1

Differential Diagnosis and Treatment of Excessive

Daytime Sleepiness

2

What is EDS?

Excessive daytime sleepinessExcessive daytime sleepiness The tendency to fall asleep during normal The tendency to fall asleep during normal

waking hourswaking hours11 Contrast with “fatigue”Contrast with “fatigue”

A desire to rest due to feelings of A desire to rest due to feelings of exhaustionexhaustion11

Symptom of underlying disorderSymptom of underlying disorder

1. Beers MH, et al. Merck Manual of Diagnosis and Therapy; 2006.

3

EDS – a common complaint

Almost ½ of all Americans report a sleep-Almost ½ of all Americans report a sleep-related problemrelated problem11

EDS is the primary complaint of 1 in 8 people EDS is the primary complaint of 1 in 8 people seen in sleep clinicsseen in sleep clinics22

More than 1 in 4 patients complain of EDS in More than 1 in 4 patients complain of EDS in the primary care settingthe primary care setting33

1. Beers MH, et al. Merck Manual of Diagnosis and Therapy; 2006; 2. Roth T & Roehrs TA; Clin Ther.,1996; 3. Kushida CA, et al. Sleep Breath; 2000.

4

EDS characteristics

Number of daily Number of daily episodes vary episodes vary

Occurs during passive Occurs during passive activitiesactivities TV watching, sitting TV watching, sitting

on a planeon a plane Occurs during more Occurs during more

active tasksactive tasks Driving, eating, Driving, eating,

speakingspeaking

1. Beers MH, et al. Merck Manual of Diagnosis and Therapy; 2006; 2. Bassetti C & Aldrich MS. Neuro Clin;1996.

5

The Consequences of EDS

6

Consequences to Self

ProductivityProductivity1,2 MotivationMotivation22

Interpersonal relationship problemsInterpersonal relationship problems22

Depression + anxietyDepression + anxiety1, 31, 3

InsomniaInsomnia11

Quality of lifeQuality of life1,2 1,2

1. Hasler G, et al. J Clin Psychiatry; 2005; 2. Daniels E, et al. J Sleep Res; 2001; 3. Theorell-Haglow J, et al. Sleep; 2006.

7

Consequences to Health

Sleepiness vs. blood pressureSleepiness vs. blood pressure11 EDS symptoms = EDS symptoms =

Sleep BPSleep BP Daytime systolic/diastolic variability Daytime systolic/diastolic variability Anger, depression, anxietyAnger, depression, anxiety More likely to get a diagnosis of More likely to get a diagnosis of

hypertension hypertension

1. Goldstein IB, et al. Am J Hypertens; 2004.

8

Consequences to Health

Sleepiness vs. CVD in older adultsSleepiness vs. CVD in older adults11 EDS symptoms = EDS symptoms =

CVD mortality CVD mortality • 200% in men; 40% in women 200% in men; 40% in women

CVD morbidity CVD morbidity • 35% more MI and CHF in men; 66% 35% more MI and CHF in men; 66%

more in womenmore in women

1. Newman AB, et al. J Am Geriatr Soc; 2000.

9

Consequences to Society

Crashes when driver falls asleepCrashes when driver falls asleep11 100,000 each year in U. S. 100,000 each year in U. S. 1,500 deaths1,500 deaths Death rate may exceed alcohol-related Death rate may exceed alcohol-related

crashescrashes ~1/2 of all work-related accidents~1/2 of all work-related accidents22 1 in 5 public accidents due to falls1 in 5 public accidents due to falls22

1. Mahowald MW. Postgrad Med; 2000; 2. Leger D. Sleep; 1994.

10

Drivers beware: sleepiness vs. drunkenness

Study compared effects on performance of Study compared effects on performance of sleep deprivation and alcoholsleep deprivation and alcohol11

Drivers who went 17-19 hours without Drivers who went 17-19 hours without sleep = drivers with 0.05% BACsleep = drivers with 0.05% BAC

Sleepy drivers responded ~50% more Sleepy drivers responded ~50% more slowly/less accuracy than fully awake slowly/less accuracy than fully awake driversdrivers

Sleepiness can compromise performance Sleepiness can compromise performance needed for road and job safetyneeded for road and job safety

1. Williamson AM & Feyer AM. Occup Environ Med; 2000.

11

Patient assessment

12

Is sleep the new vital sign?

