Quand le sommeil ne vient pas…

Quand le sommeil ne vient pas…
SERGE LESSARD MD FRCPC
PROFESSEUR ADJOINT, UNIVERSITÉ D’OTTAWA
Divulgation de l’enseignant/du présentateur
Enseignant : Serge Lessard MD FRCPC
Relations avec des intérêts commerciaux :

Subventions/soutien à la recherche : NIL

Bureau des conférenciers/honoraires :
Eli Lilly, Janssen Ortho, Lundbeck, Purdue, Servier, Paladin, Shire

Frais de consultation :NIL

Autres : NIL
Divulgation de soutien commercial
Ce programme de formation a été produit grâce au soutien financier de l’ hôpital
Montfort sous forme d’honoraire pour la conférence.
Conflits d’intérêt potentiels :

Dr Lessard a reçu des honoraires dans le passé de Servier et Paladin dont les
produits sont discutés dans le cadre du programme.
Atténuation des sources potentielles de partialité
Le contenu de la présentation est basé sur l’évidence empirique et les
lignes directrices.
Objectifs
Décrire la prévalence et l’impact de l’insomnie.
Différencier les types d’insomnie.
Évaluer les traitements pharmacologiques et non-pharmacologiques
actuels.
TRIVIA
Pour quelle chirurgie Antonio de Egas Moniz du Portugal a reçu le
Prix Nobel en médecine en 1949?
Lobotomie préfrontal
DSM 5 Sleep-Wake Disorders (p361 – p422)
A focus on INSOMNIA
What is Insomnia?
Evolving Attitudes Regarding Insomnia
NIH – 1983
Definition
Insomnia is a symptom, not a primary
disorder
Insomnia is a disorder, typically
comorbid with other disorders
Treat the primary disorder (insomnia
symptoms are sometimes addressed,
sometimes ignored)
Chronic insomnia exists and merits
treatment
Hypnotics should generally be used
only for short-term treatment
Treat insomnia as well as other
disorder(s): improvements in insomnia
may result in improvements in other
disorder(s)
Chronic insomnia occurs in the
context of medical/psychiatric
disorders
Insomnia is associated with significant
impairment in function and quality of life
Treatment
Other
NIH – 2005
Diagnostic Criteria of Insomnia
Sleep-Related Complaints1,2
•
•
•
•
•
Difficulty falling asleep
Intermittent wakefulness
during sleep
Early morning awakening
Nonrestorative sleep
Complaints may change over
time and often overlap
Daytime Impairment1,3
•
Cognition

•
Mood and energy

•
Increased anxiety, dysphoria,
fatigue, tiredness, lethargy
Psychomotor function

