Download MELATONIN

SLEEP DISORDER IN THE ELDERLY EFFECT OF MELATONIN THERAPY
DORON GARFINKEL, M.D.
HEAD, GERIATRIC PALIATIVE DEPARTMENT
SHOHAM GERIATRIC MEDICAL CENTER
PARDES – HANA,
ISRAEL
Normal Sleep & Normal Aging:
Our Internal Biological Clock
 The biological clock resides in the brain
 It helps regulate when we feel sleepy
and when we are alert
 It works in tandem with light and dark,
and our body temperature
and hormones
MELATONIN
N ACETYL -5- METHOXYTRYPTAMINE
AN INDOLE-AMINE SECRETED IN RESPONSE
TO DARKNESS FROM THE PINEAL GLAND
ITS SYNTHESIS & EXCRETION ARE REGULATED
BY AN ENDOGENOUS CLOCK LOCATED IN
THE HYPOTHALAMUS THAT IS ENTRAINED
TO THE EXTERNAL LIGHT - DARK CYCLE
MELATONIN
N ACETYL -5- METHOXYTRYPTAMINE
THE HORMONE INDUCES SLEEP THROUGH
ITS SYNCHRONIZING EFFECT ON THE
INTERNAL BIOLOGICAL CLOCK
EASILY CROSSES THE
BLOOD BRAIN BARRIER (B. B. B.)
IS RAPIDLY METABOLIZED IN THE LIVER AND
OVER 85% ELIMINATED IN THE URINE
AS 6 SULPHATOXY - MELATONIN (6 - S - MT)
EFFECT OF AGE ON
MELATONIN

THERE IS AN AGE-RELATED CHANGE IN
THE DAILY RHYTHM OF MELATONIN
 SERUM MELATONIN CONCENTRATIONS
DECREASE IN OLD AGE
 IN HEALTHY ELDERLY INSOMNIACS, 6-S MT
IS SIGNIFICANTLY LOWER AND ITS ONSET
AND PEAK TIME ARE DELAYED IN COMPARISON TO AGE MATCHED
CONTROLS WITH NO SLEEP DISTURBANCES
6 - S- MT (ug)
URINARY 6 - SULPHATOXY MELATONIN
(6- S- MT) EXCRETION
15
NORMAL
10
5
ELDERS / PATIENTS
0
18--21
21--24
00--03
03--06
COLLECTION INTERVAL (h)
06--09
EXOGENOUS MELATONIN
Therapeutic Effects
EXERTS SYNCHRONIZING EFFECTS ON CIRCADIAN
RHYTHMS - IT PHASE ADVANCES SLEEP OF
PATIENTS SUFFERING FROM
DELAYED SLEEP- PHASE SYNDROME
CAN FACILITATE THE POST - FLIGHT ADAPTATION
OF JET - LAG
RESYNCHRONIZES THE SLEEP - WAKE CYCLE
OF BLIND PEOPLE
EXOGENOUS MELATONIN
Characteristics
IS NOT ASSOCIATED WITH
SERIOUS SIDE EFFECTS
IS SHORT LIVED IN HUMANS SERUM HALF LIFE IS ONLY 40-50 MINUTES
CONTROLLED - RELEASE
MELATONIN
 ENABLES RESTORATION OF NORMAL SERUM
MELATONIN CONCENTRATIONS BY CONTROLLED
DOSAGE AND TIMING
 ACHIEVES A PHARMACOKINETIC PROFILE SIMILAR
TO THAT OF ENDOGENOUS MELATONIN SECRETED
BY THE PINEAL GLAND
 THE QUALITY OF SLEEP IS MUCH BETTER THAN
THAT ACHIEVED BY REGULAR , SHORT ACTING
MELATONIN
 COMPLIANCE IS IMPROVED ESPECIALLY IN THE
ELDERLY
RESEARCH PROJECTS
STUDY DESIGN
RANDOMIZED, PLACEBO CONTROLLED
DOUBLE - BLIND
SUBJECTS GIVEN
±
CROSSOVER DESIGN
EITHER 2mg OF
CONTROLLED - RELEASE MELATONIN
(CIRCADINTM, NEURIM PHARMACEUTICALS , ISRAEL)
OR A PLACEBO,
TWO HOURS BEFORE DESIRED BEDTIME ,
FOR THREE WEEKS - SEVERAL MONTHS
SUBJECTS

ADULTS AND ELDERLY PEOPLE LIVING
IN THE COMMUNITY WHO SUFFERED
FROM SLEEP DISTURBANCES
 INITIALLY, PEOPLE LIVING IN
MEDITERRANEAN TOWERS, A RESIDENTIAL
CENTER FOR SENIOR CITIZENS IN ISRAEL
 THEN, PATIENTS SUFFERING FROM
DIABETES MELLITUS, HEART DISEASE,
HYPERTENTION etc
± SLEEPING PILLS...
