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Sleep Disturbances
in
Fibromyalgia Patients
Robert Bennett MD, FRCP, MACR
Disclosure
Research support : Forest, Jazz, Pfizer
Advisory Boards: Lilly, Jazz
Speaker Bureaus: None
3 Key References
1) Rosenthal MS, Physiology and neurochemistry of
sleep. Am. J. Pharm. Educ., 62, 204-208, 1998
2) Passarella S et al. Diagnosis and treatment of
insomnia. Am J Health-Syst Pharm. 2008; 65:927-34
3) Moldofsky H. Rheumatic manifestations of sleep
disorders. Curr Opin Rheumatol 2010;22(1):59-63
Objectives
1)
2)
3)
4)
5)
6)
7)
Historical aspects of sleep in FM
Physiology of sleep
Insomnia
Disturbed sleep in FM patients
Evaluation of disturbed sleep in FM
Disturbed sleep and pain
Management
Objectives
1)
2)
3)
4)
5)
6)
7)
Historical aspects of sleep in FM
Physiology of sleep
Insomnia
Disturbed sleep in FM patients
Evaluation of disturbed sleep in FM
Disturbed sleep and pain
Management
THE PRINCIPLES AND
PRACTICE OF MEDICINE
DESIGNED FOR THE USE OF PRACTITIONERS
AND STUDENTS OF MEDICINE
BY
WILLIAM OSLER, M. D.
William Osler
FELLOW OF THE ROYAL COLLAGE OF PHYSICIANS, LONDON PROFESSOR OF MEDICINE IN THE JOHNS
HOPKINS UNIVERSITY AND PHYSICIAN-IN-CHIEF TO THE JOHNS HOPKINS HOSPITAL, BALTIMORE FORMERLY
PROFESSOR OF THE INSTITUTES OF MEDICINE MOOILL UNIVERSITY, MONTREAL AND PROFESSOR OF
OLINIOAL MEDICINE 1H THE UNIVERSITY CF PENNSYLVANIA PHILADELPHIA
1849 - 1919
NEW YORK
D. APPLETON AND COMPANY
1892
The Principles and Practice of Medicine
William Osler MD, 1892
“Neurasthenia”: a condition of weakness or
exhaustion of the nervous system
1. Sleeplessness is a frequent concomitant
2. The majority are moody or depressed
3. They have weariness on the least exertion
4. The aching pain in the back of the neck is the
most constant complaint
5. There are spots of local tenderness in the spine
Alpha-delta
sleep
First “Scientific” Study in FM
Delta (≈1cps)
Alpha + delta
Auditory stimulation
in a healthy control
Moldofsky et al. Psychosomatic Med. 37:341-351, 1975
Objectives
1)
2)
3)
4)
5)
6)
7)
Historical aspects of sleep in FM
Physiology of sleep
Insomnia
Disturbed sleep in FM patients
Evaluation of disturbed sleep in FM
Disturbed sleep and pain
Management
Sleep stages
A. REM sleep
B. Non-REM sleep
Stage 1 - Transition from wake to sleep
Stage 2 – Largest percentage of sleep
Stages 3 and 4 – Restorative sleep
There are 4 to 5 cycles of REM and non-REM
sleep each night
Each cycle lasts 1.5 to 2 hours
Sleep stages
REM
Stage 1
Stage 2
Stage 3
Stage 4
Polysomnography
Polysomnography
Polysomnographic data is reviewed in 30 second "epochs"











Sleep latency
Sleep efficiency
Percent time in REM and non-REM sleep
Percent time in each of the 4 sleep stages
Electro-oculogram (EOG)
The number of minutes of sleep
divided by the number of minutes in
EMG chin
bed. Normal is approximately 85 to
EMG tibialis anterior
90% or higher.
Nasal air flow
Chest and abdominal movements
Oxygen saturation
ECG
Iber, C et al. The AASM Manual for the Scoring of Sleep: American
Academy of Sleep Medicine, Westchester, IL 2007
Sleep architecture
Decreasing
frequency
Increasing
amplitude
Drowsy EEG
EOG
Eyesopen
closed
Eyes
Chin EMG
EEG leads
Beta waves
Alpha
waves(12-30
(8 – 12HZ)
HZ)
During the earliest phases of sleep, when people are drowsy the
brain produces beta waves (13–35 Hz). As the brain begins to relax
slower alpha waves (8–12 Hz) are produced. During this time when
you are not quite asleep, people may experience vivid sensations
known as hypnagogic hallucinations. Another very common event
is myoclonic jerks.
