Note: Descriptions are shown in the official language in which they were submitted.
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TITLE OF INVENTION
TREATMENT OF OBSTRUCTIVE SLEEP APNEA
FIELD OF INVENTION
[0001] The present invention relates to the treatment of sleep apnea and
snoring.
BACKGROUND OF THE INVENTION
[0002] The passive human upper airway (UA) is a collapsible tube with a
relatively high compliance; its dimensions change substantially as a function
of small
changes in infra-luminal pressure. At atmospheric luminal pressure, UA cross-
sectional
area varies considerably among different subjects with the range extending
from zero
(complete closure) to >50% of maximum area. Subjects in whom the passive UA is
closed, or nearly closed, at near atmospheric luminal pressure (susceptible
subjects)
clearly require an UA dilating force to maintain adequate inspiratory flow.
[0003] The pharynx is equipped with powerful muscles that can, when activated,
counteract its tendency to collapse even under extreme negative luminal
pressures. These
are called the pharyngeal dilators. The most powerful of these is the tongue
muscle, the
genioglossus. During wakefulness UA dilator muscles (dilators) provide the
necessary
force to permit an adequate flow through the pharynx in all subjects
regardless of how
collapsible their passive UA is. This dilator activity is substantially lost
at sleep onset
indicating that during sleep dilators are minimally active at resting levels
of respiratory
drive. During sleep, however, ventilatory demand is low and the inspiratory
flow
required to maintain normal blood gas tensions is very modest (0.2 to 0.5
1/sec, personal
observations). Subjects in whom UA can permit this level of flow without
dilator activity
can withstand the sleep-related inhibition of dilators. However, subjects in
whom passive
UA cannot permit the required flow must recruit dilators through reflex (i.e.
consciousness independent) mechanisms if they are to remain asleep. Dilators
can be
recruited reflexly via changes in blood gas tensions and in afferent activity
of
mechanoreceptors that respond to negative airway pressure. However, the same
chemical and mechanoreceptor stimuli result in arousal from sleep. Failure of
reflex
mechanisms to adequately activate the dilators will result in deterioration of
blood gas
tensions and progressive increase in inspiratory effort finally leading to
arousal. The
arousal-mediated dilator recruitment subsides when sleep resumes and the cycle
repeats.
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This results in recurrent obstructions with oxygen desaturation and arousal
from sleep, a
syndrome referred to as obstructive sleep apnea (OSA). The recurrent
desaturation and
sleep fragmentation have been shown to result in a decrease in cognitive
function and
quality of life, increased risk of occupational and recreational accidents and
an increased
risk of high blood pressure with its attendant cardiovascular complications.
It is
estimated that 4 to 8 % of adult males and 3 to 5% of adult females suffer
from clinically
significant OSA.
[0004] Snoring is another manifestation of the tendency of the human pharynx
to collapse. Here, the pharynx also collapses during sleep but the degree of
collapse is
not so extreme as to seriously impair the exchange of oxygen (02) and carbon
dioxide
(COZ): The patient continues to sleep but the vibrations caused by the passage
of air
through the narrowed floppy tube result in the noise of snoring. Snoring is
extremely
prevalent affecting approximately half of adult males and a quarter of adult
females.
Apart from its social complications, there is increasing evidence that it also
may result in
sleep fragmentation (the high upper airway resistance syndrome) and may also
predispose to high blood pressure.
[0005] Role of arousal from sleep in the pathogenesis of obstructive sleep
apnea:
[0006] When recurrent obstructive events occur during sleep, brain activity
typically shows an arousal pattern at about the time the upper airway opens
again. This
association between arousal and upper airway opening has led to a long
enduring dogma,
namely that these patients are not able to compensate for the abnormal
collapsibility of
their pharynx unless they wake up. It is thus widely believed that arousal
from sleep is a
life saving mechanism in these patients and, by extension, that any effort to
suppress
arousals is both inappropriate and potentially dangerous. Sedatives and
hypnotics are
currently contraindicated in patients with obstructive sleep apnea.
[0007] I have challenged the dogma that patients need to arouse from sleep to
open their airway in an extensive study published recently in two parts
(Younes M.
Contributions of upper airway mechanics and control mechanisms to severity of
obstructive apnea. Amer J Respir Crit Care Med.168:645-658, 2003. Younes M.
Role of
arousals in the pathogenesis of obstructive sleep apnea. Amer J Respir Crit
Care Med.