RESEARCH PROJECTS
TOOLS
A SLEEP QUESTIONNAIRE
 ASSESSMENT OF SLEEP QUALITY FOR
THREE CONSECUTIVE NIGHTS, BY WRIST
ACTIGRAPHY WHILE SUBJECTS WERE
SLEEPING AT HOME
 MOTION RECORDING ANALYSED USING
AN AUTOMATIC SCORING ALGORHYTHM
 URINE COLLECTED AT 3 HOUR INTERVALS
OVERNIGHT, URINARY 6-S MT ASSAYED BY
R.I.A. OR ELISA

STUDY PROTOCOL
URINE COLLECTION
ACTIGRAPH
(3 NIGHTS)
RUN IN
CR MELATONIN
PLACEBO
1 WEEK
WASH
OR PLACEBO
OUT
PLACEBO
PLACEBO OR
CR MELATONIN
3 WEEKS
1 WEEK
3 WEEKS
EFFECTS OF CR MELATONIN ON SLEEP
PARAMETERS IN ELDERLY PATIENTS
LATENCY
40
30
Min
20
10
PLC
MEL
0
PLC
p < .088
EFFECTS OF CR MELATONIN ON SLEEP
PARAMETERS IN ELDERLY PATIENTS
EFFECTS OF CR MELATONIN ON SLEEP
PARAMETERS IN ELDERLY PATIENTS
W.A.S.O.
80
70
Min
PLC
PLC
60
50
40
MEL
30
p < .001
IMPROVEMENT OF SLEEP QUALITY
IN ELDERLY PEOPLE BY
CONTROLLED- RELEASE MELATONIN
D. GARFINKEL, M. LAUDON, D. NOF, N. ZISAPEL
LANCET 1995; 346: 541 - 44
CONCLUSIONS
 CONTROLLED -
RELEASE MELATONIN
SIGNIFICANTLY IMPROVES SLEEP
QUALITY IN ELDERLY INSOMNIACS
IN WHOM MELATONIN OUTPUT WAS IMPAIRED
 MELATONIN REPLACEMENT THERAPY
SHORTENS SLEEP LATENCY,
IMPROVES SLEEP EFFICIENCY AND
DECREASES W.A.S.O.
IMPROVEMENT OF SLEEP QUALITY
IN DIABETIC PATIENTS
BY
CONTROLLED RELEASE
MELATONIN
Impaired nocturnal melatonin secretion
in Non-dipper hypertensive patients
Jonas M, Garfinkel D, Zisapel N,
Laudon M, Grossman E
BLOOD PRESS 12 (1); 19-24, 2003.
BENZODIAZEPINES
BENZODIAZEPINS ARE WIDELY USED IN
THE ELDERLY POPULATION FOR THE
INITIATION OF SLEEP
VERY FREQUENTLY, COMPLAINTS ABOUT
POOR SLEEP MAINTENANCE PERSIST
DESPITE BENZODIAZEPIN TREATMENT
BENZODIAZEPINES
WE REPORTED A DECREASED MELATONIN
OUTPUT IN ELDERLY PEOPLE SUFFERING FROM
INSOMNIA (Compared to Controls)
MELATONIN CAN IMPROVE SLEEP QUALITY IN
MELATONIN - DEFICIENT ELDERLY PEOPLE
MELATONIN PRODUCTION CAN BE
INHIBITED BY BENZODIAZEPINS !!!