Stage 1 sleep
Slow rolling eye movements
EOG
Chin EMG
EEG leads
Theta waves (4–7.5 Hz) with some alpha
Stage 1 is a transition period between wakefulness and
sleep. In Stage 1, the brain produces high amplitude theta
waves (4–7 Hz), which are very slow brain waves. This
period of sleep lasts only 5-10 minutes. If you awaken
someone during this stage, they might report that they
weren't really asleep.
Stage 2 sleep
Minimal eye movement
Minimal chin EMG
Theta waves (4–7 Hz)
Stage 2 lasts for approximately 20 minutes, mainly theta
waves (4–7 Hz). Then the brain begins to produce bursts
of rapid, rhythmic brain wave activity known as sleep
spindles and K-complexes. Body temperature starts to
decrease and heart rate begins to slow.
Stages 3 and 4 of non-REM sleep
Some eye movement
Predominant delta waves (0.5–3.5 Hz)
Stages 3 and 4 are often referred to as delta sleep because slow
brain waves known as delta waves (0.1 – 4 Hz) occur during this
time. Stages 3/4 are a deep sleep that lasts for approximately 30
minutes. Bed-wetting, night terrors and sleepwalking are most
likely to occur at the end of stage 4 sleep. It is followed by REM
sleep.
REM sleep
Rapid eye movements
Starts after loss of chin EMG
Bursts of alpha activity
Rapid eye movement (REM) sleep is characterized by
eye movement, increased respiration rate and increased
brain activity. . Vivid dreams often occur in this sleep
stage. Dreaming occurs is due to increased brain activity,
but voluntary muscles become paralyzed.
Sleep control mechanisms
Encephalitis lethargica
Sleep control mechanisms
Encephalitis lethargica
An epidemic that spread throughout the world
from 1977 to 1928.
1. A somnolent-opthalmoplegic form with profound
sleepiness often leading to coma and death, paralysis
of cranial nerves and expressionless faces.
2. A hyperkinetic form with restlessness, twitching of
muscles, anxiety and severe insomnia.
3. An akinetic form with muscle weakness, rigidity, and
severe insomnia (postencephalitic parkinsonism).
 Postulated cause is a mutation of the H1N1 influenza virus
? N-methyl-D-aspartate (NMDA) receptor antibody mediated
Sleep control mechanisms
Von Economo, reported that encephalitis lethargica was due to injury
to the posterior hypothalamus and rostral midbrain.
He recognized that one group of individuals infected during the same
epidemic instead had the opposite problem: a prolonged state of
insomnia that occurred with lesions of the pre-optic area and basal
forebrain.
He hypothesized that lesions of the posterior hypothalamus could
cause the disease we now call narcolepsy.
Constantin von Economo
1876
- 1931 predicted that the region of
Based on his observations, von
Economo
the hypothalamus near the optic chiasma would contain sleeppromoting neurons, whereas the posterior hypothalamus would
contain neurons that promote wakefulness.
Sleep control mechanisms
Orexin neuronal projectins
Orexin neurons originating in the posterior hypothalamus regulate
sleep and wakefulness by sending excitatory projections to the entire
CNS, with particularly dense projections to monoaminergic and
cholinergic nuclei in the brain stem.
