Pharmacotherapy of Sleep Disorders

Karl Doghramji, MD Professor of Psychiatry, Neurology, and Medicine

Director, Jefferson Sleep Disorders Center Thomas Jefferson University

Philadelphia, PA

ARS Questions

Pharmacotherapy of Sleep Disorders

Karl Doghramji, MD Professor of Psychiatry, Neurology, and Medicine

Director, Jefferson Sleep Disorders Center Thomas Jefferson University

Philadelphia, PA

Disclosure Statement

•  Consultant –  Pernix, Pfizer, Jazz, Teva, Merck, Xenosports

•  Stock Ownership –  Merck

Insomnia Disorder

A.  Dissatisfaction with sleep quantity or quality with one or more of the following: 1.  Difficulty initiating sleep (children: w/o caregiver intervention) 2.  Difficulty maintaining sleep (children: w/o caregiver intervention) 3.  Early morning awakening w/inability to return to sleep

B.  Significant distress or impairment C.  > Three nights per week D.  > Three months E.  Adequate opportunity for sleep •  Specify if:

–  With non–sleep disorder mental comorbidity –  With other medical comorbidity –  With other sleep disorder

Criteria F, G, and H not shown; not all specifiers shown DSM-5, American Psychiatric Association, 2013

10.2

17.7 16.8

9

11.7 10

Prevalence of Insomnia in the General Adult Population

Insomnia = sleep disturbance every night for 2 weeks or more, or similarly stringent criteria. Ford DE, et al. 1989. JAMA 262(11):1479-1484. Ohayon MM, et al. 1998. Compr Psychiatry. 39(4):185-197. Ohayon MM, et al. 2001. J Psychosom Res. 51(6):745-755. Ancoli-Israel S, et al. 1999. Sleep. 22(suppl 2):S347-S353. Ishigooka J, et al. 1999, Psychiatry Clin Neurosci. 53(4):515-522. Simon GE, et al. 1997. Am J Psychiatry. 154(10):1417-1423

Ancoli- Israel 1999

Perc

ent

Ford 1989

Ohayon 1998

Ohayon 2001

Ishigooka 1999

Simon 1997

0

5

10

15

20

Insomnia and Hyperarousal

Cognitive arousal

Heightened brain

metabolism

Sympathetic activation

HPA axis activation

Increased body

metabolic rate

EEG arousal

Hyperarousal

Impairments Associated with Insomnia

•  Diminished ability to enjoy family and social relationships

•  Decreased quality of life •  Increased absenteeism

and poor job performance •  Motor vehicle crashes •  Increased risk of falls

Ancoli-Israel S et al. 1999. Sleep 22(suppl 2):S347-S353

•  Impaired concentration and memory

•  Increased incidence of pain •  Enhanced risk of present

and future psychiatric disorders

•  Hypertension •  Diabetes •  Increased mortality

4.2

5.1

7.0

8.6

14.0

23.9

59.5

N=580. Ford DE, Kamerow DB (1989), JAMA 262(11):1479-1484.

Comorbid Psychiatric Disorders Point Prevalence

0 10 20 30 40 50 60

Drug abuse

Other psychiatric disorders

Alcohol abuse

Dysthymia

Major depression

Anxiety disorder

No psychiatric disorder

% of Patients

Complex Relationship Between Insomnia and Mood Disorders

Insomnia •  Is a common complaint in MDD •  Is more likely to emerge prior to, than during or after,

MDD first episode or recurrence •  Is associated with higher rates of lifetime and current

MDD and suicide •  Its presence and persistence predict future MDD •  Predicts poorer outcome in MDD (persistence, chronicity,

suicidality) •  Predicts the onset of mania in bipolar depression

McCall WV, Black CG. Current Psychiatry Reports. 2013; 15:389. Judd L, Schettler P, Akiskal H. Arch Gen Psychiatry. 2008;65(4):386-394. Cho JH, et al. Am J Psychiatry 2008 165: 1543-1550. Breslau N, et al. Biol Psychiatry. 1996;39:411-418. Ohayon and Roth, J Psychiatr Res, 2003. Perlis ML, et al. Biol Psychiatry. 1997;42:904-913

The Role of Polysomnography in the Management of Psychiatric Patients with Insomnia

•  The American Academy of Sleep Medicine has stated that there is no role for PSG in the routine management of insomnia, but that PSG can be justified if there are specific reasons to suspect a primary sleep disorder, or if the insomnia does not respond to routine care

•  Unsuspected primary sleep disorders occur in about 16% of adults with depressive disorders

McCall WV, et al. J of Clin Sleep Medicine 2009;5:454-458.