•
Reduced attention,
concentration, memory
Slowed reaction times, poor
coordination
Interpersonal, social,
occupational problems
1. Sleep disorders. In: First MB, ed. Diagnostic and Statistical Manual of Mental Disorders DSM-IV-TR®. 4th ed. Arlington, VA: American
Society; 2000:597-661.
2. Hohagen F, et al. Sleep. 1994;17:551-554.
3. Becker PM. Psychiatr Clin North Am. 2006;29(4):855-870.
Psychiatric
Insomnia Prevalence
 Approximately 30% of population has some recurring type
of sleep disruption1 (US Data)
 13.4% of population is estimated to have a chronic
problem2
 3.3 million Canadians estimated to have chronic insomnia
 Up to 50% of patients seen in clinical practice experience
difficulty sleeping1
 Insomnia is more frequent in women than men2
1.
2.
National Institutes of Health State-of-the-Science Conference Statement on Manifestations and Management of Chronic Insomnia in Adults. Sleep.
2005;28:1049-1057.
Tjepkema. M. Health Reports, Statistics Canada. 2005, vol. 17, no. 1,
Among those,
18% reported fewer than 5 hours
of sleep per night2
† Data extrapolated from Statistics Canada 2002, which states that 13.4% of the Canadian population
aged 15 years and older suffer from insomnia.
Insomnia: Prevalence and Clinical Impact
n = 2000
Satisfied or neutral with their
sleep
n = 1642, 79.7%
Without insomnia symptoms
n = 1155, 55.6%
With insomnia symptoms
n = 474, 24.2%
Dissatisfied with their sleep
n = 350, 19.8%
Without insomnia symptoms
n = 70, 3.8%
With insomnia symptoms
n = 279, 16.0%
For at least one month
n = 277, 16.0%
With daytime consequences
or significant distress
n = 232, 13.4%
Morin CM et al. Can J Psychiatry. 2011;56(9):540-548.
Sleep Maintenance: A Common Patient Complaint
2008 National Sleep Foundation (NSF) Sleep Poll found
that 65% of patients polled had sleep problems at least
a few times a week…
Only 4% diagnosed (told by physician that they had a sleep problem)
Only 2% currently receiving treatment for sleep problem
42%
Frequent Nocturnal Awakenings
Early Morning Awakenings
Difficulty Falling Asleep
Difficulty
Falling Asleep
29%
26%
Source: National Sleep Foundation. Summary of findings: 2008 Sleep in America poll. n = 1760 respondents;
www.sleepfoundation.org.
Risk Factors for Insomnia
 Advancing age
 Women – particularly during and after menopause
 K-Complex
 Comorbid medical conditions – arthritis, heart failure,
pulmonary and gastrointestinal disorders
 Psychiatric disorders – depression most common, anxiety
 Working night or rotating shifts
 Excess alcohol and drug consumption
National Institutes of Health State-of-the-Science Conference Statement on Manifestations and Management of Chronic
Insomnia in Adults. Sleep. 2005;28:1049-1057.
Insomnia Evaluation
 History
 Physical examination and testing
 Assessment tools (sleep logs, Epworth Sleepiness Scale,
etc.)
 Identify the sleep complaints
 Difficulty initiating sleep (onset)
 Difficulty staying asleep (frequent nocturnal awakenings)
 Early morning awakenings
1.
Clinical Guideline for the Evaluation and Management of Chronic Insomnia in Adults, J. Sleep Med. 2008 October 15; 4(5): 487-504.
Insomnia: Diagnostic Algorithm
Insomnia
(difficulty initiating and/or maintaining sleep associated with daytime consequences)
1
Acute insomnia
(≤ 4 weeks)
Identify trigger
•Recent death
•Loss of job
•Marital break-up
Address trigger and
consider short-term
sedative
2
Chronic insomnia
( > 4 weeks)
Daytime
impairment
Monitor/reassure
Insomnia
Screening
Questionnaire
PRIMARY SLEEP DISORDERS
C: Circadian rhythm: night owl/shift work
A: Sleep apnea: snoring, gasping
L: Restless legs, abnormal movement and/or
behaviour in sleep
SECONDARY CAUSES OF INSOMNIA
M: Mood disorders (MDD,GAD)
M: Medical disorders
M: Medications. Consider timing and dosing
S: Substance abuse
3
Primary Sleep Disorder
Treat or Refer
4
Secondary Insomnia
•Optimize treatment of primary disease
•Address sleep hygiene
•Prevent comorbid primary insomnia
5
Primary Insomnia
Refer to: Primary Insomnia Evaluation
(page 5) and Clinical Practice Guideline
Adult Primary Insomnia: Diagnosis to
Management
