Sleep-Wake Disorders - Narcolepsy, Sleep Apnea, Circadian disorders, Restless leg disorder

Franco

Narcolepsy Clinical Presentation

+symptom tetrad, associate symptoms

small number of patients have all 4

written in order of most prevalent

1. excessive daytime sleepiness (EDS) - all patients have

2. cataplexy

3. hallucinations

• hypnagogic: sleep onset

• hypnopompic: awakening

4. Sleep paralysis

associated symptoms

• fragmented night-time sleep: decreased sleep efficacy

• vivid dreams/nightmares

• weight gain, especially at symptom onset

Narcolepsy

+definition, mechanism, age of onset, causes/family hx/genetics

definition: chronic disorder of abnormal transitions into REM sleep associated with excessive daytime sleepiness

mech: caused by orexin production

age of onset: 10-20 years

possible causes: autoimmune (infection trigger)

family/genetics

• HLA DQB1*0602 gene

  • increased risk

  • present in cases linked to H1N1 vaccine

Narcolepsy Rating Scales and Scoring

ESS→ items rated from 0 (no chance) to 3 (highest chance of dosing)

• >10 = consider screening for narcolepsy with cataplexy

Functional Outcomes of Sleep Questionnaire

• each question rated from 1-4: assessing impact

• 1 = extremely dificult

• 4 = no difficulty

Karolinska Sleepiness Scales

• assesses level of sleepiness throughout the day

• >7 = drowsiness

Narcolepsy diagnosis

+cateplexy definition

EDS > 3 months with/without hypocretin deficient (CSF<110)

with or without cataplexy

cataplexy - sudden emotionally triggers episodes of muscle weakness with preserved consciousness

differential???

Non-Pharm treatment options in narcolepsy

+whats not effective

scheduled daily naps

• limit to 20 mins

routine bedtime and wakeup time

daily exercise

avoid alcohol, cataplexy triggers

reduce carbohydrates in diet

reduce sedentary activities after meals

caffeine is generally NOT effective

Pharmacotherapy options in narcolepsy with catplexy

+FDA approved vs off-label

FDA approved

Sodium Oxybate

Pitolisant

Not FDA approved

antidepressants (off label, but most commonly used)

Excessive Daytime Sleepiness

FDA approved

• modafanil/armodafanil

• soriamfetol

• pitolisant

Not FDA approved - off label

• stimulants

• sodium oxybate

Sodium Oxybate

+ached., moa, formulation/other forms, efficacy, administration, warnings/precautions, ADEs

sodium salt for GHB

sched lll. controlled substance

• only available through REMS

moa: GABA-B roeptor agonist

• increase N3 (slow-wave sleep) at the cost of REM sleep

formulation: liquid

• all still have REMS

• Lower-Sodium Oxybate

  • preferred for sodium-restricted patients

  • mix calcium, magnesium, potassium, sodium oxybate

• ER Sodium Oxybate

  • dosed one daily at bedtime

  • 6mg dose = 3mg of regular oxybate dosed 4 hours apart

effective at treating all four of narcolepsy’s core symptoms

• initial effect: 1-2 months; may take 3 months to see max effect

administration

• taken at bedtime and in the middle of the night due to short half life

  • prepare both doses prior to bedtime

  • set alarm to take second dose 4-5 hours after the first dose

• food decreases absorption, but small snack can be taken to help with nausea

• do NOT take with alcohol

  • omit one or both doses if alcohol is consumed in the evening

warnings/precautions

• misuse potential

• possible coma with overdose

• may exacerbate sleep apnea

• high sodium content (caution in: HTN, HF, Renal Disease)

Common ADEs

• nausea, dizziness, urinary incontinence, morning sleepiness, sleepwalking

• worsening of depression and anxiety

Pitolisant

+schedule, moa, effectiveness, onset, warnings/precuations, ADEs, DDIs

NOT controlled substance

• however, only available through specialty pharmacies

moa: H3 receptor inverse agonist, leading to increased histamine levels

effective for narcolepsy with cataplexy

onset: delayed

• full effects may take week to months

warnings/precautions

• QT interval prolongation

• contraindicated in severe hepatic impairment

ADEs: insomnia, nausea, anxiety

DDIs:

• CYP2D6 inhibitors: reduced dose of pitolisant by half

• CYP3A4 inducers: consider increasing dose

• may reduce effectiveness of CYP3A4 substrates

  • hormonal contraceptives: efficacy may be reduced for up to 21 days after pitlisant d/c

