new horizons in insomnia: mechanisms of action of … · insomnia: consequences ... •1999...
TRANSCRIPT
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Insomnia
Arturo Meade MD
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Goals
• Definition
• Prevalence
• Pathophysiology
• The role of Orexin
• Orexin receptor blockers
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Consequences: Daily Functioning
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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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Pathophysiology
• Increased physiological arousal
– Metabolic rate
– Sympathetic activation
– Hypothalamic-pituitary-adrenal axis
• Increased alertness– Conditioned state of hyperarousal
– Decreased sleep efficiency
– Normal MSLT
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Pathophysiology: Metabolic Rate
5 10 15 20 25 30 35
340
320
300
280
260
240
220
200
Insomniacs
Normals
TIME (Hour)
Bonnet M & Arand D. SLEEP 1995;18.
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0
20
40
60
80
100
120
140
160
180 *
* p = 0.00311 Insomnia
Patients
13 Healthy
Controls
Plasma Cortisol, 2100-0030 h
Assessment: Activation of the Stress System in Chronic Insomnia
Vgontzas AN et al. J Clin Endocrinol Metab 2001;86.
0
0.5
1
1.5
2
2.5
3
3.5*
* p = 0.00411 Insomnia
Patients
13 Healthy
Controls
Plasma ACTH, 2100-0030 h
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Insomnia treatment
• Cognitive behavioral interventions are now deemed similarly effective to hypnotic drugs in the short-term and superior in the long-term
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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
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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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Orexin/Hypocretin
• Peptide produced in the lateral hypothalamus
• Discovered in 1998
• 1999 connection with narcolepsy was discovered
• Deficient in 90% of narcoleptic patients
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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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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
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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
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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.
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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.
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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
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Suvorexant
• No withdrawal symptoms
• No rebound insomnia
• Low likelihood for abuse
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Suvorexant unanswered questions
• Comparisons vs other agents
• Almorexant clinical development halted in 2011
• Cataplexy?
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