Growing evidence shows that sleep is an Growing evidence shows that sleep is an important ingredient in good healthimportant ingredient in good health11

Few MDs address sleep quality in their Few MDs address sleep quality in their practices practices <10% of patient charts document sleep <10% of patient charts document sleep

historyhistory22

Sleep disorders are underdiagnosed, Sleep disorders are underdiagnosed, undertreated undertreated

1. Wilson JF. Am Coll Physicians; 2005; 2. Namen AM, et al. South Med J; 2001.

13

Pathophysiology of EDS EDS is not a disorder – but a symptomEDS is not a disorder – but a symptom11

CausesCauses22:: CNS abnormalities, e. g. narcolepsyCNS abnormalities, e. g. narcolepsy Sleep deficiency, e. g. sleep apneaSleep deficiency, e. g. sleep apnea Circadian imbalances, e. g. jet lag Circadian imbalances, e. g. jet lag Drug side effects, e. g. marijuanaDrug side effects, e. g. marijuana

1. Beers MH, et al. Merck Manual of Diagnosis and Therapy; 2006; 2. Roth T & Roehrs TA. Clin Ther; 1996.

14

How does the patient report symptoms? I’m tiredI’m tired I feel lazyI feel lazy I have low energyI have low energy I feel drowsyI feel drowsy I feel sleepy I feel sleepy

15

Assess for other psychiatric comorbidities Symptoms of depression?Symptoms of depression? Mood or memory problems? Mood or memory problems? Does patient fall asleep suddenly?Does patient fall asleep suddenly? Is the patient a “night owl”?Is the patient a “night owl”? Does the patient drink or take drugs?Does the patient drink or take drugs? How many hours sleep per night, including How many hours sleep per night, including

weekends and weekdays?weekends and weekdays?

16

Epworth SleepinessScale A quick, in-office testA quick, in-office test11

Assesses whether a person will get sleepy in Assesses whether a person will get sleepy in certain situationscertain situations

Use this scale for each situation:Use this scale for each situation: 0 = would 0 = would nevernever doze or sleep doze or sleep 1 = 1 = slight slight chance of dozing or sleepingchance of dozing or sleeping 2 = 2 = moderatemoderate chance of dozing or sleeping chance of dozing or sleeping 3 = 3 = highhigh chance of dozing or sleeping chance of dozing or sleeping

1. Johns MW. Sleep; 1991.

17

Epworth SleepinessScaleSitting and readingSitting and reading 00

Watching TVWatching TV 11

Sitting in a public placeSitting in a public place 11

Riding in a car as a passenger for ≥1 hourRiding in a car as a passenger for ≥1 hour 22

Lying down in the afternoon Lying down in the afternoon 22

Sitting and talking to someone Sitting and talking to someone 00

Sitting quietly after lunch (no alcohol)Sitting quietly after lunch (no alcohol) 11

Stopped for a few minutes in traffic Stopped for a few minutes in traffic while driving while driving

00

1. Johns MW. Sleep; 1991.

18

Rule out other medical conditions1

StrokeStroke Tumors/cystsTumors/cysts Vascular malformationsVascular malformations Head traumaHead trauma CNS infections (sleeping sickness)CNS infections (sleeping sickness) ParkinsonismParkinsonism Alzheimer's, other dementiasAlzheimer's, other dementias

1. Black JE, et al. Neurol Clin; 2005.

19

Differential Diagnosis

20

Most frequent causes of EDS Insufficient sleep syndromeInsufficient sleep syndrome Obstructive sleep apneaObstructive sleep apnea Substance/medication useSubstance/medication use Shift-work sleep disorder Shift-work sleep disorder Delayed sleep-phase syndromeDelayed sleep-phase syndrome NarcolepsyNarcolepsy Periodic limb movement disorders Periodic limb movement disorders