FACILITATION OF BENZODIAZEPINE
DISCONTINUATION BY
CONTROLLED-RELEASE MELATONIN
DOSE REDUCTION - Period
100
%
I
75
50
PLACEBO
25
GOAL
0
O
1
P < 0.05
2
3
4
MELATONIN
5
6 WEEKS
FACILITATION OF BENZODIAZEPINE
DISCONTINUATION BY C.R. MELATONIN
BENZODIAZEPINE DISCONTINUATION
100
PLACEBO
MELATONIN
80
%
60
40
20
0
P = .05
5
6
week
FACILITATION OF BENZODIAZEPINE
DISCONTINUATION BY C.R. MELATONIN
100
%
BZD. DOSE REDUCTION VS SLEEP QUALITY
75
7.5-
50
6.55.5-
25
~11%
0
0
O
1
2
3
4
<<< MELATONIN
5
<<<<
6 WEEKS
FACILITATION OF BENZODIAZEPINE
DISCONTINUATION BY C.R. MELATONIN
TWO YEARS AFTER TERMINATION OF THE STUDY
BENZODIAZEPINE DOSE REDUCTION
STOPPED TAKING BZD
0N C. R. MELATONIN
WITHOUT C. R. MELATONIN
78%
60%
52%
8%
REDUCED BZD DOSAGE
(Average 30% of Initial BZD Dose)
18%
STILL ON BENZIDIAZEPINES & STOPPED C. R. MELATONIN
FAILURE
22%
CONCLUSIONS
CONTROLLED - RELEASE MELATONIN
CAN FACILITATE BENZODIAZEPINE
DISCONTINUATION OR ENABLES A
SIGNIFICANT DOSE REDUCTION
OF BENZODIAZEPINES,
WHILE MAINTAINING THE SAME OR BETTER
SLEEP QUALITY
FACILITATION OF BENZODIAZEPINE
DISCONTINUATION BY MELATONIN :
A NEW CLINICAL APPROACH
D. GARFINKEL, N. ZISAPEL, J. WAINSTEIN, M. LAUDON,
Arch Int Med 159: 2456-60, 1999
‫הכנס הראשון לרפואה בגיל השלישי‬
‫‪ 28‬באפריל ‪2003‬‬
‫הפרעות שינה בקשישים‬
‫בבתי אבות ובמחלקות סיעודיות‬
‫ד"ר דורון גרפינקל‬
‫מחלקה גריאטרית פליאטיבית‬
‫שהם ‪-‬המרכז המשולב לרפואת הגיל השלישי‬
‫פרדס חנה‬
APPROACH TO SLEEP DISORDERS
IN THE NURSING HOME SETTING
SLEEP DISORDERS AND SLEEP
FRAGMENTATION ARE VERY COMMON
IN NURSING HOME RESIDENTS …
UNFORTUNATELY, THERE IS LITTLE DATA
ON THE EFFECTIVENESS OF SLEEPING
MEDICATIONS AND THE SPECIFIC
MANAGEMENT OF SLEEP DISORDERS
IN THIS SETTING.
