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

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.

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

Insomnia treatment

• Cognitive behavioral interventions are now deemed similarly effective to hypnotic drugs in the short-term and superior in the long-term

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?