21

Insufficient sleepsyndrome Have patient keep a sleep logHave patient keep a sleep log11

BedtimesBedtimes Number/time of awakeningsNumber/time of awakenings Arising timesArising times Frequency/duration of napsFrequency/duration of naps Bedtime events (food, alcohol, physical Bedtime events (food, alcohol, physical

activity)activity)

1. Beers MH, et al. Merck Manual of Diagnosis and Therapy; 2006.

22

Falling asleep vs. staying asleep Difficulty Difficulty fallingfalling asleep asleep11

Suggests delayed sleep phase syndromeSuggests delayed sleep phase syndrome Chronic psychophysiologic insomniaChronic psychophysiologic insomnia Inadequate sleep hygieneInadequate sleep hygiene Restless legs syndromeRestless legs syndrome

Difficulty Difficulty stayingstaying asleep asleep Suggests advanced sleep phase syndromeSuggests advanced sleep phase syndrome Major depressionMajor depression Sleep apneaSleep apnea Limb movement disorderLimb movement disorder Aging Aging

1. Beers MH, et al. Merck Manual of Diagnosis and Therapy; 2006.

23

Most frequent causes of EDS Insufficient sleep syndromeInsufficient sleep syndrome Obstructive sleep apneaObstructive sleep apnea Substance/medication useSubstance/medication use Shift-work sleep disorder Shift-work sleep disorder Delayed sleep-phase syndromeDelayed sleep-phase syndrome NarcolepsyNarcolepsy Periodic limb movement disorders Periodic limb movement disorders

24

Obstructive sleep apnea Absence of breathing during sleepAbsence of breathing during sleep Obstruction of airways Obstruction of airways snoring, decrease snoring, decrease

in oxygen saturation of hemoglobin, arousalin oxygen saturation of hemoglobin, arousal11 Result is disturbed sleep and EDSResult is disturbed sleep and EDS Most common diagnosis of patients with Most common diagnosis of patients with

complaint of EDS who seek care at US sleep complaint of EDS who seek care at US sleep centerscenters22

Almost 7 out of 10 patients Almost 7 out of 10 patients

1. Victor LD. Am Fam Physician; 1999; 2. Punjabi NM, et al. Sleep; 2000.

25

Obstructive sleepapnea Associated with: Associated with:

Not only CVD and obesity, but also:Not only CVD and obesity, but also: Metabolic syndromeMetabolic syndrome1 1

Untreated OSA Untreated OSA Direct/deleterious effects Direct/deleterious effects on CV function and structureon CV function and structure33

Sympathetic activationSympathetic activation Oxidative stressOxidative stress InflammationInflammation Endothelial dysfunctionEndothelial dysfunction

1. Vgontzas AN, et al. Sleep Med Rev; 2005; 2. Shamsuzzaman AS, et al. JAMA; 2003; 3. Narkiewicz K, et al. Curr Cardiol Rep; 2005.

26

Obstructive sleepapnea Systolic BP and heart rateSystolic BP and heart rate11

CRP concentrationsCRP concentrations11

May contribute to ischemia, CHF, arrhythmia, May contribute to ischemia, CHF, arrhythmia, cerebrovascular disease, strokecerebrovascular disease, stroke

Atrial fibrillation can predict OSAAtrial fibrillation can predict OSA22

49% vs. 32% who do not have OSA49% vs. 32% who do not have OSA 1 in 15 has moderate to severe OSA1 in 15 has moderate to severe OSA33

1 in 5 has mild OSA1 in 5 has mild OSA

1. Meier-Ewert HK, et al. J Am Coll Cardiol; 2004; 2. Gami AS, et al. Circulation; 2004; 3. Shamsuzzaman AD, et al. JAMA; 2003.

