
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Archives of General
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Representative terms from entire chapter:
sleep disorders