Download Treatments Introduction to the Mechanism of Action of Different

Sleep, 17:S93-596
© 1994 American Sleep Disorders Association and Sleep Research Society
Treatments
Introduction to the Mechanism of Action of
Different Treatments of Narcolepsy
David Parkes
University Department of Neurology, King's College Hospital, London,
The main characteristics of the narcoleptic syndrome include pathological daytime sleepiness, cataplexy, pre sleep dream timing, sleep paralysis, insomnia
and motor parasomnias (1-3), The classic review of
Daniels (4) highlighted the socioeconomic effects of
the illness, which are frequently as troubling to the
patient as specific symptoms. In a review of these effects, Broughton and Ghanem (5) concluded that narcolepsy was a severe, debilitating, chronic condition,
summed up in a patient quote, "Narcolepsy has almost
ruined my life ... when promotions came up I was
always bypassed. I read in a newspaper article that
amphetamines could be used to control narcolepsy,
which was described as a condition characterised by
an uncontrollable tendency to fall asleep .... Although
medication is helping, I still have a long way to go".
Unfortunately the medical treatment for narcolepsy
is still far from satisfactory. The most disabling symptom by far is daytime sleepiness, which has a significant
effect on health and safety and is a common and important cause of medical, economic and social morbidity. Data from the U.S.A. and from a recent study
by the Leicestershire police in the U.K. suggest that
falling asleep is a very important factor in road traffic
accidents, perhaps second only to alcohol as a specific
cause (6). Treatment of narcolepsy with centrally acting
sympathomimetics or other stimulants reduces but does
not eliminate somnolence or performance deficits (7).
The major problems in stimulant drug use have been
discussed in recent editorials in Sleep, stressing the
various conflicts between prescriber and user, such as
limitation of amphetamine dosage by doctors to reduce
both peripheral and central side effects, and patients'
desire for higher dosages than they are given. There is
also the problem oftherapeutic efficacy of the various
compounds-the balance between wanted and unwanted side effects (8-10). Most studies of stimulant
treatment of narcolepsy have been short, often lasting
u.K.
only a few days and without control. Plasma levels
have been uncontrolled and treatment has been assessed in many different ways, which may not truly
reflect the quality of narcoleptic life. Long-term controlled comparative studies of the different stimulants
are not available. The sympathomimetic side effects
such as sweating and effects on cardiovascular function, which are common to many central stimulant
drugs, have been difficult to quantitate. These drugs
also may aggravate insomnia. Amphetamine psychosis
occurs in our experience in approximately 0.5% of subjects with narcolepsy, sometimes even in low-dosage
treatments, for example, dextroamphetamine 20-30
mg daily.
In recognition of these problems a number of nonamphetamine derivatives have been developed in several countries for the treatment of narcolepsy, including mazindol; the selective monoamine oxidase
inhibitor, selegiline, whose metabolites are amphetamine and methylamphetamine; and modafinil.
BEHAVIORAL EFFECTS OF CENTRAL
STIMULANT DRUGS
Amphetamine will increase effort, elevate mood,
prevent fatigue, increase vigilance, prevent sleep, stimulate respiration and cause electrical and behavioral
arousal from natural or drug-induced sleep. These central stimulant effects are thought to be caused by both
cortical and brain stem reticular activating system
stimulation. Amphetamine causes a dose-related increase in subjective arousal, and the usual effect is to
produce wakefulness, alertness, self-confidence, ability
to concentrate and sometimes elation and euphoria
with increase in work perfonriance for simple tasks.
However, it is important to stress that whatever the
actual results of amphetamine on psychomotor performance tests may be, subjects often think they have
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D. PARKES
done better than they have and judgement is impaired
(11). The effects of amphetamine on alertness and mood
are largely inseparable.
Biochemically, amphetamine releases catecholamines from their neuronal storage sites but does not
greatly affect neuronal serotonin concentrations. The
basic skeleton of amphetamine is one of a sympathomimetic amine. Axelrod showed that the reuptake block
caused by amphetamine was accompanied by a threefold increase in norepinephrine and a two-fold increase
in epinephrine metabolism (12).
Norepinephrine systems of the brain are very heterogenous but present evidence indicates that catecholamines play an essential part in the control of wakefulness. In addition, nonadrenergic mechanisms are
important for at least some of the central nervous system (CNS) effects of amphetamines, which cause major
alterations in cerebral blood flow and cerebral energy
metabolism. Amphetamine causes an increase in the
incorporation of glucose into brain glycogen and an
increase in activity of the cerebral enzymes glycogen
phosphorylase and synthetase (13). As well as depletion of glutamic oxyaloacetic transaminase and glutamic pyruvate transaminase, both enzymes are involved in the regulation of brain energy metabolism
(14). Methylphenidate increases both sleeping and
waking cerebral blood flow, and this may result in
changes in RNA and protein metabolism (15).
