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INSOMNIA

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

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  1. INSOMNIA Jeffrey Lin, M.D. Fellow, Sleep Medicine Stanford University Medical Center December 3, 2008

  2. DISCLOSURES • None • Special thanks to • Dr. Philip Becker • Dr. David Neubauer • Dr. Edward Stepanski.

  3. OBJECTIVE • Pathogenesis • Prevalence • Impact • Pharmacologic treatment • Cognitive-behavioral therapy

  4. PHYSIOLOGY OF SLEEP www.ge.infn.it/~rita/fisio%20sonno_ing.htm

  5. www.douglasrecherche.qc.ca

  6. PHYSIOLOGY OF SLEEP

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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

  13. 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

  14. CAUSES OF COMORBID INSOMNIA www.sleepreviewmag.com/.../2004-05_04.

  15. DIAGNOSES ASSOCAIATED WITH CHRONIC INSOMNIA Coleman et al. JAMA 1982

  16. 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

  17. 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

  18. 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

  19. 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

  20. Katz, D. A. et al. Arch Intern Med 1998;158:1099-1107.

  21. CAR ACCIDENTS AND SLEEP DISORDERS Powell NB et al. Otolaryngol Head Neck Surg. 2002; 126:217-227

  22. 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

  23. 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

  24. 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

  25. 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)

  26. 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

  27. GABA RECEPTOR COMPLEX

  28. 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

  29. HYPNOTICS IN THE US

  30. HYPNOTICS IN THE US

  31. 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?

  32. BZRA ADVERSE EFFECTS • Residual effects • Dizziness • Headache • Somnolence • Blurred vision • Nausea/diarrhea • Fatigue • Ataxia • Anterograde amnesia • Sonambulism/complex sleep behavior

  33. 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

  34. 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

  35. 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

  36. SELECTIVE MELATONIN RECEPTOR AGONIST • Adverse events • Somnolence • Dizziness • Fatigue • Avoid with hepatic impairment

  37. 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

  38. FIRST GENERATION ANTIHISTAMINE • Potential adverse effects • Residual effects • Delirium • Dry mouth • Constipation • Blurred vision • Urinary retention • Narrow angle glaucoma exacerbation

  39. DIETARY SUPPLEMENTS • Not FDA regulated • Valerian • Kava-Kava • Melatonin • Passion flower • Skullcap • Lavender • Hops

  40. 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

  41. CBT FOR COMORBID INSOMNIA

  42. EFFICACY OF CBT FOR INSOMNIA

  43. EFFICACY OF CBT FOR INSOMNIA

  44. 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

  45. 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

  46. BEHAVIORAL TREATMENTS • Relaxation training • Progressive muscle relaxation • Guided Imagery • Biofeedback • Self-hypnosis

  47. COGNITIVE THERAPY • Cognitive restructuring • Rational-Emotive therapy • Specific techniques for rumination • Thought-stopping • Meditation techniques

  48. 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

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