III.
THE
CLINICAL
USE
OF
STIMULANT
DRUGS
IN CHILDREN
Leon Eisenberg, M.D.
From the Department of Psychiztry, Harvard Medical School, and the Maisachusetts General Hospital, Boston, Massachusetts
Based on a lecture to the American Academy of Pediatrics, October 21, 1971, Chicago, Illinois.
ADDRESS FOR REPRINTS: Massachusetts General Hospital, 32 Fruit Street, Boston, Massachusetts 02114.
SYMPOSIUM:
BEHAVIOR
MODIFICATION
BY
DRUGS
709
PEDIATRICS, Vol. 49, No. 5, May 1972
H
AVING reviewed what is known, whatis only surmised, and what is not
known about the psychopharmacology of
stimulant drug use in children, the clinician
must decide for which patient to use what
drug for how long. Medical practice does
not permit the physician the luxury of
de-ferring decisions until knowledge is certain.
His task is to weigh putative benefits
against putative risks in a strategy designed
to maximize the probability of
improve-ment for a particular patient.
The risks that concern the pediatrician
are not only those visible in the short run
during drug administration but include
effects on development, effects which may
not become apparent for some time after
treatment has been discontinued. In the
case of stimulant drugs, public controversy
has centered on behavioral rather than
pharmacological toxicity, both short and
long run. In the short run, are the drugs
be-ing used indiscriminately to stifle
indepen-dence and creativity among exceptional
children? Over the long run, does
child-hood drug use predispose to adolescent
drug addiction? Before attempting to
an-swen these questions, let us first consider
the medical indications for the use of
stimu-lants and the mode of their administration.
The clinical syndromes which respond to
stimulants are characterized by motor
rest-lessness, short attention span, poor impulse
control, learning difficulties, and emotional
lability. Current American Psychiatric
As-sociation diagnostic nomenclature1 includes
the term: “hyperkinetic reaction of
child-hood” to describe this set of symptoms; the
World Health Organization2 is proposing:
“hyperkinetic syndrome.” Both terms have
the virtue of stressing the symptom
constel-lation and of by-passing the uncertainties
surrounding cause. Many clinicians label
the same behavior “minimal brain
dysfunc-tion”3 or “minimal brain damage” in view of
the frequent association of the behavior
profile with “soft” neurologic signs,
abnor-malities on psychological tests and a history
that suggests biological rather than
psycho-social causation. Whatever the terminology,
diagnosis depends upon clinical acumen;
there are no pathognomonic findings.
Typically, the pediatrician’s help is
sought for problem behavior in the school;
the child, usually a boy, is in both
disciplin-any and academic trouble. His mother
re-ports that he cannot sit still, will not stick to
any task, is disobedient and moody. He is
likely to have been an irritable baby who
was on the go from the moment he was able
to walk. He was slow in learning to button
his clothes, to tie his shoes, he may have
had minor speech problems and his
hand-writing is still illegible. Complaints from
school, first for behavior, then for
under-achievement, have been prominent from
first grade on. More often than not, there
will be a history of a similar pattern in the
patient’s father or a sibling. The physical
examination may reveal nothing more than
clumsiness, questionable choreiform
move-ments, and some difficulty in performing
skilled motor acts. Conversation with him
elicits only complaints about the unfairness
of his teacher and laments that nobody
likes him. He may or may not appear
mark-edly restless; some such youngsters can
interview with a sympathetic adult; motor
control falls apart only in group settings,
particularly when academic demands are
superimposed. If an EEC is done, it may be
reported as showing “more slow waves than
normal for age” or “mild hemispheric
as-symetry.” Psychometric tests reveal normal
intelligence, confirm the academic lag, and
sometimes display perceptual
abnormali-ties. The diagnosis of hyperkinetic
syn-drome is based upon the history and the
symptom profile rather than upon special
tests or examinations. However, the latter
are essential for the planning of educational
remediation.
How common is this syndrome? Stewart
et
al. found it in 4% of a St. Louiselemen-tary school population, Prechtl and
Stem-men5 in 5% of Dutch grade school boys,
and Huessey#{176} in 10% of Vermont second
graders, with boys more commonly affected
than girls. In the latter two studies, it was
estimated that about 80% of the children so
identified exhibited behavior problems or
learning disorders of sufficient magnitude
to warrant intervention.