27

Physical examfor OSA Check for: Check for: 11

Obesity, especially at midriff & neckObesity, especially at midriff & neck Jaw and tongue abnormalitiesJaw and tongue abnormalities Nasal obstruction; enlarged tonsils Nasal obstruction; enlarged tonsils Expiratory wheezingExpiratory wheezing Spinal curvatureSpinal curvature Note signs of R ventricular failure Note signs of R ventricular failure

Edema, abdominal distentionEdema, abdominal distention1. Beers MH, et al. Merck Manual of Diagnosis and Therapy; 2006.

28

Most frequent causes of EDS Insufficient sleep syndromeInsufficient sleep syndrome Obstructive sleep apneaObstructive sleep apnea Substance/medication useSubstance/medication use Shift-work sleep disorder Shift-work sleep disorder Delayed sleep-phase syndromeDelayed sleep-phase syndrome NarcolepsyNarcolepsy Periodic limb movement disorders Periodic limb movement disorders

29

Substance/medication use

EDS can be a sign of drug-dependent and EDS can be a sign of drug-dependent and drug-induced sleep disordersdrug-induced sleep disorders11 Chronic use of stimulantsChronic use of stimulants Hypnotics, sedativesHypnotics, sedatives Antimetabolite therapyAntimetabolite therapy OCs; thyroid medicationsOCs; thyroid medications Withdrawal from CNS depressantsWithdrawal from CNS depressants

1. Beers MH, et al. Merck Manual of Diagnosis and Therapy; 2006.

30

Substance/medication use

Review the patient’s Rx drug useReview the patient’s Rx drug use Check for interactions,high dosesCheck for interactions,high doses

Inquire about OTC medicationsInquire about OTC medications Diphenhydramine, anticholinergicsDiphenhydramine, anticholinergics

Take alcohol history Take alcohol history Interaction with Rx or OTCs?Interaction with Rx or OTCs?

Ask about recreational drug useAsk about recreational drug use

1. Beers MH, et al. Merck Manual of Diagnosis and Therapy; 2006.

31

Most frequent causes of EDS Insufficient sleep syndromeInsufficient sleep syndrome Obstructive sleep apneaObstructive sleep apnea Substance/medication useSubstance/medication use Shift-work sleep disorderShift-work sleep disorder Delayed sleep-phase syndromeDelayed sleep-phase syndrome NarcolepsyNarcolepsy Periodic limb movement disorders Periodic limb movement disorders

32

Shift-work disorder

Circadian rhythm sleep disorderCircadian rhythm sleep disorder11

Internal/environmental sleep-wake Internal/environmental sleep-wake cadence out of synchcadence out of synch

Insomnia, EDS, or bothInsomnia, EDS, or both11

~10% of the night and rotating shift work ~10% of the night and rotating shift work populationpopulation22

4-fold 4-fold in sleepiness-related accidents, in sleepiness-related accidents, absenteeism, depressionabsenteeism, depression22

1. Beers MH, et al. Merck Manual of Diagnosis and Therapy; 2006; 2. Drake CL, et al. Sleep; 2004.

33

Shift-work disorder

Resolves as body clock realignsResolves as body clock realigns11

Fixed-shift work is preferableFixed-shift work is preferable Full-time night or eveningFull-time night or evening

Rotating shifts should go clockwiseRotating shifts should go clockwise Day Day Evening Evening Night Night

Helpful: Bright light, masks, white noiseHelpful: Bright light, masks, white noise Short tShort t1/21/2 hypnotics, wake-promoting drugs hypnotics, wake-promoting drugs

used judiciouslyused judiciously1. Beers MH, et al. Merck Manual of Diagnosis and Therapy; 2006.