Allesi CA & Schnelle JF. Sleep Med Rev 2000; 4(1): 45 - 56 (Review Article)
SLEEP DISTURBANCES AMONG
NURSING HOME RESIDENTS
SLEEP DISTURBANCES WERE COMMON AMONG THE RESIDENTS
ACTIGRAPHY OF DEMENTED LONG TERM
PATIENTS SHOWED SLEEP EFFICIENCY OF 75%,
A MEAN SLEEP ONSET LATENCY OF ONE
HOUR, A MEAN W.A.S.O. OF MORE THAN
TWO HOURS, MORE THAN 13 HOURS WERE
SPENT IN BED
Fetveit A, Bjorvatn B. Int J Geriatr Psychiatry 2002; 17: 604 - 9
THE SLEEP OF OLDER PEOPLE
IN HOSPITAL AND NURSING HOMES
THE MAIN CAUSES OF SLEEP
DISTURBANCES IN BOTH SETTINGS WERE:
NEEDING TO GO TO THE TOILET,
NOISE
PAIN
AND
DISCOMFORT
Ersser & al. J Clin Nurs 1999; 8(4): 360 - 8
APPROACH TO SLEEP DISORDERS
IN THE NURSING HOME SETTING
A VARIETY OF FACTORS CONTRIBUTE TO THESE SLEEPING DIFFICULTIES
 AGE RELATED CHANGES IN SLEEP
 THE HIGH PREVALENCE OF DEMENTIA, DEPRESSION,
MEDICAL ILLNESS AND MEDICATIONS THAT AFFECT SLEEP
 RESPIRATORY DISTURBANCES OF SLEEP
 LIFESTYLE CHARACTERISTICS SUCH AS:
INACTIVITY, LARGE AMOUNTS OF TIME SPENT IN BED,
LACK OF BRIGHT LIGHT EXPOSURE AND POOR SLEEP HYGIENE
AND THE DISRUPTIVE NIGHT-TIME NURSING HOME ENVIRONMENT
Allesi CA & Schnelle JF. Sleep Med Rev 2000; 4(1): 45 - 56 (Review Article)
THE IMPACT OF SEDATIVE-HYPNOTIC USE
ON SLEEP SYMPTOM IN ELDERLY
NURSING HOME RESIDENTSS
145 institutionalized elderly subjects, mean age
83.0 (range 65 - 105 years) in 12 nursing homes
At baseline:
One or more sleep related complaints were present
in 65% of the residents. No relationship was found
between use of sedative - hypnotic agent
and the presence or absence of sleep complaints.
AFTER 6 MONTHS OF FOLLOW UP:
Improvement in functional status was significantly
associated with improved sleep (p< 0.005).
Monane M, Glynn RJ, Avorn J. Clin Pharmacol Ther 1996; 59(1): 83
THE IMPACT OF SEDATIVE-HYPNOTIC USE
ON SLEEP SYMPTOM IN ELDERLY
NURSING HOME RESIDENTSS
CONCLUSIONS:
THERE WAS NO RELATIONSHIP
BETWEEN DECREASED USE OF
SEDATIVE - HYPNOTIC AGENTS
AND WORSENED SLEEP, OR
BETWEEN THEIR INCREASED USE
AND IMPROVED SLEEP REPORTS
Monane M, Glynn RJ, Avorn J. Clin Pharmacol Ther 1996; 59(1): 83
THE SLEEP OF OLDER PEOPLE
IN HOSPITAL AND NURSING HOMES
NO DISCERNIBLE DIFFERENCE WAS FOUND
IN QUALITY OF SLEEP AND WHETHER
PATIENTS FELT RESTED OR NOT,
BETWEEN THOSE
PATIENTS ON HYPNOTIC MEDICATION
AND THOSE WHO WERE NOT
Ersser & al. J Clin Nurs 1999; 8(4): 360 - 8
THE NURSING HOME AT NIGHT:
EFFECT OF AN INTERVENTION ON
NOISE, LIGHT AND SLEEP
CONCLUSIONS:
The significant reduction in noise and light
events … did not lead to significant improvement
in the day sleep and most night sleep measures
AN INTERVENTION THAT COMBINES BOTH BEHAVIORAL
AND ENVIRONMENTAL STRATEGIES AND THAT ADDRESSES
DAYTIME BEHAVIORAL FACTORS ASSOCIATED WITH
POOR SLEEP (eg. Excessive time in bed)
WOULD POTENTIALLY BE MORE EFFECTIVE IN
IMPROVING THE NIGHT SLEEP & THE QUALITY OF LIFE
OF NURSING HOME RESIDENTS.
SLEEP PATTERNS AND MORTALITY AMONG
ELDERLY PATIENTS IN A GERIATRIC HOSPITAL
Sleep disturbances were studied as a mortality
risk in 272 institutionalized elderly patients
Mortality after two years was significantly
higher in the nighttime insomnia, daytime
sleepiness and sleep onset delay groups.
Sleep disturbances may be one of the
symptoms indicating poor health
or functional deficits, and be an
independent risk factor for survival.