Present studies do not define which of these biochemical actions is most important in the treatment
of the narcoleptic syndrome. The great majority of
research has focused on the catecholamines, and there
is far less information about other neurotransmitters,
including putative sleep peptides. Despite this uncertainty, the best-informed guess is probably that brain
noradrenaline mechanisms are central to central stimulant drug actions, and that serotonin is involved in
the pathophysiology of cataplexy.
Cerebrospinal fluid, autoradiographic, postmortem
and positron emission tomography studies in life in
the narcoleptic syndrome have focused on catecholamine systems. The results of such studies suggest there
is a reduction in the number of alpha-l adrenoceptors
as judged by reduced levels of 3H-prazosin binding in
the cerebral cortex, red nucleus and substantia nigra,
but an increase in inferior olives. Additionally, an increase in 3H-spiperone binding and llC-racloporide
uptake has been reported in caudate and putamen,
indicating a possible increase in D2 receptor affinity
(16-19). To what extent these results are consequent
upon stimulant drug treatment is uncertain. However,
the actions of CNS-stimulant drugs, including modafinil, have been linked to the adrenergic system, although amphetamine has widespread actions as stressed
above.
Sleep, Vol. 17, No.8, 1994
Despite much work, notably by Hayaishi, on the
physiological control of mammalian sleep-wake systems by prostaglandins D and E, studies of cerebrospinal fluid prostaglandin concentration in human narcoleptics have not revealed a basic defect. The ratio of
these two prostaglandins, which have opposing effects
on sleep and wakefulness, is similar in narcoleptic and
control subjects (20), and no major abnormalities have
been shown in canines with narcolepsy. A number of
intriguing observations remain unexplained. These include expression of human leucocyte antigen (HLA)
DR antigens in the brain in neurological disease (21)
as well as the observation of HLA type dependence of
cytokine production (22). The connection between cytokines, fever and sleep is being explored.
If noradrenergic mechanisms are central to the action of CNS-stimulant drugs, it will be vital to dissect
the separate peripheral and central actions of different
adrenergic agonist and antagonist drugs in subjects with
the narcoleptic syndrome. At present there are few or
no data available on the detailed effects of amphetamine on lachrymation, salivation, heart rate beat-tobeat variation, pupillary diameter and other peripheral
autonomic actions under the control of alpha-l receptor mechanisms in subjects with narcolepsy. The possibility of an autonomic defect in untreated subjects
has often been raised, but no conclusive evidence has
been presented. Qualitative and quantitative peripheral studies of the adrenergic system have proved difficult and, despite refinements of sweat testing, particularly at the Mayo Clinic, and developments in
pupillometry, exact quantification of peripheral side
effects remains difficult. This is the first essential element, however, in the exact evaluation of important
advances, such as the introduction of modafinil in the
treatment of subwakefulness or daytime sleepiness.
TREATMENT OF CATAPLEXY
In 1960 Akimoto and his colleagues found that imipramine had a dramatic effect on cataplexy, although it
did not control sleep attacks (23). Desmethylimipramine, clomipramine and, recently, other 5HT2 reuptake inhibitors as well as viloxazine have been used to
control this symptom with varying success (24,25).
Clomipramine is the present treatment of choice for
cataplexy. It will completely abolish attacks in many
subjects and reduce the frequency in others. The combination of clomipramine with central stimulant drugs
does not alter blood pressure. Clomipramine does not
affect daytime sleepiness but, in combination with amphetamines, may lead to a reduction in the amphetamine dosage required to control sleepiness. Increase
in appetite with steady weight gain, impaired ejaculation and occasional tolerance limit the usefulness of
clomipramine (26).
NARCOLEPSY TREATMENTS
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TABLE 1. Subjective retrospective report oftreatment effects in the narcoleptic syndromefor treatment with central stimulant
drug alone, anticataplectic drug alone and combined treatment
Narcoleptic subjects (n = 183; 34 not treated, 149 treated)
Control
subjects
(n = 188)
Sleep latency
(minutes)
ESS score
(score units:
0-24)
CP score
(score units:
0-600)
Insomnia
(score units:
0-100)
Total sleep
time (hours)
27.5
(27.7)
4.5
(3.3)
CNS stimulant plus
anticataplectic drug
(n = 52)
Total
group
no
treatment
(n = 183)
Off
treatment
On
treatment
Off
treatment
On
treatment
Off
treatment
On
treatment
15.6
(26)
19.5
(3.1)
14.6
(29)
20.2
(2.9)
16.6
(31)
15.1**
(5.5)
19.1
(24)
18.7
(3.3)
19.3
(23)
15.8
(5.4)
15.0
(25)
20.6
(2.0)
16.1
(20)
16.4**
(4.6)
CNS stimulant drug
(n = 78)
Anticataplectic drug
(n = 19)
28
(44)
335
(121)
310
(121)
240**
(121)
351
(92)
282*
(133)
381
(III)
288**
(137)
28
(24)
44
(29)
42
(28)
49*
(26)
53
(30)
53
(29)
41
(30)
45
(25)
7.4
(1.1)
6.9
(1.6)
7.4
(1.7)
7.1*
(1.4)
6.8
(1.8)
6.6
(1.8)
6.9
(1.8)
6.6
(1.5)
Note: No. of subjects differs among the comparisons.