Comorbid Conditions •  Sleep disorders

–  Sleep apnea –  Restless legs syndrome –  Periodic limb movement

disorder –  Circadian rhythm disorders

•  Alzheimer’s disease •  Arthritis: osteoarthritis and

rheumatoid arthritis •  Chronic back pain •  Cancer •  Cardiac disease: congestive heart

failure, myocardial infarction, nocturnal angina, dyspnea

•  Diabetes mellitus •  End-stage renal disease •  Functional bowl syndromes •  GERD •  Huntington’s disease •  Menopause •  Nocturia •  Nocturnal angina •  Chronic pain •  Parkinson’s disease •  Progressive supranuclear

palsy •  Pulmonary disorders (e.g.,

COPD) •  Thyroid disease

Richardson G, Doghramji K. 2005. Insomnia: Specialist’s Edition. Clinical Symposia 55(1):1-39.

Treatment Approaches for Insomnia

•  Address comorbid problems. •  Examples:

–  Antidepressants for major depression –  Proton pump inhibitors for GERD –  Mood stabilizers for mania –  Medication change for iatrogenic insomnia

•  Address insomnia directly –  Effective for a broad range of patients –  Includes behavioral therapy and hypnotic medications

•  Above two approaches may be combined

Depressed Insomniacs Who Receive a Hypnotic in Conjunction with Their SSRI Have Better Acute

Outcomes

•  Better quality of life and higher overall response rates (eszopiclone)

•  Higher overall remission rates •  Superior self-reported sleep

McCall WV, et al.. J Clin Sleep Med 2010; 6:322-329. Fava M, et al.. Biol Psychiatry. 2006 Jun 1;59(11):1052-60. Fava M, et al. J Clin Psychiatry. 2011 Jul;72(7):914-28.

Psychological and Behavioral Treatments for Primary Insomnia

*Standard Treatment according to American Academy of Sleep Medicine Morgenthaler T, et al. Sleep. 2006;29:1415. Bootzin RR, Perlis ML. 1992. J Clin Psychiatry (53 Suppl):37-41.

Techniques Method Stimulus control therapy* If unable to fall asleep within 20 minutes, get

OOB and repeat as necessary Relaxation therapies* Biofeedback, progressive muscle relaxation

Restriction of time in bed (sleep restriction)

Decrease time in bed to equal time actually asleep and increase as sleep efficiency improves

Cognitive therapy Talk therapy to dispel unrealistic and exaggerated notions about sleep

Paradoxic intention Try to stay awake

Sleep hygiene education Promote habits that help sleep; eliminate habits that interfere with sleep

Cognitive-Behavioral Therapy* Combines sleep restriction, stimulus control and sleep hygiene education with cognitive therapy

The Do’s of Sleep Hygiene

•  Awaken at the same time every morning •  Increase exposure to bright light during the day •  Establish a daily activity routine •  Exercise regularly in the morning and/or afternoon •  Set aside a worry time •  Establish a comfortable sleep environment •  Do something relaxing prior to bedtime •  Try a warm bath

Hauri PJ. In: Hauri PJ, ed. Case Studies in Insomnia; New York, NY: Plenum; 1991:65.

The Don’ts of Sleep Hygiene

Avoid… • Alcohol • Caffeine, nicotine, and other stimulants • Exposure to bright light during the night • Exercise within 3 hours of bedtime • Heavy meals or drinking within 3 hours of bedtime • Using your bed for things other than sleep (or sex) • Napping, unless a shiftworker • Watching the clock • Trying to sleep • Noise • Excessive heat/cold in room

Hauri PJ. In: Hauri PJ, ed. Case Studies in Insomnia; New York, NY: Plenum; 1991:65.