Manabe K & al. Gerontology 2000; 46(6): 318 - 22
Nocturnal Respiratory Disturbances
INTRODUCTION :
Chronic hypoxia due to alveolar
hypoventilation and/or disturbance
in ventilation/perfusion ratio,
are usually the result of a variety of
cardiopulmonary & neurological maladies
whose prevalence is increasing with age.
Nocturnal Respiratory Disturbances
INTRODUCTION :
Breathing problems in general & sleep apnea
in particular, are both increasing with age
and represent the main causes for clinically
significant, chronic night hypoxia
Sleep disturbances may aggravate hypoxia
and lead to increased mortality and morbidity
Nocturnal Respiratory Disturbances
in a Prolonged Care Geriatric Institution
RESULTS:
RESPIRATORY
RDI
*
Normal
0 - 10
Mild
10 - 15
Moderate
15 - 25
Severe
> 25
DISTURBANCE
INDEX
(R D I)
No. PATIENTS
(%)
4 (8%)
5 (10%)
27 ( 53%)
15 (29%)
* RESPIRATORY DISTURBANCE INDEX : APNEA + HYPOPNEA
AS A
PORTION OF TOTAL SLEEP
Nocturnal Respiratory Disturbances
in a Prolonged Care Geriatric Institution
CONCLUSIONS:
IN SPITE OF NORMAL OR ONLY MILDLY
IMPAIRED RESULTS OF BOTH
THE SUBJECTIVE SLEEP REPORTS AND
ARTERIAL BLOOD GASES & SPIROMETRY
A SIGNIFICANT NIGHT HYPOXIA ACCOMPANIED
WITH MANY PERIODS OF RESPIRATORY
DISTURBANCES (APNEA / HYPOPNEA) WERE
FOUND IN MOST OF THE SAME SUBJECTS
Seleznev I, & al. Unpublished Data
Nocturnal Respiratory Disturbances
in a Prolonged Care Geriatric Institution
CONCLUSIONS:
ALL SUBJECTS WITH SIGNIFICANT
NOCTURNAL RESPIRATORY DISTUEBANCES
WERE OFFERED THERAPY (CPAP) .. …
HOWEVER...
ONLY 3 ELDERS AGREED TO TRY
THIS NON INVASIVE TREATMENT !
Seleznev I, & al. Unpublished Data
MELATONIN FOR TREATMMENT OF
SUNDOWNING
IN ELDERLY PERSONS WITH DEMENTIA
COHEN - MANSFIELD J, GARFINKEL D, LIPSON S.
Arch Gerontol & Geriatr 31: 65-76, 2000
Nocturnal Respiratory Disturbances
in a Prolonged Care Geriatric Institution
OBJECTIVES:
. Determine the prevalence of hypoxia in
elderly people living in a nursing home
. Find out whether this hypoxia was
influenced by the circadian rhythm
. Look for correlations between apparent
maladies or clinical manifestations and
relevant laboratory respiratory findings.
Seleznev I, & al. Unpublished Data
Nocturnal Respiratory Disturbances
in a Prolonged Care Geriatric Institution
Patients :
Elderly volunteers living in a nursing home at
the Shoham Geriatric Center Pardes-Hana, Israel
Exclusion criteria :
* Significant disability defined as Karnofski
Performance Index < 50
* Significant cognitive impairment MMSE score<18
* Unstable medical conditions
Seleznev I, & al. Unpublished Data
Nocturnal Respiratory Disturbances
in a Prolonged Care Geriatric Institution
Methods :
 Subjective assessment of the quality of sleep (a questionnaire)
 Objective assessment of sleep quality was performed in
all subjects in their own bed by 8 channel polysomnography
.
 Pulmonary function assessments were performed using
bedside Spirometry in the evening before polysomnography
Arterial blood gases were determined in the morning
following polysomnography.
These measurements were used to calculate several
parameters, enabling a quantitative comprehensive evaluation
of sleep and breathing patterns
Nocturnal Respiratory Disturbances
in a Prolonged Care Geriatric Institution
RESULTS:
87% of the subjects had PaO2 above 70
mmHg, 9% had values of 55 - 70 mmHg,
only 4% had a PaO2 below 55 mmHg.
The severity of dyspnea (according to the
NYHA Functional Classification) had a
significant positive correlation with PaCO2
(p=0.034, R=0.306) and negative correlation
with PaO2 (p=0.015, R=0.348).
