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
1) Historical aspects of sleep in FM
2) Physiology of sleep
3) Insomnia
4) Disturbed sleep in FM patients
5) Evaluation of disturbed sleep in FM
6) Disturbed sleep and pain
7) Management
Objectives
Objectives
1) Historical aspects of sleep in FM
2) Physiology of sleep
3) Insomnia
4) Disturbed sleep in FM patients
5) Evaluation of disturbed sleep in FM
6) Disturbed sleep and pain
7) Management
THE PRINCIPLES AND
PRACTICE OF MEDICINE
DESIGNED FOR THE USE OF PRACTITIONERS AND STUDENTS OF MEDICINE
BY WILLIAM OSLER, M. D.
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
NEW YORK D. APPLETON AND
COMPANY 1892
William Osler
1849 - 1919
The Principles and Practice of MedicineWilliam Osler MD, 1892
“Neurasthenia”: a condition of weakness or exhaustion of the nervous system
1. Sleeplessness is a frequent concomitant2. The majority are moody or depressed3. They have weariness on the least exertion4. The aching pain in the back of the neck is the most constant complaint5. There are spots of local tenderness in the spine
Alpha-deltasleep
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) Historical aspects of sleep in FM
2) Physiology of sleep
3) Insomnia
4) Disturbed sleep in FM patients
5) Evaluation of disturbed sleep in FM
6) Disturbed sleep and pain
7) Management
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
Sleep stages
REMStage 1Stage 2Stage 3Stage 4
Polysomnography
PolysomnographyPolysomnographic 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) EMG chin EMG tibialis anterior Nasal air flow Chest and abdominal movements Oxygen saturation ECG
The number of minutes of sleep divided by the number of minutes in bed. Normal is approximately 85 to 90% or higher.
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
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.
Beta waves (12-30 HZ)
Eyes openEyes closed
Alpha waves (8 – 12 HZ)EEG leads
Chin EMG
EOG
Stage 1 sleep
Slow rolling eye movements
Theta waves (4–7.5 Hz) with some alpha
Chin EMG
EOG
EEG leads
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
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.
Minimal eye movement
Minimal chin EMG
Theta waves (4–7 Hz)
Stages 3 and 4 of non-REM sleep
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.
Some eye movement
REM sleep
Starts after loss of chin EMG
Rapid eye movements
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 mechanismsEncephalitis lethargica
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).
An epidemic that spread throughout the world from 1977 to 1928.
Sleep control mechanismsEncephalitis lethargica
Postulated cause is a mutation of the H1N1 influenza virus
? N-methyl-D-aspartate (NMDA) receptor antibody mediated
Sleep control mechanisms
Constantin von Economo1876 - 1931
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.
Based on his observations, von Economo predicted that the region of the hypothalamus near the optic chiasma would contain sleep-promoting neurons, whereas the posterior hypothalamus would contain neurons that promote wakefulness.
Sleep control mechanismsOrexin 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.
SleepAwake
Sleep control mechanisms
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) Historical aspects of sleep in FM
2) Physiology of sleep
3) Insomnia
4) Disturbed sleep in FM patients
5) Evaluation of disturbed sleep in FM
6) Disturbed sleep and pain
7) Management
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 – definition
Riemann et al. Pharmacopsychiatry. 2011 Jan;44(1):1-14.
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
9) Hypertension
10) Depression / anxiety
11) Coronary heart disease
12) Increased mortality
Sleep loss may transiently improve depression
Hyperarousal Sleep disturbance
Neurobiologicalalterations
Dysfunctional behavior
Stressors
Long-termconsequences
Insomnia – mechanisms
Am J Psychiatry 2004; 161:2126–2129
Insomnia – mechanisms
(A) Patients with insomnia: brain areas where metabolism was not decreased in waking and sleep states
(B) Healthy subjects: brain areas where metabolism, while awake, was higher than in patients with insomnia
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), 3. Cognitive system (prefrontal cortex)
Objectives
1) Historical aspects of sleep in FM
2) Physiology of sleep
3) Insomnia
4) Disturbed sleep in FM patients
5) Evaluation of disturbed sleep in FM
6) Disturbed sleep and pain
7) 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
Moldofsky et al. Psychosomatic Med. 37:341-351, 1975
Auditory stimulation in
healthy controls
ECG
R. leg
L. leg
Chin EMG
EEG leadsNormal sleep
α-EEG sleep
Alpha – delta 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
Sergi et al. Eur Resp J 1999; 14:203-208
R. EOG
L. EOG
EEG
EEG
Air flux
Thorax
EMG
Abdomen
%O2 sat.