Sleep control mechanisms
Sleep
Awake
VLPO = ventrolateral pre-optic nucleus (GABA & galanin)
ORX = orexin nucleus (orexins)
LC = locus ceruleus (nor-adrenaline)
Raphe = raphe magnus (serotonin)
TMN = tubermammilary nucleus (histamine)
Objectives
1)
2)
3)
4)
5)
6)
7)
Historical aspects of sleep in FM
Physiology of sleep
Insomnia
Disturbed sleep in FM patients
Evaluation of disturbed sleep in FM
Disturbed sleep and pain
Management
Insomnia – definition
DSM-IV criteria for primary insomnia:
1) A complaint of difficulty falling asleep, staying
asleep or non-restorative sleep
2) Duration of ≥1 month
3) Causes clinically significant distress or impairment
4) Does not occur exclusively during the course of a
mental disorder
5) Is not due to another medical or sleep disorder or
effects of medications/substance abuse
Insomnia - consequences
1) Fatigue / malaise
2) Impaired attention, concentration, memory
3) Vocational dysfunction
4) Daytime sleepiness
5) Motivation / energy / initiative reduction
6) Proneness for errors / accidents at work or while driving
7) Tension headache
8) Obesity / diabetes
Sleep loss may transiently
improve depression
9) Hypertension
10) Depression / anxiety
11) Coronary heart disease
12) Increased mortality
Riemann et al. Pharmacopsychiatry. 2011 Jan;44(1):1-14.
Insomnia – mechanisms
Stressors
Hyperarousal
Dysfunctional
behavior
Sleep
disturbance
Neurobiological
alterations
Long-term
consequences
Insomnia – mechanisms
Am J Psychiatry 2004; 161:2126–2129
Insomnia – mechanisms
Interacting neural networks are involved in the
neurobiology of insomnia:
1. General arousal system (ascending reticular
formation and hypothalamus),
2. Emotion-regulating system (hippocampus,
amygdala, and anterior cingulate cortex),
(A) Patients with insomnia: brain areas where metabolism was not
3. Cognitive
cortex)
decreased insystem
waking and (prefrontal
sleep states
(B) Healthy subjects: brain areas where metabolism, while awake,
was higher than in patients with insomnia
Objectives
1)
2)
3)
4)
5)
6)
7)
Historical aspects of sleep in FM
Physiology of sleep
Insomnia
Disturbed sleep in FM patients
Evaluation of disturbed sleep in FM
Disturbed sleep and pain
Management
Sleep disturbances in FM
 Insomnia
 α intrusion rhythm
 cyclic alternating rhythm (CAP)
 Periodic limb movements (PLM/RLS)
 Snoring and arousals
 Apnea and hypopnea
 Periodic breathing
 Bruxism
First “Scientific” Study in FM (1975)
Delta (≈1cps)
Alpha + delta
Auditory
stimulation in
healthy
controls
Moldofsky et al. Psychosomatic Med. 37:341-351, 1975
Alpha – delta sleep
Normal sleep
EEG leads
Chin EMG
ECG
R. leg
L. leg
α-EEG sleep
Cyclic alternating pattern (CAP) in FM
J Rheumatol 2004; 31:1193–9
Cyclic Alternating Pattern: A New Marker
of Sleep Alteration in Patients with
Fibromyalgia?
Maurizio Rizzi, Piercarlo Sarzi-puttini, Fabiola Atzeni, Franco Capsoni,
Arnaldo Andreoli, Marica Pecis, Stefano Colombo, Mario Carrabba,
Margherita Sergi
Found CAP pattern in 68% FM patients vs 45% controls.
Hypothesized that CAP in FM maybe a result of chronic pain
reducing sleep efficiency, causing more CAP and more
arousals and increasing the occurrence of periodic breathing.
Cyclic alterating pattern in FM
R. EOG
L. EOG
EEG
EEG
EMG
Air flux
Thorax
Abdomen
%O2 sat.
Sergi et al. Eur Resp J 1999; 14:203-208
Upper airway resistance syndrome
Sleep 2004 May 1;27(3):459-66
The upper airway resistance syndrome (UARS) is a form of
sleep-disordered breathing in which repetitive increases in
resistance to airflow within the upper airway lead to brief
arousals and daytime somnolence.
Patients do not meet criteria for obstructive sleep apnea.
Now considered to be same as
“cyclic alterating rhythm”
Manometry and pneumotachographic are the "gold
standard" for diagnosis.
Periodic leg movements (PML)
• PLM is a repetitive cramping or jerking of the legs
during sleep; it can range from a small movements
in the ankles and toes, to wild flailing of all 4 limbs
• PLM is the 4th leading cause of insomnia
• PLM affects about 5% of total population
• More common in women (~20% of females age ≥ 50)
• PLM affects about 60% of all FM patients
Natarajan R. Review of periodic limb movement and restless leg syndrome.