How “real” is it? That is, are these
chil-dren different from their peers on objective
examination on is this merely an epithet
ap-plied to an annoying child? Douglas and
colleagues, employing direct classroom
ob-servation, found such children less attentive
and more disruptive than their peers.
More-over, Campbell, et al.8 compared
hyperki-netic and control children on four
“dimen-sions” of cognitive style and found them
more impulsive, more field dependent,
more distractable, and slower in
automati-zation.
How “significant” is it? That is, are we
dealing with an evanescent or an enduring
phenomenon with major consequences for
development? In a 5-year follow-up
com-panison of 37 such children with a like
num-ben of classroom controls, the hyperkinetic
children had a significantly higher failure
rate in all academic subjects and displayed
far more behavior problems. Moreover,
several studies of adolescent and young
adult psychiatric inpatients with “soft”
neu-rological signs’#{176}42 have identified histories
that in retrospect suggest hyperkinetic
fin-pulse disorder or minimal brain dysfunction in almost a third of the patients.
What causes the syndrome? We simply
do not know. A single cause is unlikely; the
behavior is a final common pathway for the
expression of diverse pathologies. Clinical
experience suggests that it runs in families;
a genetic basis is supported by data from a
foster care study’3 Complications of
preg-nancy and partunition have been shown to
be associated with overactive disorganized
behavior in an epidemiologic study of a
school guidance referral group;15 yet a
matched comparison of the pediatric
histo-nies of hyperkinetic versus other clinic
pa-tients failed to reveal reliable differences.16
It can follow encephalitis17 and is seen with
brain damage18 but these factors account
for only a minority of cases.
What is the pathophysiology of the
hy-perkinetic syndrome? Again we do not
know. Wender19 has proposed that there is
an underlying defect in the function of
mo-noaminergic neurons; the therapeutic
effec-tiveness of sympathomimetic drugs is
as-cribed to their known ability to amplify
noradrenergic effects in the central nervous system. Testing this hypothesis is difficult
because we lack methods to measure
cen-tral neurotransmitters in human subjects.
Peripheral metabolism and physiology may
not reflect central effects.2#{176}Thus, although
cause may be identified in a minority of
cases, it remains obscure in most;
patho-physiology can only be guessed at. Yet our
failure to understand cause and mechanism
does not diminish the reality of the clinical
phenomena and the personal suffering that
confront us. Medicine, this audience will
not need reminding, is an empirical
profes-sion.
I have recapitulated in brief and
sum-mary form a very considerable literature.2’
It provides persuasive evidence that we are
dealing with a syndrome that affects
signifi-cant numbers of children, that persists and
that carries with it a high rate of behavior
disturbance and academic failure. This is
no matter of “suppressing the normal
sig-ARTICLES
nificant psychopathology. It is thus
incum-bent upon the physician to consider those
methods of treatment which may modify an
otherwise potentially ominous course.
Of the available methods, by far the most
effective and the best documented is the
use of the stimulant drugs,
dextroampheta-mine and methylphenidate,2227 agents that
in these children suppress overactivity and
impulsivity and lengthen attention span.
There is little to choose between them, a
given child sometimes responding to one
rather than the other, but both require
close attention to dosage. Unfortunately, far
too many clinicians abandon treatment
af-ter a brief and inadequate trial of
medica-lion. Appropriate strategy is to begin with a
minimal dose, 5 mg of dextroamphetamine
or 10 mg of methylphenidate, to be given
once each morning with breakfast. At 2- to
3-day intervals, if no improvement in
be-havior results, dosage should be increased
in like increments. If significant benefit
ob-tains in the morning hours but wears off
be-fore the early afternoon, a second minimal
dose should be added with lunch, to a
max-imum daily dose of 40 mg of
dextroamphet-amine or 80 mg of methylphenidate. On
this regime, some % to % of hyperkinetic
children will show marked to moderate
benefit. Usually, benefit is unequivocal.
Once a child has responded, if a single dose
is omitted, he returns to baseline behavior,
and the change is immediately apparent to
his school teacher and to his parents.
The most common side effects are
insom-nia and anorexia; both may disappear
within a week or two even if dosage is held
steady. Tolerance to anonexogenic effects is,
of course, precisely what limits severely the
usefulness of these agents in treating
obe-sity. Insomnia can be minimized by limiting
the drug to morning and noon hours,
ano-rexia by administering the drug with meals.
