Lecture 61 - Pharmacotherapy of Sleep Disorders

Question 1

DISEASE STATES, MEDICATIONS, SUBSTANCES ASSOCIATED WITH INSOMNIA

Answer 1

anxiety, caffeine, modafinil, amphetamines, beta-agonists, beta blockers, nicotine, thyroid meds, mood disorders, bupropion, decongestants, methylphenidate

Question 2

DSM‐5 – INSOMNIA DISORDERS

Answer 2

Difficulties with sleep initiation (latency), sleep maintenance, and/or early‐morning awakening
Takes place at least 3 nights per week
Present for at least 3 months

Question 3

MEDICATION CHOICES BASED ON SLEEP COMPLAINTS

Answer 3

sleep onset only
sleep maintenance only
sleeo onset and sleep maintenance

Question 4

Sleep onset only

Answer 4

zaleplon, triazolam, eszopiclone, zolpidem, ramelteon

Question 5

Sleep maintenance only

Answer 5

suvorexant, doxepin, eszopiclone, zolpidem

Question 6

Sleep onset and sleep maintenance

Answer 6

eszopiclone, zolpidem, temazepam

Question 7

TREATMENT OF INSOMNIA DISORDERS

Answer 7

1st line treatment is non-pharmacological: Sleep hygiene principles are necessary and should be counseled by the pharmacist
The z‐hypnotics (zolpidem, eszopiclone, zaleplon) are the most commonly used sleep medications: * Initial dose of zolpidem is lower in women and elderly – 5 mg
* Eszopiclone (Lunesta®) is FDA‐approved for long‐term (6 months) use – patients
complain of metallic taste
* 3A4 substrates – metabolism is impacted by 3A4 inhibition and induction
* Somnolence, dizziness, ataxia, headaches
* Can cause parasomnias – unusual actions while a person is sleeping – is a warning on all medications used for sleep
* Controlled substances – potential for misuse
* Additive effects with other CNS depressants

Question 8

Benzodiazepines can be used for insomnia

Answer 8

*Temazepam is the benzodiazepine used for sleep
*Drowsiness, dizziness, cognitive impairment, increased fall risk
All medications FDA‐approved for insomnia have sleep behaviors warning

Question 9

Melatonin Receptor Agonists

Answer 9

Ramelteon: Contraindicated with
fluvoxamine; GI upset, next day somnolence, hyperprolactinemia, prolactinoma
Tasimelteon: FDA‐approved for non‐24 sleep‐ wake disorder in adults
1A2 substrates: watch for 1A2 inducers and inhibitors

Question 10

OREXIN RECEPTOR ANTAGONISTS (C‐IV)

Answer 10

suvorexant
lemborexant
daridorexant

Question 11

Suvorexant

Answer 11

• 10 mg within 30 minutes of bedtime and at least 7 hours to sleep
• Contraindicated in narcolepsy – causes
  narcolepsy‐like side effects
• 3A4 substrate

Question 12

Lemborexant

Answer 12

• 5 mg at bedtime with at least 7 hours to sleep
• Contraindicated in narcolepsy - causes narcolepsy like side effects
• 3A4 substrate

Question 13

Daridorexant

Answer 13

• 25 mg at bedtime with at least 7 hours to sleep
• Contraindicated in narcolepsy – causes narcolepsy‐like side effects
• 3A4 substrate

Question 14

Doxepin

Answer 14

• TCA - low doses exert effect through H1 receptor antagonism
• Anticholinergic side effects

Question 15

Trazodone

Answer 15

• Not FDA approved for insomnia
• Long half-life may see daytime hangover

Question 16

Mirtazapine

Answer 16

• Clinically used as a sleep agent, especially in patients with depression who have difficulty sleeping

Question 17

Quetiapine

Answer 17

• Low dose quetiapine is not recommended for use in insomnia unless there is a co-morbid psychiatric disorder

Question 18

OTC Antihistamines and Natural Products

Answer 18

Diphenhydramine/Doxylamine
* Not recommended by AASM
* Anticholinergic SEs - avoid in elderly pts
Melatonin/Valerian/Chamomile:
* Melatonin can be considered in jet lag and patients with low melatonin levels; 1A2 substrate
* German chamomile contains a BZD‐like compound; allergic reactions in patients with daisy or ragweed allergies, inhibits 1A3, 2C9, 2D6, 3A4

Question 19

Choosing Treatment - Drugs or Not?