34

Most frequent causes of EDS Insufficient sleep syndromeInsufficient sleep syndrome Obstructive sleep apneaObstructive sleep apnea Substance/medication useSubstance/medication use Shift-work sleep disorder Shift-work sleep disorder Delayed sleep-phase syndromeDelayed sleep-phase syndrome NarcolepsyNarcolepsy Periodic limb movement disorders Periodic limb movement disorders

35

Delayed-sleep phase syndrome Sleep cycle out of synch with desired wake Sleep cycle out of synch with desired wake

timestimes11

Problem: Going to sleep and awakening late Problem: Going to sleep and awakening late (3AM and 10AM)(3AM and 10AM)

If earlier wake times are necessary, then EDS If earlier wake times are necessary, then EDS can resultcan result Poor performance in work/school Poor performance in work/school

Improved sleep hygiene is keyImproved sleep hygiene is key

1. Beers MH, et al. Merck Manual of Diagnosis and Therapy; 2006.

36

Most frequent causes of EDS Insufficient sleep syndromeInsufficient sleep syndrome Obstructive sleep apneaObstructive sleep apnea Substance/medication useSubstance/medication use Shift-work sleep disorder Shift-work sleep disorder Delayed sleep-phase syndromeDelayed sleep-phase syndrome NarcolepsyNarcolepsy Periodic limb movement disorders Periodic limb movement disorders

37

Narcolepsy

Pathologic sleepiness, sudden loss of muscle Pathologic sleepiness, sudden loss of muscle tone (cataplexy), fragmented sleep, sleep tone (cataplexy), fragmented sleep, sleep paralysisparalysis11

Affects 1 out of 2,000 peopleAffects 1 out of 2,000 people22

140,000 Americans140,000 Americans22

Delay of 10 yr from onset to diagnosis is Delay of 10 yr from onset to diagnosis is commoncommon11

The cause is unknownThe cause is unknown

1. Beers MH, et al. Merck Manual of Diagnosis and Therapy; 2006; 2. Ohayon MM, et al. Neurology; 2002.

38

Narcolepsy - Pathophysiology Cause? – Cause? – hypocretin-secreting neurons hypocretin-secreting neurons1,21,2

Regulate arousal state in hypothalamusRegulate arousal state in hypothalamus Marker – REM sleep during Marker – REM sleep during ≥≥2 daytime naps2 daytime naps33

DysfunctionalDysfunctional switching to REM sleep switching to REM sleep wakefulness during sleepwakefulness during sleep33

Patients are mentally awake but physically Patients are mentally awake but physically in REM sleep – sleep paralysis syndrome.in REM sleep – sleep paralysis syndrome.

1. Thannickal TC, et al. Neuron; 2000; 2. Sutcliffe JG & de Lecea. Nat Rev Neurosci; 2002; 3. Scammell T. Ann Neurol; 2003.

39

Narcolepsy - Pathophysiology Genetic predispositionGenetic predisposition11

Familial clusteringFamilial clustering 10- to 40-fold 10- to 40-fold vs. general population vs. general population

Hallmark symptom – cataplexyHallmark symptom – cataplexy Bilateral weaknessBilateral weakness22

Prevalence ~ 75%Prevalence ~ 75%22

1. Nishino S, et al. Sleep Med Rev; 2000; 2. Beers MH, et al. Merck Manual of Diagnosis and Therapy; 2006.

40

Narcolepsy – Diagnosis Diagnostic for narcolepsyDiagnostic for narcolepsy11

History of cataplexyHistory of cataplexy Nocturnal polysomnographyNocturnal polysomnography MSLTMSLT

Differential diagnosisDifferential diagnosis11

Lesions of brain stem, hypothalamusLesions of brain stem, hypothalamus Encephalitis, metabolic disordersEncephalitis, metabolic disorders

Urine and blood exams can confirm non-Urine and blood exams can confirm non-narcoleptic EDSnarcoleptic EDS11

1.Beers MH, et al. Merck Manual of Diagnosis and Therapy; 2006.

41

Most frequent causes of EDS Insufficient sleep syndromeInsufficient sleep syndrome Obstructive sleep apneaObstructive sleep apnea Substance/medication useSubstance/medication use Shift-work sleep disorder Shift-work sleep disorder Delayed sleep-phase syndromeDelayed sleep-phase syndrome NarcolepsyNarcolepsy Periodic limb movement disordersPeriodic limb movement disorders

42

Periodic limb movement disorders Abnormal twitching/kicking of legs during Abnormal twitching/kicking of legs during

sleepsleep11

Interferes with nocturnal sleep Interferes with nocturnal sleep EDS EDS ~10% of adults~10% of adults22

Restless legs syndromeRestless legs syndromeMore common in middle/later yearsMore common in middle/later yearsCreeping/crawling sensationsCreeping/crawling sensations

Abnormalities in dopamine transmissionAbnormalities in dopamine transmission22

1.Beers MH, et al. Merck Manual of Diagnosis and Therapy; 2006; 2. Hornyak M, et al. Sleep Med Rev; 2006.

