INSOMNIA & SLEEP DISORDERS

W. Klugh Kennedy, PharmD, BCPP, FASHP, FCCPProfessor of Pharmacy Practice and Psychiatry Mercer University (Savannah Campus)Memorial University Medical Center

2015

OBJECTIVES• Describe the types of insomnia and associated symptoms• Recognize social situations, medications and medical conditions that may lead to insomnia• Define treatment plans for insomnia• Be able to select an appropriate pharmacologic agent for different types of insomnia• Understand and define treatment plans for other sleep disorders such as Circadian Rhythm Disorders and Narcolepsy

BACKGROUND• We spend about one-third of our lives asleep.

• Sleep-Wake Cycle• Usually lasts 25 hours, so there is some internal

“resetting” required.• The reticular activating system maintains wakefulness

and when activity here declines, sleep occurs.

CIRCADIAN RHYTHM

SLEEP CYCLENon-Rapid Eye Movement (NREM) -- 75%

Stage 1 • Drowsiness

Stage 2 • Light sleep, mild muscle relaxation• Heart rate slows, body temperature decreases

Stage 3 & 4

• Deepest sleep (delta-sleep)

Rapid Eye Movement (REM) -- 25%

REM Sleep

• Slow-wave state of sleep• Brain becomes electrically and metabolically activated• Increase in cerebral blood-flow• Generalized muscle atonia, vivid dreams, fluctuations in respiratory and cardiac rate

NREM

REM

How much sleep do we need?

AGE Amount

Infants ~16 hours per day

Babies and Toddlers(6 months to 3 years)

10-14 hours per day

Children 9-12 hours per day (decreases an hour every 3 years from 6 to 12)

Teenagers ~9 hours per night

Adults 7-8 hours per night

Older Adults 7-8 hours per day

Pregnant Women Usually require ~3 hours more sleep than usual

SLEEP & WAKE DISORDERSDSM-5 Categorizations

Insomnia Disorder Hypersomnolence Disorder Narcolepsy Breathing-Related Disorders• Obstructive Sleep Apnea Hypopnea• Central Sleep Apnea• Sleep-Related Hypoventilation

Circadian Rhythm Disorders Parasomnias• Non-REM Sleep Arousal Disorders• Nightmare Disorder• REM Sleep Behavior Disorder

Restless-Legs Syndrome Substance/Medication-

Induced Sleep Disorder Other Specified Insomnia

Disorders Unspecified Insomnia

Disorders Other Specified

Hypersomnolence Disorders Unspecified

Hypersomnolence Disorders Other Specified Sleep-Wake

Disorders

How do we measure sleep?• Subjective Questioning• But not too subjective

• Objective Studies• Polysomnography (PSG)• Multiple Sleep Latency Test (MSLT)• Maintenance of Wakefulness Test (MWT)

INSOMNIA

INSOMNIA

“Difficulty falling asleep, maintaining sleep, arising, or not feeling rested despite a sufficient opportunity to sleep.”

Prevalence• In the United States, people report:• >50% experienced insomnia during their lifetime• 40% get less than 7 hrs of sleep every night• 15% report some type of daytime impairment• Elderly: up to 80%• Chronic insomnia make up 6-15% of cases

INSOMNIA• Cost• $35 billion per year

•Diagnosis• Physicians detect insomnia in only about 50% of

those experiencing it• Primary Providers often rate their knowledge

regarding as insomnia as fair or poor

Complications from Insomnia

Associated Factors• Gender• Age• Situational Stressors• Environmental• Poor Sleep Hygiene• Psychiatric Conditions• General Medical Conditions• Substances and Medications• Unemployment• Lower Socioeconomic Status

Insomnia Classification• Transient• Lasts a few days, usually associated with stressful situation• Examples: jet lag, a stressful event, change in work

schedule

• Short-Term• Lasts up to 4 weeks and is usually associated with acute or

situational stress• Examples: death of loved one, medical illness, surgery

recovery

• Long-Term• Lasts more than 4 weeks• Examples: caffeine misuse, chronic stress, secondary to

underlying condition

Causes of InsomniaMedical Illnesses• Cancer• Chronic Pain• Restless Leg Syndrome (RLS)• Sleep Apnea• Incontinence• Allergies• Menopause/Hot Flashes• Asthma and Chronic

Obstructive Pulmonary Disease (COPD)

• Dementia• Fibromyalgia• Irritable Bowel Syndrome (IBS)• Arthritis• Seizure Disorders

Mental Illnesses• Depression• Generalized Anxiety Disorder• Panic Disorder• PTSD• Substance Abuse• Somatoform Disorders• Adjustment Disorders• Personality Disorders

Inadequate Sleep Hygiene• Daytime napping• Inconsistent sleep schedule• Eating, exercise, caffeine

and/or nicotine• Etc.

