Sleep Disorders

Joel C. Marrs, Pharm.D., BCPSClinical Assistant Professor

OSU/OHSU College of PharmacyOSU/OHSU College of PharmacyApril 17, 2008

Learning Objectives

Distinguish between the different categories of sleep disorders and identify specific causes of eachdisorders and identify specific causes of each.Explain the epidemiology and pathophysiology of insomnia, restless leg syndrome, narcolepsy, and obstructive sleep apnea.obstructive sleep apnea. Recognize the common signs and symptoms associated with insomnia, restless leg syndrome, narcolepsy, and obstructive sleep apnea.p pSummarize the key components of appropriate sleep hygiene.Differentiate between the pharmacokinetic parametersDifferentiate between the pharmacokinetic parameters and side effect profiles of the different prescription and non-prescription sleep agents.

Learning ObjectivesLearning Objectives

Assess the appropriateness of insomnia treatment for pp ppatients with psychiatric illness and for the elderly.Explain the non-pharmacologic and pharmacologic treatment of restless leg syndrome.treatment of restless leg syndrome.Describe pharmacologic treatments available for patients with narcolepsy.U d t d th t t t f b t ti lUnderstand the treatment of obstructive sleep apnea.Recommend an appropriate treatment regimen for a patient with insomnia, restless leg syndrome, or g ynarcolepsy, if given a specific case.

I iInsomnia

Insomnia TermsInsomnia Terms

LPS = Latency to Persistent SleepLPS = Latency to Persistent Sleep QOS = Quality of SleepSOL Sl O t L tSOL = Sleep Onset Latency TST = Total Sleep TimeWASO = Wake After Sleep Onset

What is Insomnia?What is Insomnia?

The perception or complaint of poor qualityThe perception or complaint of poor quality sleep because of one of the following:• Difficulty falling asleep• Difficulty falling asleep• Waking up frequently during the night with

difficulty returning to sleepdifficulty returning to sleep• Waking up to early in the morning

Unrefreshing sleep• Unrefreshing sleep

Types of InsomniaTypes of Insomnia

Transient insomniaCause: brief adjustment reaction, rotating shifts, international travelDuration: few daysDuration: few days

Short-term insomniaCause: significant life stressor (e.g., illness, job change bereavement dissolution of a relationship)change, bereavement, dissolution of a relationship)Duration: 4-28 days

Chronic insomniaCause: primary insomnia, circadian rhythm sleep disorder, chronic medical condition, psychiatric illnessDuration: 1 month to several yearsy

EpidemiologyEpidemiologyInsomnia is the most common sleep disorder in pthe USIncidence increases with ageWomen > MenIncreased incidence:• Low socioeconomic status• Divorced, widowed, or separated• Recent stress• Recent stress• Depression• Drug or ETOH abuse

Sleep AwakeningsSleep Awakenings

1.21.41.6

enin

gs

0.60.8

1

r of A

wak

e

00.20.4

Num

ber

Younger Patients Older Patients

Female Male

McCall WV. Prim Care Companion J Clin Psychiatry 2004;6:9-20.

Elderly Sleep ComplaintsElderly Sleep ComplaintsAwakes not Rested (n = 9282; mean age = 74 years)

Daytime Napping

Trouble Falling Asleep

Awakes too Early

Nocturnal Awakening

Insomnia

Daytime Napping

Any Chronic Complaint

Difficulty Initiating Sleep

0 20 40 60

Percentageg

Foley DJ, et al. Sleep 1995;18:425-432.

Perceived Quality of SleepPerceived Quality of Sleep60

405060

age

2030

Perc

enta

010 P

0 1 to 3 >/=4

Number of Medical Conditions

Fair/Poor Good Excellent/Very goodFoley D, et al. J Psychosom Res 2004;56:497-502.

Drugs Associated with Insomniag

CNS stimulantsDextroamphetamine

DecongestantsPhenylephrine• Dextroamphetamine

• Methylphenidate• Mixed amphetamines

Antihypertensives

• Phenylephrine• Pseudoephedrine

Hormones• CorticosteroidsAntihypertensives

• Alpha-blockers• Beta-blockers• Methyldopa

Corticosteroids• Thyroid medications

Psychotropics• Atypical antidepressantsy p

• ReserpineRespiratory medications

• Albuterol

yp p• MAO-I• SSRI

Other• Theophylline

Chemotherapy• ETOH• Caffeine• Nicotine

Ancoli-Israel S. J Clin Psychiatry 2005;66(suppl 9):24-30.

