Sleep Disorders Unit 1

Stages of Sleep: 

NONREM:

• Stage 1: light sleep 

• Stage 2: intermediate sleep, sleep spindles 

• Stage 3: DELTA WAVES, restorative, healing, parasomnias present here

REM: flaccid body, electrically/metabolically active

• Increased heart rate, increased blood flow
  
  

Sleep Patterns and Aging → as age INCREASES, REM sleep DECREASES, and more awake

Insomnia

Hyper-arousal State

→ increased metabolic rates preventing sleep onset or maintenance 

Major Symptoms…

1. Falling asleep (sleep latency) 

2. Staying asleep (sleep maintenance) ((WASO))

3. Feeling rested (restorative sleep)

4. Daytime functioning (concentration/fatigue)

Types of Insomnia…

1. Transient (e.g., stress-induced)

2. Short-term insomnia (=< 3 months)

3. Long-term (3x a week for => 3 months)

Drug-Induced Insomnia: 

1. Alcohol 

2. ABX → fluoroquinolones

3. Antidepressants → TCAs, SSRIs, MAOIs

4. Antihypertensives → B-blockers, CCBS, clonidine, diuretics

5. Corticosteriods

6. Nicotine

7. Amphotericin B

Withdrawal Insomnia: 

CNS depressants → rebound insomnia

1. Alcohol

2. Antihistamines 

3. Barbiturates 

4. Benzodiazepines 

   1. MUST taper off of 

5. Antidepressants

Cognitive Behavioral Therapy (CBT-I)

→ first line treatment for chronic insomnia 

1. Behavioral 

2. Cognitive 

3. Educational 

Aimed to identify and change maladaptive behaviors

Wake Promoting NT Details…

1. Norepinephrine - attention and alertness, cessation associated with loss of muscle tone

2. Acetylcholine - cholinergic basal forebrain neurons: arousal and REM sleep promotion 

3. Histamine - promotes/maintains wakefulness

4. Serotonin - 5H2A stimulation causes insomnia 

5. Orexin - suppresses REM and NREM sleep 

6. Glutamate - motor atonia during REM sleep

OTC Antihistamines for sleep…

→ may be considered for short-term insomnia

1. Tachyphylaxis occurs within days 

2. Cognitive impairment due to anticholinergic properties 

   1. Avoid in the elderly

3. SUPPRESSES REM sleep 

4. Paradoxical reactions 

Dosing Diphenhydramine: 25-50 mg at bedtime for 2-3 days

PRESCRIPTION SLEEP AIDS:

FDA Approved:

1. Benzodiazepines 

2. Melatonin agonists 

3. Selective BZD Agonists (Z-Drugs) 

4. TCAs

5. Dual Orexin Receptor Antagonists

DO NOT USE BARBITURATES AS SLEEP AIDS

Benzodiazepine Black Box Warning

→ risk of abuse, misuse, addiction, physical dependence, and withdrawal reactions 

• Habit forming

• Caution with prescribing Benzos with OPIOIDS and other CNS-depressing medications

Need to be gradually tapered and not abruptly stopped: Seizure, acute withdrawal symptoms

Benzo MOA:

allosteric modulation at GABA alpha-1 subtype receptors

→ bind and enhance GABA signaling, allowing for more chloride to enter (polarizing)

BENZOS ARE CONSIDERED FIRST-LINE TREATMENT FOR SHORT-TERM MANAGEMENT OF INSOMNIA 

Benzodiazepine Comparison for Insomnia Treatment…

1. Temazepam (Restoril)

   1. Intermediate duration onset of action

2. Triazolam (Halcion)

   1. ULTRA FAST 15-30 minute onset of action 

      1. Therefore GOOD use for SLEEP LATENCY PROBLEMS

Benzodiazepine Dosing…

Temazepam (Restoril)

• 7.5 mg - 30 mg 

Triazolam (Halcion) 

• 0.125 mg - 0.25 mg (more potent drug)

Benzodiazepine Metabolism (LIVER)