43

Periodic limb movement disorders

Often occurs in narcolepsy and OSAOften occurs in narcolepsy and OSA11

Seen in pregnancy, renal/hepatic failure, Seen in pregnancy, renal/hepatic failure, anemia and other disordersanemia and other disorders

Sleep history/partner’s testimony Sleep history/partner’s testimony Test: Iron, anemia, kidney/liver functionTest: Iron, anemia, kidney/liver function Dopamine agonists can be helpfulDopamine agonists can be helpful

1.Beers MH, et al. Merck Manual of Diagnosis and Therapy; 2006; 2. Hornyak M, et al. Sleep Med Rev; 2006.

44

When to refer?

45

Know when to treatand when to refer Can condition be treated via sleep hygiene?Can condition be treated via sleep hygiene?

Insufficient sleep syndromeInsufficient sleep syndrome Substance/medication useSubstance/medication use Delayed sleep-phase syndromeDelayed sleep-phase syndrome Shift-work sleep disorder Shift-work sleep disorder

Counsel on sleep architectureCounsel on sleep architecture Do blood work, RFTs/LFTsDo blood work, RFTs/LFTs Prescribe sedatives prudently Prescribe sedatives prudently

46

Know when to treatand when to refer Refer when diagnosis appears to be:Refer when diagnosis appears to be:

Obstructive sleep apneaObstructive sleep apneaPulmonologist, sleep clinic, surgeonPulmonologist, sleep clinic, surgeon

NarcolepsyNarcolepsyNeurologist, sleep clinic Neurologist, sleep clinic

Periodic limb movement disordersPeriodic limb movement disorders Internist, endocrinologist, sleep clinicInternist, endocrinologist, sleep clinic

47

The sleep clinic

Sleep studies evaluate EDS as well as OSA, Sleep studies evaluate EDS as well as OSA, narcolepsy, periodic limb movement disordersnarcolepsy, periodic limb movement disorders

PolysomnographyPolysomnography11

Data accumulated from patient as s/he Data accumulated from patient as s/he sleeps sleeps

Quantifies sleep adequacyQuantifies sleep adequacy Determines what causes EDSDetermines what causes EDS

1. AARC-APT. Respir Care; 1995.

48

The sleep clinic - Polysomnography MeasuresMeasures11::

EEGEEG Eye movementsEye movements Heart rateHeart rate OO22 saturation saturation Muscle tone & activityMuscle tone & activity

All-night testAll-night test

1. AARC-APT. Respir Care; 1995; 2. Beers MH, et al. Merck Manual of Diagnosis and Therapy; 2006.

49

The sleep clinic – MSLT Multiple Sleep Latency Test Multiple Sleep Latency Test

Complimentary test for narcolepsyComplimentary test for narcolepsy11

Assesses speed of sleep onsetAssesses speed of sleep onset REM sleep is monitoredREM sleep is monitored All-day test: 8-10 hoursAll-day test: 8-10 hours High ESS scores ~ Low MSLT scoresHigh ESS scores ~ Low MSLT scores22

1. Beers MH, et al. Merck Manual of Diagnosis and Therapy; 2006; 2. Chervin RD, et al. J Psychosom Res; 1997.

50

Treatment

51

Non-pharmacologictreatment Rationale – To improve natural sleepRationale – To improve natural sleep Counsel patients on good sleep hygieneCounsel patients on good sleep hygiene11