J Postgrad Med 2010;56:157-6
Restless legs syndrome
J Clin Sleep Med 2010;6(5):423-427
Conclusions:
There is a high prevalence and odds of having
RLS in FM patients.
Clinicians should routinely query FM patients
regarding RLS symptoms because
treatment of RLS can potentially improve
sleep and quality of life in these patients.
RLS symptoms
FM patients = 33%
Healthy controls = 3.1%
RLS associations
Hereditary (~50%)
Uremia (~50%)
Narcolepsy (~50%)
Pregnancy (~20%)
Diabetes
REM sleep behavioral disorder
Parkinson’s disease
Hypothyroidism
Iron deficiency (ferritin ≤ 50 ng/ml)
Some drugs
(TCAs, SSRIs, DA, L-thyroxine, tramadol, benadryl)
Opioid / benzodiazapine withdrawal
Sleep apnea
Sleep apnea
 Excessive daytime sleepiness
*Epworth score usually ≥ 15
 Loud snoring - more prominent in
obstructive sleep apnea
 Abrupt awakenings with shortness of breath
– more prominent in central sleep apnea
 Observed episodes of apnea during sleep
 Awakening with a dry mouth or sore throat
 Morning headache
 Difficulty losing weight
 Hypertension, gastric reflux, arrythmias
Obstructive sleep apnea
Central sleep apnea
Central
Objectives
1)
2)
3)
4)
5)
6)
7)
Historical aspects of sleep in FM
Physiology of sleep
Insomnia
Disturbed sleep in FM patients
Evaluation of disturbed sleep in FM
Disturbed sleep and pain
Management
Epworth sleepiness scale
(http://epworthsleepinessscale.com)
How likely are you to doze off or fall asleep in the
following situations, in contrast to feeling just tired?
SITUATION
Score
1. Sitting and reading
2. Watching TV
ANALYSIS
3. Sitting
inactive in a public place
Score
of 1-6 getting
4. As
a passenger
in aenough
car for sleep
an hour
0 = no chance,
1= slight chance
2 = moderate chance
3 = high chance
Score of 4-8 the average score
5. Lying down to rest in the afternoon
Score of 9-15 very sleepy and need further evaluation
6. Sitting and talking to someone
Score of ≥16 dangerously sleepy and urgently need
7. Sitting quietlyspecialist
after a lunch
without alcohol
evaluation/polysomnogram
8. In a car, while stopped for a few minutes in traffic
Restless legs questionnaire
(1) Do you have uncomfortable feelings or sensations
in the legs (or urge to move the legs) while sitting
or lying down?
Crawling
Tingling
Cramping
Creeping
(2) Is the Score
discomfort
worse when
of 4was
provides
90% resting?
Pulling
Painful
diagnostic
sensitivity
Electric
Itchy
(3) Is the discomfort
Gnawing improved
Aching or resolved with
walking?
(4) Is the discomfort worse in the evening or
nighttime?
Hening WA et al. The Johns Hopkins diagnostic interview for
the restless legs syndrome. Sleep Med 2003;4:137-41
Periodic limb movement disorder (PLMD)
(nocturnal myoclonus)
Diagnostic considerations:
 80% of RLS patients have periodic
1) Patient has RLS
limb movement disorder (PLMD)
2) Report from sleep partner
 Paradoxically only 30% PLMD
have RLS *
3) patients
Polysomnogram
4) Response to dopamine agonist
* A diagnosis of PLMS requires 3 periods of ≥30 movements
followed by partial arousal or awakening
Polysomnography
SLEEP 2003;26(6):754-60
SLEEP 2003;26(6):754-60
 Polysomnography is indicated when a sleep-related
breathing disorder or periodic limb movement disorder is
suspected, initial diagnosis is uncertain, treatment fails, or
precipitous arousals occur with violent or injurious behavior.
 Polysomnography is not indicated for the routine evaluation
of transient insomnia, chronic insomnia, insomnia
associated with psychiatric disorders or insomnia
associated with fibromyalgia or chronic fatigue syndrome.