1. Phase 1 (decreased metabolism with age) DAT

   1. Diazepam

   2. Alprazolam

   3. Triazolam 

2. Phase 2 (minimal changes with age) ((good for older adults and hepatic impairment) LOT

   1. Lorazepam 

   2. Oxazepam 

   3. Temazepam

Z-DRUGS

Selective BZD Receptor Agonists: Zolpidem, Zaleplon, Eszopiclone

Z-Drug Pharmacokinetics and Efficacy…

1. Zolpidem (Ambien)

   1. Metabolism: CYP3A4

   2. Sleep latency useful 

   3. ER formulation good for WASO 

   4. ER formulation good for chronic use (6 months) 

2. Zaleplon (Sonata)

   1. Metabolism: Aldehyde Oxidase 

   2. Sleep latency useful

   3. NOT FOR WASO

   4. NOT FOR CHRONIC USE

3. Eszopiclone (Lunesta)

   1. 6-7 hour half life 

   2. Metabolism: CYP3A4 

   3. Sleep latency useful 

   4. WASO useful 

   5. Chronic use useful (6 months)

SAFETY ISSUES WITH BENZOS AND Z-DRUGS…

• Sedation/dizziness

• CNS depression

• Amnesia

• Psychomotor retardation and impairment 

• Z-Drugs = complex sleep behaviors

• Disinhibition, Dysphoria, Headache

• Dementia RISK 

• Fall RISK 

• Withdrawal

FDA OTHER Approved Medication for Insomnia…

Ramelteon - melatonin receptor agonist

• Non controlled drug effective for sleep latency 

• NOT EFFECTIVE for WASO

• Expensive 

Suvorexant, Lemborexant, Daridorexant - orexin antagonists

• Complex Sleep problems 

• CYP3A4 Substrate 

• Effective for both latency and WASO

• Controlled substance 

Doxepin - histamine antagonism at low doseses 

• Anticholinergic properties, sedation dizziness

• Effective for WASO

Dual Orexin Antagonists (DORA)

MOA: turn off wake signal 

Indication: initiating AND maintaining sleep (WASO)

Warnings: 

• Sleep paralysis, cataplexy, narcolepsy, next day driving impairment 

OK with mild-moderate sleep apnea 

Suvorexant 20 mg before bed 

Dual Orexin Antagonists (DORA) DRUGS

Suvorexant (Belsomra): moderate CYP3A4 inhibitor, 5 mg recommended dose

• Sleep onset or sleep maintenance 

• Hepatic metabolism 

Lemborexant (Dayvigo) - mild CYP3A4 inhibitor, hepatic metabolism 

• Sleep onset or sleep maintenance 

Daridorexant (Quviviq) - moderate CYP3A4i

• Sleep onset or sleep maintenance 

• CI: narcolepsy

Dual Orexin Antagonists (DORA) ADR:

1. Next day somnolence 

2. Narcolepsy associated events, hypnagogic hallucinations

3. Abnormal dreams 

4. Headache 

5. Suvorexant - cough, dry mouth, diarrhea, dizziness

Ramelteon 

M1 and M2 melatonin receptor agonist

• M1 promotes sleep onset 

• M2 synchronizes sleep-wake phases

DOSE: 8 mg at bed time

• NEED AT LEAST 7 HOURS OF SLEEP AFTER TAKING

NOT recommended for patients with severe OSA or severe hepatic impairment 

→ increases prolactin levels in women and decreases testosterone levels in men 

• Men may have female symptoms as a result of the increased prolactin levels 

MAXIMAL Effect: required 3 weeks of usage

DDIs: CYP1A2, CYP3A4, Donepezil, Doxepin, CYP2C9 inhibitors 

• CYP1A2/CYP3A4 inhibitors INCREASE ramelteon concentration 

• CYP1A2/CYP3A4 inducers DECREASE ramelteon concentration

melatonin for circadian rhythm disorders

short term use, 0.5-10 mg

• 3-5 hours before bed time

MAY decrease sleep latency and delayed sleep disorder

• CYP1A2 inhibitor

Antidepressant Sleep Medications

NON-FDA Approved Agents → Antidepressants 

1. Trazodone (Desyrel) 50 - 150 mg QHS

2. Mirtazapine (Remeron) 7.5 - 15 mg QHS

Place in therapy: comorbid  depression/substance use disorder alternative 

(at lower doses compared to antidepressant doses)

Doxepin (Silenor) for insomnia 

→ low dose histamine receptor antagonism 

• 3 mg - 6 mg at bedtime 

CI:

• Hypersensitivity to doxepin 

• Co admin with monoamine oxidase inhibitors 

• Untreated narrow angle glaucoma or severe urinary retention 

• Warning with concurrent use with other antihistamines 

NOT recommended in patients who have SEVERE OSA

Primary Indication by Therapeutic Class…

1. Benzodiazepines/Z-Drugs

   1. Both sleep onset and WASO

   2. Triazolam = sleep ONSET only

   3. Zolpidem SL and Zaleplon = sleep ONSET only 

2. Dual Orexin Receptor Antagonists (Suvorexant, Lemborexant, Daridorexant)

   1. Both sleep onset and WASO

3. Melatonin/Melatonin Receptor Agonists (Ramelteon)

   1. Sleep onset ONLY

4. Sedating Antidepressant - low dose doxepin 

   1. Sleep Maintenance (WASO) ONLY

5. Sedating antihistamines - diphenhydramine, hydroxyzyine 

6. Antipsychotics - quetiapine/olanzapine

General Treatment Algorithm for:

• Short Term insomnia…

  • CBTi

  • Sleep hygiene

  • Short acting Benzodiazepines

  • Ramelteon 

    • IF NO WORK?