Prescription Agents for Insomnia

•  FDA-non-approved for insomnia –  Sedating antidepressants –  Antipsychotics –  Anticonvulsants

•  FDA-approved hypnotics –  Benzodiazepine receptor

agonists (BzRA’s) •  Benzodiazepines •  Nonbenzodiazepines

–  Melatonin receptor agonist –  H-1 receptor antagonist –  Orexin receptor antagonist

Arousal and Sleep-Promoting Systems

Modified from Fuller, et al. J Biol Rhythms. 2006.

A. B.

Hypocretins and The Sleep Arousal Switch

Adapted from Saper CB, et al. Nature. 2005;437(7063):1257-1263

Sedating Antidepressants

•  Advantages –  Many have sedating side effects –  At appropriate doses, effective for mood and anxiety disorders –  Low abuse risk –  Large dose range

•  Disadvantages –  At low doses, efficacy not well established for insomnia –  Daytime sedation (most have long half lives), anticholinergic

effects, weight gain, and other systemic side effects; drug-drug interactions

These agents are not FDA approved for insomnia. Kupfer DJ, Reynolds CF III. N Engl J Med. 1997;336:341-346. Sharpley AL, et al. Biol Psychiatry. 2000;47:468-470. Karam-Hage M, Brower KJ. Psychiatry Clin Neurosci. 2003;57:542-544. National Institutes of Health State of the Science Conference Statement. Sleep. 2005;28:1049-1057.

Atypical Antipsychotics

•  Advantages –  At appropriate doses, effective for psychotic disorders –  Low abuse potential –  Sedation

•  Disadvantages –  Not well investigated in primary insomnia –  Daytime sedation, anticholinergic effects, weight gain –  Low risk of extrapyramidal symptoms –  Possible glucose and lipid abnormalities

These agents are not FDA approved for insomnia. Kupfer DJ, Reynolds CF III. N Engl J Med. 1997;336:341-346. Sharpley AL, et al. Biol Psychiatry. 2000;47:468-470. Karam-Hage M, Brower KJ. Psychiatry Clin Neurosci. 2003;57:542-544. National Institutes of Health State of the Science Conference Statement. Sleep. 2005;28:1049-1057.

Initiation vs. Maintenance Insomnia

11 pm 7 am

Middle Terminal

Initial

W, wake; S, sleep

Benzodiazepine Receptor Agonists: The Benzodiazepines

Medication Dosage Range† (mg)

Onset of Action Half-life (h)

Short-term Limitation?

Estazolam 0.5 – 2 Rapid 10 - 24 Yes

Flurazepam 15 – 30 Rapid 47 - 100 Yes

Quazepam 7.5 – 15 Rapid 39 - 100 Yes

Temazepam 7.5 – 15 Slow-Intermediate 9.5 -12.4 Yes

Triazolam 0.25 – 0.50 Rapid 1.5 - 5.5 Yes

†Normal adult dose. Dosage may require individualization MICROMEDEX. http://www.micromedex.com PDR. www.PDR.net

Selective Benzodiazapine Receptor Agonists Zaleplon Zolpidem Zolpidem

ER

Eszopiclone

Dose – mg [elderly]

5,10,20 [5] 5,10 [5] 6.25,12.5 [6.25] 1,2,3 [1]

Tmax (hours) 1 1.6 1.5 1

Half-life [elderly] (hrs.)

1 2.5 [2.9] 2.8 [2.9] 6 [9]

Sleep latency ↓ ↓ ↓ ↓

Wake After Sleep Onset

-- -- ↓ ↓

Total sleep time ↑

(20 mg)

↑ ↑ ↑

Schedule IV IV IV IV

Sonata® [package insert] King Pharmaceuticals. Feb 2009.http://www.kingpharm.com/products/product_document.cfm?brand_name=Sonata&product_specific_name=CIV&document_type_code=PI. Accessed Aug 4, 2011. Ambien® [package insert] sanofi-aventis US LLC; Aug 2010. http://products.sanofi.us/ambien/ambien.pdf. Accessed Aug 4, 2011; Ambien CR® [package insert] sanofi-aventis US LLC; Oct 2010. http://products.sanofi.us/ambien_cr/ambienCR.html. Accessed Aug 4, 2011. Lunesta® [package insert]. Sunovion Pharmaceuticals Inc. Nov 2010. http://www.lunesta.com/PostedApprovedLabelingText.pdf. Accessed Aug 4, 2011.