Objectives
1)
2)
3)
4)
5)
6)
7)
Historical aspects of sleep in FM
Physiology of sleep
Insomnia
Disturbed sleep in FM patients
Evaluation of disturbed sleep in FM
Disturbed sleep and pain
Management
Dysfunctional sleep and pain
Chicken or Egg?
Chronic
Pain
Disturbed
sleep
?
Dysfunctional sleep and pain
Clin J Pain Volume 27, Number 5, June 2011
A night of poor sleep was followed by increased pain
ratings the following day and a day of increased pain
was followed by a night of poor sleep.
Dysfunctional sleep and pain
SLEEP 2007;30(4):494-505
MEASUREMENTS:
 Nocturnal Polysomnography (PSG)
 Wrist Actigraphy
 Sleep and Pain Diaries
 Diffuse Noxious Inhibitory Controls (DNIC)
Dysfunctional sleep and pain
FA underwent 8 forced awakenings
(one per hour) on nights 3-5.
Impaired sleep is associated with reduced
activation of the inhibitory pain pathway
Bottom line:
Frequent sleep disruptions
cause a reduction in the
descending inhibitory
control system for pain
Dysfunctional sleep and pain
Chronic
Pain
Disturbed
sleep
?
Sleep improvement
reduces pain
FIQ sleep vs pain VAS (r=0.7, p<0∙001)
Spaeth et al. Annals of the Rheumatic Diseases (in press)
Objectives
1)
2)
3)
4)
5)
6)
7)
Historical aspects of sleep in FM
Physiology of sleep
Insomnia
Disturbed sleep in FM patients
Evaluation of disturbed sleep in FM
Disturbed sleep and pain
Management
Management of FM
associated sleep disorders
1) Explore sleep hygiene and behavioral issues
2) Look for an associated primary sleep disorder:
 RLS/PLM, sleep apnea, UARS, bruxism
Cramps
3) Review current medications for sleep
4) Review all previous treatments
Carpal tunnel
sideBursitis
effects
Spinal OA
Spinal stenosis
OA hip or knee
5) Assess for nocturnal pain generators
6) Screen for depression and anxiety
Modified from Abad VC et al. Sleep Med ReV 2008;12:211-228
CBT for insomnia
JAMA. 2001;285:1856-1864
Comment:
Young and middle-age patients with sleep-onset insomnia can
often derive significantly greater benefit from CBT than
pharmacotherapy. CBT should be considered a first line
intervention for chronic insomnia.
Basic principles of CBT
 Sleep hygiene
 Stimulus control
 Sleep restriction
Sleep hygiene
1) Maintain a regular sleep schedule
2) Sleep as long as necessary to feel rested (usually 7 to
8 hours for adults) and then get out of bed
3) Adjust the bedroom environment to decrease stimuli
(light, sound, temperature)
4) Try not to force sleep (see “sleep restriction”)
5) Resolve concerns or worries before bedtime
6) Avoid caffeinated beverages after lunch
7) Avoid alcohol and tobacco in late afternoon and
evening
8) Exercise regularly, preferably more than 4 hours prior
to bedtime
9) Avoid daytime naps that are longer than 20 to 30
minutes or occur late in the day
Stimulus control
Rationale: Patients with insomnia often associate
1) Patients
should
not go
to the
bedfear
untilofthey
sleepy
their
bed and
bedroom
with
not are
sleeping.
2) Set
an alarm
wake
at thethe
same time
The
longer
they clock
stay intobed
thethem
stronger
every morning,
including weekends.
association
becomes.
3) They should not engage in activities that reward them
for being awake, such as eating or watching TV.
4) They should not spend more than 20 minutes in bed
awake.
5) If they are awake after 20 minutes, they should leave
the bedroom and engage in a relaxing activity.
6) They should not return to bed until they feel tired.
7) If they return to bed and still cannot sleep within 20
minutes, the process should be repeated.
Sleep restriction therapy
Rationale:
patients
withininsomnia
stay inthe
bed
trying
1)
DecreaseMany
the time
spent
bed to equal
time
that
to the
get to
sleep.reports
Sleep restriction
drive
patient
sleeping therapy
(but notincreases
less thanthe
5 hours
to sleep by limiting the total time allowed in bed.
per night)
2) The patient reports the amount of sleep obtained the
previous night and the amount of time spent in bed.