Regular sleep scheduleRegular sleep schedule Restrict time in bedRestrict time in bed Sleep-conductive environmentSleep-conductive environment ExerciseExercise Avoid stimulantsAvoid stimulants Incorporate relaxation techniquesIncorporate relaxation techniques

1. Beers MH, et al. Merck Manual of Diagnosis and Therapy; 2006

52

Pharmacotherapy – Hypnotics Rationale – To treat insomniaRationale – To treat insomnia Sleep-onset insomniaSleep-onset insomnia

Use drugs with shorter tUse drugs with shorter t1/21/2 Zalepon, zolpidem, triazolamZalepon, zolpidem, triazolam

Sleep-maintenance insomniaSleep-maintenance insomnia Use drugs with longer tUse drugs with longer t1/21/2

Temazepam, eszopiclone Temazepam, eszopiclone

1. Beers MH, et al. Merck Manual of Diagnosis and Therapy; 2006

53

Pharmacotherapy – Hypnotics Use with caution in elderly, pulmonary Use with caution in elderly, pulmonary

insufficiency insufficiency To To tolerance, use lower doses for brief tolerance, use lower doses for brief

periods; taper off slowlyperiods; taper off slowly In patients who continue to have EDS, stop or In patients who continue to have EDS, stop or

switch the drug switch the drug Monitor for amnesia, hallucinations, Monitor for amnesia, hallucinations,

incoordination, fallsincoordination, falls

1. Beers MH, et al. Merck Manual of Diagnosis and Therapy; 2006

54

Pharmacotherapy –Stimulants Rationale – To improve alertness Rationale – To improve alertness Methylphenidate, amphetaminesMethylphenidate, amphetamines Indirect-acting sympathomimeticsIndirect-acting sympathomimetics11

Produce behavioral activation and Produce behavioral activation and increased arousal, motor activity, alertnessincreased arousal, motor activity, alertness

Used mostly for EDS; ineffective for Used mostly for EDS; ineffective for cataplexycataplexy1, 21, 2

Immediate- or extended-release formsImmediate- or extended-release forms11

1. Mitler MM & Hayduk R. Drug Saf; 2002; 2. Littner M, et al. Sleep; 2001.

55

Pharmacotherapy –Stimulants MPH and the amphetamines are Schedule IIMPH and the amphetamines are Schedule II

Carry the risk of substance abuse/illicit useCarry the risk of substance abuse/illicit use Rebound hypersomnia or tolerance to alerting Rebound hypersomnia or tolerance to alerting

agent can occuragent can occur11

Switch to a different drug class or provide Switch to a different drug class or provide drug holidaydrug holiday

1. Black JE, et al. Neuro Clin; 2005.

56

Pharmacotherapy – Modafanil Rationale – To promote wakefulnessRationale – To promote wakefulness Approved for narcolepsy-associated EDSApproved for narcolepsy-associated EDS Ill-defined MOA (not a stimulant)Ill-defined MOA (not a stimulant)11

Activates hypocretin-secreting neuronsActivates hypocretin-secreting neurons1,21,2

Does not control cataplexyDoes not control cataplexy11

Long-acting – once-daily dosingLong-acting – once-daily dosing Peak plasma concentrations – 2-4 hrPeak plasma concentrations – 2-4 hr33

Small afternoon booster dose can be usedSmall afternoon booster dose can be used44

1. US Modafinil. Ann Neurol; 1998; 2. Willie JT, et al. Neuroscience; 2005; 3. Provigil PI; 2004; 4. Beers MH, et al. Merck Manual of Diagnosis and Therapy; 2006.