Adult Insomnia: Assessment to Diagnosis. http://www.topalbertadoctors.org/cpgs.php?sid=18&cpg_cats=79.
17
18
Tool: Insomnia Screening Questionnaire
Never
Rarely
Occasionally
Most
nights/
days
Always
1
Do you have trouble falling asleep?
1
2
3
4
5
2
Do you have trouble staying asleep?
1
2
3
4
5
3
Do you wake up unrefreshed?
1
2
3
4
5
4
Do you take anything to help you sleep?
1
2
3
4
5
5
Do you use alcohol to help you sleep?
1
2
3
4
5
6
Do you have any medical conditions that disrupt
your sleep?
1
2
3
4
5
7
Have you lost interest in hobbies or activities?
1
2
3
4
5
8
Do you feel sad, irritable, or hopeless?
1
2
3
4
5
9
Do you feel nervous or worried?
1
2
3
4
5
10
Do you think something is wrong with your body?
1
2
3
4
5
11
Are you a shift worker or is your sleep schedule
irregular?
1
2
3
4
5
Movement
disorders
12
Are your legs restless and/or uncomfortable before
bed?
1
2
3
4
5
13
Have you been told that you are restless or that
you kick your legs in your sleep?
1
2
3
4
5
Parasomnias
14
Do you have any unusual behaviours or
movements during sleep?
1
2
3
4
5
15
Do you snore?
1
2
3
4
5
16
Has anyone said that you stop breathing, gasp,
snort or choke in your sleep?
1
2
3
4
5
17
Do you have difficulty staying awake during the
day?
1
2
3
4
5
Insomnia
Psychiatric
disorders
Circadian rhythm
disorder
Sleep disordered
breathing
Adult Insomnia: Assessment to Diagnosis. http://www.topalbertadoctors.org/cpgs.php?sid=18&cpg_cats=79.
EPWORTH SLEEPINESS
SCALE
0-9= NORMAL
10-24 ---11-15
? MILD TO MODERATE APNEA
16 OR ABOVE
? SEVERE APNEA OR NARCOLEPSY
Defining and Diagnosing Insomnia
 What are the associated impairments?
 Sleepiness2
 Fatigue1
 Reduced attention, concentration, or memory2
 Mood disturbances1
 Reduced motivation1
 Accidents2
 Worries about sleep2
1. International Classification of Sleep Disorders 2nd ed (ICSD-2). American Academy of Sleep Medicine, 2005.
2. Becker PM. Psychiatr Clin North Am. 2006;29(4):855-870.
Possible Consequences of Insomnia
Insomnia is associated with high costs and diverse and
multiple adverse effects1,2
•
1.
2.
Estimated annual direct and indirect costs: $93 to $108
billion2 (1994 US Study)
NIH Consensus and State-of- the-Science Statements. 2005;22(2):1-30.
Roth T, Culpepper L. Clin Symp. 2008;58(1):3-32.
Chronic pain
Treatment Goals for Insomnia
 Restore and improve sleep quality and duration1
 Attempt to reduce time to sleep onset and time awake in
the middle and end of the night
 Prevent progression from transient, short-term insomnia
to chronic insomnia2
 Reduce contribution of, and impact on, comorbid
conditions2
1.
2.
Clinical Guideline for the Evaluation and Management of Chronic Insomnia in Adults, J. Sleep Med. 2008 October 15; 4(5): 487-504.
Roth T, Culpepper L. Clin Symp. 2008;58(1):3-32.
MENTAL
STOP
Reassess the patient’s lifestyle, sleep environment,
and sleep behaviours prior to any therapeutic
prescription
27
Management: Behavioural Therapies
First-line treatment
o Behavioural therapies are the foundation of the management of insomnia
Strong evidence for the efficacy of behavioural therapy
(level I)
Therapies include:
Sleep hygiene
Stimulus control
Sleep restriction
Relaxation therapy
• Mindfulness-based stress reduction
o Cognitive behavioural therapy
o
o
o
o
Sleep Hygiene: Discussion Point
How do you assess sleep hygiene?
Educate participants about the following:
o Caffeine
o Alcohol
o Nicotine
o Heavy exercise within 3 hours of bedtime
o Consuming large meals, liquids, and alcohol close to bedtime
o An uncomfortable sleep environment (noise, light, movement, temperature)
o Clock checking/watching
o Maintaining a quiet, dark, safe, and comfortable sleep environment
o Winding down for ~ 2 hours before bedtime
o Establishing and maintaining a sleep routine
Current Management Strategies
 Pharmacological Therapy
 OTC – antihistamines, herbal, alcohol
 Nonbenzodiazepines
 Benzodiazepines
 Melatonin receptor agonists
 Off-label drugs
 Sedating antidepressants – trazodone, amitriptyline, others
 Atypical antipsychotics – risperidone, others
1.
.
Roth T, Culpepper L. Clin Symp. 2008;58(1):3-32.
Limitations of Current Insomnia Treatments
Benzodiazepines1


