Insomnia Arturo Meade MD
Goals Definition Prevalence Pathophysiology The role of Orexin Orexin receptor blockers
Consequences: Daily Functioning
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.
Pathophysiology Increased physiological arousal Metabolic rate Sympathetic activation Hypothalamic-pituitary-adrenal axis Increased alertness Conditioned state of hyperarousal Decreased sleep efficiency Normal MSLT
Pathophysiology: Metabolic Rate 340 320 Insomniacs Normals 300 280 260 240 220 200 5 10 15 20 25 30 35 TIME (Hour) Bonnet M & Arand D. SLEEP 1995;18.
Assessment: Activation of the Stress System in Chronic Insomnia 3.5 3 2.5 2 1.5 1 0.5 0 Plasma ACTH, 2100-0030 h * 11 Insomnia Patients * p = 0.004 13 Healthy Controls 180 * 160 140 120 100 80 60 40 20 0 11 Insomnia Patients Plasma Cortisol, 2100-0030 h * p = 0.003 13 Healthy Controls Vgontzas AN et al. J Clin Endocrinol Metab 2001;86.
Insomnia treatment Cognitive behavioral interventions are now deemed similarly effective to hypnotic drugs in the short-term and superior in the longterm
Drugs indicated for insomnia Generic Brand 1/2(hrs) Dosage (mg) Drug class Flurozepam Dalmane 48-120 15-30 BZD Tamazepam Restoril 8-20 15-30 BZD Triazolam Halcion 2-6 0.125-0.25 BZD Esatazolam Prosom 8-24 1-2 BZD Quazepam Doral 48-120 7.5-15 BZD Zolpidem Ambien 1.5 2.4 5-10 BZRA Zaleplon Sonata 1 5-20 BZRA Eszopiclone Lunesta 5-7 1-3 BZRA ZolpidemER Ambien CR 1.5 2.4 6.25-12.5 BZRA Zolpidem SL Intermezzo 1.4 3.6 1.75-3.5 BZRA Ramelteon Rozerem 1.5-5 8 MT agonist Doxepin Silenor 15 3-6 TCA
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.
Orexin/Hypocretin Peptide produced in the lateral hypothalamus Discovered in 1998 1999 connection with narcolepsy was discovered Deficient in 90% of narcoleptic patients
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)
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 13 2014 for the treatment of insomnia Schedule IV of the control substance act
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
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.
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.
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
Suvorexant No withdrawal symptoms No rebound insomnia Low likelihood for abuse
Suvorexant unanswered questions Comparisons vs other agents Almorexant clinical development halted in 2011 Cataplexy?