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3
169:623-633, 2004). In the first of these (Amer J Respir Crit Care Med.168:645-
658,
2003), I documented in detail what I, and many others, have noted for many
years,
namely that patients with OSA often develop lengthy periods of stable
breathing during
sleep. I did raise the following question: How can one conclude that arousal
is necessary
for compensation in a patient who shows lengthy periods of stable breathing,
without
arousal, at certain times during the night? There were three possible
explanations: 1)
Passive collapsibility of the pharynx varies from time to time, with periods
of stable
breathing occurring when collapsibility is less severe. 2) Transition into
deep sleep (so-
called delta sleep) was responsible. It is common knowledge that OSA patients
usually
develop stable breathing if they enter delta sleep and some investigators had
shown in
normal subjects that pharyngeal dilator activity tends to be higher in delta
sleep. The
prevailing view was, therefore, that delta sleep is inherently associated with
higher
dilator activity that counteracts the anatomic defect in this sleep state. 3)
Patients who
develop periods of stable breathing are capable of mounting effective
compensation
without arousal.
[0008] In the aforementioned study (Amer J Respir Crit Care Med.168:645-658,
2003), I explored the first two possibilities. With respect to the first
possibility, I found
that, although passive collapsibility of the pharynx varies somewhat from time
to time,
the extent of this variability can in no way explain periods of stable
breathing in most
patients. Furthermore, I found that delta sleep does not inherently lead to
increased
pharyngeal stability. Thus, I concluded that when a patient displays a period
of stable
breathing without arousals at some point during the night the patient has
demonstrated
that he/she can mount effective compensation without arousal via innate reflex
mechanisms.
[0009] While this conclusion clearly challenged the dogma that arousal from
sleep is necessary for compensation, it raised the interesting following
question: If a
patient can compensate for the abnormal anatomy at some points) during the
night, why
does he/she develop recurrent obstructions with arousal during other parts of
the night?
[0010] In the second component of the study (Amer J Respir Crit Care Med.
169:623-633, 2004), I suggested that premature occurrence of arousal preempts
an
orderly response that would otherwise be mounted by reflex mechanisms as a
result of
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some increase in chemical drive to breathe (increased COz and/or decreased OZ
level in
the blood). According to this hypothesis, the premature occurrence of arousal
sets the
stage for recurrence of the obstruction by causing a ventilatory overshoot
(overcompensation) that reduces chemical drive to breathe promoting re-
obstruction
upon resumption of sleep. Thus, the proposal was that arousals are not only
unnecessary,
but that they also are a major contributor to the severity of obstructive
apnea. I further
suggested that stable breathing occurs during delta sleep because of the high
arousal
threshold in this state, which permits chemical drive to increase to a higher
level,
increasing the possibility of adequately activating the dilators without
arousal. A large
body of evidence was presented in this study (Amer J Respir Crit Care Med.
169:623-
633, 2004) in support of these hypotheses. Thus I found that:
[0011] 1) The temporal relation between arousal from sleep and upper airway
opening at the end of the obstructive episode does not support the contention
that arousal
is the mechanism by which upper airway opens. Thus, in 17% of cases, upper
airway
opening occurred without arousal. In a further 22% of cases, arousal occurred
after the
airway had opened (i.e. opening occurred prior to arousal). Furthermore, in an
additional
30% of cases the occurrence of arousal did not result in opening immediately.
Rather
upper airway opening occurred later. This type of temporal relation strongly
favoured an
incidental association between arousal and opening rather than one in which
arousal
causes the opening. Because both arousal and arousal-independent reflex
activation of
dilators are triggered by the same mechanisms, the threshold for both may be
reached at
the approximately the same time.
[0012] 2) The time of upper airway opening was the same whether arousal
occurred before or after upper airway opening or did not occur at all.
[0013] 3) Where upper airway opening occurred before or without arousal, the
increase in air flow was more than adequate to restore a normal ventilation.
Thus,
arousal is not required to insure that the response is adequate.
(0014] 4) When arousal occurred at the time of opening or soon after, the
increase in air flow was markedly increased and was well beyond what is
required. This
CA 02490484 2004-12-17
ventilatory overshoot is expected to promote recurrence of the obstruction as
pointed out
above.
[0015] 5) The likelihood of occurrence of a second obstruction was
significantly
increased when arousal occurred at the end of the first induced obstruction.
This
confirms the adverse effect of arousal.
SUMMARY OF INVENTION
[0016] I have now found that, in many patients, arousal from sleep is not only
unnecessary but promotes recurrence of obstruction and an increased severity.
