Sublingual melatonin is used for several reasons, as
follows:
- to improve the quality of sleep in those with an
age-related decline in melatonin;(1); - to reestablish a normal
circadian sleep rhythm in those suffering from disturbed sleep patterns
relating to jet lag, shift-work, and in delayed sleep phase syndrome
(DSPS);(1) - in circadian rhythm disorders in the blind, in sleep
disturbances relating to depression, Alzheimer's Disease, and relating to
benzodiazepine and nicotine withdrawal.(1)
Melatonin is a neuro-hormone produced in the pineal
gland located in the center of the brain and is associated with inducing a
sedative effect. During conditions of dim light, special retinal
photoreceptors spontaneously release norepinephrine, activating neural
pathways that run to the pineal gland, through the suprachiasmatic nuclei
(SCN) in the hypothalamus, resulting in pineal synthesis of melatonin, and
its passive diffusive secretion into the bloodstream.(23) However, light
of sufficient intensity reaching the retinal tissues hyperpolarizes these
special photoreceptors, preventing pineal melatonin synthesis.(23) The
photoreceptors mediating this process are different from the rod and cone
photoreceptors that produce colour and light perception.(24) Some blind
people who evidence no pupillary light reflexes or visual perception still
have light-induced suppression of melatonin synthesis.(23,25)
Most
aspects of physiology and behavior are time-integrated by sensitive
biological clock mechanisms centered in the suprachiasmatic nuclei (SCN)
of the hypothalamus, which acts on neural and endocrine pathways to
regulate a variety of different circadian rhythms so that internal states
vary predictably over a 24-hour cycle.(26) (The word circadian is made up
of two Latin roots; circa = about, and diem = day). The suprachiasmatic
nuclei are comprised of approximately 10,000 neurons and if these nuclei
are destroyed, the ability to express overt circadian rhythms is
destroyed.(27,28) The circadian mechanisms associated with the SCN are
autonomous, and individual neurons from the SCN demonstrate clock
regulation that is so powerful that the rhythms of a single neuron can be
recorded continuously for several weeks with only the slightest deviation
from a 24 hour cycle.(26,29) In terms of hypothalamic SCN sleep
regulation, most people achieve a satisfactory sleep-wake circadian rhythm
over each 24-hour day.
However, due to age-related decline in
endogenous melatonin synthesis, jet travel over time zones, or shift work,
a discrepancy can arise between the established biological "sense" of
time, and the actual local time. Such desynchronization causes the
biological clock to impose a sleep-wake rhythm that is out of synch with
local time, resulting in sleep deficits and numerous minor physiological
and psychological complaints.(30) A condition of chronic desynchronization
that typically requires clinical management is delayed sleep-phase
syndrome (DSPS). In this condition, the person is unable to attain sleep
in the common nocturnal time-rame because the SCN clock delays the sleep
phase of the sleep-wake rhythm until 2 AM to 3 AM. Clinicians observe that
the sleep duration [say 7-8 hours] and quality [required sleep stages are
achieved] in DSPS are considered to be normal. Thus, the point of
awakening is correspondingly delayed [shifted forward by approximately 4
hours] until around 11 AM. Patients with DSPS usually find it difficult to
function well if they are required to rise in the early hours of the
morning.
Melatonin is thought to act in at least two ways in
relation to maintaining a restful sleep pattern. Firstly, melatonin is
known to produce a sedative effect in animals and humans. This sedative
effect is thought to stem from enhanced gamma aminobenzoic acid (GABA)
receptor binding, producing an inhibitory action on the reticular
activating system, which mediates wakefulness.(31-33) Melatonin is
necessary to turn-down imposed wakefulness, but such sedation is not
sufficient for the establishment of sleep. Sleep like wakefulness is
imposed, but by another set of neurological properties mediated by the SCN
circadian clock governing the sleep-wake rhythm. A rising melatonin plasma
level commensurate with room darkness facilitates the onset of sedation,
and this presumably matches a mounting SCN clock commitment to impose
sleep. The second way melatonin acts to ensure a restful sleep pattern
pertains to SCN clock synchronization. As the seasonal dark-light pattern
varies throughout the year, the SCN clock must adapt to the way sleep
requirements change in real time. Endogenous melatonin is thought to act
as an entrainment agent to accomplish this adaptation.(3,34,35)
Entrainment is the complex process of re-synchronizing the
biological clock with real time. Critical incremental changes in dim light
timing, serve as entrainment information for re-setting the clock. The SCN
neurons are able to decipher the trending darkness pattern, mirrored in
the corresponding dark-mediated melatonin plasma levels. SCN neurons
continuously perceive shifts in melatonin as a function of the dark-light
cycle, adapting the clock imposed sleep-wake rhythm throughout the year
accordingly.