Upper airway resistance syndrome
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.Manometry and pneumotachographic are the "gold standard" for diagnosis.
Sleep 2004 May 1;27(3):459-66
Now considered to be same as “cyclic alterating rhythm”
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 syndromeJ Clin Sleep Med 2010;6(5):423-427
RLS symptomsFM patients = 33%Healthy controls = 3.1%
Conclusions:
There is a high prevalence and odds of having RLS in FM patients.
Clinicians should routinely query FM patients regarding RLS symptoms becausetreatment of RLS can potentially improve sleep and quality of life in these patients.
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 apneaExcessive 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 apneaObserved episodes of apnea during sleepAwakening with a dry mouth or sore throatMorning headacheDifficulty losing weightHypertension, gastric reflux, arrythmias
Obstructive sleep apnea
Central sleep apnea
Central
Objectives
1) Historical aspects of sleep in FM
2) Physiology of sleep
3) Insomnia
4) Disturbed sleep in FM patients
5) Evaluation of disturbed sleep in FM
6) Disturbed sleep and pain
7) Management
SITUATION Score
1. Sitting and reading
2. Watching TV
3. Sitting inactive in a public place
4. As a passenger in a car for an hour
5. Lying down to rest in the afternoon
6. Sitting and talking to someone
7. Sitting quietly after a lunch without alcohol
8. In a car, while stopped for a few minutes in traffic
How likely are you to doze off or fall asleep in the following situations, in contrast to feeling just tired?
0 = no chance, 1= slight chance2 = moderate chance 3 = high chance
Epworth sleepiness scale(http://epworthsleepinessscale.com)
ANALYSIS
Score of 1-6 getting enough sleep
Score of 4-8 the average score
Score of 9-15 very sleepy and need further evaluation
Score of ≥16 dangerously sleepy and urgently need
specialist evaluation/polysomnogram
(1) Do you have uncomfortable feelings or sensations in the legs (or urge to move the legs) while sitting or lying down?
(2) Is the discomfort was worse when resting?
(3) Is the discomfort improved or resolved with walking?
(4) Is the discomfort worse in the evening or nighttime?
Restless legs questionnaire
Hening WA et al. The Johns Hopkins diagnostic interview for the restless legs syndrome. Sleep Med 2003;4:137-41
Crawling TinglingCramping CreepingPulling PainfulElectric ItchyGnawing Aching
Score of 4 provides 90% diagnostic sensitivity
* A diagnosis of PLMS requires 3 periods of ≥30 movements followed by partial arousal or awakening
Periodic limb movement disorder (PLMD)(nocturnal myoclonus)
1) Patient has RLS
2) Report from sleep partner
3) Polysomnogram
4) Response to dopamine agonist
*
Diagnostic considerations:
80% of RLS patients have periodic limb movement disorder (PLMD)
Paradoxically only 30% PLMD patients have RLS
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) Historical aspects of sleep in FM
2) Physiology of sleep
3) Insomnia
4) Disturbed sleep in FM patients
5) Evaluation of disturbed sleep in FM
6) Disturbed sleep and pain
7) Management
ChronicPain
Disturbedsleep
Chicken or Egg?
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
Dysfunctional sleep and pain
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
ChronicPain
Disturbedsleep
Dysfunctional sleep and pain
?