In
accordance with the present invention, delaying arousals, using appropriate
sedatives/hypnotics, allows the reflex mechanisms to compensate without
arousal and
mitigate the severity of the disorder. There are two important caveats,
however:
[0017] 1) It may be argued that, by delaying the arousal, blood gas tensions
may
have to deteriorate to unacceptable levels before reflex mechanisms succeeded
in
restoring airway patency. This issue was addressed in the same study (Amer J
Respir
Crit Care Med. 169:623-633, 2004). Thus, in this study patients were placed on
Continuous Positive Airway Pressure (CPAP). Obstructive events were induced by
suddenly lowering CPAP level. While on CPAP, chemical drive is perfectly
normal
because upper airway resistance is normal. By determining how long it takes
(after
induction of obstruction) to open the airway when arousal does not occur, it
is possible
to estimate how much COZ and 02 in the blood need to deteriorate, relative to
their
desirable values (i.e. on CPAP), to effect opening without arousal. I found
that, while in
a minority of patients large changes in chemical drive are required, in the
majority the
changes in blood gas tensions required to open the airway are very modest. I
estimated
that in the average patient an increase in PCOZ of 2 mmHg and a decrease in OZ
saturation of 3% would suffice. These changes are clinically very acceptable.
Because
the latency to opening without arousal and the latency to arousal when arousal
occurred
were, on average, similar the same findings indicated that in most patients
arousal
threshold is quite low; arousal occurs when only minor increases in chemical
drive
develop. These findings indicated that, in most patients, the arousal
threshold can be
safely increased.
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6
[0018] 2) By necessity, sedatives/hypnotics must be administered systemically.
As such, they reach all parts of the brain and not only the areas responsible
for arousal.
Because sedatives/hypnotics are basically depressants to nervous tissue, the
possibility
exits that a sedative may suppress reflex activation of pharyngeal dilators at
the same
time it suppresses arousal. Such an occurrence would defeat the purpose of
delaying
arousal; namely to permit reflex mechanisms to activate the dilators. If
suppression of
reflex activation and suppression of arousal are of equal magnitude, nothing
is gained
and the net effect would simply be a delay in upper airway opening with
worsening of
the blood gas tensions. Accordingly, for a sedative/hypnotic to be effective
in therapy of
OSA it should suppress arousal without suppressing, or without suppressing as
much,
the reflex activation of dilators. In this fashion reflex activation of
dilators can progress
to higher level while sleep continues.
[0019] While the effect of a number of sedative/hypnotic drugs on reflex
activation of dilators has been studied, my recent findings indicate that the
important
variable to be considered is not whether a particular drug enhances or
depresses reflex
activation. Rather, the important question is the relative effect of the drug
on arousal and
reflex activation mechanisms. A drug that depresses arousal may be suitable
even if it
depressed reflex activation provided the former effect is greater. On the
other hand, a
drug that enhances reflex activation may be unsuitable if it concurrently
accelerates
arousal.
[0020] In sumary, my recent findings lead to two novel conclusions:
[0021] 1) Selected patients with obstructive sleep apnea can be treated by
sedativesllrypnotics. This notion is not only novel, it is almost heretical;
these drugs are
currently contraindicated in OSA patients. Suitable patients are those who a)
develop
arousals frequently at or near the end of obstructive events, b) demonstrate
an ability to
compensate in the absence of arousals by, for example, developing periods of
stable
breathing during sleep or where some of the obstructive events are relieved
prior to the
appearance of arousal and c) have a low arousal threshold as demonstrated by
brief
duration of obstructive events and only modest changes in 02 saturation prior
to arousal.
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[0022] 2) The potential effectiveness of a drug in treating OSA is measured
not
by its independent effect on reflex activation of airway dilators but, rather,
by measuring
the balance of its effects on arousability and reflex responses of dilators.
This is novel in
that, so far, research into drug treatment of OSA has focused on finding drugs
that
potentiate the activity of dilators without regard to the drugs' effects on
arousability.
[0023] Accordingly, in one aspect of the present invention, there is provided
a
method for treating obstructive sleep apnea comprising the use of sedative or
hypnotic
drugs that have been shown to increase arousal threshold (the level of
respiratory stimuli
required to cause arousal from sleep) without depressing, or without
depressing as much,
the reflex activation of pharyngeal dilator muscles.
BRIEF DESCRIPTION OF DRAWINGS
[0024] Figure lA is a graphical representation of the response of genioglossus
activity (EMG~ to increasing PC02 with and without a sedative drug;
[0025] Figure 1B is a graphical representation of the response of genioglossus
activity (EMG~ to increasing PC02 with and without a drug that enhances reflex
response of the dilator but concurrently reduces arousal threshold;
[0026] Figure 2 shows separately the electroencephalogram (EEG), neck muscle
electrical activity (EMG"~k), genioglossus activity (EMGg~, diaphragm activity
(EMGa;a) and chamber C02 concentration in experimental animals for experiments
conducted herein and described below;
[0027] Figure 3 shows the peak genioglossus activity in rats in experiments
described below using pentobarbital;
[0028] Figure 4 shows tracings of baseline activity as determined in the
experiments described below;
[0029] Figure 5 shows the peak genioglossus activity in rats in experiments
described below using Phenobarbital; and
[0030] Figure 6 shows the peak genioglossus activity in rats in experiments
described below using diphenhydramine.
