2 Disclosure Research support : Forest, Jazz, Pfizer Advisory Boards: Lilly, JazzSpeaker Bureaus: None
3 3 Key ReferencesRosenthal MS, Physiology and neurochemistry of sleep. Am. J. Pharm. Educ., 62, , 1998Passarella S et al. Diagnosis and treatment of insomnia. Am J Health-Syst Pharm. 2008; 65:927-34Moldofsky 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 InsomniaDisturbed sleep in FM patientsEvaluation of disturbed sleep in FMDisturbed sleep and painManagement
5 Objectives Historical aspects of sleep in FM Physiology of sleep InsomniaDisturbed sleep in FM patientsEvaluation of disturbed sleep in FMDisturbed sleep and painManagement
6 NEW YORK D. APPLETON AND COMPANY 1892 THE PRINCIPLES ANDPRACTICE OF MEDICINEDESIGNED FOR THE USE OF PRACTITIONERS AND STUDENTS OF MEDICINEBY 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 PHILADELPHIANEW YORK D. APPLETON AND COMPANY 1892William Osler
7 The Principles and Practice of Medicine William Osler MD, 1892 “Neurasthenia”: a condition of weakness or exhaustion of the nervous system1. 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
9 First “Scientific” Study in FM Delta (≈1cps)Alpha + deltaAuditory stimulation in a healthy controlMoldofsky et al. Psychosomatic Med. 37: , 19759
10 Objectives Historical aspects of sleep in FM Physiology of sleep InsomniaDisturbed sleep in FM patientsEvaluation of disturbed sleep in FMDisturbed sleep and painManagement
11 Sleep stages REM sleep Non-REM sleep Stage 1 - Transition from wake to sleepStage 2 – Largest percentage of sleepStages 3 and 4 – Restorative sleepThere are 4 to 5 cycles of REM and non-REM sleep each nightEach cycle lasts 1.5 to 2 hours
14 PolysomnographyPolysomnographic data is reviewed in 30 second "epochs"Sleep latencySleep efficiencyPercent time in REM and non-REM sleepPercent time in each of the 4 sleep stagesElectro-oculogram (EOG)EMG chinEMG tibialis anteriorNasal air flowChest and abdominal movementsOxygen saturationECGThe 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
16 Drowsy EEG Eyes closed Eyes open Beta waves (12-30 HZ) EOGEyes openChin EMGEEG leadsBeta 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 EOGChin EMGEEG leadsTheta waves (4–7.5 Hz) with some alphaStage 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 movementPredominant 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 activityStarts after loss of chin EMGRapid 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 lethargicaAn 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 mechanismsVon 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 projectinsOrexin 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 AwakeVLPO = 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 InsomniaDisturbed sleep in FM patientsEvaluation of disturbed sleep in FMDisturbed sleep and painManagement
27 Insomnia – definition DSM-IV criteria for primary insomnia: 1) A complaint of difficulty falling asleep, staying asleep or non-restorative sleep2) Duration of ≥1 month3) Causes clinically significant distress or impairment4) Does not occur exclusively during the course of amental disorder5) Is not due to another medical or sleep disorder or effects of medications/substance abuse
28 Sleep loss may transiently improve depression Insomnia - consequencesFatigue / malaiseImpaired attention, concentration, memoryVocational dysfunctionDaytime sleepinessMotivation / energy / initiative reductionProneness for errors / accidents at work or while drivingTension headacheObesity / diabetesHypertensionDepression / anxietyCoronary heart diseaseIncreased mortalitySleep loss may transiently improve depressionRiemann et al. Pharmacopsychiatry Jan;44(1):1-14.