Answer 19

CBT and behavioral therapies are first‐line

Question 20

DSM‐5 CRITERIA – OBSTRUCTIVE SLEEP APNEA

Answer 20

Patient must have evidence of at least 5 obstructive apneas per hour of sleep confirmed by polysomnography
Symptoms include excessive daytime sleepiness, snoring, pauses in breathing during sleep, headache, irritability, sore throat, erectile dysfunction, impaired memory, GERD, mood disturbance
Clinically, there is greater recognition that many patients have both apnea and insomnia – both need to be treated with apnea treated first

Question 21

AASM Guideline 2017 Diagnositc Testing for Sleep Apnea

Answer 21

Polysomnography only if there is significant cardiorespiratory disease, potential respiratory muscle weakness due to a neuro‐muscular condition, sleep‐related hypoventilation, chronic opioid medication use, history of stroke, or severe insomnia

Question 22

TREATMENT OF SLEEP APNEA

Answer 22

Weight loss (adjunctive rather than curative), smoking cessation, avoid alcohol and CNS depressants, sleep on side rather than back
If a patient is overweight/obese and comes for evaluation for insomnia, consider assessment for sleep apnea prior to initiating medications
CPAP – continuous positive airway pressure
Excessive daytime sleepiness (EDS) can be treated with modafinil or armodafinil – need to review CPAP adherence first and possibility of RLS or PLMS
When considering treating apnea and insomnia, ensure that the obstructive apnea is addressed before recommending sedative/hypnotic drug therapy

Question 23

THE NARCOLEPSY TETRAD

Answer 23

EDS – Occurs in 100% of patients, generally more severe in Type I narcolepsy (narcolepsy with cataplexy or hypocretin deficiency syndrome): *Patients may feel refreshed after a ap, but sleepiness returns after 1 – 2 hours
*Automatism – patient appears to be fully awake but lacks awareness of actions secondary to sleepiness (may be misdiagnosed as absence seizures)
Cataplexy, hallucinations, sleep paralysis, all four symptoms

Question 24

Cataplexy

Answer 24

sudden loss of muscle tone triggered by emotion – 75% of patients
*Usually develops within 3 – 5 years of EDS onset, but may be longer
*Patient remains conscious, lasts less than a few minutes
*Weakness begins with facial and neck muscles, spreads to trunk/limbs
*Mild may be drooping of eyelids or mouth, feeling of weakness

Question 25

Hallucinations

Answer 25

30% ‐ 60% of patients
*Brief, dream‐like, usually visual (may be auditory or tactile)
*Occurs during transition between wakefulness and sleep
*Hypnagogic – during sleep onset (more common)
*Hypnopompic – on awakening

Question 26

Sleep Paralysis

Answer 26

25% ‐ 50% of patients
*Partial or total paralysis at the onset or termination of sleep, muscles are inhibited but brain is aware of the physiologic change
*Subjectively frightening for patients – aware but unable to move

Question 27

All four symptoms

Answer 27

10-33% of patients

Question 28

Treatment of narcolepsy - cataplexy

Answer 28

• Sodium oxybate (Xyrem®) – GHB – high sodium content
• Xywav® ‐ For adults and children aged 7 or older, also approved for idiopathic hypersomnia in adults – lower sodium content
• Lumryz® ‐ For adults only – ER dosage form, once nightly dosing, high sodium content

Question 29

Treatment of Narcolepsy - Excessive daytime sleepiness

Answer 29

• Modafinil/armodafinil: associated with possible life‐threatening rash
• Sodium oxybate
• Pitolisant and solriamfetol recently FDA‐approved for EDS

Question 30

Pitolisant (wakix)

Answer 30

H3 receptor antagonist/ inverse agonist
Contraindicated in severe hepatic impairment
Prolongs QT interval
2D6/3A4 substrate - reduce dose by 50% with strong 2D6 inhibitors or patients who are known 2D6 poor metabolizers; 3A4 inducers decrease exposure by 50%, dose adjustments may be needed
Weak 3A4 inducer - may reduce effectiveness of oral contraceptives
Avoid use with centrally‐acting H1 receptor antagonists (OTC antihistamines)

Question 31

SOLRIAMFETOL (SUNOSI®) C‐IV

Answer 31

Dopamine norepinephrine reuptake inhibitor (DNRI)
Indicated for improvement in wakefulness in adults with excessive daytime sleepiness due to narcolepsy or obstructive sleep apnea
Moderate renal impairment – start 37.5 mg, may increase to 75 mg after at least 7 days; severe renal impairment – starting and max dose = 37.5 mg
Warnings: B/P and HR increases – avoid in unstable CV disease and arrhythmias; use caution in patients with a history of psychosis or bipolar disorder – decrease dose or discontinue if psychiatric symptoms develop; use with caution with dopaminergic drugs

Question 32

Shift work sleep disorder

Answer 32

Modafinil and armodafinil are the drugs of choice, taken 1 hour before the work period starts during “wake time”

Question 33

Restless Legs Syndrome

Answer 33

Drug Therapy:
* Gabapentin enacarbil – prodrug of gabapentin, FDA‐approved for RLS, growing evidence base for effectiveness, may be considered first‐line
* Dopamine agonists (IR formulation) – pramipexole or ropinirole
* Iron supplementation may be considered