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Sleep Stage Eye Movements Motor Movements

HR, BP, Respirations

Cerebral Activity

Stage 1 Slow, rolling movements

Moderate activity

Slows Decreases

Stage 2 Slow, rolling movements

Moderate activity

Slows Decreases

Stages 3 & 4 (i.e., deep sleep)

Slow, rolling movements

Moderate activity

Slows Decreases

REM Sleep Clusters of rapid eye movements

Suppressed w loss of muscle

tone

Increases, variable

Increases

Chart adapted from: Porth CM, Sleep and Sleep Disorders. In: Pathophysiology: Concepts of Altered Health States. 8th edition. Porth CM, Matfin G, eds.

Philadelphia: Wolters Kluwer Health; 2009.

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SCN

Forebrain/ThalamusAttention, memory,

emotion, psychomotor performance,

sensorimotor integration

Hypothalamus

Anterior pituitary Hormone levels

HypothalamusBody temperature, metabolism, ANS

function, sleep-wake cycles

Brain stem reticular formation

ANS function, sleep-wake cycles

Pineal gland Melatonin

Light impulses throughretina a,b

Chart adapted from: Porth CM, Sleep and Sleep Disorders. In: Pathophysiology: Concepts of Altered Health States. 8th edition. Porth CM, Matfin G, eds. Philadelphia: Wolters Kluwer Health; 2009.

a Light = inhibitory signalsb Dark (i.e., lack of light) = stimulating signals

https://www.researchgate.net/figure/40454967_fig1_ Figure- 1-Physio log y-of-Melaton in-Secre tion-Me lat onin

MT1 Receptors in SCN

Forebrain/ThalamusAttention, memory,

emotion, psychomotor performance,

sensorimotor integration

Hypothalamus

Anterior pituitary Hormone levels

HypothalamusBody temperature, metabolism, ANS

function, sleep-wake cycles

Brain stem reticular formation

ANS function, sleep-wake cycles

Pineal gland Melatonin

Melatonin

Activation of MT1 receptors is the likely mechanism of how melatonin regulates sleep2

Activation of MT2 receptors is the likely mechanism of how melatonin influences circadian rhythm phase shifts2

Adapted from: http://www.brightenyourlife.info/images/slide4.jpg

Phase Response Curve

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Jet-Lag SWSD 1o Insomnia DSPSDose 0.5-8mg on

arrival day, continue for 2-5

days

2-12mg for up to 4 weeks

2-3mg prior to bedtime for up

to 29 weeks

5mg prior to bedtime for up

to 1 week

0.3-5mg for up to 9 months

Formulation IR IR, CR, FR, SR CR, FR, SR IRROA PO PO PO PO

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Design N patients Intervention ResultsRandomized, double-blind,

placebo-controlled crossover trial

22 Melatonin or placebo 5mg PO QD x 4 weeks between 1900 and2100 hours, 1 week washout period, received other treatment x 4 additional weeks

20/22 patients finished the study àsleep onset latency was significantly reduced while subject were taking melatonin as compared with both placebo and baseline

Strengths Limitations Conclusion

• No ADEs noted• Study design allowed

patients to select their baseline bedtime and duration of sleep àpermitting investigators the ability to compare their natural sleep pattern with that of the imposed sleep period (2400 to 0800 hours)

• No evidence that melatonin altered total sleep time

• Melatonin did alter subjective measures of sleepiness, fatigue or alertness

• Small sample size• Crossover design – each

patient served as his or her own control

• Not well controlled• Dose response relationships,

possibility of relapse after discontinuation, not explored

• Melatonin 5mg 3-4 hours prior to bedtime was an effective treatment for patients with DSPS

Design N trials ResultsCochrane Systematic

Review10 8/10 trials found that

melatonin, taken close to the target bedtime at destination time of 2200 –0000 hours, decreased jet-lag from flights crossing 5+ time zones.

Other findings ConclusionDaily doses of melatonin ranging from 0.5-5mg were shown to be similarly effective; however, patients fell asleep faster and better after 5mg vs. 0.5mg

2mg slow-release melatonin suggested a relative ineffective short-lived higher peak concentration vs. 0.5-5mg (NNT = 2)

Start taking two nights prior to flight and continue for 4 nights after arrival

Reports suggested that patients with epilepsy, and patients taking warfarin may be harmed by concurrent administration with melatonin

Melatonin was remarkable effective in preventing jet lag

Safety and efficacy was proven for occasional short-term use

Should be recommended to adult travelers flying across 5+ time zones, particularly on an eastward flight

Design N patients InterventionRandomized, double-blind,

placebo-controlled crossover trial

10 Random order of 0.3mg, 1.0mg melatonin or placebo 60 minutes prior to bedtime for 7 days.

Study was setup for patient to receive each intervention dose with a 5-day washout period in between

After each 7 day treatment, nighttime EEG records were collected

ResultsTreatment; mean (and SD)

Sleep variable Placebo MT 0.3mg MT 1.0mg% waking stage in

total recording time15.7 (15.6) 15.5 (15.9) 17.3 (18.8)

No. of awakenings 6.4 (5.1) 6.5 (4.2) 5.9 (2.4)Total time waking

stage, min73.8 (74.1) 72.1 (76.4) 83.0 (90.7)

There were no significant differences in sleep EEG, the amount or subjective quality of sleep or side effects between the placebo, 0.3-mg melatonin or 1.0-mg melatonin treatments.

Strengths Limitations Conclusion• Exclusion criteria ruled

out confounders at baseline (e.g., all other sleep disorder diagnoses were excluded)

• Small sample size• Findings are difficult to

interpret because of the variability of the same (e.g., age)

• Crossover study – each patient served as his or her own control

• Melatonin did not produce any sleep benefit in this sample of patients with primary insomnia

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