31 Insomnia – mechanismsInteracting 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 statesHealthy 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 InsomniaDisturbed sleep in FM patientsEvaluation of disturbed sleep in FMDisturbed sleep and painManagement
33 Sleep disturbances in FM Insomniaα intrusion rhythmcyclic alternating rhythm (CAP)Periodic limb movements (PLM/RLS)Snoring and arousalsApnea and hypopneaPeriodic breathingBruxism
34 Auditory stimulation in healthy controls First “Scientific” Study in FM (1975)Delta (≈1cps)Alpha + deltaAuditory stimulation in healthy controlsMoldofsky et al. Psychosomatic Med. 37: , 197534
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; 31:1193–9Cyclic 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 SergiFound 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. EOGL. EOGEEGEEGEMGAir fluxThoraxAbdomen%O2 sat.Sergi et al. Eur Resp J 1999; 14:
38 Now considered to be same as “cyclic alterating rhythm” Upper airway resistance syndromeSleep 2004 May 1;27(3):459-66The 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 limbsPLM is the 4th leading cause of insomniaPLM affects about 5% of total populationMore common in women (~20% of females age ≥ 50)PLM affects about 60% of all FM patientsNatarajan 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 becausetreatment of RLS can potentially improve sleep and quality of life in these patients.RLS symptomsFM patients = 33%Healthy controls = 3.1%
43 Sleep apnea Excessive daytime sleepiness *Epworth score usually ≥ 15 Loud snoring - more prominent in obstructive sleep apneaAbrupt 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
46 Objectives Historical aspects of sleep in FM Physiology of sleep InsomniaDisturbed sleep in FM patientsEvaluation of disturbed sleep in FMDisturbed sleep and painManagement
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? SITUATIONScore1. Sitting and reading2. Watching TV3. Sitting inactive in a public place4. As a passenger in a car for an hour5. Lying down to rest in the afternoon6. Sitting and talking to someone7. Sitting quietly after a lunch without alcohol8. In a car, while stopped for a few minutes in traffic0 = no chance,1= slight chance2 = moderate chance3 = high chanceANALYSIS Score of 1-6 getting enough sleepScore of 4-8 the average scoreScore of 9-15 very sleepy and need further evaluationScore of ≥16 dangerously sleepy and urgently need specialist evaluation/polysomnogram
48 Score of 4 provides 90% diagnostic sensitivity Restless legs questionnaireDo 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 withwalking?(4) Is the discomfort worse in the evening or nighttime?Score of 4 provides 90% diagnostic sensitivityCrawling TinglingCramping CreepingPulling PainfulElectric ItchyGnawing AchingHening 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 RLSPatient has RLSReport from sleep partnerPolysomnogramResponse to dopamine agonist** A diagnosis of PLMS requires 3 periods of ≥30 movements followed by partial arousal or awakening
51 SLEEP 2003;26(6):754-60SLEEP 2003;26(6):754-60Polysomnography 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 InsomniaDisturbed sleep in FM patientsEvaluation of disturbed sleep in FMDisturbed sleep and painManagement
53 ? Dysfunctional sleep and pain Chicken or Egg? Disturbed sleep Chronic PainDisturbed sleep?
54 Dysfunctional sleep and pain Clin J Pain Volume 27, Number 5, June 2011A 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 ActigraphySleep and Pain DiariesDiffuse 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 PainDisturbed 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 InsomniaDisturbed sleep in FM patientsEvaluation of disturbed sleep in FMDisturbed sleep and painManagement
61 Management of FM associated sleep disorders Explore sleep hygiene and behavioral issuesLook for an associated primary sleep disorder:RLS/PLM, sleep apnea, UARS, bruxismReview current medications for sleep side effectsReview all previous treatmentsAssess for nocturnal pain generatorsScreen for depression and anxietyCrampsCarpal tunnelBursitisSpinal OASpinal stenosisOA hip or kneeModified 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 hygieneStimulus controlSleep 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 bedAdjust the bedroom environment to decrease stimuli (light, sound, temperature)Try not to force sleep (see “sleep restriction”)Resolve concerns or worries before bedtimeAvoid caffeinated beverages after lunchAvoid alcohol and tobacco in late afternoon and eveningExercise regularly, preferably more than 4 hours prior to bedtimeAvoid daytime naps that are longer than 20 to 30 minutes or occur late in the day
65 Stimulus controlRationale: 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 sleepySet 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 Diagnosisand Treatment, Informa UK Ltd, London p.277.
67 FDA approved drugs for the treatment of insomnia Sleep onset insomnia use a short-acting medication:ZolpidemCapelinTriazolamLorazepamRamelteonSleep maintenance insomnia use a longer-acting medication :Low dose doxepinZolpidem EREszopliconeTemazepamEstazolamFrom: UpToDate 2011Drug Action Dose (mg) Half-life (h)Estazolam BzRA 1–2 10–24Flurazepam BzRA 15– –120Temazepam BzRA 15–30 8–20Triazolam BzRA –Quazepam BzRA 7.5–15 48–120Zolpidem BzRA 5– –3.8Zolpidem ER BzRA 6.25–Zaleplon BzRA 5–Eszopiclone BzRA 1–Ramelteon MtRa –2.6Type 1 indicates benzodiazepines, type 2 indicatesnon-benzodiazepines, and type 3 indicates melatonin.
68 Slow wave sleep enhancers GABA reuptake inhibitor:TiagabineGABA enhancer:Sodium oxybate (not approved for FM)Selective GABAA agonistGaboxadol (not available in USA)VDCC α2δ calcium channel modulators:Gabapentin/pregabalin5-HT[2A] receptor antagonist:Ritanserin, ketanserin (not available in USA)GGABA rec. subunits
69 Drugs and sleep architecture OnsetDurationREMSWSBenzodiazapines↑↔↓Benzo. Receptor↔ Anti-histamines (old)↓↓ ↑Anti-histamines (newer)Anti-epileptics (old)Anti-epileptics (newer)TCAs and SARIsSSRIs and SNRIs ↔RamelteonSodium oxybateTiagabinePsychostimulantsβ adrenergic blockersα adrenergic blockersCorticosteroids
70 Low dose cyclobenzaprine J Rheumatol. Epub Sep 2, 2011An 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
74 Future Directions Individualized management of insomnia Widespread adoption of CBT as an initial management strategyImproved non-benzodiazepinesDevelopment of Orexin modulatorsNewer 5-HT receptor antagonists