1. Fibromyalgia Patients
Sleep Disturbances in
Fibromyalgia Patients
Robert Bennett MD, FRCP, MACR

2. Disclosure Research support : Forest, Jazz, Pfizer
Advisory Boards: Lilly, Jazz
Speaker Bureaus: None

3. 3 Key References
Rosenthal MS, Physiology and neurochemistry of sleep. Am. J. Pharm. Educ., 62, , 1998
Passarella S et al. Diagnosis and treatment of insomnia. Am J Health-Syst Pharm. 2008; 65:927-34
Moldofsky H. Rheumatic manifestations of sleep disorders. Curr Opin Rheumatol 2010;22(1):59-63

4. Objectives 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

5. Objectives 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

6. NEW YORK D. APPLETON AND COMPANY 1892
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

7. 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

8. Alpha-delta sleep

9. First “Scientific” Study in FM
Delta (≈1cps)
Alpha + delta
Auditory stimulation in a healthy control
Moldofsky et al. Psychosomatic Med. 37: , 1975 9

10. Objectives 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

11. Sleep stages REM sleep 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

12. Sleep stages
REM
Stage 1
Stage 2
Stage 3
Stage 4

13. Polysomnography

14. 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)
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

15. Sleep architecture
Decreasing frequency
Increasing amplitude

16. Drowsy EEG Eyes closed Eyes open Beta waves (12-30 HZ)
EOG
Eyes open
Chin EMG
EEG leads
Beta waves (12-30 HZ)
Alpha waves (8 – 12 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.

17. 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.

18. 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.

19. 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.

20. REM sleep Rapid eye movements Starts after loss of chin EMG
Bursts of alpha activity
Starts after loss of chin EMG
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.

21. Sleep control mechanisms
Encephalitis lethargica

22. Sleep control mechanisms
Encephalitis lethargica
An epidemic that spread throughout the world from 1977 to 1928.
A somnolent-opthalmoplegic form with profound sleepiness often leading to coma and death, paralysis of cranial nerves and expressionless faces.
A hyperkinetic form with restlessness, twitching of muscles, anxiety and severe insomnia.
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

23. Constantin von Economo
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.
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.
Constantin von Economo

24. 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.

25. Sleep control mechanisms
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)

26. Objectives 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

27. 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

28. Sleep loss may transiently improve depression
Insomnia - consequences
Fatigue / malaise
Impaired attention, concentration, memory
Vocational dysfunction
Daytime sleepiness
Motivation / energy / initiative reduction
Proneness for errors / accidents at work or while driving
Tension headache
Obesity / diabetes
Hypertension
Depression / anxiety
Coronary heart disease
Increased mortality
Sleep loss may transiently improve depression
Riemann et al. Pharmacopsychiatry Jan;44(1):1-14.

29. Dysfunctional behavior
Insomnia – mechanisms
Stressors
Hyperarousal
Sleep disturbance
Dysfunctional behavior
Neurobiological
alterations
Long-term
consequences

30. Insomnia – mechanisms
Am J Psychiatry 2004; 161:2126–2129

31. 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)
Patients with insomnia: brain areas where metabolism was not decreased in waking and sleep states
Healthy subjects: brain areas where metabolism, while awake, was higher than in patients with insomnia

32. Objectives 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

33. 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

34. Auditory stimulation in healthy controls
First “Scientific” Study in FM (1975)
Delta (≈1cps)
Alpha + delta
Auditory stimulation in healthy controls
Moldofsky et al. Psychosomatic Med. 37: , 1975 34

35. Alpha – delta sleep Normal sleep EEG leads Chin EMG ECG R. leg L. leg
α-EEG sleep

36. 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.

37. 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:

38. Now considered to be same as “cyclic alterating rhythm”
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.
Manometry and pneumotachographic are the "gold standard" for diagnosis.
Now considered to be same as “cyclic alterating rhythm”

39. 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

40. Restless legs syndrome
J Clin Sleep Med 2010;6(5):
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%

41. 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

42. Sleep apnea

43. 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

44. Obstructive sleep apnea

45. Central sleep apnea
Central

46. Objectives 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

47. 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
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
0 = no chance,
1= slight chance
2 = moderate chance
3 = high chance
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

48. Score of 4 provides 90% diagnostic sensitivity
Restless legs questionnaire
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?
Score of 4 provides 90% diagnostic sensitivity
Crawling Tingling
Cramping Creeping
Pulling Painful
Electric Itchy
Gnawing Aching
Hening WA et al. The Johns Hopkins diagnostic interview for the restless legs syndrome. Sleep Med 2003;4:137-41

49. (nocturnal myoclonus)
Periodic limb movement disorder (PLMD)
(nocturnal myoclonus)
Diagnostic considerations:
80% of RLS patients have periodic limb movement disorder (PLMD)
Paradoxically only 30% PLMD patients have RLS
Patient has RLS
Report from sleep partner
Polysomnogram
Response to dopamine agonist *
* A diagnosis of PLMS requires 3 periods of ≥30 movements followed by partial arousal or awakening

50. Polysomnography

51. 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.