Zolpidem Dosing Recommendations

U.S. Food and Drug Administration. Jan 11, 2013. http://www.fda.gov/Drugs/DrugSafety/ucm334033.htm. Accessed Jan 16, 2013.

Dosing recommendations in current drug label for zolpidem

FDA’s proposed new dosing recommendations for zolpidem

Men and Women: 10 mg once daily, immediately before bedtime

Women: 5 mg once daily, immediately before bedtime Men: 5 or 10 mg once daily, immediately before bedtime

Men and Women: 12.5 mg once daily, immediately before bedtime

Women: 6.25 mg once daily, immediately before bedtime Men: 6.25 or 12.5 mg once daily, immediately before bedtime

Eszopiclone Dosing Recommendations

•  Decrease in starting dose to 1 mg •  Can be increased to 2-3 mg

–  Caution when taking 3 mg for driving, activities that require mental alertness the day after

•  Women and men are equally susceptible •  Rationale: 3 mg can cause impairment in driving,

memory, and coordination following >11 hours

U.S. Food and Drug Administration. (n.d.). http://www.fda.gov/Drugs/DrugSafety/ucm397260.htm. Accessed May 17, 2014.

Zolpidem Variants

EdluarTM [package insert] Meda Pharmaceuticals Inc; Oct 2010. http://www.edluar.com/EDLUAR-PI.pdf. Accessed May 7, 2012; Intermezzo [package insert] Transcept Pharmaceuticals Inc (November, 2011) and Purdue Pharma LLP. December, 2011. http://app.purduepharma.com/xmlpublishing/pi.aspx?id=i. Accessed May 7, 2012. Zolpimist Oral Spray [package insert] ECR Pharmacuticals. 2010. http://www.ecrpharma.com/images/Zolpimist%20Product%20Insert.pdf Accessed May 7, 2012

Zolpidem Zolpidem SL Zolpidem Oral Spray

Zolpidem SL

Dose – mg [elderly]

5,10 [5] 5,10 [5] 5,10 [5] Men: 3.5 Women: 1.75

[1.75]

MOTN, 4 hours remaining until AM awakening

Tmax (hours) 1.6 1.4 0.9 1.3

Half-life [elderly] (hrs.)

2.5 [2.9] 2.9 2.7 2.5

Newer Hypnotics

Rozerem® [package insert]. Takeda Pharmaceuticals America Inc. No 2010. http://www.rozerem.com/en/?. Accessed Aug 4, 2011; Silenor [package insert]. San Diego, CA: Somaxon; 2010.. Accessed Aug 4, 2011. Belsomra package insert, accessed 8/13/14

Ramelteon Doxepin Suvorexant

Mechanism Melatonin agonist

H1 antagonist Orexin antagonist

Dose – mg [elderly]

8 3,6 [3] 10-20

Tmax (hours) 0.75 3.5 2

Half-life [elderly] (hrs.)

1-2.6 15.3 12

Sleep latency ↓ -- ↓

Wake After Sleep Onset

-- ↓ ↓

Total sleep time -- -- ↑

Schedule None None IV

Sleep Pattern: Therapeutic Implications

•  Initial insomnia only –  Zaleplon –  Zolpidem –  Ramelteon

•  Middle insomnia only –  Doxepin low dose –  Zolpidem SL MOTN

•  Initial and middle insomnia –  Zolpidem ER –  Eszopiclone –  Suvorexant

Adverse Effects of Hypnotics •  Benzodiazepine receptor agonists

–  Daytime sedation, psychomotor and cognitive impairment (depending on dose and half-life)

–  Rebound insomnia –  Respiratory depression in vulnerable populations

•  Melatonin receptor agonist –  Headache, somnolence, fatigue, dizziness –  Not recommended for use with fluvoxamine due to CYP 1A2 interaction

•  H1 receptor antagonist –  Somnolence/sedation –  Nausea –  Upper respiratory tract infection

•  Orexin receptor antagonist –  Somnolence –  Risk of impaired alertness and motor coordination, including impaired

driving; increases with dose –  Contraindicated in narcolepsy

Mitler MM. Sleep. 2000;23:S39-S47. Holbrook AM et al. CMAJ. 2000;162:225-233. MICROMEDEX. Available at: www.micromedex.com; Package inserts for various compounds. Charney DS et al. In: Hardman JG, Limbird LE, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 10th ed. 2001:399-427.

