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INSOMNIA. Jeffrey Lin, M.D. Fellow, Sleep Medicine Stanford University Medical Center December 3, 2008. DISCLOSURES. None Special thanks to Dr. Philip Becker Dr. David Neubauer Dr. Edward Stepanski. OBJECTIVE. Pathogenesis Prevalence Impact Pharmacologic treatment

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insomnia

INSOMNIA

Jeffrey Lin, M.D.

Fellow, Sleep Medicine

Stanford University Medical Center

December 3, 2008

disclosures
DISCLOSURES
  • None
  • Special thanks to
    • Dr. Philip Becker
    • Dr. David Neubauer
    • Dr. Edward Stepanski.
objective
OBJECTIVE
  • Pathogenesis
  • Prevalence
  • Impact
  • Pharmacologic treatment
  • Cognitive-behavioral therapy
physiology of sleep
PHYSIOLOGY OF SLEEP

www.ge.infn.it/~rita/fisio%20sonno_ing.htm

definition of insomnia
DEFINITION OF INSOMNIA
  • NHLBI: Subjective patient complaint of difficulty falling asleep, difficulty staying asleep, poor quality sleep, or inadequate sleep despite adequate opportunity.
  • DSM-IV definition
    • Difficulty initiating or maintaining sleep for at least 1 month
    • Nonrestorative sleep persisting for at least 1 month
    • Accompanied by clinically significant impairment in daytime functioning
  • Research criteria
    • Sleep latency > 30 minutes
    • Sleep efficiency < 85%
    • Sleep disturbance > 3 times per week

NHLBI working group on Insomnia. Bethesda, Md: NHLBI; 1998. NIH Publication 98-4088

Ringdahl EN et al. J Am Board Fam Pract. 2004; 17:212-219

sleep patterns in insomnia
SLEEP PATTERNS IN INSOMNIA
  • Sleep onset insomnia
    • Difficulty falling asleep
    • Longer time to sleep onset
  • Sleep maintenance insomnia
    • Difficulty staying asleep
    • Frequent nocturnal awakenings
  • Sleep offset insomnia
    • Waking too early in the morning
  • Nonrestorative sleep
    • Fatigue despite adequate sleep duration

DSM-IV-TR. 4th ed. 2000:597-661

Czeisler CA et al. Harrison’s Principles of Internal Medicine” 15th ed. 2001: 155-163

duration of insomnia
DURATION OF INSOMNIA
  • Transient insomnia: episodic
    • Acute illness
    • Jet lag
    • Shift change
  • Short-term insomnia: few days to 3 weeks
    • Major life event
    • Substance abuse
  • Chronic insomnia : longer than 3 weeks
    • Chronic illness
    • Psychiatric illness

NHLBI working group on Insomnia. Bethesda, Md: NHLBI; 1998. NIH Publication 98-4088

epidemiology of insomnia
EPIDEMIOLOGY OF INSOMNIA
  • 30-50% of American adults experience insomnia during a 1 year period
  • Prevalence of chronic/severe insomnia is 10%
  • 49% of adults surveyed were dissatified with their sleep > 5 nights per month
  • 50% of patients presenting to primary care physicians experience insomnia

NHLBI working group on Insomnia. Bethesda, Md: NHLBI; 1998. NIH Publication 98-4088

Smith MT, et al. Am J psychiatry. 2002; 159:5-11

Hajak G et al. Eur Psychiatry. 2003; 18:201-8

Ringdahl EN et al. J Am Board Fam Pract. 2004; 17:212-219

women and insomnia
WOMEN AND INSOMNIA
  • Women are at greater risk for insomnia than men
  • Influenced by hormonal cycles
    • The menstrual cycle
      • 36% during menstruation
      • 14% during late luteal phase
    • During and after pregnancy
    • During the peri/postmenopausal period

Miller EH. Clin Cornerstone. 2004;6(Suppl 1B):s8-s18

Katz DA, McHorney CA. J Family Pract. 2003:51:229-235

Krystal AD. Clin Cornerstone. 2004;6(Suppl 1B)s19-s28

Shaver JLF. Nurs Clin N Am. 202;37:707-718

age and insomnia
AGE AND INSOMNIA
  • Age-related changes in sleep architecture
    • Increased in light/transitional sleep
    • Reduction in slow-wave sleep
    • Decline in overall sleep time
  • Comorbid illness
    • Age-related illnesses
    • Side effects of medications
    • Primary sleep disorders
  • Social factors
    • Bereavement
    • Sleep patterns altered by retirement

Ringhahl EN, Peireira SL, Delzell JJ. Am Board Fam Pract. 2004;17:212-219

primary vs comorbid insomnia
PRIMARY VS. COMORBID INSOMNIA
  • Primary insomnia
    • Sleep disturbance that can not be explained by any underlying medical, psychiatric, or environmental problem
    • Sleep disturbance that persists after the resolution of the original trigger
  • Comorbid insomnia
    • Sleep disturbance is comorbid with an underlying problem
causes of comorbid insomnia
CAUSES OF COMORBID INSOMNIA

www.sleepreviewmag.com/.../2004-05_04.