Medical Conditions Causing InsomniaInsomnia

Cardiovascular GastrointestinalAnginaArrhythmiasHeart failure

R i t

GERDUlcers

NeurologicRespiratory

AsthmaCOPDSl

DeliriumEpilepsyParkinson’s disease

PSleep apneaChronic painEndocrine

PregnancyPsychiatric

DepressionDiabetesHyperthyroidism

ManiaAnxietySubstance abuse

Jackson CW, Curtis JL. Sleep Disorders. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds. Pharmacotherapy, 6th edition. New York:McGraw-Hill. 2005:1321-1332.

Sleep Cycle

Stage 1 REM (Stage 5)20 25% f l2-5% of sleep

Initiate sleep

20-25% of sleep

Dreaming sleep

Stage 2 Stage 450% of sleep

Light sleep (alpha)

10-15% of sleep

Restorative sleep

Stage 35% of sleep

Deep sleep (delta)

Sleep Cycle

Dopheide JA, Stimmel GL. Sleep Disorders. In: Koda-Kimble MA, Young LY, Kradjan WA, Guglielmo BJ, eds. Applied Therapeutics: The Clinical Use of Drugs, 8th edition. Maryland, Lippincott, Williams & Wilkins, 2005:77-1-77-22.

Pathophysiology of InsomniaPathophysiology of Insomnia

Sleep cycle may be normal in patients withSleep cycle may be normal in patients with primary insomniaSleep pattern alterations in elderlySleep pattern alterations in elderly

Stages 1 & 2 increasedStages 3 & 4 decreased (2% per decade)Stages 3 & 4 decreased (2% per decade)% REM sleep decreasedSuprachiasmatic nucleus deteriorates with ageSup ac as a c uc eus de e o a es ageDecreased secretion of endogenous melatoninMissing or weak external cues

Assessment QuestionsAssessment QuestionsHow much do you sleep during the day?y p g yAt what times of day do you tend to sleep?What is the effect of your sleeping patterns on your daytime ability to function?daytime ability to function?What time do you go to bed at night?Do you snore?Do you have leg discomfort at bedtime?How often do you wake during the night, and when you do how long does it take you to fall back asleep?do, how long does it take you to fall back asleep?What time in the morning do you wake up?What time do you get up for the day?

McCall WV. J Clin Psychiatry 2004;6:9-20.

DSM-IV Diagnostic Criteria of P i I iPrimary Insomnia

Predominant complaint is difficulty initiating or p y gmaintaining sleep or non-restorative sleep for at least 1 month.Sleep disturbance (or associated daytime fatigue)Sleep disturbance (or associated daytime fatigue) causes clinically significant distress or impairment in social, occupational, or other important areas of functioningfunctioning.Sleep disturbance does not occur exclusively during the course of narcolepsy, breathing-related disorder, circadian rhythm sleep disorder or a parasomniacircadian rhythm sleep disorder, or a parasomnia.Disturbance does not occur exclusively during the course of another mental disorder.Disturbance is not caused by the direct physiologic effects of a substance or a general medical condition

Treatment GoalsTreatment Goals

Determine the type of insomnia presentDetermine the type of insomnia presentImprove/resolve insomnia symptomsO ti i ff ti f di tiOptimize effectiveness of medications

Target specific symptomsAddress underlying problemCombine with nonpharmacologic measures

Minimize side effects of medicationsImprove quality of lifeImprove quality of life

Nonpharmacologic TreatmentNonpharmacologic Treatment

Stimulus controlStimulus controlRelaxation therapyP d i l i t tiParadoxical intentionSleep restrictionCognitive-behavioral therapy (CBT)

Greater improvements in sleep parametersGreater improvements in sleep parameters than behavioral techniques or pharmacologic therapy alone

Morin CM, et al. Sleep 1999;22:1134-1156.

Sleep HygieneMaintain homeostatic drive for sleep

A id l t i ti d il iAvoid naps, sleep restriction, daily exerciseMinimize circadian factors of alertness

Keep regular awakening time limit exposure to brightKeep regular awakening time, limit exposure to bright light within 30 min of bedtime

Minimize drug effectsNo tobacco, limit caffeine, limit ETOH

Minimize arousals in sleep settingA id i ft 6 idi ti b fAvoid exercise after 6 pm, avoiding eating before bedtime, keep bedroom quiet and dark, bedtime ritual, use bedroom for sleep only

Lu BS, et al. Chest 2006;130:1915-1923.