Weight charts should be maintained. If
ei-then symptom is persistent, dosage will
have to be reduced in the effort to titrate
benefit against side effect. A rare child may
exhibit an idiosyncratic psychotic response
which, in the few instances reported, has
remitted with cessation of drug use.28’29
The next major point to be stressed is
that the child is likely to require treatment
for a prolonged period. Although some
chil-dren develop tolerance to the drug’s main
effects and may require a dose increment,
the great majority do not. Even more
strik-ing is the lack of evidence of pharmacologic
habituation; at the maximum dosage, even
after several years of use, the drug may be
discontinued between one day and the next
with no evidence of withdrawal symptoms.
This is in striking contrast to the chronic
use of barbiturates, steroid hormones, and
other pharmacologic agents which must be
withdrawn gradually to avoid serious
con-sequences. The dilemma is to know at what
time to terminate drug treatment when a
good result is maintained. Our practice is to
discontinue its use over each long school vacation, to allow the child to restart school
without medication, and to resume it only if
the syndrome recurs. Some children may
re-quine 3 to 5 years of treatment; others with
milder disorders as little as 6 months.
The final and most important point is
that drug treatment alleviates motor and
at-tentional disorders that interfere with
learn-ing, both academic and social, but it does
not produce learning; rather, it makes it
possible. Effective treatment no more than
begins with medication; remedial education
and parent counseling are essential if
teacher and parent are to help the child to
resume a normal developmental course.
How rapidly he will progress is a function
of the severity of his perceptual handicaps
and family problems on the one hand, and
of the adequacy of educational assistance
and family therapy on the other.
Unfortu-nately, some physicians disdain the
symp-tomatic relief offered by medication, and
others rely too exclusively upon it. Few
un-derstand that the hyperkinetic syndrome is
a chronic disorder requiring long-term,
closely monitored care, much like epilepsy.
Although there is convincing data on the
benefit from treatment over the short run,
no careful follow-up of a comprehensively
and continuously treated group has yet
been reported. In part, this is because the
symptoms (the restlessness and the
dis-tractability) have led to premature
opti-mism about the fate of the learning
prob-lems and the behavior disorder associated
with the syndrome. Whether we are dealing
with secondary elaborations of the primary
symptoms (that is, the cumulative
conse-quences of not having learned earlier and
having developed a negative self-image by
having been blamed unfairly) or whether
these are part and parcel of the basic
syn-drome is unclear. Whatever be the case, the
emerging follow-up data provide
compel-ling reason for the physician to take the
child under his care and to monitor his
course through adolescence.#{176}
It may now be appropriate to return to
the two questions raised at the outset: are
these drugs mind control agents to suppress
rebellion against excessively rigid teachers
and school? Does their use in children lead
to drug abuse when these children become
adolescents?
As to the first question, there is simply no
information about what stimulant drugs
would do if administered to normal
chil-dren. There are obvious ethical reasons why
we cannot give stimulants to normal
chil-dren to satisfy academic curiosity even on
so important an issue. Since the
phenome-non is age-related, studies with adult
volun-teens help not at all. But let us be clear:
overactivity and distractability can occur
un-den at least three sets of circumstances in
which drug use would be grossly
mnappropni-ate and medically reprehensible. The first is
the child who exhibits intense anxiety in
the midst of grossly disorganized family
life. It is the physician’s task in the
diagnos-tic evaluation to explore this possibility; if
it is identified, then the therapeutic task is
to restore family equilibrium before
enter-taming the use of medication. The second is
the fidgetiness and inability to concentrate
that can be produced by hypoglycemia in a
child who is malnourished and regularly
has no breakfast. Food is the appropriate
“pharmacologic” treatment for such
prob-lems. No physician worthy of the name
would treat hunger with
dextroampheta-mine. The third differential point to be
con-sidered in diagnosis is the character of the
classroom; if it is overcrowded, if the
teacher is incompetent (on simply
over-whelmed )
,
and if the classroom (as wastrue in one situation I encountered ) is
above a busy fire station, then what is
needed is attention to the classroom setting
and not to the chaotic activity which will
characterize the majority of the children in
such a classroom. Those who point out the
danger of the indiscriminate use of
stimu-lant drugs do so with justification. Any
po-tent agent can be abused, including this
class of drugs. Where I differ from them is
in their exclusive preoccupation with the
possibility of misuse, a preoccupation that
leads to abandoning the hyperkinetic child
along with the drug. Furthermore, the myth
that stimulants make hyperkinetic children
into conforming robots is arrant nonsense.