contributing factors to development of insomnia
Predisposing factors

Personality

Sleep-wake cycle

Circadian rhythm

Coping mechanisms

Age

Precipitating factors

Situational

Environmental

Medical

Psychiatric

Medications

Perpetuating factors

Conditioning

Substance abuse

Performance anxiety

Poor sleep hygiene

CONTRIBUTING FACTORS TO DEVELOPMENT OF INSOMNIA

Hauri PJ. Clin chest med. 1998; 19:157-168

Spielman AJ et al. Psychiatr Clin North Am. 1987; 10:541-553

cognitive behavioral model of insomnia
Dysfunctional Cognition

Worry over sleep loss

Rumination over consequences

Unrealistic expectations

Misattributions/ amplifications

Arousal

Emotional

Cognitive

Physiologic

Consequences

Mood Disturbances

Fatigue

Performance impairments

Social discomfort

Maladaptive Habits

Excessive time in bed

Irregular sleep schedule

Daytime napping

Sleep-incompatible activities

COGNITIVE BEHAVIORAL MODEL OF INSOMNIA

Morin CM. Insomnia: Psychological Assessment and Management. New York, NY: Guilford; 1993

consequences of insomnia
CONSEQUENCES OF INSOMNIA
  • Worsens psychiatric disorders
  • Prolongs medical illnesses
  • Reduced quality of life
  • Higher absenteeism
  • Increased accident risk
  • Higher health care costs
  • Cognitive impairment

Benca RM. J Clin Psychiatry. 2001;62(suppl 10):33-38

depression and insomnia
DEPRESSION AND INSOMNIA
  • Insomnia is both a risk factor for depression and a consequence of depression
  • Could effective management of insomnia decrease the incidence of depression?
  • Could effective management of insomnia modify the risk for relapsing depression?

LustbergL, Reynolds CF. Sleep Med Rev. 2000;3:253-262

car accidents and sleep disorders
CAR ACCIDENTS AND SLEEP DISORDERS

Powell NB et al. Otolaryngol Head Neck Surg. 2002; 126:217-227

economic impact of insomnia
ECONOMIC IMPACT OF INSOMNIA
  • Direct Cost
    • Drugs: $1.97 Billion (41% prescription)
    • Services: $11.96 Billion
  • Indirect Costs
    • Decreased productivity
    • Higher accident rate
    • Increased absenteeism
    • Increased comorbidity
  • Total Annual Cost: $30-$107 billion

Walsh JK, Engelhardt CL. Sleep. 1999;22(suppl 2):S386-393

Stoller MK. Clin Ther. 1994;16:873-879

Chilcott LA, Shapiro CM. Pharmacoeconomics. 1996;10(suppl 1):1-14

pharmacologic treatment
Historic trials

Fermented beverages

Plant preparations

Laudanum (opium/alcohol)