• avoid use with centrally acting H1 antagonists

Modanfinil and Armodafinil

+sched., moa, effects, warnings/precautions, ADEs, DDIs

schedule IV controlled substance

• slower onset and provides tonic dopamine reuptake inhibition compared to stimulants

moa: dopamine reuktake inhibitors + possibles effect on hypocretin and histamine

Armodofanil = R - enantiomer

• longer half-life and more potent

• no difference in efficacy

effects:

• rapid (usually within a couple of days)

warnings/precautions

• Stevens-Johnson syndrome

• cardiovascular risk: avoid in patients with hx of left ventricular hypertrophy or mitral valve prolapse

ADEs: headache, nausea, anxiety

DDIs: major CYP3A4 substrate

• also moderate inducer of CYP3A4

  • may decrease efficacy of oral contraceptives

• food delays absorption

Solriamfetol

+sched, moa, indications, warnings/precautions, ADEs, administrations

schedule IV controlled substance

moa: DA and NE reuktake inhibitor

indications: FDA-approved for EDS associated with narcolepsy pr obstructive sleep apnea

• effects seen within first week

• long duration of action compared to other meds for EDS

warnings/precautions

• HTN and tachycardia: avoid unstable cardiovascular disease

ADEs:

• headache, nausea, anorexia, insomnia, anxiety

Should be taken on empty stomach at least 9 hours before bedtime

Narcolepsy Guidelines

+strong, conditional → pediatrics

Strong

• modafanil

• pitolisant

• sodium oxybate

• solriamfetol
  

Conditional

• armodafinil

• dextroamphetamine

• methylphenidate

Pediatrics

• modfanil

• sodium oxybate

Obstructive Sleep Apnea (OSA)

+definition, prevalence

def: airway blockage during sleep that interrupts breathing

prevalence increases with age

Obstructive Sleep Apnea (OSA) Risk Factors

+physical characteristics, age/gender, disorders, conditions

physical characteristics:

• excessive weight

  • overweight: 2x the risk

  • Obesity (BMI>35): 4x the risk

• obstructive tonsils and adenoids

• large neck circumference

• craniofacial abnormalities

age: > 40

male

menopause/pregnancy

endocrine disorders:

• hypothyroidism

• Cushing’s syndrome

• PCOS

Smoking

CHF

opioid use

OSA Diagnostic Criteria

Polysomnography (PSG) showing > 5 obstructive apneas/hyopneas per hour (apnea hypogea index, or AHI) PLUS one of the following:

• disturbance in nocturnal breathing (snoring, snorting, gasping, or pauses during)

• fatigue, daytime sleepiness, or unresting sleep

OR

PGS showing AHI > 15

OSA Screening and Severity

• Screening

  • Sleep Apnea Clinical Score – based on history of snoring, witnessed apneas, neck circumference and hypertension

  • Berlin Questionnaire – 10-item questionnaire assessing snoring and breathing patterns, daytime sleepiness and hypertension

  • STOP-Bang Questionnaire – 8-item self-rated survey of symptoms and risk factors

• Severity

  • Mild – AHI 5 to < 15

  • Moderate – AHI 15 to < 30

  • Severe – AHI ≥ 30

OSA Clinical Presentation

EDS not explained by other factors

Snoring

Nocturnal gasping, choking, pauses in breath

non-refreshing sleep: poor concentration, irritability

difficulty falling/staying asleep

morning headache

Complication of OSA

Cardiovascular disease

Chronic Kidney Disease

Diabetes: worse glycemic control

Motor vehicle accidents

AHI >20: increased risk of stroke and arrhythmia

AHI > 30: increased mortality risk

Non-Pharm therapy

Continuous positive airway pressure (CPAP) devices

• if CPAP is not helping: screen for adherence

• most critical intervention for OSA

weight loss → meds??

exercise

smoking cessation

adjustments of sleeping position

surgical procedures

OSA Pharmacotherapy

+airway obstruction and EDS pharmacotherapy: FDA-approved, off-label

Medication improving airway obstruction

• FDA-approved: Tirzepetide (Zepound)

• Off-label: IN corticosteroids

EDS pharmacotherapy

• FDA-approved: modafinil/Armodafinil

• FDA-approved: Solriamefetol

• Off-label: Stimulants

Tirzepatide (Zepound)

+indications, efficacy, moa

indications: FDA-approved for moderate-to-severe OSA in adults with obesity, in conjunction with reduced-calorie diet and increased physical activity

• only first medication to be FDA-approved specifically to reduce sleep apnea

  • all other drugs targets EDS

GLP-1 receptor agonist/GIP receptor agonist

• weight loss

• GI side effects

• reduction of appetite

• pancreatitis

Circadian Rhythm Disorders definition

“biological clock” - dictates sleep sleep cycle using light and darkness guess

• without light cues the clock continues to function → lasts slightly longer than 24 hours

a group of disorders in which the circadian rhythm does not align with the person’s sleep-wake cycle causing:

• hard time initiating sleep

• difficulty maintaining sleep

• waking too early and unable to go back to sleep

• nonrestorative poor-quality sleep

Many also cause EDS and increase risk of medical comoborties

Types of Circadian Disorders

● Delayed sleep-wake phase disorder (DSWPD)

● Advanced sleep-wake phase disorder (ASWPD)

● Jet lag disorder

● Shift work sleep disorder

● Irregular sleep-wake rhythm disorder (ISWRD)

● Non-24-hour sleep-wake disorder (N24SWD)

General Treatment Principles

+how they are IDed, modalities

ID through actigraphy or sleep log

• actigraphy: wearable devices that can track rest/activity cycles

• sleep log: patient tracks sleep activity using a journal

Three main modalities

1. Behavioral modifications/sleep hygiene techniques

2. Light therapy when waking light therapy when waking

3. Melatonin 1-2 hours before desired sleep time

Melatonin

+moa, effective, formulations, administration, well-tolerated

moa: endogenous M1, M2, and M3 agonist

effective doses as low as 0.5 mg nightly

• IR preparations preferred

taken 1-2 hours before desired time of sleep onset

well tolerated: may cause sedation and vivid dreams

Shift Work Sleep Disorder

+definition, treatment

●Occurs in with shift work (i.e., evening shift, overnight shift)

○- Variability in sleep-wake scheduled

○- Unnatural timing of light exposure

●Treatment recommendations

1. Non-pharmacologic strategies: cessation of shift work, sleep scheduling (maintaining circadian rhythm even when not working)

2. Light exposure therapy upon waking

3. Melatonin ~1 hour before sleep

4. Modafinil and armodafinil are both approved for shift-work disorder-related EDS (dosed about 1 hour before start of shift)

N24SWD → Non-24-hour sleep-wake disorder (N24SWD)

+definition, Treatment goals/regimen

●Disorder in which a patient is unable to align their circadian rhythm with the external 24-hour day

○Typically, sleep becomes longer and longer

●Most common in blind individuals who lack light perception

○Occurs in an “unknown” number of sighted people

●Goal: Synchronize patient’s circadian rhythm with 24-hour day to reduce symptoms

Treatment recommendations in totally blind individual

• Behavioral modifications (adjustment of daily cues such as food, activity, etc.)

• Cannot use light therapy (for obvious reasons)

• Pharmacotherapy is a mainstay of treatment

  • Melatonin

  • Tasimelteon (FDA-approved)

Most well studied in sighted individuals

• Melatonin and bright light therapy

Tasimelteon

+moa, ADEs, DDIs,

moa: M1 and M2 receptor agonist with greater affinity for M2 receptor

Adverse effects:

• Headache

• Elevated ALT

• Abnormal dreams

Many drug interactions: CYP1A2 and CYP3A4 substrate

• CYP1A2 inhibitors (e.g., fluvoxamine) – avoid use

• CYP1A2 inducers (e.g., smoking) – tasimelteon ↓ by ~ 40%

• CYP3A4 inhibitors (e.g., ketoconazole) – tasimelteon ↑ by ~50%

• CYP3A4 inducers (e.g., rifampin) – tasimelteon ↓ by ~90%, avoid use

Restless leg disorder

+definition, diagnosis

Urge to move the legs and uncomfortable sensations characterized by:

• Starting or worsening at rest

• Relieved by movement

• Worse in evening/night

Occurs at least twice a week for at least 3 months and causes significant impairment or distress

Often a life-long illness

RLS Associated Symptoms

Periodic limb movements of sleep (PLMS)

• Involuntary contractions of legs during sleep

• Typically occurring during the first 4 hours of sleep

• Insomnia and poor sleep quality

• Excessive daytime sleepiness

RLS Etiology/Cause

Idiopathic in many cases

• Genetic component

Several conditions associated with increased risk

• Parkinsons

• Psychiatric disorder (e.g., depression, anxiety) may have bidirectional relationship

Can be caused by brain iron deficiency or medications

• Pregnancy, anemia, end-stage renal disease

Proposed RLS pathophys

1. decreased iron

2. issues with transfers in and out of brain

Medication Induced RLS

+agents

• Antipsychotics​

  • "-pine" antipsychotics most frequently reported ​
    (quetiapine, olanzapine, clozapine)