Restlessness, distractability, and impulsivity
are constraints on freedom, not freedom;
the child is not free to behave; he is driven.
Is a child whose attention is commanded by
every passing sight and sound, meaningful
and meaningless alike, to be considered
“in-dependent?” Is a child who is not learning
to read, when most of his classmates are, in
any sense expressing “creativity?” Stimulant
drugs reduce fidgeting, not purposeful
mo-ton activity; they lessen distractibility so
that the child can concentrate but what he
chooses to monitor is his decision; they
di-minish impulsivity so that his behavior is
more reflective. There can be no argument
that they should not be given except after a
thorough diagnostic evaluation, except
un-den careful medical supervision and except
with informed parental consent. These are
the appropriate guarantees of proper use.
What of potential for adolescent drug
abuse? One of the remarkable aspects of
stimulant drug use with children in contrast
to adolescents is its consistent failure to
produce euphoria. If the child notes a
change in feeling tone, he is apt to report
sadness or drowsiness rather than feeling
high. Most children have to be reminded to
take their medicine; few ask for it. Those
who feel positive about it do so because
ARTICLES 713
stupid or bad. For example, several
chil-dren in our practice experienced repeated
unprovoked crying spells in the early weeks
of treatment. When offered the choice of
stopping the medication, they rejected this
option because they considered the
class-room accolades they were now receiving
well worth the price in discomfort. The
point to be emphasized is that it is the
“high” produced by these agents in the
ado-lescent that leads to repeated usage. Since
children do not become euphoric, there is
no motivating force for drug abuse.
Taking a drug over a prolonged period of
time under medical prescription and
man-agement is a very different matter from
ei-then being encouraged to experiment with
them or watching your parents employ
cocktails, “downers” and “uppers” at their
own initiative in order to get through a
stressful life. I am unaware of any studies
which suggest that epileptic children on
an-ticonvulsants, diabetic children on insulin,
children with rheumatic carditis on
prophy-lactic sulfonamides, or asthmatics on
ste-roids are at any higher risk than the rest of
the adolescent population for drug abuse.
We are planning studies on just such
groups, none having been carefully
sun-veyed to the best of our knowledge, with
the expectation that they may be less likely,
rather than more likely, to become drug
abusers because of having learned to take
medicine for the proper business of
sup-pressing illness.
But these theoretical arguments are no
substitute for empirical data. What are the
facts? Unfortunately, there are no data
other than one preliminary study by our
group which bears on this question.3’ Dr.
Maurice Laufer of Providence, one of the
pioneers in stimulant drug therapy, was
good enough to give our staff permission to
contact the parents of 110 children whom
he had treated with dextroamphetamine for
hyperkinetic impulse disorder some 10 to 15
years earlier. A letter was sent to each
fam-ily, explaining the purpose of the study and
asking them to indicate their willingness to
cooperate. Eighty agreed to do so; of these,
63 completed the lengthy questionnaire sent
to them. We hope to locate the missing
re-spondents. Although a 60% response rate to a
mailing is by most experience surprisingly
good, and although the respondents did not
differ in any significant way from the missing
cases by history, the attrition in the sample
limits the confidence to be placed in the
data. To summarize the information we do
have, the patients had now attained a mean
age of 20; as children, 40% had received
medi-cation for less than 6 months; only 30% for
more than 3 years. Of the 63, only three
were known to their parents to have tried
marijuana, none as frequent users. Not a
single one of these former patients was
re-ported to have experimented with other
drugs, although four were described as
drinking to excess. In the absence of a
con-trol sample, one can only compare these
data to general experience : a contemporary
college-aged population might include half
who were experienced with marijuana and
some 10% who had tried lysergic acid,
mes-caline, on psilocybin.
Obviously, I am not recommending
pro-phylactic use of amphetamine in children to
keep them from becoming acid heads as
ad-olescents. I am suggesting that there is, to
the present, no evidence to support the
hys-tenia about stimulant drug use in children
as a source of adolescent drug abuse.
