01 marrs sleep disorders.ppt - drtedwilliams.net · what is insomnia?what is insomnia? the...
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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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