* p < 0.01 **p < 0.001.
RETROSPECTIVE SURVEY OF TREATMENT
FOR THE NARCOLEPTIC SYNDROME
To study the benefits and adverse effects of central
stimulant drug and anti cataplectic drug treatment of
the narcoleptic syndrome in subjects with a history of
excessive daytime sleepiness and cataplexy, a retrospective analysis of drug effects was made in 183 subjects. Results are summarized in Table 1. The treatment period extended from 1 to 40 years. Although
retrospective studies of this nature are subject to many
pitfalls, the propensity to daytime sleepiness and cataplexy was only marginally reduced in the long term
by such treatment, although individual responses varied widely. The effect of eNS-stimulant drug treatment
on propensity to cataplexy was similar to that of clomipramine alone, in keeping with the common clinical
observation that cataplexy is dependent on alertness
level and that eNS-stimulant drugs alone may give
adequate control of this symptom. Amphetamines and
related compounds caused a minor reduction in estimated night sleep total sleep time and an increase in
sleep latency with deterioration in subjective insomnia
rating (27).
During prolonged treatment in these subjects, spontaneous reports of subjective adverse effects attributed
by the subjects to treatment with central stimulant
drugs was recorded (Table 2). Possible treatment-associated side effects were infrequent, but the survey
group excluded early symptomatic complaints during
treatment; subjects who could tolerate these effects generally reported symptoms were dose-dependent and of
mild to moderate severity. In this subject group no
clinically significant psychiatric or cardiovascular ef-
fects related to central stimulant drug treatment were
reported.
An individual subject's reported perception of the
effect of central stimulant drug treatment is shown in
Table 3. The result of central stimulant drug treatment
is different from person to person depending on the
setting, mental state and personality of the individual.
It is essential that these factors, and also the personality
of the subject, are considered in the treatment of narcolepsy.
TABLE 2. Side effects in long-term treatment with CNSstimulating and anticataplectic drugs. Values shown are percentages of subjects reporting specific side effect in response
to question: "Do you attribute any side effect to treatment for
the narcoleptic syndrome? If so, please specify"
Side effects
Appetite increase
Appetite decrease
Weight increase
Weight decrease
Indigestion
Palpitations
Pain heart region
Irritability
Sweating
Sleeplessness
Constipation
Dry mouth
Impaired sexual function
CNS
stimulant
alone
(n = 78)
2
7
10
3
2
2
8
6
6
3
6
Clomipramine
alone
(n = 19)
10
3
4
6
3
Combined
stimulant
clomipramine
(n = 52)
I
3
9
2
2
I
2
3
2
5
Side effects also described on CNS-stimulant drugs include headache, hand tremor, itchy nose, change in focusing and skinrash;
effects on clomipramine include increased thirst, hot flushes and
difficulty in focusing.
Sleep, Vol. 17, No.8, 1994
D. PARKES
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TABLE 3.
No treatment
Less confident
Easy-going
Passive
Politically central
Negative
Indecisive
Depressed
Frustrated
Considerate
Quiet
Asleep
Superficial
Uncompetitive
Drive as knight of road
"The human race is
a failed biological
experiment and the
sooner I get out
of it, the better"
Personality changes
Amphetamine
Confident
Ambitious
Aggressive
Politically right
Positive
Decisive
High
Irritable
Intolerant
Talkative
Awake
Philosophical
Competitive
Drive as bat out of hell
"When I retire I am
looking forward to
studying other
branches of
science and
appreciating what
a wonderful world
we live in"
ASSESSMENT OF CNS-STIMULANT DRUG
ACTION
A test battery for evaluation of eNS-stimulant drugs
should include assessment of sleep and wakefulness,
tests of psychomotor function, and physiological studies. There is some correlation between the results of
different objective and subjective rating scales of sleepiness and wakefulness, including the Multiple Sleep
Latency Test and the Epworth Sleepiness Scale (r =
0.5) (28). New techniques including ambulatory home
monitoring and prolonged motor activity recording are
likely to prove useful in addition to established methods of physiological measurement, including evoked
potential studies.
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