Risk of memory impairment, confusion, sedation, falls

May fail to improve sleep, particularly with long-term use

Development of tolerance and dependence
Non-benzodiazepine agents (zolpidem, zopiclone, etc.)2


Risk of memory cognitive impairment, sedation, and motor in-coordination

Drug dependence and rebound insomnia
Antidepressants3

1.
2.
3.

Risk of sedation, falls and injury

Anticholinergic effects

Cardiotoxicity
Glass et al. BMJ. 2005; 331:1-7.
NIH Consensus and State-of- the-Science Statements. 2005;22(2):1-30.
Conn and Madan. Drugs Aging. 2006; 23: 271-287.
Limitations of Current Insomnia Treatments
(cont’d)

Antipsychotics1
•
Risk of excessive sedation, falls
•
Gait disturbance
•
Increased mortality
Conventional high-dose antihistamines1,2
•
Risk of cognitive function, delirium, sedation
•
Anticholinergic effects
•
Impaired daytime functioning
Antihistamines, antidepressants, antipsychotics should not be used as a treatment for
insomnia because the risks of using these agents outweigh their benefits 1
1.
2.
Conn and Madan. Drugs Aging. 2006; 23: 271-2872.
NIH Consensus and State-of- the-Science Statements. 2005;22(2):1-30.
.
Review of Insomnia
Treatment Options with
Discussion of Mechanism
of Actions
“Ideal” Pharmacologic Treatment
Ideal
Treatment
Pharmacokinetic
Properties
• Quickly absorbed
• No active metabolites
• Optimal half-life
Physiologic
Effects
• Rapid onset of action
• Physiological sleep
pattern
• Mechanism other than
general CNS depression
• Sleep maintenance
• Improved daytime
function
Bartholini G. Imidazopyridines in Sleep Disorders, 1988.
Side
Effects
•
•
•
•
•
•
No residual sedation
No respiratory depression
No tolerance
No physical dependence
No rebound insomnia
No effect on memory
Wake-Sleep Cycle Reflects Balance Between Opposing
Neurotransmitter Systems
•
ORX
LC
TMN
Raphe
Awake

VLPO
eVLPO
On
ORX
Sleep
Tendency to sleep is
determined by balance of
sleep-promoting systems and
wake-promoting systems
VLPO
eVLPO

LC
TMN
Raphe
Off
Saper CB, et al. Nature. 2005;437(7063):1257-1263.
Sleep promoting: GABA,
Galanin (VLPO:Ventrolateral
preoptic nucleus, Dorsal reticular
formation and basal forebrain))
Wake promoting: Orexin,
Histamine, Norepinephrine,
Serotonin (Locus coerulus,
raphe nucleus,
hypothalamus—
tuberomammilary nucleus
“TMN”)
Most Prescription Sleep Aids Enhance GABA Inhibition
GABA is the predominant inhibitory transmitter
The most often used insomnia agents enhance GABA
inhibition of wake-promoting systems, tipping scale towards
sleep
 Benzodiazepine-binding site: Zolpidem, Zopiclone,
Flurazepam,
Temazepam, Triazolam, etc
 Barbiturates
ORX
Sleep
VLPO
eVLPO
LC
TMN
Raphe
Off
Saper CB, et al. Nature. 2005;437(7063):1257-1263.
Common Prescription Medications Used to Treat Insomnia
Product
Mechanism of
Action
Approved For
Insomnia
Indication(s)
Zopiclone
GABA Agonist
Yes
Treatment of Insomnia
Zolpidem
GABA Agonist
Yes
Treatment of Insomnia
Temazepam
Benzodiazepine
Yes
Treatment of Insomnia
Trazodone
H1 and alpha1
antagonist
No
Treatment of Depression
Amitriptyline
TCA
No
Treatment of Depression
Silenor
Selective H1
Antagonist
Yes
Treatment of Insomnia
Health Canada Drug Database, Feb. 2013.
Off-label Use of Medications for Insomnia
Drug Class
BenzodiazepinesAnxiolytics
Antidepressants
Atypical
Antipsychotics
Agent
Peak
Concentration±
(Tmax, h)
t1/2
(h)
Dose Range
(mg)*
Alprazolam
1-3
12-14
0.25-2
Clonazepam
1-2
35-40
0.25-2
Lorazepam
1-3
12-15
0.5-2†
Amitriptyline
2-12
20-30
10-75
Mirtazapine
~2
20-40
15-45
Trazodone
1-2
5-9
50-150
Olanzapine
3.5
36
2.5-20
Quetiapine
1-3
2-3
25-300
*Dosages indicated for oral tablet formulations.
†Oral and sublingual formulations available.
The onset of action for off-label medications cannot be provided as these agents are not indicated for insomnia and
pharmacokinetics/pharmacodynamics have not been studied in insomnia.
±
Tricyclic antidepressants
NE
amitriptyline (Elavil)………low
amoxapine (Asendin)…… high
clomipramine (Anafranil). low
desipramine (Norpramin) high
doxepin (Silenor)…….
low
imipramine (Tofranil)……. low
maprotiline (Ludiomil)…… high
nortriptyline (Pamelor)….. mod
protriptyline (Vivactil)…… high
trimipramine (Surmontil).. low
5HT
high
low
high
low
low
low
low
low
low
low
Ach
high
mod
high
low
mod
mod
low
mod
mod
high
Sed
high
low
high
low
high
mod
mod
mod
low
high
Comments
pain, Mgr HA
tetracyclic
OCD; SSRI-like
activating
used for insomnia
pain; enuresis
tetracyclic
chronic pain
most activating
Quetiapine and Norquetiapine
Benzodiazepine Receptor Agonists
Drug Class
Non-Benzodiazepines
Benzodiazepines
Agent
Onset of
Action
t1/2
(h)
Dose Range
(mg)#
Zolpidem
~ 20 min
2.6
5-10±
Zopiclone
<1h
5
5-7.5
Triazolam
< 1 h*
~ 11
0.125-0.5
Temazepam
1-3 h*
9
15-30
Nitrazepam
1-3 h*
30
5-10
Flurazepam
< 1 h*
2.5†
15-30
*Onset of action based on e-CPS benzodiazepine product monographs: fast (< 1 h); intermediate (1-3 h); slow (> 3 h).
#Dosage range for normal adults.
± A new drug submission (NDS) for the 5 mg dose of sublingual zolpidem has been submitted.
† The mean elimination t
1/2 of the final active and principal metabolite, desalkyl flurazepam, is ~ 75 hours.
ZOLPIDEM
Selective binding to the BZ1 receptor‡
With a high affinity ratio of the α1/α5 subunits‡
This selective binding of zolpidem on the BZ1 receptor
is not absolute, but it may explain the preservation of
deep sleep (stages 3 and 4) in human studies of
zolpidem tartrate at hypnotic doses1†‡
Adapted from Farrell SE and Fatovich TM.3
† Comparative clinical significance has not been established.
‡ Clinical significance is unknown.
-------

