The Effect of Melatonin on Sleep and Ventilatory Control in Obstructive Sleep Apnea

OSA is a common sleep disorder characterized by repeated collapse of the upper airway during
sleep causing bouts of hypercapnia and hypoxia, typically followed by arousal,
hyperventilation and a subsequent apnea. The resultant swings in blood gases and fragmented
sleep have been associated with major neurocognitive and cardiovascular sequelae. Although
the commonly cited statistics are that 4% of middle aged US men and 2% of US women have
symptomatic OSA, these figures may be underestimates. However despite its prevalence and well
recognized consequences, treatment of OSA remains unacceptable due to poor adherence to and
variable efficacy of existing therapies, leading many to advocate for further research into
underlying mechanisms to identify new therapeutic targets.

During sleep ventilatory control is dominated by the level of CO2 and O2 in the blood.
Arterial CO2 has the greatest influence, with increasing CO2 stimulating an increase in
ventilatory drive and vice versa. Ventilatory drive not only determines the level of activity
of the thoracic pump muscles, but also the upper airway dilator muscles. Consequently the
upper airway is susceptible to collapse when CO2, and therefore neural drive to the upper
airway muscles, is low. Loop gain is an engineering method used to measure the stability of
the negative feedback chemoreflex control system, calculated as the ratio of the ventilatory
response to the disturbance which elicited the response. Higher LG equals less stable
control, as a disproportionately large ventilatory response will result in a greater degree
of hypocapnia and subsequent reduction in ventilatory drive. Thus high LG contributes to
propagating apneas. Supporting this is evidence that OSA patients have higher LG than non-OSA
and LG correlates with the apnea hypopnea index (AHI). Additionally, treatments such as
supplemental oxygen and acetazolamide which reduce LG significantly reduce AHI. However these
treatments essentially counteract high LG, rather than treating the cause of high LG.

LG includes "plant" (respiratory apparatus) and "controller" (chemoreflex) gain components.
OSA patients exhibit abnormalities in chemoreflex control which increase the sensitivity to
blood gases and thus increase controller and LG. These abnormalities normalize with
continuous positive airway pressure (CPAP) treatment, indicating they are induced by OSA
itself. Intermittent hypoxia, as occurs during repeated apneas, induces lasting changes in
the neural control of breathing which induces the same abnormalities and increased controller
gain as is seen in OSA. Therefore it is thought that the IH experienced in OSA contributes to
worsening of OSA by inducing changes to the neural control of breathing which increase
controller and LG. The cellular changes induced by IH are dependent on the formation of
reactive oxygen species (ROS) and both animal and human studies have shown antioxidant
treatment prior to IH experimentally blocks these neural changes. Thus antioxidants may be a
suitable alternative treatment in OSA, by treating the actual cause of high LG. Indeed there
have been two published studies showing vitamins and N-acetyl-cysteine reduced AHI in OSA
patients.

Melatonin is a hormone produced in the pineal gland of the brain which is most well-known for
its critical role in regulating sleep and the circadian clock. However it is also a potent
antioxidant which not only acts as a direct free radical scavenger, but it also stimulates
synthesis of other antioxidants. Unlike most antioxidants it also crosses all cell membranes
easily, allowing it to cross the blood brain barrier and also enter intracellular
compartments such as mitochondria where ROS production is highest. Owing to the fact that
most antioxidants become reactive species themselves once they have been oxidized, many
antioxidants become toxic and cause disease with prolonged high doses. For this reason most
antioxidants are unsuitable as a long-term treatment option in OSA. However melatonin does
not have this problem because as it is oxidized it converts into multiple different
metabolites all of which have various antioxidant functions. This adds to its efficacy as it
neutralizes an extremely wide range of radical species. Consequently melatonin is non-toxic
at even extremely high doses and extended use. Indeed melatonin has been found effective in
treating multiple diseases in humans associated with ROS and oxidative stress, such as
diabetes, chronic obstructive pulmonary disease and multiple sclerosis. Of particular
interest is that OSA is intimately associated with metabolic disorder, with the two
conditions having compounding negative consequences on cardiovascular disease, and melatonin
has been shown to improve hypertension, oxidative stress and blood lipid profiles in
metabolic disorder. For these reasons, we propose that melatonin may be a safe long term
treatment option in OSA patients that are unable to tolerate CPAP, which may block the neural
changes induced by IH, thereby reducing controller and LG and therefore reducing AHI.
Additionally, melatonin treatment may have added benefits associated with preventing ROS
induced morbidities of both OSA and metabolic disorder.

Melatonin production is inhibited by light and normally peaks around 2am. However OSA exhibit
much lower levels of melatonin with a lower peak at around 6am. OSA is associated with
chronic systemic oxidative stress and endogenous levels of melatonin play a critical role in
regulation of total antioxidant status. Therefore this abnormal pattern of melatonin
production in OSA likely contributes to exacerbation of oxidative stress and also to sleep
and cognitive deficits in OSA, as this would delay the circadian sleep phase, making it
difficult for patients to fall asleep and adding to mental fatigue during the morning.
Therefore, in addition to its antioxidant activity, melatonin treatment in OSA may have
additional benefits via normalizing sleep phase. Thus the primary focus of this study will be
to investigate the effects of melatonin treatment in OSA on waking chemoreflex control and
ventilatory stability as assessed via LG and AHI during sleep, but we also intend to assess
if there are additional sleep and cardiovascular benefits of melatonin treatment, by
assessing melatonin blood serum phase resetting effects, sleep quality, blood pressure and
electrocardiogram (ECG).

Inclusion Criteria:

- Male

- Ages 18-70 years

- No other sleep disorders

- Severe OSA (≥30 apnea hypopnea index)

Exclusion Criteria:

- Females

- Smokers (quit ≥ 1 year ago acceptable)

- Abnormal lung function (FEV1 and FVC < 80% predicted)

- Any known cardiac (apart from treated hypertension with acceptable drugs, see below),
pulmonary (including asthma), renal, neurologic (including epilepsy), neuromuscular,
hepatic disease, or patients with diabetes.

- History of driving or other accidents due to sleepiness or an ESS > 18.

- Prior or current use of melatonin.

- Use of serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors,
ACE inhibitors or any drugs which interfere with the renin-Angiotensin system,
Losartan (or other Angiotensin II type 1 receptor antagonists), non-specific calcium
channel blockers (L channel specific are acceptable), anti-inflammatories, vitamins or
any antioxidants.

- Use of any medications that may affect sleep or breathing.

- A psychiatric disorder, other than mild depression; e.g. schizophrenia, bipolar
disorder, major depression, panic or anxiety disorders.

- Substantial alcohol (>3oz/day) or use of illicit drugs.

- More than 10 cups of beverages with caffeine (coffee, tea, soda/pop) per day.