In-deed, Donald Klein of Hillside Hospital,3’
in studying the developmental histories of
drug-abusing adolescents, identified, in
trospect, symptoms of hyperkinetic
disor-ders in 20 to 30%, none of whom had been
treated with stimulant drugs as children.
May one be permitted the speculation that,
had they been treated successfully, they
might have had less need to seek drugs as
anodynes?
Despite the lack of evidence that
stimu-lant-drug-treated hyperkinetic children
become adolescent drug abusers, even the
remote possibility of such an outcome
justi-fies the call for more follow-up studies than
are now at hand. Unfortunately, the whole
matter has become so politicized that the
very fact that an investigator has studied
stimulant drugs has been used to attack the
714
the matter.33 But if we rule out of court the
testimony of those with competence to
in-vestigate the problem, I remain mystified as
to how the public is to learn what it needs
to know in order to reach informed
deci-sions on policy matters. And the regulation
of drugs is very much a matter in the center
of the public arena.
Stimulant drugs are grossly abused in
American society. The only medical
condi-lions in which they have been
demon-strated to be effective are the hyperkinetic
syndrome and narcolepsy. #{176}Their temporary
effects in obesity and depression are far
outweighed by the risk they pose for
habit-nation. Yet physicians continue to
pre-scribe them almost indiscriminately; they
are manufactured in entirely excessive
amounts; they circulate through an
exten-sive black market. They constitute a major
public health hazard in view of their
poten-tial for producing a flagrant psychosis
which closely mimics schizophrenia.34
Whatever faith we place in legal controls,
an approach not conspicuously successful in
containing the heroin pandemic, there is no
excuse for poor medical practice and
uneth-ical pharmaceutical promotion. Recent ef.
fonts by medical societies to exhort their
members to limit drug use to legitimate
in-dications represent a much to be
ap-plauded, if somewhat belated, step in the
right direction. It would indeed be
regretta-ble if the patients for whom stimulants
have been shown to be strikingly effective
were to be denied access to them by
draco-nian legislation resulting from the failure of
other measures of control. I am not dealing
in rhetorical hyperbole. This has happened
in other countries. And the cost to our
pedi-atric patients would be considerable. The
hyperkinetic syndrome is no mere matter of
a developmental phase to be endured until
it is “outgrown.” The data from the
longitudi-nal studies reviewed earlier provide
evi-dence for persisting educational handicap
and enduring behavior disorder. Stimulant
drugs, though only one element in a
pro-gram of treatment, can be key factors in
en-O Clinical experience also supports their use in Parkinsonism and in the management of epilepsy.
abling the child to benefit from remedial
education and parent counseling.
Continu-ing pediatric supervision is essential to
sue-cess in rehabilitating what we are
begin-ning to see as a chronic disorder, about
which we have much yet to learn.
In January of this year, the Office of
Child Development of the U.S. Department
of Health, Education and Welfare
con-vened a “Conference on the Use of
Stimu-lant Drugs in the Treatment of
Behav-iorally Disturbed Young School Children.”
The 15 panel participants included five
members of this Academy. I can think of no
better way to conclude this paper than by
quoting the last three paragraphs of the Conference Report.35
Clinical pharmacologists have repeatedly found
that drugs may act differently in children than in adults. To use medicines of all kinds effectively in children, more specialists must be trained in drug investigation-pharmacologists who can develop basic knowledge about the action of drugs in the developing organism. There is the obvious need for better and more precisely targeted drugs for the
whole range of severe childhood behavior
disor-ders. This requires intense research and training efforts. Such efforts provide the means for develop-ing, testing, and delivering better treatment pro-grams. There is a similar need for research in the techniques of special education and also a need to
make these techniques available to children who
can benefit. It would appear to be a sound Federal investment to conduct such research and
train-ing.
In summary, there is a place for stimulant medi-cations in the treatment of the hyperkinetic behav-ioral disturbance, but these medications are not the only form of effective treatment. We recommend a code of ethical practices in the promotion of medi-cines, and candor, meticulous care, and restraint on
the part of the media, professionals, and the pub-lie. Expanded programs of continuing education
for those concerned with the health care of the
young, and also sustained research into their prob-lems, are urgently needed.
Our society is facing a crisis in its competence
and willingness to develop and deliver authentic
knowledge about complex problems. Without such
knowledge, the public cannot be protected against half-truths and sensationalism, nor can the public
advance its concern for the health of children.
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