Special Issues In Prescribing Hypnotics

•  Abuse liability •  Parasomnias and amnestic behavior •  Long term use •  Tolerance and rebound •  Use in vulnerable populations

Long-Term Intermittent Treatment with Zolpidem Extended- Release

1° endoint of this 25-week study was the patient global impression of treatment aid to sleep. The difference between treatment groups was P<.0001 for each visit. Similarly, the 2° endpoint, the clinician global impression of treatment aid to sleep, was also P<.0001 for all time points. Krystal AD, et al. SLEEP. 2008;31(1):79-90

Patient Global Impression of Treatment Aid to Sleep

Placebo (n=349)

Zolpidem extended- release 12.5 mg (n=667)

Twelve Months of Nightly Zolpidem Does not Lead to Dose Escalation

The percent of participants in the placebo and zolpidem groups that increased (Panel A) or decreased (Panel B) relative to month 1 the number of capsules (i.e., dose) that they self-administered in month 4 and 12. Percents increasing and decreasing within a group do add to 100% as a percent within each group did not change. A greater percentage of zolpidem versus placebo participants decreased dose in month 4 and 12 (χ2 = 11.22, P < 0.001).

Roehrs TA et al. SLEEP. 2011;34(2):207-212.

Long-Term Continuous Treatment with Eszopiclone

**P ≤ 0.01 vs. placebo ‡P ≤ 0.0001 vs placebo Krystal et al. SLEEP. 2003:26;793-799. Roth et al. Sleep Medicine In Press, 2005.

ESZ 3 mg ESZ 3 mg

Med

ian

Min

utes

Aw

ake

Afte

r Fal

ling

Asl

eep

0

10

20

30

40

50

60

1 2 3 4 5 6

PBO ESZ 3 mg

7 8 9 10 11 12

Open Label

Months

‡ ‡ ‡ ** ‡ **

Double Blind

N=788

Long-Term Continuous Treatment with Ramelteon

*p<0.05 Mayer G, et al. SLEEP 2009;32(3):351-360

Parasomnias and Hypnotics

•  Limited to spontaneous reports •  Sleep-driving i.e., driving while not fully awake; preparing

and eating food, making phone calls, or having sex. Amnesia for events

•  FDA label change applies to all manufacturers of sedative hypnotic drugs

FDA March 14, 2007. http://www.fda.gov/bbs/topics/NEWS/2007/NEW01587.html

Risk Factors for Zolpidem-Induced Parasomnias

•  Co-use of alcohol or sedatives •  Use at doses exceeding the maximum recommended

dose •  Sleep disorder: OSA or PLMS •  H/O parasomnia •  Ingestion at unusual bedtime •  Ingestion while agitated or not typically asleep •  Ingestion when sleep deprived •  Poor management of pill bottles •  Living alone

Poceta JS. J Clin Sleep Med. 2011;7(6):632-638 FDA March 14, 2007.

Vulnerable Populations

•  Respiratory compromise (COPD, OSA) •  Elderly •  Women •  History of D/A use disorders •  Pregnancy •  Multiple medication users (sedation mainly) •  Hepatic impairment •  Depression •  Pediatric patients: Not indicated

Selected Guidelines for Hypnotic Use

•  Comprehensive evaluation; specific treatment for comorbidities •  Caution in patients with respiratory and hepatic impairment,

substance use disorders, or who are already taking sedatives; avoid alcohol; not approved for children; avoid during pregnancy

•  Use lowest effective dose, lower dose in elderly (and in women for certain compounds)

•  Take at bedtime (or MOTN for zolpidem SL low dose) •  7-8 hours in bed (or minimum of 4 hours for zolpidem SL low

dose) •  Efficacy may be improved on empty stomach •  Gradual discontinuation •  Follow-up visits

Neubauer DN. Pharamcotherapeutic approach to insomnia in adults. In: Barkoukis et al, eds. Therapy in Sleep Medicine. Elsevier Saunders, 2012, pp. 172-180

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