Chapter 68 - Sleep Disorder Flashcards
What are the primary types of sleep disorders that are managed with medications:
- Chronic insomnia
- Restless legs syndrome (RLS)
- Narcolepsy
Another common sleep disorder is:
- Obstructive sleep apnea
–> primarily treated with non-drug measures,
(continuous positive airway pressure (CPAP)
Characteristics of insomnia
- diagnosis?
- Difficulty falling asleep (sleep initiation or sleep latency)
- Reduced sleep duration and/or poor sleep quality (awakenings after sleep onset)
A diagnosis of chronic insomnia occurs when the patient has (despite adequate opportunity to sleep):
- Symptoms at least 3x per week
- For at least 3 months
Non drug ttmt of insomnia
- Cognitive behavioral therapy for insomnia (CBT-I) is preferred and includes changes to sleep hygiene that can reduce the need for drugs
- Treat any underlying medical conditions that may be contributing (pain, shortness of breath due to heart failure, anxiety, bipolar disorder, depression, alcoholism)
- Discontinue medications that can worsen insomnia
Natural Products for insomnia
- Melatonin (3 - 5 mg in the evening)
. Jet lag
. + others CNS depressants –> drowsiness, daytime somnolence
. It is a substrate of CYP 450 1A2, and prolonged effects may be observed with CYP1A2 inhibitors (ciprofloxacin, fluvoxamine). - Valerian
. Few adverse risks: liver toxicity; the significance of this risk is unclear. - Drinking chamomile tea in the evening to feel calmer
Medications that can worsen insomnia
1- Acetylcholinesterase inhibitors (donepezil) (Dementia)
2- Alcohol
3- Antiretrovirals (emtricitabine, INSTls)
4- Aripiprazole (Abilify)
5- Atomoxetine (Strattera)
6- Bupropion (Antidepressant)
7- Caffeine
8- Decongestants (pseudoephedrine)
9- Diuretics (due to nocturia)
10- Fluoxetine (Prozac), if taken late in the day
11- Steroids
12- Stimulants (methylphenidate, phentermine)
13- Varenicline (for smoking cessation and ttmt of dry eyes)
thought process of insomnia management
- Non-drug ttmt: CBT-I
- Sleep problem persists?
1) Need help falling asleep?
- Eszopiclone
- Zolpidem
- Ramelteon
- Zaleplon
2) Need help staying asleep?
- Eszopiclone
- Zolpidem
- Doxepin (TCA)
- Suvorexant (Orexin Antagonist)
3) Need help falling and staying asleep?
- Eszopiclone
- Zolpidem
- What do we prefer, nonbenzo or benzo for long term? Why?
- What dose and duration of action do we want for all meds?
In patients using prescription drugs long-term, non-benzodiazepines are preferred over benzodiazepines
- Decreased risk of physical dependence
- Fewer daytime cognitive effects
The lowest effective dose should be used for all medications to minimize adverse effects
Treatment should be limited to the shortest duration possible.
- What are some OTC meds that pts could self treat with?
- For how long can they use them?
Patients may self-treat insomnia with OTC first-generation antihistamines, such as:
- Diphenhydramine (Antihistamine)
- Doxylamine (Unisom - Antihistamine)
While these can help short-term, they should not be used long-term for the treatment of insomnia.
The American Academy of Sleep Medicine (AASM) guidelines state that the following treatments are not recommended for chronic use:
- Diphenhydramine (Antihistamine)
- Melatonin
- Tiagabine (Anticonvulsant)
- Trazodone (serotonin modulator)
- Valerian
- What Benzo can be used short term?
- Beers criteria for insomnia?
- Benzo for elderly pts?
Benzodiazepines (e.g., temazepam) can be tried for short-term treatment (such as from acute trauma) if there is no substance abuse history or current use of opioids.
According to Beers Criteria, the following are considered potentially inappropriate in patients aged 65 years and older.