57

Pharmacotherapy – Modafanil isomer Isomer formulation – Isomer formulation – rr-modafanil or -modafanil or

armodafanil – also being evaluated armodafanil – also being evaluated Once daily for EDSOnce daily for EDS22

r-r-isomer Tisomer T1/2 1/2 = 10-14 hr vs. 3-4 hr for = 10-14 hr vs. 3-4 hr for s-s-

isomerisomer Higher peak concentrations vs. racemic Higher peak concentrations vs. racemic

mixturemixture No efficacy/safety advantage over modafainilNo efficacy/safety advantage over modafainil22

1. Harsh JR, et al. Curr Med Res Opin; 2006; 2. Dinges DF, et al. Curr Med Res Opin; 2006.

58

Pharmacotherapy – Sodium oxybate Rationale – To treat EDS, narcolepsyRationale – To treat EDS, narcolepsy FDA-approved for treatment FDA-approved for treatment of EDS and of EDS and

cataplexycataplexy in narcolepsy in narcolepsy11

MOA largely unknownMOA largely unknown22 Rapidly acting hypnotic (TRapidly acting hypnotic (Tmaxmax 0.5-1.25 hr) 0.5-1.25 hr)22

Short tShort t½½ (0.5-1 hr) (0.5-1 hr)22

duration of stages 3, 4 sleepduration of stages 3, 4 sleep First REM sleep First REM sleep , then with continued , then with continued

use, REM sleep use, REM sleep 1. FDA. FDA Talk Paper; 2002; 2006; 2. Xyrem PI; 2005.

59

Pharmacotherapy – Sodium oxybate Studies show efficacy in Studies show efficacy in cataplexy and cataplexy and

EDSEDS1, 2, 31, 2, 3

cataplexy attacks, ESS scorescataplexy attacks, ESS scores Can be used with modafinilCan be used with modafinil44

nightly awakeningsnightly awakenings Dosing: twice nightlyDosing: twice nightly

Taken HS, then at 2.5-4 hrs after the sleep Taken HS, then at 2.5-4 hrs after the sleep beginsbegins

1. Xyrem. Sleep Med. 2005; 2. Xyrem. Sleep; 2003; 3. Xyrem. Sleep; 2002; 4. Xyrem. Sleep Med; 2004; 5. Bogan RK. Sleep. 2005; 6. Xyrem PI, 2005.

60

Pharmacotherapy – Sodium oxybate Potential drug of abuse (CIII)Potential drug of abuse (CIII)11

Enforced as Schedule I Enforced as Schedule I Special distribution requirementsSpecial distribution requirements22

Use of a central pharmacyUse of a central pharmacy Registration of prescribing MD Registration of prescribing MD Pharmacy verification of MD’s eligibility Pharmacy verification of MD’s eligibility

to prescribeto prescribe Registration/required reading of Registration/required reading of

materials by patient materials by patient 1. FDA. FDA Talk Paper; 2002; 2006; 2. Xyrem PI; 2005.

61

Continuous positiveairway pressure Rationale – To correct OSARationale – To correct OSA Reverses EEG slowing for both REM sleep Reverses EEG slowing for both REM sleep

and wakefulnessand wakefulness11

Improves symptoms of EDSImproves symptoms of EDS11

MSLT scoresMSLT scores Persistent EDS 2° to obesityPersistent EDS 2° to obesity

Used at home but pressure is set in sleep Used at home but pressure is set in sleep clinic firstclinic first

1. Morisson F, et al. Chest; 2001.

62

Surgery

RationaleRationale – To correct anatomical flaws– To correct anatomical flaws UPPP is the most common procedureUPPP is the most common procedure

Enlarges airwaysEnlarges airways Submucosal tissue resection from Submucosal tissue resection from

tonsillar pillars; adenoid resectiontonsillar pillars; adenoid resection Not suitable for obese patientsNot suitable for obese patients

Trachestomy – last resort Trachestomy – last resort May take May take ≥1 year to heal≥1 year to heal

1. Beers MH, et al. Merck Manual of Diagnosis and Therapy; 2006

63

Conclusions

EDS EDS quality of life; can cause serious quality of life; can cause serious consequences consequences

EDS may be a sign of sleep apnea, EDS may be a sign of sleep apnea, narcolepsy or a symptom of another condition narcolepsy or a symptom of another condition

Patients who complain of EDS should be Patients who complain of EDS should be assessed in a step-wise manner to rule out assessed in a step-wise manner to rule out the various conditions that can cause it the various conditions that can cause it

Know when to treat and when to referKnow when to treat and when to refer