PharmacologicPharmacologic TreatmentTreatment

Ideal HypnoticIdeal Hypnotic

Rapid onset of actionRapid onset of actionShort duration of action (6-8 hr)Mi i l ff t l hit tMinimal effect on sleep architectureNo tolerance effectMinimal side effectsNo hangover effectNo hangover effectNo abuse/addition potential

Morin AK, et al. Pharmacotherapy 2007;27:89-110.

OTCAntihistamines

Di h h d i (B d l®)Diphenhydramine (Benadryl®)Onset of action: 30 minutesUsual dose: 25-50 mg po qhs (↑ dose = ↑ SE)Usual dose: 25 50 mg po qhs (↑ dose ↑ SE) Combo products with APAP (Tylenol PM®)SE:

Next day sedationImpaired cognitive functionUrinary retention Blurred vision Orthostatic hypotensionDizzinessPalpitations

OTCAntihistamine

Doxylamine (Unisom Sleep Tabs®)Onset of action: 30 minutesAdult usual dose: 25 mg po qhs (↑ dose = ↑ SE) SE:

Dry mouth• Dry mouth• Blurred vision• Urinary retention• Excitement• Nervousness

Benzodiazepines

Benzodiazepine ReceptorsBenzodiazepine Receptors

GABA Receptor SubunitsGABA Receptor Subunitsα-1 subunits

mediate sedationα-2

mediate anxiolytic and myorelaxation effectsα-3 subunitsα-3 subunits

mediate anxiolytic and myorelaxation effectsα 5 subunitsα-5 subunits

Mediate cognition and processing

Da Settimo F, et al. Current Medicinal Chemistry 2007;14:2680-2701.

Benzodiazepines (BZD)Benzodiazepines (BZD)MOA: binds to BZD receptor and potentiates the p pinhibitor activity of GABAOnset of action: dependent upon BZDLiver metabolizedDependence:

Chronic use (stopping causes rebound insomina)Taper by 25% per week and then lowest dose every other dayy

Tolerance:Shorter acting quicker to develop tolerance

FDA Approved BZDs for InsomniaDose (mg)Dose (mg)

Drug OOA DOA T1/2 Adults Elderly Indication

Estazolam R I 10-24 1-2 0.5-1 SM*

Flurazepam R L 50-120 15-30 NR SM*p

Quazepam R L 39 7.5-15 NR SM*

Temazepam I I 5-17 7.5-30 7.5 SM*

Triazolam R S 1.9-3.9 0.125-0.25 0.125 SO*

OOA = onset of action; DOA = duration of action; SM = sleep maintenance; SO = sleep onset; NR = not recommended; R = Rapid; I = intermediate; L = long

* = FDA approved for short term (7-10 days) management of insomniaapp o ed o s o t te ( 0 days) a age e t o so a

Morin AK, et al. Pharmacotherapy 2007;27:89-110.

Safety of BZDs in ElderlySafety of BZDs in ElderlyS/E:• Memory impairment• Over-sedation• Psychomotor retardation (increase risk of falls)• Psychomotor retardation (increase risk of falls)• Withdrawal symptoms• Paradoxical disinhibition

D i• Depression• LOT

• LorazepamLorazepam• Oxazepam• Temazepam

NonbenzodiazepineS d ti H tiSedative-Hypnotics

(NSH)(NSH)

FDA Approved NSHs for InsomniaDose (mg)Dose (mg)

Drug OOA DOA T1/2 Adults Elderly Indication

BRAEszopiclonea R I 6 2-3 1 SM

Zolpidem IRb R S 2.5 10 5 SO; SM

Zolpidem CRb,c R S 2.5 12.5 6.25 SO; SM

Zaleplonb R S 1 10 5 SO; SMMRARamelteon R S 1-3 8 8 SO

OOA = onset of action; DOA = duration of action; SM = sleep maintenance; SO = sleep onset; R =OOA onset of action; DOA duration of action; SM sleep maintenance; SO sleep onset; R Rapid; I = intermediate; BRA = benzodiazepine receptor agonist; MRA = melatonin receptor agonistaFDA approved for chronic insomnia bFDA approved for short term (7-10 days) management of insomniacCR formulation recommended for sleep maintenance

Morin AK, et al. Pharmacotherapy 2007;27:89-110.