Chloral hydrate

Barbiturates

Current trials

Antihistamines

Benzodiazepine hypnotics

Nonbenzodiazepine hypnotics

Selective melatonin receptor agonist

Investigational compounds

PHARMACOLOGIC TREATMENT
most commonly used drugs for insomnia
Trazodone

Zolpidem

Amitriptyline

Mirtazapine

Temazepam

Quetiapine

Zaleplon

Clonazepam

Hydroxyzine

Alprazolam

Lorazepam

Olanzapine

Flurazepam

Doxepin

Cyclobenzaprine

Diphenhydramine

MOST COMMONLY USED DRUGS FOR INSOMNIA

Walsh et al, 2005

current fda approved insomnia treatment meds
CURRENT FDA-APPROVED INSOMNIA TREATMENT MEDS
  • Benzodiazepine receptor agonists
    • Benzodiazepine hypnotics
      • Temazepam (Restoril)
      • Flurazepam (Dalmane)
    • Nonbenzodiazepine hypnotics
      • Zolpidem (Ambien)
      • Zaleplon (Sonata)
  • Selective melatonin receptor agonist
    • Ramelteon (Rozerem)
benzodiazepine receptor agonists
BENZODIAZEPINE RECEPTOR AGONISTS
  • Gamma aminobutyric acid (GABA)
    • Predominate inhibitory neurotransmitter in CNS
    • A primary inhibitory neurotransmitter in the ventrolateral preoptic nucleus (VLPO)
  • GABAa receptor complex
    • Pentameric structure
    • Modulates chloride ion channel
    • Hyperpolarizes neurons
benzodiazepine receptor agonists29
BENZODIAZEPINE RECEPTOR AGONISTS
  • Bind to the bezodiazepine receptor site
  • Enhances GABA activation of chloride ion channel
  • Promote sleep by sedating effect
  • Absorption allows rapid sleep onset
  • Eliminated half-life and dose determines the duration of action
  • Immediate and controlled-release formulations
bzra prescribing guidelines
BZRA PRESCRIBING GUIDELINES
  • Bedtime dosing
  • Avoid hazardous activities after dose
  • Allow sufficient time in bed
  • Dose adjustments
    • Elderly and debilitated patients
    • Hepatic impairment
  • Nightly vs. as needed dosing
  • Middle of the night dosing?
  • Taper dose on discontinuation?
bzra adverse effects
BZRA ADVERSE EFFECTS
  • Residual effects
  • Dizziness
  • Headache
  • Somnolence
  • Blurred vision
  • Nausea/diarrhea
  • Fatigue
  • Ataxia
  • Anterograde amnesia
  • Sonambulism/complex sleep behavior
bzra discontinuation effects
BZRA DISCONTINUATION EFFECTS
  • Rebound insomnia: sleep worsened relative to baseline for 1-2 days
  • Recrudescence: return of original insomnia symptoms
  • Withdrawal: new cluster of symptoms not present prior to treatment
selective melatonin receptor agonist
SELECTIVE MELATONIN RECEPTOR AGONIST
  • Ramelteon (Rozerem)
  • MT1: attenuation of circadian alerting signal
  • MT2: circadian phase reinforcement or shifting
  • Acts on the suprachiasmatic nucleus
  • Influences the circadian rhythm effects on the sleep-wake cycle
  • No abuse liability, not a DEA controlled substance
selective melatonin receptor agonist36
SELECTIVE MELATONIN RECEPTOR AGONIST
  • FDA approved for sleep onset insomnia
  • No limitation on duration of use
  • Non-sedating
  • Single dose: 8 mg
  • Take about 30 minutes prior to bedtime
  • Half-life: 1-2.6 hrs
selective melatonin receptor agonist37
SELECTIVE MELATONIN RECEPTOR AGONIST
  • Adverse events
    • Somnolence
    • Dizziness
    • Fatigue
  • Avoid with hepatic impairment
first generation antihistamine
FIRST GENERATION ANTIHISTAMINE
  • Postsynaptic histaminic and muscarinic blockade
  • Diphenhydramine
  • Regulated by the FDA
  • Half-life: 8 hrs
  • Rapid tolerance to sedating effects
  • Pill strengths (mg): 25, 37.5, 50
first generation antihistamine39
FIRST GENERATION ANTIHISTAMINE
  • Potential adverse effects
    • Residual effects
    • Delirium
    • Dry mouth
    • Constipation
    • Blurred vision
    • Urinary retention
    • Narrow angle glaucoma exacerbation
dietary supplements
DIETARY SUPPLEMENTS
  • Not FDA regulated
  • Valerian
  • Kava-Kava
  • Melatonin
  • Passion flower
  • Skullcap
  • Lavender
  • Hops
cognitive behavioral treatment for insomnia
COGNITIVE-BEHAVIORAL TREATMENT FOR INSOMNIA
  • Indications
    • Primary Insomnia
      • Psychophysiological Insomnia
      • Inadequate Sleep Hygiene
    • Comorbid Insomnia
      • With a medical condition
      • With a mental disorder
  • Important to combine both cognitive and behavioral components
behavioral treatments
BEHAVIORAL TREATMENTS
  • Sleep hygiene education
    • Specific behaviors will directly interfere with the ability to sleep
    • The behaviors can be changed with education
    • No sufficient as a ‘stand alone’ treatment
  • Sleep restriction therapy
    • Increased propensity to sleep by increasing homeostatic sleep drive with partial sleep deprivation
    • Systematic reduction of time in bed to the amount of total sleep time from sleep log data
    • Increase time in bed by 15 minutes only when sleep efficiency exceeds 90% for 5 nights
behavioral treatments47
BEHAVIORAL TREATMENTS
  • Stimulus control therapy
    • Assumes that there is a learned associated between wakefulness and the bedroom
    • To break the cycle, the patient must not spend time wide awake in the bedroom
    • Go to bed only when sleepy
    • Do not use the bedroom for sleep-incompatible activities
    • Leave the bedroom if awake for more than 20 minutes
    • Return to bed only when sleepy
    • Do not nap during the day
    • Arise at the same time every morning
behavioral treatments48
BEHAVIORAL TREATMENTS
  • Relaxation training
    • Progressive muscle relaxation
    • Guided Imagery
    • Biofeedback
    • Self-hypnosis
cognitive therapy
COGNITIVE THERAPY
  • Cognitive restructuring
  • Rational-Emotive therapy
  • Specific techniques for rumination
    • Thought-stopping
    • Meditation techniques
cognitive therapy50
COGNITIVE THERAPY
  • Five domains of cognitive activity hypothesized to contribute to insomnia
    • Worry and rumination
    • Attentional bias and monitoring for sleep-related threat
    • Unhelpful beliefs about sleep
    • Misperception of sleep and daytime deficits
    • The use of safety behaviors that maintain unhelpful beliefs
objective51
OBJECTIVE
  • Pathogenesis
  • Prevalence
  • Impact
  • Pharmacologic treatment
  • Cognitive-behavioral therapy