Causes of InsomniaMedication Induced Insomnia• Decongestants• Appetite Suppressants• Stimulants• Steroids• Antidepressants• Beta-agonists• Beta-blockers• Diuretics• Dopamine agonists/replacement• Hypoglycemics• Thyroid Hormones• CNS Depressant Withdrawal

TREATMENT OF INSOMNIA

Pharmacotherapy of Insomnia• Part of an overall plan to deal with the causes and used for well-defined time• Should only be considered adjunctive therapy for short-term and chronic insomnia• Used SHORT-TERM for managing symptoms• NOT a permanent solution!

BENZODIAZEPINES

Benzodiazepines (BZDs)• Class IV Substances• Used when:• Immediate response needed• Non-pharmacologic measures do not work• Short-term use

• FDA-Approved for Insomnia: Half-Life Onset of Action• Triazolam (Halcion®) SHORT 15 – 30 minutes• Estazolam (ProSom®) INTERMEDIATE 30

minutes• Temezepam (Restoril®) INTERMEDIATE 45 minutes• Quazepam (Doral®) LONG 30 minutes• Flurazepam (Dalmane®) VERY LONG 30 minutes

• Effect: Increase sleep time and reduce time to onset of sleep

BZDs• Use LOWEST effective dose• Avoid residual daytime sedation

• Use for a SHORT DURATION (only 2-4 weeks) and intermittently• Not indicated for chronic use, may develop tolerance

• AVOID in substance abuse and respiratory impairment• Monitor for escalating doses or early refill requests• Anterograde amnesia• Can worsen depression• Use caution in elderly (Beers List – pretty much all hypnotics)• Pregnancy: Category X• Withdrawal: Anxiety, depression, nightmares, rebound insomnia• TAPER DOSE prior to discontinuing to avoid

NON-BZDSPharmacologic Options

Non-BZDsClass Drugs

NBRAs (“Z”-Drugs) • Zolpidem (Ambien®)• Zaleplon (Sonata®)• Eszopiclone (Lunesta®)

Melatonin Agonist • Ramelteon (Rozerem®)

Zolpidem (Ambien®)Drug (Trade)

What you need to know:

Zolpidem

Ambien® Ambien CR®Intermezzo®

Usual dose: 5-10mg PO 30 min before HS Duration: IR: 5 hours (fall asleep) CR: Released over longer period of time (stay asleep)Onset: 10-20 minutes• Lacks anticonvulsant action, muscle-relaxant properties, and respiratory depressant effects• Lower risk of tolerance and withdrawal• Avoid in obstructive sleep apnea• Must be hepatically adjusted (half dose)• Controlled release formulation available (Ambien CR®) as well as SL tablets and Oral Spray (Edluar® and Zolpimist®) and the SL Intermezzo® which may be taken during nighttime awakenings• Women clear zolpidem slower than men• Adverse Effects may include HA, dizziness, daytime somnolence, GI complaints• Psychotic symptoms, sensory distortions, parasomnias, amnesia...

Zaleplon (Sonata®)Drug (Trade)

What you need to know:

Zaleplon Sonata®

Usual dose: 5-20mg PO before HSDuration: <4 hours Onset: 10-20 min

• FDA Approved for Short-Term Treatment of Insomnia to improve sleep onset• May cause fewer problems in AM due to 1 hour half-life• No apparent rebound insomnia, withdrawal symptoms, daytime anxiety, sedation, or impairment• Can be given late and preserves all sleep stages• Low risk of dependence• Food can delay onset and dose should be reduced in elderly, liver disease, concomitant cimetidine use• Side Effects: dizziness, headache, somnolence, nausea

Eszopiclone (Lunesta®)Drug (Trade)

What you need to know:

Eszopiclone (Lunesta®)

Usual Dose: 2-3mg adults, 1-2mg elderlyDuration: 8 hours, longer in elderlyOnset: 30 min

• 3mg for sleep maintenance• 1mg for elderly having trouble falling asleep• Morning effects possible if taken late• Can be used for chronic insomnia• Food causes delayed onset• Less tolerance risk• Metallic aftertaste (34%)• HA, dizziness, unpleasant dreams

What

the…?

Ramelteon (Rozerem®)Drug (Trade)

What you need to know:

Ramelteon (Rozerem®)

Melatonin AgonistUsual Dose: 8mgDuration: 8 hoursOnset: 20 minutes?• Not a controlled substance!• No dependence/tolerance• May use long-term• Do not take with high-fat meal• Avoid in liver dysfunction• AE: HA, fatigue, dizziness, nausea, increased prolactin levels

Your dreams miss you!