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g
GENERAL DESCRIPTION OF INVENTION
[0031] The balance between the effect of a drug on respiratory arousal
threshold
(the level of respiratory stimuli required to cause arousal from sleep) and on
reflex
response of dilators to respiratory stimuli can be assessed in several ways.
One suitable
approach is the one depicted in Figures lA and 1B. A suitable respiratory
stimulant is
applied in increasing amount during sleep. The stimulant may be an increasing
level of
inspired C02 or a decreasing level of inspired 02 concentration. Stimulus
intensity is
progressively increased until arousal occurs, as judged by the
electroencephalogram. The
activity of a suitable dilator muscle (e.g. the genioglossus) is concurrently
recorded and
the activity level immediately preceding arousal is recorded. This activity
(EMG~max;
see Figures lA and 1B) represents the maximum amount of activation that can be
attained during sleep by respiratory stimuli. This procedure is performed with
and
without the administration of a test drug. In Figure 1A, the test drug is a
sedative drug
and, in Figure 1B, the test drug is one that enhances reflex response but
concurrently
reduces arousal threshold. An increase in dilator activity immediately
preceding arousal
indicates a favourable balance between effects on arousal and on reflex
activation of
dilators. Such studies can be made on humans but preliminary testing in
experimental
animals would be prudent.
[0032] The approach just outlined (Figures lA and 1B) was implemented in a
freely behaving intact rat. The animal was instrumented with chronic
electrodes to
measure brain activity as well as activities in the genioglossus, neck muscles
and
diaphragm. After recovery, while the rat was naturally sleeping, the C02
concentration
in the chamber housing the rat was increased in a ramp-like fashion until
arousal was
evident in the electroencephalogram. Figure 2 shows an example of the
responses
obtained. This figure shows sequentially the electroencephalogram (EEG), neck
muscle
electrical activity (EMGn~k), genioglossus activity (EMG~, diaphragm activity
(EMG~) and chamber C02 concentration. As chamber CO2, increases there was an
increase in activities of both the diaphragm and genioglossus. Arousal
occurred at the
arrow as evidenced by the changes in the EEG and EMGn~k. The maximum
genioglossus activity reached just before arousal was noted (EMGggmax). Such
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9
observations were made when the animals received a drug before the monitoring
or
received a placebo injection.
[0033] So far three drugs have been tested in the manner described above.
These
are pentobarbital and phenobarbital, both of the barbiturate family, and
diphenhydramine, a sedating antihistamine. All three drugs gave similar
results. Figure
3, which is representative of the two other _ drugs as well, shows the effect
of
pentobarbital in mildly sedating doses in the rat (5 and 10 mg/kg). Figures 5
and 6 show
the results with phenobarbital and diphenhydramine respectively. As can be
seen,
EMG~max increased in a dose-dependent fashion with drug administration, a
favourable response.
[0034] Although the current findings indicate that three specific drugs meet
the
requirements for potential effectiveness in OSA, a person skilled in the art
would
recognize other members of the same families of drugs (barbiturates,
antihistamines), or
members of other drug families would have similar properties (favourable
balance
between effects on arousal and reflex activation of dilators). A person
skilled in the art
would also recognize that modifications to the drugs may be implemented to
enhance
their desired action and/or to reduce side effects. Such modifications fall
within the
scope of the invention.
[0035] An interesting finding from this study was that not only did
genioglossus
activity just prior to arousal increase, but this muscle's activity was also
higher during
sleep while animals breathed room air, prior to delivering the C02 ramp. An
example of
baseline activity (prior to C02 stimulation) in one animal following placebo,
Smg/kg and
l0mg/kg pentobarbital is shown in Figure 4. This finding which was common to
all three
drugs tested, indicating that drugs in these two classes (barbiturates,
antihistamines) are
effective in treating snoring and not only obstructive sleep apnea. Clearly,
an increase in
dilator activity without an increase in chemical drive results in a more
patent airway
during sleep, which should mitigate snoring.
[0036] Accordingly, in a further aspect of the present invention, there is
provided a method for treating snoring comprising the use of a sedative or
hypnotic drug
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that, in addition to sedation, results in an increase in pharyngeal dilator
muscle activity
during room air breathing.
SUMMARY OF DISCLOSURE
[0037] In summary of this disclosure, the present invention provides methods
of
treating obstructive sleep apnea and snoring by the administration of certain
drugs.
Modifications are possible within the scope of this invention.