- benzodiazepines
- non-benzodiazepine hypnotics (e.g., zolpidem)
- first-generation antihistamines
If benzodiazepines are used, lorazepam, oxazepam and temazepam (L-0-T) are preferred in the elderly due to the lower risk of adverse reactions)
Eszopiclone
- Brand
- Dose
- Brand: Lunesta (Eyyy ya amar)
- C- IV
- Dose: 1-3 mg PO QHS
Start with 1 mg immediately before bed and increase to 2 mg or 3 mg if necessary
Zolpidem
- Brand
- Dose
- Ambien, Ambien CR: IR and ER tablets
- Zolpimist: Oral spray (5 mg/spray)
- Edluar, Intermezzo: SL tablets
C·IV
1) Ambien, Edluar, Zolpimist
- Female/Elderly: 5 mg PO/SL/spray QHS
- Male: 5-10 mg PO/SU spray QHS
2) Ambien CR:
- Female/Elderly: 6.25 mg PO QHS
- Male: 6.25-12.5 mg PO QHS
3) Intermezzo:
- Female/Elderly: 1.75 mg SL QHS
- Male: 1.75-3.5 mg SL QHS
Zaleplon
- Brand
- Dose
- Sonata
- C-IV
- Dose: 5-20 mg PO QHS
BOXED WARNINGS of hypnotics
Complex sleep behavior can lead to serious injury or death
- Sleep-walking
- Sleep-driving
- Engaging in other activities while not fully awake
WARNINGS for hypnotics
- Inc risk of CNS depression and next-day impairment with < 7-8 hours of sleep (especially with higher doses or coadministration of CNS depressants or alcohol)
- Abnormal thinking and behavioral changes (can worsen depression)
- Respiratory depression
- Increased risk for hazardous sleep-related activities (sleep-driving)
- Potential for abuse and dependence (can cause withdrawal symptoms if used longer than 2 weeks)
CONTRAINDICATIONS of hypnotics
History of complex sleep behavior
SIDE EFFECTS of hypnotics
- Somnolence, dizziness
- Ataxia
- Headache
- Can cause parasomnias (unusual actions while sleeping, which the patient may be unaware of),
- Lightheadedness
- “Pins and needles” feeling on the skin
- Eszopiclone: dysgeusia (altered sense of taste)
- What do we worry about with hypnotics?
- Do we prefer them over benzo? Why?
- Drug food interactions?
- C-IV drugs; risk of physical (physiological) dependence, abuse (addiction) and tolerance
- Preferred over benzodiazepines for first-line treatment due to less abuse, dependence and tolerance
- Do not take with fatty food, a heavy meal or alcohol
Eszopiclone, Zaleplon and Zolpidem Drug Interactions
- Use caution in combination with potent CYP3A4 inhibitors (Protease inhibitors, ketoconazole, itraconazole, erythromycin and clarithromycin).
- Can cause additive effects when used with other sedating drugs, including most pain medications, muscle relaxants, antihistamines, mirtazapine (Remeron), trazodone and alcohol.
Orexin Receptor Antagonists moa
- The orexin neuropeptide signaling system promotes wakefulness.
- Orexin receptor antagonists block the orexin neuropeptide signaling system, resulting in drowsiness.
Lemborexant
- brand
- dose
Orexin receptor antagonist
DayVigo
C-IV
C-IV
- Dose: 5-10 mg PO QHS if at least 7 hours of sleep remaining
- Use 5 mg with weak CYP3A4 inhibitors
- Avoid use with strong or moderate CYP3A4 inhibitors
Suvorexant
brand
DDI
orexin receptor antagonist
Belsomra
C-IV
- Dose: 10-20 mg PO QHS if at least 7 hours of sleep remaining
- Use 5 mg with moderate CYP3A4 inhibitors and do not exceed 10 mg daily
- Avoid use with strong CYP3A4 inhibitors
(when pt cant stay asleep)
CONTRAINDICATIONS of Orexin Receptor Antagonists
Narcolepsy
WARNINGS of Orexin Receptor Antagonists
- Worsening depression/suicidal ideation
- Sleep paralysis
- Hallucinations
- Cataplexy-like symptoms (sudden loss of muscle tone)
- Increased risk for complex sleep behavior
- Daytime impairment (risk inc with other CNS depressants)
SIDE EFFECTS of Orexin Receptor Antagonists
Somnolence, headache, dizziness, abnormal dreams
How should you take ORA?
When are they not recommended
Should be taken on an empty stomach (food delays absorption)
Not recommended in patients with severe hepatic impairment
Mode of action of Melatonin Receptor Agonists
- Agonists at the melatonin receptors, MTl and MT2.
- This promotes sleepiness and regulates the circadian rhythm to coordinate the sleep-wake cycle.
Ramelteon Brand & dose
Rozerem
- 8 mg PO QHS
Tasimelteon brand & dose
Hetlioz, Hetlioz LQ
20 mg PO QHS
Tasimelteon (Hetlioz) is indicated for non-24 hour sleep-wake disorder;
Hetlioz LQ is an oral suspension that may be used in children as young as 3 years of age
Melatonin Receptor Agonists
- SE
- Is it a controlled substance?
- How should you take them?
- CI?
SIDE EFFECTS
- Somnolence, dizziness
NOTES
- Not a controlled substance
- Do not take with fatty food
Contraindicated with fluvoxamine (CYP1A2 inhibitor) (increases serum concentration of ramelteon)
Tricyclic Antidepressant MOA
- Inhibit norepinephrine and 5-HT reuptake
- They also block acetylcholine and histamine receptors which contribute to side effects (somnolence).