OTHER AGENTS

Other AgentsClass Drugs

Sedating Antidepressants

• Mirtazapine (Remeron®) 15mg• Trazodone (Desyrel®) 50 – 150mg• Doxepin (Silenor®) 10 - 50mg

Antihistamines • Diphenhydramine (Benadryl®) 25 – 50mg• Doxylamine (Unisom®) 25 – 50mg• Hydroxyzine (Atarax®, Vistaril®) 25 –

50mg

Atypical Antipsychotics*

• Quetiapine (Seroquel®) 50 - 100mg• Olanzapine (Zyprexa®) 5 – 10mg

Antihypertensive • Prazosin 1- 6mg/day

Mirtazapine (Remeron®)Drug (Trade) What you need to know:

Mirtazapine (Remeron®)

Class: AntidepressantDOSING: 15mg adult 15mg elderly Renal/Hepatic dose adjustments requiredHALF-LIFE: 20-40 hours

• NOT FDA-Approved for Insomnia• Increases risks of RLS and periodic limb movements• May be useful for insomnia in depression• Available in 15mg tablets• May cause increased appetite and weight gain along with constipation and asthenia• Lower doses tend to be more sedating

Trazodone (Desyrel®)Drug (Trade) What you need to know:

Trazodone(Desyrel®)

Class: AntidepressantDOSING: 50-150mg adult 25-50mg elderlyONSET: 1 hourHALF-LIFE: 5-9 hours• NOT FDA-Approved for Insomnia• Often used with SSRIs if patient is experiencing insomnia related to their use• Limited efficacy data for insomnia• Little anticholinergic activity• Long-term use is acceptable• Adverse Effects: priapism (<0.1%), orthostatic hypotension nausea, xerostomia, blurry vision

AntihistaminesMedications What you need to know:

Diphenhydramine Benadryl® OTC

Doxylamine Unisom® OTC

Hydroxyzine Atarax® RxVistaril® Rx

• Adverse Effects: Dizziness, headache, blurry vision, hypotension, photosensitivity, constipation, dry mouth, increased liver enzymes• Often a hangover effect is experienced• Avoid in patients with urinary retention problems and closed angle glaucoma• Inappropriate for use in elderly (Beers Criteria)• Not effective for chronic insomnia because tolerance develops after 1-2 weeks of continued use; consider “off night” after 3 days use• Counsel patients not to use Tylenol PM for sleep.

ALTERNATIVE/HERBAL TREATMENT

Alternative/Herbal TreatmentClass Drug

Herbal/Alternative • Valerian• Melatonin• Kava-Kava* (illegal in the USA)

ValerianTherapy What it Does: What you need to know:

Valerian Root

(valeriana officinalis)

sedative, anxiolytic, antidepressant, anticonvulsant, hypotensive and antispasmodic effects

• One of the most common OTCs used for sleep• Evidence Grade C (conflicting)• Causes CNS depression and muscle relaxation• Safe for short-term use, long-term safety not determined• Does not work until 2-3 weeks after initiation• Usually well-tolerated, may have GI distress, morning sedation, headache• Avoid in patients with hepatic disease and in pregnancy• Do not take with EtOH, benzos, other hypnotics• Interacts with drugs metabolized by CYP3A4

Valerian Flower

MelatoninTherapy About What you need to know:

Melatonin

(N-acetyl-5-methoxytryptamine)

Hormone produced from tryptophan which is secreted by pineal gland. Exogenous OTC Melatonin is synthetically produced to mimic the natural hormone.

• DOSE: 5mg PO 3-4 hours prior to HS• May be useful in treating abnormalities of the circadian clock (i.e. shift work, jet lag, blind)• Adverse Effects: sedation, headache, depression, tachycardia, pruritus• Avoid in pregnancy

OTHER SLEEP DISORDERS

• Sleep Apnea• Circadian Rhythm Disorder• Narcolepsy

SLEEP APNEA

SLEEP APNEA• Neurological condition that results in periods of breathing cessation about 10-25 times per hour• Brain will respond and patient awakens usually with no memory of the episode• Types: • Obstructive Sleep Apnea (OSA)• Most common• Usually due to physical blocking (obesity, tonsils, tongue, thyroid)

• Central Sleep Apnea (CSA)• 10% of all apneas• Due to delay of brain signal for breathing• Idiopathic• Requires O2 as treatment

• Diagnosis: Polysomnography (PSG)

Treatment: Obstructive Sleep Apnea• Weight Loss• Smoking Cessation• Positional changes• CPAP (face-mask)• Oral Appliances• Avoid CNS depressants• Modafanil and Armodafanil (Provigil® and Nuvigil®) to improve daytime sleepiness• Methylphenidate or stimulants classically used • Surgical