Desynchronization is a condition of failed adaptation and is
represented in the concept of a phase-shift. In other words, the
sleep-phase of the sleep-wake circadian rhythm has been shifted to another
time that is out of synch with real time. Usually the sleep-phase is
pushed or shifted forward, meaning sleep is postponed or delayed. The
overt use of exogenous melatonin can induce entrainment to correct for
desynchronization.(17,34-36) Such entrainment may provide completely
satisfactory management of jet-lag, shift work, or more challenging sleep
aberrations as seen in DSPS, depression, or Alzheimer's disease. In more
challenging categories, physician or pharmacist guidance may be more
appropriate than self-medication alone.
Melatonin showed that it can entrain the free-running circadian
rhythms of blind people and it has been used to treat the symptoms of
circadian maladaptation associated with delayed sleep-phase
syndrome.(17,35,36) Dagan et. al. described the results of a 6-week
clinical trial using 5 mg of melatonin for treating 61 DSPS patients.(17)
The mean duration of sleep before treatment was 8 hours and 21 minutes,
demonstrating that delayed sleep-phase syndrome is not about the lack of
sleep but rather about the timing of sleep onset. The mean pretreatment
sleep onset and waking times were respectively 3:09 AM and 11:31 AM.
Melatonin was administered at 10:00 PM, five hours before the average
pretreatment sleep onset time. A survey of the patients was conducted
between 12 and 18 months after the 6-week melatonin treatment ended. The
response rate was 59 of the 61 original patients. Of this 59 patients, 54
(91.5%) reported relapse to their pretreatment sleeping patterns within
one year after stopping the melatonin treatment.
However, 17 (28.8%) respondents reported that their relapse occurred
within one week of discontinuing melatonin. Dagan and his fellow
investigators stated that their findings confirm earlier evidence that
melatonin was effective in changing the sleep-wake patterns of DSPS
patients. However, the finding that the new sleep patterns were not
permanently retained suggests that exogenous melatonin does not cause a
fundamental and permanent change in sleep regulation, thus DSPS patients
may need to use melatonin on a regular basis.(17)
Lewy and fellow
investigators generated a phase-response curve (PRC) to melatonin that
demonstrated circadian phase advances when melatonin is administrated in
the late afternoon and evening, and circadian phase delays when it is
administrated in the later hours of sleep and the morning.(36) Their
observations offer some basis on how to empirically time a melatonin dose
in DSPS, but also in better managing sleep problems associated with shift
work and on going episodes of jet lag.
The impact of melatonin use on driving
performance remains a central concern. One published investigation was
conducted by the University of Zurich Travel Clinic, in the Institute of
Social and Preventative Medicine.(19) Researchers investigated the effects
of melatonin on driving performance parameters in 20 men and women aged
21-57 years. On each testing day, subjects received 5 mg or placebo, taken
at 4:30 PM. One hour later, a test series was performed consisting of a
medical examination, body sway measurement, and a standardized driving
computer test battery to assess attention, reaction time, power of
concentration, and sensomotor coordination. Sleepiness of the subjects was
measured on three occasions during each test session using the Stanford
Sleepiness Scale questionnaire.
Results:
In
assessing the results, the investigators reported that only one of the 16
main variables of the driving computer test battery (selective attention
tested by signal-detection) was significantly affected by melatonin.