- Silenor is the branded formulation of generic doxepin that is FDA-approved for treatment of insomnia.
Doxepin brand & dose
- Silenor
- Dose: 3-6 mg PO QHS
3 mg if >= 65 years (Even though we dont like TCA for elderly)
BOXED WARNINGS of doxepin
- Increase in suicidal thoughts or actions in some children, teenagers or young adults within the first few months of treatment or when the dose is changed
CONTRAINDICATIONS & SE of doxepin
CI: Requires a 2-week washout for MAO inhibitors
SE: Somnolence, possibility of anticholinergic side effects
What drugs are used off label for sleep?
May be used off-label for sleep (not recommended by guidelines):
- Generic doxepin
- Trazodone
- Mirtazapine (Remeron - atypical tetracyclic antidepressant)
Benzodiazepines moa
These drugs enhance GABA, an inhibitory neurotransmitter, causing CNS depression.
List the benzo drugs that are FDA-indicated for insomnia:
- Temazepam (Restoril)
- Estazolam
- Quazepam (Doral)
- Flurazepam
- Triazolam (Halcion)
- What are some risks with benzos?
- When are benzos CI?
- Benzos and elderly
- Warning with benzos?
- SE of benzos
- Estazolam DDI:
- Triazolam DDI and warnings
- C-IV drugs
- Risk of physical (physiological) dependence, abuse (addiction) and tolerance
- Increase risk of falls, use with caution in those at high risk
- Cross the placenta; contraindicated in pregnancy due to observed teratogenicity
- Lorazepam, oxazepam and temazepam (L-O-T) are preferred for elderly patients;
- temazepam can be used for sleep;
- lorazepam and oxazepam are indicated for anxiety
WARNINGS
Complex sleep behaviors (Sleep-driving) have been noted
SIDE EFFECTS
Drowsiness, dizziness/ inc fall risk, cognitive impairment
NOTES
Estazolam:
- Do not use with potent CYP3A4 inhibitors (ketoconazole, itraconazole)
Triazolam:
- Associated with higher rebound insomnia and daytime anxiety;
- Contraindicated with azole antifungals, protease inhibitors and other CYP3A4 Inhibitors
Antihistamin MOA
Compete with (block) histamine Hl receptors.
Diphenhydramine brand dose
Benadryl, store brands
Rx and OTC
Dose: 50 mg PO QHS
Doxylamine
- Unisom Sleep Tabs
- Sleep Aid
- Store brands
OTC
Dose: 25 mg PO QHS
SE with antihistamine
- Sedation (tolerance to sedative effects can develop after 10 days of use)
- Confusion (can exacerbate memory difficulty)
- Antihistamines may cause paradoxical excitation in young children; do not use doxylamine in children < 12 years
- Peripheral anticholinergic side effects:
. Dry mouth
. Urinary retention (makes it very difficult for males with BPH to urinate)
. Dry/blurry vision
. Constipation - Best to avoid use in BPH (can worsen symptoms) and glaucoma (can elevate IOP) NOTES
- Risk of mix-up; some OTC Unisom branded-products are diphenhydramine
What is RESTLESS LEGS SYNDROME
- (RLS) is an urge to move the lower legs, which is sometimes described as a “creeping” sensation.
- It is worse at night and is relieved with movement.
- RLS is thought to be due to a dysfunction of dopamine in the brain’s basal ganglia circuits.
- What is the Primary treatment of RLS
- What formulations of these drugs should we use?
Primary Ttmt:
- Dopamine agonists
- Anticonvulsant gabapentin
These are dopamine agonists primarily used in longer-acting formulations for Parkinson
- Pramipexole (Mirapex)
- Ropinirole (Requip)
- For RLS, the immediate-release formulation is taken 1 - 3 hours before bedtime.
What is Rotigotine?
Counseling tips?
- Neupro
- Dopamine agonist that comes in a patch formulation (used for both PD and RLS).
The patch is applied once daily
- Do not apply a heat source over the patch
- Remove the patch before an MRI procedure
- Rotate sites to avoid skin irritation
- SE with dopamine agonists
- How could you minimize these SE?
- What should you monitor for?
- Orthostasis, somnolence & nausea that is dose-related
- Titrated dose up slowly
- Patients should be monitored for:
– Psychiatric SE (hallucinations, abnormal dreams)
– Movement disorders
- What are the forms of gabapentin used for RLS?
- How should it be taken?
- What time should it be taken?
- Gabapentin enacarbil (Horizant) is an extended-release form of gabapentin approved for postherpetic neuralgia (PHN) and RLS.