Seleznev I, & al. Unpublished Data
Nocturnal Respiratory Disturbances
in a Prolonged Care Geriatric Institution
RESULTS:
99 patients met our criteria but only 51
volunteered to participate (14 men, 37 women)
average age 82.1± 6.89 (range 70 to 95).
36 patients had hypertension, 20 suffered from
ischemic heart disease (7 also had CHF), 11 had
COPD; Depression was diagnosed in 7,
diabetes mellitus in 6, previous CVA in 5
hypothyroidism in one.
Seleznev I, & al. Unpublished Data
Nocturnal Respiratory Disturbances
in a Prolonged Care Geriatric Institution
RESULTS:
The subjective assessment of sleep quality
according to the sleep questionnaire:
57% complained of severe sleep disorders
27% had mildly-moderately disturbed sleep
16% reported a good night sleep
No correlation was found between
subjective sleep quality and nocturnal
oxygen saturation, PaO2 and PaCO2.
Seleznev I, & al. Unpublished Data
Nocturnal Respiratory Disturbances
in a Prolonged Care Geriatric Institution
RESULTS:
Pulmonary Functions (FEV1)
Number of
Patients
FEV1
Average ± SD
8
86.36 ± 6.48
Mild
24
69.56 ± 5.69
Moderate
11
50.85 ± 4.93
Severe
4
29.15 ± 8.71
SEVERITY *
Normal
* Normal > 80%, Mild 60 - 80%, Moderate 40 - 60%, Severe < 40%
of the expected value
Seleznev I, & al. Unpublished Data
Nocturnal Respiratory Disturbances
in a Prolonged Care Geriatric Institution
RESULTS:
Extent of Nocturnal Apnea and Oxygen Desaturation
SEVERITY
Apnea Index *
Periods of Oxygen
Saturation Bellow 90%
(% of Total Sleep Time ) **
Normal
26 (51%)
14 (27%)
Mild
23 (45%)
22 (43%)
Moderate – Severe
2 (4%)
15 (30%)
* Apnea Index : normal 0 - 5, mild 5 - 10, moderate to severe > 10
** Saturation of Oxygen < 90% : normal = 0, mild < 10%,
moderate - severe > 10% of Total Sleep Time
APPROACH TO SLEEP DISORDERS
(IN THE NURSING HOME SETTING)
SLEEP DISORDERS
SHOULD BE HANDLED BY THE PHYSICIAN
IN THE SAME CLINICAL APPROACH AS THAT USED
FOR OTHER SYMPTOMS OR SIGNS:
FIRST OF ALL,
DEFINE THE UNDERLYING CAUSE
& MAKE THE CORRECT DIAGNOSIS
Evaluating Causes of Insomnia

Situational factors that are major stressors such as a life
trauma or an upcoming important event

Environmental factors such as too much noise, temperature
that are too hot or too cold, or working a night shift

Factors related to medications, both prescription and
nonprescription (i.e. CNS stimulants/ activating
antidepressants)

Medical problems such as pain, endocrine, menopause,
BPH, incontinence, CHF, PUD/GERD, COPD, allergic
rhinitis, seizure d/o
APPROACH TO SLEEP DISORDERS
(IN THE NURSING HOME SETTING)
1. RULE OUT AND TREAT SITUATIONS LEADING TO
SECONDARY SLEEP DISORDERS PARTICULARY
SLEEP APNEA (PATIENT’S STORY, ANXIETY,
DEPRESSION, PHYSICAL, IMAGING & LAB FINDINGS).
2. NO APPARENT UNDERLYING CAUSE FOR SLEEP
DISORDER and ADVANCED AGE CONSIDER A PRIMARY MELATONIN DISORDER
3. A. PROVE IT: CHECK OVERNIGHT URINE FOR 6-STM
B. CONSIDER A THERAPEUTIC TRIAL WITH 2mg OF
CONTROLLED - RELEASE MELATONIN . . .. . OR
4. TRY A SLEEPING PILL… PREFERABLY NOT A
BENZODIAZEPINE AS THE FIRST CHOISE