However, even those values were still within normal range. Subjective
sleepiness was increased by melatonin, although this affect became
significant only after the prolonged concentration task. Neither the
medical examination nor the body sway test demonstrated signs of drug
influence.
Conclusion:
The researchers concluded
that overall the results of the computer test battery demonstrated no
objective adverse impact of melatonin on driving performance. However, due
to the increased subjective sleepiness after administration of melatonin,
caution should be exercised when driving under the influence of melatonin.
Melatonin may cause epileptic seizure in the susceptible. Dopamine
is considered an endogenous down-regulator of seizure activity and
melatonin is capable of causing a decrease in dopamine output within areas
of the brain thought to participate in the control of epileptic
seizure.(20) Melatonin is an effective treatment for biological rhythm
related insomnia, but it is not necessarily an effective treatment for
psycho physiologically related
insomnia.(17)
Contraindications
Melatonin is not to
be used by people with seizure disorders, during pregnancy or the
breast-feeding period, or together with sedatives, or immuno-suppressive
drugs. Do not operate a motor vehicle or machinery for at least 3 hours
after taking any kind of melatonin-based products.
Melatonin may interact adversely when used in
combination with medications for improving sleep. One study found a
combination of melatonin and zolpidem had reports of nausea, vomiting,
amnesia, and somnambulia (sleep-walking) to the point of
incapacitation.(15) Melatonin may potentiate the anticoagulant and
antiplatelet actions of medications or herbs used to modulate blood
clotting.(1) Melatonin may have the ability in diabetic patients to impair
glucose utilization and increase insulin resistance.(1)
Because
contraceptive drugs can elevate endogenous melatonin, concomitant use of
melatonin could be associated with melatonin adverse effects.(1)
Flumazenil can inhibit the effect of melatonin.(1) Fluvoxamine
significantly inhibits the elimination of melatonin.(21) In one study, a
17-fold higher (P<.05) area under the concentration-time curve and a
12-fold higher (P<.01) serum peak concentration of melatonin was
found.(21)
Melatonin can decrease the effectiveness of Nifedipine
GITS monotherapy in the modulation of blood pressure.(22) Lusardi et. al.
found in a placebo-controlled, double-blind, and cross-over study with 47
well controlled mild to moderate hypertensive patients on 30-60 mg daily
of Nifedipine GITS, that when 5 mg of melatonin was added nightly over 4
weeks, there was a daily average increase in systolic blood pressure of
6.5 mmHg and in diastolic blood pressure of 4.9 mmHg, with an average
increase in heart rate of 3.9 beats per minute. The DBP and HR were
particularly evident during the morning and the afternoon hours.
The administration of melatonin is usually well
tolerated, but it can be associated with mild adverse effects.
Dollins et. al. using higher than normal doses of 10, 20, 40 or 80 mg in
20 healthy males found that all doses compared to placebo significantly
decreased oral temperature, the number of correct responses in auditory
vigilance, response latency in reaction time, and self reported vigor.(12)
Other reports include headache, transient depressive symptoms, fatigue,
confusion, drowsiness, mild tremor, mild anxiety, dizziness, and abdominal
cramps.(1,12-17)
Dagan et. al. found in a six-week treatment
course with 61 DSPS patients, using 5 mg at 10 pm, that 57.4 percent
reported no adverse effects, 34.4 percent reported slight daytime fatigue,
and 8.2 percent reported headaches and nausea.(17)
Use 1 tablet sublingually at bedtime, or as directed by
a physician. Use up to 3 tablets daily. The sublingual route compared
to the oral route is expected to provide a more consistent bioavailability
of melatonin.
Early pharmacokinetic studies indicated that 30 to 60
percent of an oral dose is metabolized during the first pass in the
liver.(2) Furthermore, absorption of melatonin via the gut is thought to
be highly variable.(3) One investigation using 80 mg in gelatin capsule
form administered to 5 young males demonstrated a 25-fold variation in the
concentrationtime curve (350 to10,000 times higher than the usual
nocturnal peak).(4)
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