- The tablet is taken with food and must be swallowed whole (it cannot be crushed or chewed).
- For RLS, it is taken at 5:00 PM daily.
- The IR formulation of gabapentin is used off-label as a less expensive alternative.
What is Narcolepsy?
- Excessive daytime sleepiness with cataplexy (sudden loss of muscle tone) and sleep paralysis.
- Causes sudden daytime “sleep attacks” due to poor control of normal sleep-wake cycles.
- The sleep attacks last a few seconds to several minutes.
- Patients have difficulty managing daily activities with narcolepsy; they can fall asleep while at work, school or in the middle of a conversation.
- Sleep quality at night is poor.
DRUG TREATMENT of narcolepsy
- Stimulants: Modafinil or armodafinil
- Sodiumoxybate (Xyrem)
- Calcium, magnesium, potassium and sodium oxybate (Xywav)
both of which are derived from the inhibitory neurotransmitter GABA.
Several of the stimulants used for ADHD have an indication for narcolepsy:
- Dextroamphetamine (Dexedrine, ProCentra and Zenzedi)
- Dextroamphetamine/amphetamine (Adderall)
- Various methylphenidate formulations (Methylin, Ritalin)
What are some stimulants for Wakefulness for narcolepsy
- Modafinil (Provigil)
C-IV
Dose: 200mg PO QAM - Armodafinil (Nuvigil)
R-isomer of modafinil
C-IV
Dose: 150-250 mgPOQAM
Stimulants for Wakefulness:
- Warning
- SE
- Other indications
WARNINGS
- Avoid with pre-existing cardiac conditions
- Caution with hepatic or renal dysfunction
- Psychiatric disorders
- Tourette’s syndrome
SIDE EFFECTS
- Severe rash, can be life-threatening (Stevens-Johnson syndrome)
- Headache
- Insomnia
- Anxiety
- Nausea
NOTES
Other indications include:
- Obstructive sleep apnea (to help with excessive daytime sleepiness)
- Shift work disorder
Sodium Oxybates for narcolepsy moa
These drugs are derived from GABA and are indicated for narcolepsy with cataplexy.
They help with sleep at night and are generally used with daytime stimulants.
Sodium oxybate
- Brand
- warning
- Sodium oxybate (Xyrem)
- Calcium, magnesium, potassium and sodium oxybates (Xywav)
- Oral solution
C-III (narcolepsy)
C-I (illicit use) - These are “date rape” drugs (the sedative GHB); a REMS program is required to ensure use only by patients with narcolepsy with cataplexy
Dose of Sodium Oxybates for narcolepsy
- Start 2.25 grams PO QHS and take again 2.5- 4 hours later
- Titrate to effect; dosing range -6-9 grams/night
- Take in 1⁄4 cup water at least 2 hours after eating; lie down immediately after taking and stay in bed; sleep onset typically occurs within 5-15 minutes after taking the first dose
Sodium Oxybates BBW, CI, SE, dietary concerns
BOXED WARNINGS
- Strong CNS depressant; respiratory depression, coma and death can result; risk is increased when taken with other CNS depressants
- Restricted access through the Xywav and Xyrem REMS Program
CONTRAINDICATIONS
Use with sedative-hypnotics or alcohol
WARNINGS
Depression, suicide, psychosis, anxiety, sleepwalking
SIDE EFFECTS
Dizziness, confusion, nausea
NOTES
High sodium content; limiting dietary sodium intake may be required
Other Oral Medications for Narcolepsy
Other available treatments shown in the table below are approved by FDA to improve wakefulness in narcolepsy.
Histamine-3 (H3) Receptor Antagonist/Inverse Agonist
Pitolisant /Wakix)
Approved for adult patients with excessive daytime
sleepinessassociatedwith narcolepsy
CONTRAINDICATIONS
Severe hepatic impairment
WARNINGS
QT prolongation
SIDE EFFECTS
Insomnia, nausea,anxiety, headache
Solriamfetol
- MOA
- Brand
- Approved for:
- CI
- Warnings
- SE
- Dopamine and Norepinephrine Reuptake Inhibitor (DNRI)
- Sunosi
- Approved for adult patients with excessive daytime sleepiness associated with narcolepsy or obstructive sleep apnea
CONTRAINDICATIONS
Concomitant MAO inhibitors or within 14 days of discontinuation
WARNINGS
Increase in blood pressure and heart rate, psychiatric symptoms (Anxiety, irritability)
SIDE EFFECTS
Headache, nausea, decreased appetite, insomnia, anxiety
Counseling tips for Antihistamines & Stimulants for Wakefulness
Antihistamines
■ Can cause anticholinergic effects.
Stimulants for Wakefulness
■ Take in the morning to avoid difficulty falling asleep at night.