Zolpidem PharmacokineticsZolpidem Pharmacokinetics

100120140

plas

ma

(ng/

ml)

406080

100

pide

m p

ntra

tion

(

02040

0 5 0 0 0 40 0 0Zo

lco

ncen

0.0 0.5 1.0 2.0 3.0 4.0 6.0 8.0

Time (hr)

12.5 mg Zolpidem CR 10 mg Zolpidem IR

Ambien CR Package Insert. Bridgewater, NJ: Sanofi-aventis; 2006.

Side EffectsDrug Side Effect

Zolpidem IR/ER Headache, somnolence, dizziness, difficulty with coordinationcoordination

Zaleplon Somnolence, dizziness, lightheadedness, difficulty with coordination

Eszopiclone Headache, somnolence, unpleasant taste dry mouthunpleasant taste, dry mouth

Ramelteon (<1%) Somnolence, dizziness, h d hheadache, nausea

Sl A t Effi P t

EfficacySleep Agent Efficacy Parameter

Zolpidem IR (Ambien®) ↑ TST↓ WASO↓ Sleep Latency

Zolpidem ER (Ambien CR®) ↓ WASO↓ Sleep Latency↓ Sleep Latency

Zaleplon (Sonata®) ↑ TST ↓ Sleep Latency↑ Sleep Quality

Eszopiclone (Lunesta®) ↑ TST↓ WASO↓ WASO↓ Sleep Latency↓ Nap time

R lt (R ®) ↑ TSTRamelteon (Rozerem®) ↑ TST↓ Sleep latency

Trazodone (Desyrel®)Trazodone (Desyrel®)MOA: triazolopyridine which is a specific py pinhibitor of serotonin (5-HT). Antagonist at 5-HT1A, 5-HT1C, and 5-HT2 receptorsDose: 25-100 mg po hsDose: 25-100 mg po hsHalf-life: Adults (6.4 hrs); elderly (11.6 hrs)1 trial in primary insomnia without depressionp y pEfficacy:

↑ Sleep quality↓ Sleep latency↓ Sleep latency↑ Next day sedation↑ Difficulty awakening

Tricyclic Antidepressants (TCA)Tricyclic Antidepressants (TCA)MOA: Inhibit the reuptake of 5-HT and NE, p ,block H1 receptors and alpha receptorsStrong sedation

AmitriptylineDoxepinClomipramineClomipramine

Moderate sedationImipraminep a eDesipramineNortriptyline

Medicare Part DMedicare Part D ExclusionsExclusions

BenzodiazepinesBarbituratesOTC’s

Insomnia medicationsBrand name products

Non-formularyNon preferred (needing prior authorization)Non-preferred (needing prior-authorization)2nd or 3rd tier

Maximum # per month

Case QuestionCase QuestionAL is a 75-year-old female who complains of y pawakening in the middle of the night for the past few months. Which of the following sleep agents would be most beneficial for AL basedagents would be most beneficial for AL based on her sleep complaints?

a. triazolamb. diphenhydraminec. ramelteond. zolpideme flurazepame. flurazepam

Restless Leg SyndromeRestless Leg Syndrome(RLS)(RLS)

What is RLS?What is RLS?

The symptomatic urge to move the legsThe symptomatic urge to move the legs that is usually accompanied or caused by uncomfortable or unpleasant sensationsuncomfortable or unpleasant sensations deep within the legs.

Ryan M, et al. Journal of Pharmacy Practice 2007;20:430-448.

Epidemiology of RLSOccurs in 7-10% general populationFemale > male25-30% patients with the following risk factors will have secondary RLS:

Iron deficiencyIron deficiencyPregnancyEnd-stage renal disease (uremia)Anemia

Prevalence and disease severity increase with agePossible genetic etiologyPossible genetic etiology

Family history of RLS reported in 40-90% of patients with idiopathic RLS

McCrink L, et al. Sleep Med. 2007;8:73-83.Phillips B, et al. Arch Int med. 2000;160:2137-41.

Sun ER, et al. Sleep 1998;21:371-77.