• Serotonergic agents​

  • SSRIs

  • Mirtazapine​

• Opioid withdrawal

• Promethazine

• Antihistamines

• Lithium​

• Topiramate

• Zonisamide

• Beta-Blockers

RLS Assessment

+labs

Serum ferritin – levels < 50 mcg/L associated with greater symptom severity

• Recommended to regularly measure serum iron in patients with RLS

Polysomnography – not diagnostic

Multiple suggested immobilization test (m-SIT)

• Patient reclines with legs outstretched for 60 minutes and observe

RSL Rating Scales

FYI MOSTLY ????????????????//

RLS Treatment Approach

1. check iron lab

• replenish if low

2. Address exacerbating factors

• untreated OSA

• Sunstances/medications

3. Pharmacotherapy ONLY if non pharm insufficient

Iron Supplementation

+levels, preferred formulations

Iron supplementation is recommended to treat RLS if:

• Serum ferritin levels ≤ 75 mcg/L, OR

• Transferrin saturation < 20%

IV ferric carboxymaltose is the preferred option

• Other IV iron options are likely effective, but lacking in evidence

Other iron may only be used if ferritin is > 75 mcg/L

• Poorly absorbed if serum ferritin is ≥ 50-75 mcg/L

• Limited by tolerability (e.g., constipation)

Nonpharm Treatment of RLS

●Address exacerbating factors (see slide 112)

●Good sleep hygiene

●Exercise, especially with lower body resistance

• Pneumatic pressure therapy

  • Leg bands that activate peroneal nerves to sustain muscle activation

Pharmacotherapy RLS Agent List

+FDA approved vs off-label

●Alpha-2-delta ligands

○Gabapentin enacarbil (FDA-approved)

○Gabapentin (off-label)

○Pregabalin (off-label)

●Dopamine agonists

○Pramopexole (FDA-approved)

○Ropinirole (FDA-approved)

○Rotigotine transdermal (FDA-approved)

○Carbidopa/Levodopa (off-label)

Other agents: opioid agonists for severe or refractory RLS, dipyridamole

Gabapentin Enacarbil

+indication, moa, formulations, dosing/administration, dose adjustments

Prodrug of gabapentin specifically approved for RLS

Usual dose once daily around 5 pm with meal

Not interchangeable with other gabapentin products

• Difference in oral bioavailability

• Considered similar in terms of efficacy/safety for RLS

• Gabapentin enacarbil has not been studied for other conditions gabapentin treats (e.g., epilepsy)

• more predictable than gabapentin

Alpha-2-Delta Ligand Safety

+ADEs, warnings/precautions, dose adjustments,

Common adverse effects: dizziness, somnolence

Warnings and Precautions

• Suicidal thoughts and behaviors

• Driving impairment

• Drug reaction with eosinophilia and systemic symptoms (DRESS)

Renal dose adjustment

Risk of misuse, especially in patients with comorbid opioid use disorder

In pregnancy, may increase risk of preterm birth and small for gestational age

Dopamine Agonists

+place in therapy, onset, effective, warnings/precautions, ADEs,

Have been considered first-line agents for RLS

• No longer the case due to risk of augmentation

• May still be used short-term (i.e., intermittent RLS) or if alpha-2-delta ligand is ineffective or poorly tolerated

Rapid onset of action

• Should be taken 1-3 hours before expected onset of symptoms

Generally considered to be equally effective to one another

warnings/precautions

• compulsive behavior

  • not recommended if patient has impulse disorders or comorbid conditions increasing risk of impulsive behavior

Common adverse effects: nausea, headache, somnolence

May still be used in patients with comorbid depression, daytime symptoms, fall risk

• Possible benefit in depression

• Low fall risk compared to alpha-2-delta ligands

Augmentation

Gradual worsening of RLS symptoms caused by dopamine agonists

• Levodopa > pramipexole = ropinirole > rotigotine transdermal

• Higher doses are more likely to cause augmentation

Clinical presentation

• Increased severity of symptoms

• Faster onset of symptoms while at rest

• Symptoms occurring earlier in the day

• Spreading to other body parts

May be irreversible

• Sudden discontinuation of dopamine agonists may lead to severe rebound RLS

RLS Guidelines

+strong, conditional, short-term use only, iron deficiency

strong

• gabapentin encarbil

• gabapentin

• pregabalin

conditional

• Dipyridamole

• Extended-release oxycodone and other opioids

short-term use only

• Levodopa

• Pramipexole

• Transdermal rotigotine

• Ropinirole

iron deficiency

• IV ferric carboxymaltose

• IV low molecular weight iron dextran

• IV ferumoxytol

• Ferrous sulfate