3) The clinician then computes the sleep efficiency
(reported time asleep divided by the reported time in
bed).
4) The time in bed is increased by 15 to 30 minutes once
the sleep efficiency exceeds 85 percent.
5) This process is repeated until the patient reports
improved sleep without residual daytime sleepiness.
Spielman et al. Insomnia: Sleep restriction therapy. Insomnia Diagnosis
and Treatment, Informa UK Ltd, London 2010. p.277.
FDA approved drugs for the
treatment
of
insomnia
Sleep onset insomnia use a short-acting
medication:
Action
Zolpidem
Capelin 1 BzRA
Estazolam
Triazolam1 BzRA
Flurazepam
Temazepam
1 BzRA
Lorazepam
Triazolam
1 BzRA
Ramelteon
Drug
Dose (mg)
1–2
15–30
15–30
0.125–0.25
Quazepam
1 BzRA
7.5–15
Zolpidem
2 BzRA
5–10
Sleep maintenance
insomnia
use
Zolpidem
ER medication
2 BzRA : 6.25–12.5
acting
Zaleplon
2 BzRA
5–20
Low dose doxepin
Eszopiclone
2 BzRA
1–3
Zolpidem 3ER
Ramelteon
MtRa
8
Half-life (h)
10–24
48–120
8–20
2.4
48–120
a1.4–3.8
longer2.8
1.0
6.0
1–2.6
Eszoplicone
Type 1 indicates
benzodiazepines, type 2 indicates
Temazepam
non-benzodiazepines, and type 3 indicatesFrom:
melatonin.
UpToDate 2011
Estazolam
Slow wave sleep enhancers
GABA reuptake inhibitor:
Tiagabine
GABA enhancer:
Sodium oxybate (not approved for FM)
Selective GABAA agonist
Gaboxadol (not available in USA)
VDCC α2δ calcium channel modulators:
Gabapentin/pregabalin
5-HT[2A] receptor antagonist:
Ritanserin, ketanserin (not available in USA)
GGABA rec.
subunits
Drugs and sleep architecture
Benzodiazapines
Benzo. Receptor
Anti-histamines (old)
Anti-histamines (newer)
Anti-epileptics (old)
Anti-epileptics (newer)
TCAs and SARIs
SSRIs and SNRIs
Ramelteon
Sodium oxybate
Tiagabine
Psychostimulants
β adrenergic blockers
α adrenergic blockers
Corticosteroids
Onset
Duration
REM
SWS
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Low dose cyclobenzaprine
J Rheumatol. Epub Sep 2, 2011
An 8 week study of cyclobenzaprine (1–4 mg hs) in 37 FM subjects and
36 controls.
Subjects had to have the α-EEG sleep anomaly in ≥40% epochs of
non-REM sleep
Low dose cyclobenzaprine
% Change
% Change
P-value
Cyclobenz.
Placebo
Pain
- 26.1
0.00
0.04*
Fatigue
- 14.0
+ 4.30
0.13
Tenderness
- 30.1
+ 3.20
0.03*
HAD depression
- 22.2
+ 10.4
0.02*
Total sleep time
+ 12.3
0.00
0.10
Sleep efficiency
+ 15.6
+ 3.6
0.09
% Stage 3 sleep
+ 16.2
- 2.80
0.17
% Stage 4 sleep
- 28.6
+ 22.9
0.03*
RLS / PLM management
Relaxing bedtime routine
 General measures
Regular stretching
Minimize caffeine, alcohol, tobacco
Avoid exercise 2 h before sleep
Cold compress application
 Correct iron deficiency


Anti-nausea drugs
OTC antihistamines
Stop “aggravating” drugs
Antidepressants (TCAs and SSRIs)
Antipsychotics
Dopamine agonists
Tramadol
 Gabapentin, pregabalin, valproate
 Clonidine
 Clonazepam
 Opioids
Carbidopa
Levodopa
Pramipexole
Ropinirole
Pergolide
Cabergoline
Sleep apnea management
Future Directions
1. Individualized management of
insomnia
2. Widespread adoption of CBT as an
initial management strategy
3. Improved non-benzodiazepines
4. Development of Orexin modulators
5. Newer 5-HT receptor antagonists