Pathophysiology of RLSPathophysiology of RLS

Dopaminergic hypothesisDopaminergic hypothesisDopaminergic mechanisms involved in spinal flexor reflex controlDopamine agonists provide symptomatic relief of RLSDopamine agonists provide symptomatic relief of RLSLack of dopamine or the presence of dopamine antagonists causes or worsens symptoms of RLS

Iron deficiency hypothesisTherapeutic benefit of iron administrationTherapeutic benefit of iron administrationLower iron levels in substantia nigraLower iron and ferritin in CSF with normal serum iron

Ryan M, et al. Journal of Pharmacy Practice 2007;20:430-448.

Diagnostic Criteria for RLSEssential Diagnostic Criteria

Symptomatic urge to move legs usually accompanied or caused by uncomfortable/unpleasant sensations in legscaused by uncomfortable/unpleasant sensations in legsSymptoms begin or worsen during periods of restSymptoms are partially or totally relieved by movementSymptoms are at its worst or only occurs in the evening or atSymptoms are at its worst or only occurs in the evening or at night

Supportive Clinical FeaturesFamily historyFamily historyResponse to dopaminergic therapyPeriodic limb movements (while asleep or awake)

Associated FeaturesAssociated FeaturesNatural clinical course of the disorderSleep disturbancesTypically normal neurologic exam resultsTypically normal neurologic exam results

Allen PP, et al. Sleep Med. 2003;4:101-119.

Types of RLSIntermittent RLS

Less than daily frequency of symptomsLess than daily frequency of symptomsTroublesome enough to require treatment

Daily RLSDaily RLSDaily frequency of symptoms Troublesome enough to require daily treatmentg q y

Refractory RLSDaily frequency with worsening symptomsy q y g y pFailed daily monotherapy treatment

Silber MH, et al. Mayo Clin Proc. 2004;79:916-22.

Role of Sleep Studies in Diagnosis of RLSRLS

Polysomnography not required forPolysomnography not required for diagnosis, but useful to rule out other potential sleep disorderspotential sleep disorders>90% patients with RLS will have periodic limb movements in sleeplimb movements in sleepPeriodic limb movements also can occur d i k f l i RLSduring wakefulness in RLS

RLS Treatment GoalsRLS Treatment Goals

Decrease nights with RLS symptomsDecrease nights with RLS symptomsDecrease symptom severityD i htti k iDecrease nighttime awakeningsDecrease day time sleepinessImprove quality of sleepImproving overall quality of lifeImproving overall quality of life

Nonpharmacologic Treatment of RLSRegular exerciseGood sleep hygieneRecommend mental alertness activities Discontinue drugs that may precipitate or aggravate RLS

NicotineNicotineCaffeineAlcoholAntidepressants: SSRI’s, TCA’sAntiemetics: metoclopramide, prochlorperazineD i t i tDopamine antagonistsDiphenhydramine

Silber MH, et al. Mayo Clin Proc. 2004;79:916-22.Hening W, et al. Sleep. 1999;22:970-999.

Intermittent RLS

Nonpharmacologic

Pharmacologic

Dopamine AgonistsLevodopa/ Carbidopa

Low potency Opioid

BZDspp

Silber MH, et al. Mayo Clin Proc. 2004;79:916-22.

Iron Replacement TherapyIron Replacement TherapyCheck iron studies (ferritin, TSAT)Check iron studies (ferritin, TSAT)Only effective if patient is iron deficientRecommended treatment if ferritin levelRecommended treatment if ferritin level < 50 μg/LNo clinical trials of iron replacement in RLSNo clinical trials of iron replacement in RLS has been performedDosing recommendations:Dosing recommendations:

200 mg elemental iron daily (2-3 divided doses)doses)

Levodopa/CarbidopaIndication: Intermittent or daily RLSStrength: 25 mg/100 mg (IR or CR)g g g ( )Dosing: ½-1 tab in the evening, at bedtime, or upon awakening during the nightA id t ki ith hi h t i f dAvoid taking with high-protein foods Augmentation (in up to 70% of patients)

Worsening of symptoms earlier in the day after anWorsening of symptoms earlier in the day after an evening dose of levododpa/carbidopa

Rebound (20-35% of patients)Recurrence of RLS in the early morningRecurrence of RLS in the early morning

SE: N/V, insomnia, hallucinations

Dopamine AgonistsIndication: Intermittent or Daily RLS (DOC)FDA approved (Non-ergot-derived):