Modafanil (Provigil®) & Armodafanil (Nuvigil®)Drug (Trade) What you need to know:

Modafanil and Armodafanil (Provigil® and Nuvigil®)

CNS Activating; exact MOA unknownDOSING: Modafanil 200mg qAM Armodafanil 150-250mg qAM Hepatic adjustment required• Schedule IV• Less abuse potential than stimulants• May reduce effectiveness of oral birth control• Onset: ~2 hours • AE: Headache (34%), insomnia, anxiety, SJS (rare)

CIRCADIAN RHYTHM DISORDERS

CIRCADIAN RHYTHM DISORDERS• Examples: Shift Work and Jet Lag• Non-Pharmacologic Interventions• Adjusting sleep schedule prior to event• Avoid naps, EtOH, stimulants

• Pharmacologic Interventions• Melatonin• Zolpidem for 3 nights

NARCOLEPSY

NARCOLEPSY• Chronic, incurable disorder characterized by irrepressible sleep attacks and cataplexy• Patient moves directly into REM sleep without NREM period• Symptoms:• Excessive Daytime Sleepiness• Cataplexy • Loss of muscle tone in face or limb muscles induced by emotions or

laughter• May be subtle (limp) or dramatic (drops to the floor)

• Hallucinations• Hypnagogic• Hypnopompic

• Sleep paralysis

• Genetic link

NARCOLEPSY: Treatment• Schedule naps, approximately one to two lasting ~20 min/day• No EtOH, caffeine, nicotine

For EDS• 1st line: Wake Promoting Agents• Modafinil (Provigil®) and R-enantiomer armodafinil

(Nuvigil®)

• 2nd line: Stimulants• Methlyphenidate (Ritalin®) and Amphetamines

• SSRIs/SNRIs (last line)

NARCOLEPSY: TreatmentFor Cataplexy• Sodium Oxybate (Xyrem®)• Scheduled Substance: C-III (medical use) and C-I (illicit use)• FDA approved for cataplexy in patients with narcolepsy• Changes sleep architecture by decreasing night-time

awakenings and increasing REM sleep• Prescribers MUST be enrolled in Xyrem Success Program• Must enroll in post-marketing surveillance program• First Rx can only be written for a ONE MONTH supply and following

Rxs for only THREE month supply at a time• Dosing: • Initial: 4.5/day in two divided doses (one at HS and second in 2.5

to 4 hours)• Maximum: May increase up to 9mg/day

• Taken on empty stomach

SLEEP HYGIENECOUNSELING

SLEEP HYGIENE STRATEGIES

• Maintain regular hours of going to bed and arising• Do not eat heavy meals 2-3 hours before bedtime but do not go to bed hungry – try a light snack.• Avoid napping during the daytime.• Only use the bed for sleep, sexual activity or pillow fights – Don’t watch TV in bed.• Exercise daily but NOT within 2 hours of sleep• Minimize cigarette smoking and caffeine intake – none after noon!

SLEEP HYGIENE STRATEGIES• Avoid “clock-watching” – try facing clock AWAY • Release worrisome thoughts before bedtime• Do not stay in bed if unable to sleep – get up for 30 minutes and then try again• Make the bedroom as comfortable and dark as possible (black out curtains, blinds, etc.)• Avoid alcohol as a sleep aid• IF YOU SNORE frequently, see your doctor!

Conclusion• The physiologic process of sleep is essential to normal restorative

functioning in humans• Untreated sleep deprivation increases risk for multiple medical disorders and makes underlying medical problems difficult to treat -- it may also increase mortality

• When non-pharmacologic options do not offer optimal benefit, drug therapy may be utilized

• Benzodiazepines, Non-Benzodiazepine Hypnotics, Sedating Antidepressants, Antihistamines or Alternative Therapies may be viable options for sleep aid

• Other sleep disorders include sleep apnea, circadian rhythm disorders and narcolepsy and all require different approaches to treatment

• Pharmacotherapy should be used for the shortest periods possible to alleviate symptoms -- they are NOT a cure -- always consider there may be more to the problem than just the inability to sleep

References• Diagnostic and Statistical Manual of Mental Disorders: DSM-5. Washington, D.C.: American Psychiatric Association, 2013. Print.• Erman MK. Therapeutic options in the treatment of insomnia. J Clin Psychiatry. 2005;66 (suppl9);18-23.• Lande RG, Gragnani C. Nonpharmacologic approaches to the management of insomnia. J Am Osteopath Assoc. 2010;110(12):695-701.• Stahl, Stephen M. Stahl's Essential Psychopharmacology: Prescriber's Guide. 5th ed. New York: Cambridge, 2014. Print.