Insomnia. Arturo Meade MD

Transcription

1 Insomnia Arturo Meade MD

2 Goals Definition Prevalence Pathophysiology The role of Orexin Orexin receptor blockers

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10 Consequences: Daily Functioning

11 Insomnia: Consequences Decreased quality of life Increased healthcare costs Increased absenteeism Decreased productivity Increased risk for developing psychiatric disorders Increased accident risk Chesson A Jr. et al. SLEEP 2000;23. Sateia MJ et al. SLEEP 2000;23.

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14 Pathophysiology Increased physiological arousal Metabolic rate Sympathetic activation Hypothalamic-pituitary-adrenal axis Increased alertness Conditioned state of hyperarousal Decreased sleep efficiency Normal MSLT

15 Pathophysiology: Metabolic Rate Insomniacs Normals TIME (Hour) Bonnet M & Arand D. SLEEP 1995;18.

16 Assessment: Activation of the Stress System in Chronic Insomnia Plasma ACTH, h * 11 Insomnia Patients * p = Healthy Controls 180 * Insomnia Patients Plasma Cortisol, h * p = Healthy Controls Vgontzas AN et al. J Clin Endocrinol Metab 2001;86.

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24 Insomnia treatment Cognitive behavioral interventions are now deemed similarly effective to hypnotic drugs in the short-term and superior in the longterm

25 Drugs indicated for insomnia Generic Brand 1/2(hrs) Dosage (mg) Drug class Flurozepam Dalmane BZD Tamazepam Restoril BZD Triazolam Halcion BZD Esatazolam Prosom BZD Quazepam Doral BZD Zolpidem Ambien BZRA Zaleplon Sonata BZRA Eszopiclone Lunesta BZRA ZolpidemER Ambien CR BZRA Zolpidem SL Intermezzo BZRA Ramelteon Rozerem MT agonist Doxepin Silenor TCA

26 Efficacy of drug treatments for chronic insomnia Benzodiazepines: polysomnography, SL decreased by 10 minutes, by sleep diary 19 minutes. Non-benzodiazepines: polysomnography, SL decreased by 12.8 minutes, by sleep diary 17 minutes. Antidepressants: polysomnography, SL decreased by 7 minutes, by sleep diary 12 minutes.

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33 Orexin/Hypocretin Peptide produced in the lateral hypothalamus Discovered in connection with narcolepsy was discovered Deficient in 90% of narcoleptic patients

34 Disorders and physical conditions potentially ameliorated by pharmacological activation or inhibition of orexin system Therapeutic Approach Disorders or Physical Conditions Activating orexin system Narcolepsy and other hypersomnia, Pain,Diet-induced obesity (OX2R-selective) Inattentiveness, apathy. Inhibiting orexin system, Insomnia, Jet lag Diet-induced obesity (OX1R-selective) Drug addiction (OX1R-selective)

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36 Suvorexant Orexin receptor antagonist Orexin peptides A and B bind selectively to OX1R and OX2R Drugs that bind to both receptors are referred as DORAs Approve by the FDA on August for the treatment of insomnia Schedule IV of the control substance act

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43 Suvorexant Oral absorption rapid, peak concentrations of T max 2 h. Meals delay absorption Metabolized by CYP3A4 No dose adjustment needed for age or race Oral clearance is inversely related to BMI Concentration 15% higher at 9 hrs in patients with BMI >30kg/m2

44 Suvorexant Hepatic impairment mild to moderate no dose adjustment needed. No dose adjustment is required in renal impairment No significant changes on sleep architecture on 22 healthy volunteers noted.

45 Suvorexant OSA 26 patients with mild to moderate OSA AHI treatment difference (suvorexant-placebo) was 2.7. Wide inter- intra-individual variability meaningful effects cannot be excluded.

46 Suvorexant COPD 25 patients with mild to moderate COPD No respiratory depression noted by measure of the oxygen saturation, in 4 nights. Wide inter- and intra-individual variability, clinically meaningful respiratory effects in COPD cannot be excluded

47 Suvorexant No withdrawal symptoms No rebound insomnia Low likelihood for abuse

48 Suvorexant unanswered questions Comparisons vs other agents Almorexant clinical development halted in 2011 Cataplexy?

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