Ropinirole (Requip®)Pramipexole (Mirapex®)

Dosing:Ropinirole 0.25 mg 2 hours before major RLS symptoms start

Increase by 0.25 mg q2-3 days until reliefMax doses 4 mg daily (usual dose 2 mg or less)

Pramipexole 0 125 mg 2 hrs before major RLS symptoms startPramipexole 0.125 mg 2 hrs before major RLS symptoms startIncrease by 0.125 mg q2-3 days until relief Max dose 2 mg daily (usual dose 0.5 mg or less)

Onset of action: 90-120 minutesOnset of action: 90 120 minutesAugmentation can occur (10-30 % of patients) Longer T1/2 reduces occurrence of rebound symptomsSE: N/V constipation insomnia fluid retentionSE: N/V, constipation, insomnia, fluid retention, hallucinations, sleep attacks

OpioidsIndication: Intermittent and Daily RLSClinical trial data:

PropoxyphenePropoxypheneOxycodoneTramadol

Dosing:P h l t 100 200Propoxyphene napsylate 100-200 mgPropoxyphene HCL 65-130 mgCodeine 30-60 mg (+/- APAP)Tramadol 50-100 mgg

Short-acting opioids for intermittent symptoms (hydrocodone, oxycodone, codeine)Long-acting opioids for daily symptoms (oxycodone SR)SE N ti ti t l it hiSE: Nausea, constipation, tolerance, itching

BenzodiazepinesIndications: Intermittent RLSClinical trial data:

BZDs (clonazepam, temazepam, triazolam)BRAs (zolpidem, zaleplon)

Dosing:Dosing:Triazolam 0.125-0.5 mgZolpidem 5-10 mgZaleplon 5-10 mgTemazepam 15-30 mg

Abuse potential: Controlled substance (III-IV)Abuse potential: Controlled substance (III IV)SE: memory impairment, over-sedation, psychomotor retardation (Increase risk of falls), withdrawal symptomswithdrawal symptoms

Daily RLS

Nonpharmacologic

Pharmacologic

Dopamine Agonists GabapentinLow potency Opioid

Silber MH, et al. Mayo Clin Proc. 2004;79:916-22.

AnticonvulsantsIndication: Daily RLS or Refractory (adjuvant)Clinical trial data:

Gabapentin (Neurontin®)CarbamazepineValproic Acid

D iDosing: Gabapentin: initial dose 100-300 mg

Average dose 1300-1800 mg/dayQHS dosing for bedtime symptomsQHS dosing for bedtime symptoms TID dosing for symptoms throughout the day

CarbamazepineValproic acid p

Consider for patients with neuropathy, documented failure or intolerance to dopaminergic medicationsSE: sedation, dizziness, fluid retention, weight gainSE: sedation, dizziness, fluid retention, weight gain

Refractory RLS

Nonpharmacologic

Pharmacologic

Change to a high-potency opioid

Add a BZD, Opioid, or

Change to another

Change to Gabapentin p y pp ,

GabapentinDopamine Agonist

p

Silber MH, et al. Mayo Clin Proc. 2004;79:916-22.

Strategies to Resolve Augmentation

Dosage reduction or discontinuation ofDosage reduction or discontinuation of dopaminergic medicationAbrupt discontinuation of dopaminergicAbrupt discontinuation of dopaminergic medication may result in severe rebound of RLS causing 48 72h of insomniaof RLS causing 48-72h of insomniaAddition of opioids to dopaminergic t t t i t titreatment may improve augmentation

NarcolepsyNarcolepsy

What is NarcolepsyWhat is NarcolepsyComplex disease with multiple symptoms:p p y p

Excessive daytime sleepinessCataplexyp yHypnagogic hallucinationsSleep paralysis

Cataplexy: A debilitating medical condition in which a person suddenly feels weak and collapses at moments ofsuddenly feels weak and collapses at moments of strong emotion such as laughter, anger, fear or surprise.

Epidemiology of NarcolepsyEpidemiology of Narcolepsy

Prevalence: 1/2000 in general populationPrevalence: 1/2000 in general population1st degree relative has 40-fold increased risk of developing narcolepsyrisk of developing narcolepsyPrevalence men = womenOnset < 25 y/o (most common)Cataplexy occurs in 60-90% of patients p y pwith narcolepsy

Longstreth WT, et al. Sleep 2007;30:13-26.