      • Trazodone, 

      • Different benzodiazepine

      • Suvorexant 

• Chronic Insomnia 

  • CBTi

  • Sleep hygiene/treat underlying medical 

  • Benzodiazepine

Individualized Medication Management…

1. Dual Orexin Receptor Antagonists 

   1. Sleep-onset and sleep-maintenance 

2. Doxepin

   1. Sleep-maintenance only 

   2. Vulnerabilry to substance use disorder 

3. Ramelteon 

   1. Sleep-onset insomnia 

4. Antidepressants 

   1. Treatment resistant insomnia 

   2. Comborbid depression, anxiety, pain 

5. Antipsychotics 

   1. Treatment resistant insomnia 

   2. Comborid depression, psychosis

How Long to Continue Treatment?

1. Short term insomnia: < 4 weeks 

   1. Most hypnotics for short term 

2. Long Term > 6 months 

   1. Zolpidem

   2. Eszopiclone 

   3. Ramelteon 

   4. DORAs

Insomnia and Pregnancy?

→ CBTi-preferred 

→ Doxylamine

→ Zolpidem for severe refractory insomnia

NARCOLEPSY

- exaggerated excessive daytime sleepiness

• Sleep attacks 10-20 minutes 

• Cataplexy (sudden loss of muscle tone) 

• Sleep paralysis 

• hypnagogic/hypnopompic hallucinations 

Type 1: cataplexy → orexin deficient

Type 2: NO cataplexy → NOT orexin deficient

Modafinil 1st line treatment for excessive day time drowsiness

Oxybate 1st line treatment for cataplexy or combo of EDS/cataplexy

Modafinil (Provigil) 

Standard treatment for narcolepsy 

→ targets XS  daytime sleepiness 

→ NOT EFFECTIVE for cataplexy 

MOA: targets dopamine transporter 

Dose: 200-400 mg/day

ADE: headache, insomnia, nervousness, nausea, steven johnsons syndrome

Stimulants for Narcolepsy…

→ Dextroamphetamine (Dexedrine)

→ Methylphenidate (Ritalin) 

Up to 60 mg/day

Targets: Norepinephrine/Dopamine Transporter

Solriamfetol (Sunosi)

→ treatment for excessive daytime sleepiness 

• Mixed DA/NE reuptake inhibitor (super bupropion) 

• ADE: nausea, decreased appetite, insomnia, anxiety 

• AVOID with MAOIs

Pitolisant (Wakix) 

• Histamine-3 receptor antagonist/inverse agonist 

Oxybate (Xyrem and Xywav)

Only FDA approved treatment for narcolepsy associated cataplexy

→ GABA-B receptor and GHB agonist 

• Decreases time spent in REM sleep → increase NREM sleep 

• Do NOT take with other CNS depressants 

DOSING:

• 1st dose at bedtime, 2.5-4 hour after take second dose

Contains HIGH SODIUM CONTENT therefore avoid in heart failure/sodium restriction patients

OSA Treatment Cascade…

1. Nasal CPAP + weight loss 

2. ADD Modafinil, Armodafinil, or Solriamfetol

OSA Management…

• 1st line: 

  • Weight loss

  • CPAP

• Pharmacolgocal

  • AVOID CNS DEPRESSANTS

  • Modafinil (FDA approved for daytime sleepiness associated with OSA)

  • Tirzepatide (Zepbound)

Restless Leg Syndrome

Linked to CNS iron deficiency in the substantia nigra

• URGE to move

Modify Reversible Causes: 

• Iron deficiency (KEEP Ferritin > 75, transferrin sat > 20%)

• Medication-induced: SRIs, DA antagonists, antihistamines

Pharmalogical Approaches: 

• First line: alpha-2 delta ligans (gabapentinoids) 

  • Gabapentin, pregabalin

• Dopaminergic agonists are NOT first line therapy due to iatrogenic worsening (augmentation of RLS symptoms with long term use)

• Opioids (oxycodone, methadone) 

Gabapentinoids for RLS…

• Gabapentin enacarbil approved for RLS

  • Pro-drug formulation bypasses saturable absorption issues 

• Normal Gabapentin absorption is saturated with increased doses

• 600 mg dose at 5:00 pm with food 

ADE: somnolence, sedation, peripheral edema, weight gain

Dopamine Agonists for RLS…

Bind to D2 receptors in the striatum

ADE: psychotic behavior, impulsive behaviors, augmentation 

Gambling, hypersexuality, spending

• Ropinirole 0.25 mg

• Pramipexole 0.125 mg

• Rotigotine (transdermal patch) (1 mg/24 hour) 

• Levodopa/carbidopa 100 mg 

RISK OF Augmentation: drug makes symptoms of RLS worse not better with use

Is sleep hygiene counseling/application alone able to help insomnia

NO, needs to be in adjunct with CBTi

doxepin latency or WASO?

sleep maintenance

benzos

Alprazolam Xanax

Diazepam Valium

Lorazepam Ativan

Clonazepam Klonopin

Temazepam Restoril

Chlordiazepoxide Librium

Midazolam Versed

Triazolam Halcion

Flurazepam Dalmane

Oxazepam Serax

Clorazepate Tranxene