Sleep improvement reduces pain
Spaeth et al. Annals of the Rheumatic Diseases (in press)
FIQ sleep vs pain VAS (r=0.7, p<0∙001)
Objectives
1) Historical aspects of sleep in FM
2) Physiology of sleep
3) Insomnia
4) Disturbed sleep in FM patients
5) Evaluation of disturbed sleep in FM
6) Disturbed sleep and pain
7) 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
3) Review current medications for sleep side effects
4) Review all previous treatments
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
CrampsCarpal tunnelBursitisSpinal OASpinal stenosisOA hip or knee
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.
JAMA. 2001;285:1856-1864
CBT for insomnia
Basic principles of CBT
Sleep hygiene
Stimulus control
Sleep restriction
1) Maintain a regular sleep schedule2) Sleep as long as necessary to feel rested (usually 7 to
8 hours for adults) and then get out of bed3) 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 bedtime6) Avoid caffeinated beverages after lunch7) Avoid alcohol and tobacco in late afternoon and
evening8) Exercise regularly, preferably more than 4 hours prior
to bedtime9) Avoid daytime naps that are longer than 20 to 30
minutes or occur late in the day
Sleep hygiene
Rationale: Patients with insomnia often associate their bed and bedroom with the fear of not sleeping. The longer they stay in bed the stronger the association becomes.
Stimulus control
1) Patients should not go to bed until they are sleepy2) Set an alarm clock to wake them at the same time
every morning, including weekends.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.
Rationale: Many patients with insomnia stay in bed trying to get to sleep. Sleep restriction therapy increases the drive to sleep by limiting the total time allowed in bed.
Sleep restriction therapy
1) Decrease the time spent in bed to equal the time that the patient reports sleeping (but not less than 5 hours 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.
Drug Action Dose (mg) Half-life (h)
Estazolam 1 BzRA 1–2 10–24Flurazepam 1 BzRA 15–30 48–120Temazepam 1 BzRA 15–30 8–20Triazolam 1 BzRA 0.125–0.25 2.4Quazepam 1 BzRA 7.5–15 48–120Zolpidem 2 BzRA 5–10 1.4–3.8Zolpidem ER 2 BzRA 6.25–12.5 2.8Zaleplon 2 BzRA 5–20 1.0Eszopiclone 2 BzRA 1–3 6.0Ramelteon 3 MtRa 8 1–2.6
Type 1 indicates benzodiazepines, type 2 indicatesnon-benzodiazepines, and type 3 indicates melatonin.
FDA approved drugs for the treatment of insomniaSleep onset insomnia use a short-acting
medication:Zolpidem Capelin TriazolamLorazepam Ramelteon
Sleep maintenance insomnia use a longer-acting medication :Low dose doxepinZolpidem ER EszopliconeTemazepam Estazolam From: UpToDate 2011
Slow wave sleep enhancers
GABA reuptake inhibitor: Tiagabine
GABA enhancer:Sodium oxybate (not approved for FM)
Selective GABAA agonistGaboxadol (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
Onset Duration REM SWS
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 ↔ ↓ ↓ ↔
Drugs and sleep architecture
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
Cyclobenz.
% Change
PlaceboP-value
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*
Low dose cyclobenzaprine
RLS / PLM management
General measures
Correct iron deficiency
Stop “aggravating” drugs
Dopamine agonists
Gabapentin, pregabalin, valproate
Clonidine
Clonazepam
Opioids
Relaxing bedtime routineRegular stretchingMinimize caffeine, alcohol, tobaccoAvoid exercise 2 h before sleep Cold compress application
CarbidopaLevodopaPramipexoleRopinirole Pergolide Cabergoline
Anti-nausea drugsOTC antihistamines Antidepressants (TCAs and SSRIs) AntipsychoticsTramadol
Sleep apnea management
Future Directions
1. Individualized management of insomnia
2. Widespread adoption of CBT as an initial management strategy
3. Improved non-benzodiazepines4. Development of Orexin modulators5. Newer 5-HT receptor antagonists
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