Pathophysiology of NarcolepsyPathophysiology of Narcolepsy

Thought to be caused by loss of neuronsThought to be caused by loss of neurons containing hypocretin (orexin) in CNSHypocretin produced in posterior andHypocretin produced in posterior and lateral hypothalamus & is thought to regulate the maintenance of wakefulnessregulate the maintenance of wakefulness & REM sleep suppression

M i ll l d d i k f lMaximally released during wakefulnessCauses increased muscle tone

Role of Sleep Studies in DiagnosisRole of Sleep Studies in Diagnosis

Polysomnography and multiple sleep latency test (MSLT)

Confirmation of diagnosisPolysomnographpy used to rule-out other possible causes of hypersomniaMSLT used to determine degree of daytime sleepiness

Narcolepsy Treatment GoalsNarcolepsy Treatment Goals

Restore normal daily function by eliminating daytime sleepinessg y pReduce frequency of hypnagogic hallucinationshallucinationsReduce frequency of sleep paralysisR d f f t lReduce frequency of cataplexy

Nonpharmacologic TreatmentNonpharmacologic Treatment

Education on therapeutic expectations ofEducation on therapeutic expectations of managementAvoidance of sleep loss or circadianAvoidance of sleep loss or circadian rhythm disturbances G d l h iGood sleep hygienePlanned naps to provide temporary alertness

FDA Approved Narcolepsy MedicationsDrug Schedule FDA-Approved

IndicationFDA-Approved

Dosages

Dextroamphetamine C-II Narcolepsy; ADHD 5 – 60 mg/dayDextroamphetamine C II Narcolepsy; ADHD w/ hyperactivity

5 60 mg/day

Methylphenidate C-II Narcolepsy; ADHD 5 – 60 mg/day

Modafinil C-IV Excessive sleepiness

associated with Narcolepsy; OSA;

100 – 200 mg/day

p ySWSD

Sodium oxybate C-III Excessive sleepiness and

3 – 9 gm per total nightly dosesleepiness and

cataplexy in patients with Narcolepsy

nightly dose

ADHD = attention-deficit hyperactivity disorder; FDA = U.S. Food and DrugADHD attention deficit hyperactivity disorder; FDA U.S. Food and Drug Administration; OSA = obstructive sleep apnea; SWSD = shift work sleep disorder

Roth T. J Clin Psychiatry 2007;68[suppl 13]:16-19.

Pharmacologic Treatment of C t lCataplexy

Sodium oxybate (GHB) (Zyrem®)Sodium oxybate (GHB) (Zyrem®)Starting dose: 2.25 gm in bed, then 2.25 gm 2.5-4 hr latergm 2.5 4 hr laterTitrate by 1.5 gm/day q1-2wksMax dose: 9 gm/dayMax dose: 9 gm/day

SE di i HA itiSE: dizziness, HA, nausea, vomiting, confusion, depression, urinary incontinence sleep walking enuresisincontinence, sleep walking, enuresis

Pharmacologic Treatment of C t lCataplexy

Sodium oxybate, contSodium oxybate, contAdvantages: improved sleep quality, decreased daytime sleepiness & cataplexy, tolerance not y p p y,demonstrated

Disadvantages: Schedule III, short half-life requires patient to wake 2.5-4 hrs after taking first dose for a second dose, enuresis & sleepwalking may occur, only available via Z S PZyrem Success Program

Tricyclic Antidepressants for the T t t f C t lTreatment of Cataplexy

Indication: Narcolepsy with cataplexyCli i l t i l d tClinical trial data:

Imipramine (> NE and 5-HT blockade vs Dopamine)Protriptyline (> NE blockade than 5-HT or Dopamine)

D iDosing: Imipramine 25-100 mg

Limited by sedative propertiesProtriptyline 15 30 mgProtriptyline 15-30 mg

Strong anticholinergicMore effective than SSRIs (decrease in cataplexy and hallucinationshallucinationsCan develop tolerance and rebound cataplexy if abruptly discontinued SE: Anticholinergic effectsSE: Anticholinergic effects

Serotonin Reuptake Inhbitors for the Treatment of CataplexyTreatment of Cataplexy

Indication: Narcolepsy with cataplexyClinical trial data:

Fluoxetine (5-HT)Venlafaxine (NE & 5-HT)