52. Objectives 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

53. ? Dysfunctional sleep and pain Chicken or Egg? Disturbed sleep
Chronic Pain
Disturbed sleep ?

54. 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.

55. Dysfunctional sleep and pain
MEASUREMENTS:
Nocturnal Polysomnography (PSG)
Wrist Actigraphy
Sleep and Pain Diaries
Diffuse Noxious Inhibitory Controls (DNIC)

56. Dysfunctional sleep and pain
FA underwent 8 forced awakenings (one per hour) on nights 3-5.

57. 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

58. Dysfunctional sleep and pain
Chronic Pain
Disturbed sleep ?

59. 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)

60. Objectives 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

61. Management of FM associated sleep disorders
Explore sleep hygiene and behavioral issues
Look for an associated primary sleep disorder:
RLS/PLM, sleep apnea, UARS, bruxism
Review current medications for sleep side effects
Review all previous treatments
Assess for nocturnal pain generators
Screen for depression and anxiety
Cramps
Carpal tunnel
Bursitis
Spinal OA
Spinal stenosis
OA hip or knee
Modified from Abad VC et al. Sleep Med ReV 2008;12:

62. 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.

63. Basic principles of CBT
Sleep hygiene
Stimulus control
Sleep restriction

64. Sleep hygiene Maintain a regular sleep schedule
Sleep as long as necessary to feel rested (usually 7 to 8 hours for adults) and then get out of bed
Adjust the bedroom environment to decrease stimuli (light, sound, temperature)
Try not to force sleep (see “sleep restriction”)
Resolve concerns or worries before bedtime
Avoid caffeinated beverages after lunch
Avoid alcohol and tobacco in late afternoon and evening
Exercise regularly, preferably more than 4 hours prior to bedtime
Avoid daytime naps that are longer than 20 to 30 minutes or occur late in the day

65. Stimulus control
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.
Patients should not go to bed until they are sleepy
Set an alarm clock to wake them at the same time every morning, including weekends.
They should not engage in activities that reward them for being awake, such as eating or watching TV.
They should not spend more than 20 minutes in bed awake.
If they are awake after 20 minutes, they should leave the bedroom and engage in a relaxing activity.
They should not return to bed until they feel tired.
If they return to bed and still cannot sleep within 20 minutes, the process should be repeated.

66. Sleep restriction therapy
Decrease the time spent in bed to equal the time that the patient reports sleeping (but not less than 5 hours per night)
The patient reports the amount of sleep obtained the previous night and the amount of time spent in bed.
The clinician then computes the sleep efficiency (reported time asleep divided by the reported time in bed).
The time in bed is increased by 15 to 30 minutes once the sleep efficiency exceeds 85 percent.
This process is repeated until the patient reports improved sleep without residual daytime sleepiness.
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.
Spielman et al. Insomnia: Sleep restriction therapy. Insomnia Diagnosis
and Treatment, Informa UK Ltd, London p.277.

67. FDA approved drugs for the treatment of insomnia
Sleep onset insomnia use a short-acting medication:
Zolpidem
Capelin
Triazolam
Lorazepam
Ramelteon
Sleep maintenance insomnia use a longer-acting medication :
Low dose doxepin
Zolpidem ER
Eszoplicone
Temazepam
Estazolam
From: UpToDate 2011
Drug Action Dose (mg) Half-life (h)
Estazolam BzRA 1–2 10–24
Flurazepam BzRA 15– –120
Temazepam BzRA 15–30 8–20
Triazolam BzRA –
Quazepam BzRA 7.5–15 48–120
Zolpidem BzRA 5– –3.8
Zolpidem ER BzRA 6.25–
Zaleplon BzRA 5–
Eszopiclone BzRA 1–
Ramelteon MtRa –2.6
Type 1 indicates benzodiazepines, type 2 indicates
non-benzodiazepines, and type 3 indicates melatonin.

68. 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

69. Drugs and sleep architecture
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

70. 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

71. Low dose cyclobenzaprine
% Change
Cyclobenz.
Placebo
P-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
0.10
Sleep efficiency
+ 15.6
+ 3.6
0.09
% Stage 3 sleep
+ 16.2
- 2.80
0.17
% Stage 4 sleep
- 28.6
+ 22.9

72. RLS / PLM management General measures Correct iron deficiency
Relaxing bedtime routine
Regular stretching
Minimize caffeine, alcohol, tobacco
Avoid  exercise 2 h before sleep
Cold compress application
General measures
Correct iron deficiency
Stop “aggravating” drugs
Dopamine agonists
Gabapentin, pregabalin, valproate
Clonidine
Clonazepam
Opioids
Anti-nausea drugs
OTC antihistamines
Antidepressants (TCAs and SSRIs) Antipsychotics
Tramadol
Carbidopa
Levodopa
Pramipexole
Ropinirole
Pergolide
Cabergoline

73. Sleep apnea management

74. Future Directions Individualized management of insomnia
Widespread adoption of CBT as an initial management strategy
Improved non-benzodiazepines
Development of Orexin modulators
Newer 5-HT receptor antagonists