Dosing:Dosing: Fluoxetine 60 mg

Larger than usual depression dosingVenalafaxine 75-375 mg

Less stimulating and shorter half-life vs fluoxetineER formulation available

Better tolerated than TCAsSE: Insomnia, headache, anxiety, nervousness, nauseanausea

Monoamine Oxidase Inhibitors for th T t t f C t lthe Treatment of Cataplexy

Medications:Tranylcypromine (Parnate®)Phenelzine (Nardil®)

Generally reserved for patients who fail to obtain benefit from other therapiesLimited by side effects, including tyramine reaction

Obstructive Sleep Apnea Obst uct e S eep p ea(OSA)

Epidemiology of OSAEpidemiology of OSA

2-4% of middle-aged persons have OSA2 4% of middle aged persons have OSAPrevalence:

M l 3 1Men : premenopausal women = 3:1Men : postmenopausal women = 2:1

Two times as likely to develop OSA if first degree relative with OSAMale patients w/ OSA have significantly greater risk of fatal and nonfatal CV eventsg

Pathophysiology of OSAPathophysiology of OSA

Primary characteristic: collapse of upperPrimary characteristic: collapse of upper airway during sleepHypoventilation causes hypercapnia &Hypoventilation causes hypercapnia & acidosisSti l t l t i CNSStimulates arousal centers in CNSCauses increased respiratory & pharyngeal-muscle activityObstruction resolves with arousal of patientpMuscles relax, patient returns to sleep

Pathophysiology of OSAPathophysiology of OSA

Potential causes of airway collapsePotential causes of airway collapseObesityNasal polypsNasal polypsEnlarged tonsils, uvula, tongueDecreased activity of dilator muscles inDecreased activity of dilator muscles in pharynx

Pathophysiology of OSAPathophysiology of OSA

ComplicationsComplicationsIncreased right and left ventricular afterloadDecreased left ventricular complianceDecreased left ventricular complianceIncreased pulmonary artery pressuresIncreased myocardial oxygen demandIncreased myocardial oxygen demandSympathetic discharge with arousal increased BP & HRincreased BP & HRDecreased cerebral blood flow & oxygenation

Diagnosis of OSADiagnosis of OSA

Patient presents with risk factors: obesityPatient presents with risk factors: obesity, increased neck circumference, craniofacial abnormalities hypothyroidism acromegalyabnormalities, hypothyroidism, acromegaly

Hi h i k i t d ithHigh risk associated with:Snoring, persistent daytime sleepiness or d i hil d i idrowsiness while drivingObesity or hypertension

Role of Sleep Studies in DiagnosisRole of Sleep Studies in Diagnosis

Polysomnography over two nights is goldPolysomnography over two nights is gold standard diagnostic test

Used to determine amount of continuousUsed to determine amount of continuous positive airway pressure neededFew sleep centers available may takeFew sleep centers available, may take months for patient to receive study

Diagnosis of OSADiagnosis of OSA

Diagnosis without polysomnographyDiagnosis without polysomnographyUse of standard clinical scales to predict probability of OSAprobability of OSAHome oximetry monitoring with self-adjusting CPAP to determine amount of continuousCPAP to determine amount of continuous positive airway pressure needed

OSA Treatment GoalsOSA Treatment Goals

Decrease frequency of apnea-hypopneaDecrease frequency of apnea hypopnea events per hour of sleep

Restore normal daily function by li i ti d ti l ieliminating daytime sleepiness

Nonpharmacologic TreatmentNonpharmacologic Treatment

Continuous positive airway pressure (CPAP)Continuous positive airway pressure (CPAP) First-line for patients w/ severe OSA or OSA with cardiac diseaseOSA with cardiac diseaseMost effective therapy

Oral appliances to reposition mandible and pp popen airwaySecond-line if CPAP unsuccessfulSecond line if CPAP unsuccessful

Nonpharmacologic TreatmentNonpharmacologic Treatment

Surgical procedure to open airwayg p p ySecond-line if CPAP unsuccessful

Lifestyle modificationsWeight lossAvoidance of alcohol or other sedativesAvoidance of sleep in supine position may

ili f d i b dutilize foam wedge in bedSmoking cessation

Pharmacologic TreatmentPharmacologic Treatment

Insufficient evidence to support the use of medications for treatment of OSAmedications for treatment of OSA

Modafinil effective for patients on CPAP therapy with continued excessive daytime sleepiness

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