Psychiatric Association and the Psychiatric Community

Zolpidem Use Increasingly Ends in Emergency Room Visits An
increasing number of visits to the emergency room are being attributed
to the sleep medication zolpidem.

The Substance Abuse and Mental Health Services Administration
(SAMHSA) reported this week that ER visits involving adverse reactions
to zolpidem rose nearly 220 percent, from 6,111 visits in 2005 to 19,487
visits in 2010.

Patients aged 45 and older represented about three-quarters of such
visits in 2010. Female patients appear to be more affected, experiencing
a 274% increase in ER visits involving zolpidem use, compared with
male patients who saw a 144% increase. In 2010, females accounted for
more than two-thirds of all ER visits related to zolpidem.
Impact of a US Food and Drug Administration Drug Safety Communication on Zolpidem
Dosing: An Observational Retrospective Cohort
Jonathan L. Harward, PharmD; Valerie B. Clinard, PharmD; Michael R. Jiroutek, DrPH, MS;
Beverly H. Lingerfeldt, RPh, CDE; and Andrew J. Muzyk, PharmD
Recently, the US Food and Drug Administration (FDA) issued a drug safety communication
regarding its dosing in women.
Objective: To compare compliance with FDA-approved dosing for zolpidem in women before
and after a drug safety communication, and to evaluate compliance based on pharmacy location
and prescriber type.
Results: A total of 14,156 prescriptions for zolpidem were included in the primary analysis.
Sixteen percent of prescriptions dispensed were in compliance with FDA recommendations
following the FDA alert. A statistically significant increase was observed in compliance with FDAapproved dosing for zolpidem (odds ratio = 1.49; 95% CI, 1.35–1.65; P < .0001) postdrug safety
communication.
The most common adverse events with oral zolpidem tartrate
seen at statistically significant differences from placebo were:1
In short-term treatment
(up to 10 nights)†
In long-term treatment‡
• Drowsiness (2%)
• Dizziness (1%)
• Diarrhea (1%)
• Dizziness (5%)
• Drugged feelings (3%)
Headache (7%) was also observed in
short-term treatment (up to 10 nights).†
SUBLINOX is not indicated for the
long-term treatment of insomnia.
SSRI=Selective serotonin reuptake inhibitor
† During short-term treatment (up to 10 nights) with zolpidem tartrate at doses up to 10 mg.
‡ During longer-term treatment (28 to 35 nights) with zolpidem tartrate at doses up to 10 mg.
References: 1. SUBLINOX Product Monograph, Valeant Canada Limited, July 2011. 2. Tjepkema M. Insomnia. (Component of Statistics Canada catalogue no. 82-003XPE2005001; ISSN: 0840-6529) Health Reports 2005;17(1):8-25. 3. Farrell SE, Fatovich TM. Benzodiazepines. In: Shannon MW, et al, Haddad and Winchester’s Clinical
Management of Poisoning and Drug Overdose. 4th ed. Philadelphia, PA: Saunders, 2007.
r
m
 Safety profile can be problematic
a
c Tolerance to the sedative effect across time
o Dependence concern and issues in discontinuation
l
o
g
i

Side effect profile commonly includes next-day residual sedation, amnesia,
headaches, and dizziness
1. Imovane ® Product Monograph, Sanofi Aventis Canada Inc., October 2009
2. Sublinox ® Product Monograph, Valeant Canada Limited, August 2012
Silenor Mechanism of
Action
Histamine and the Wake-Sleep Cycle
1.
2.
3.
4.
Szabadi E. Br J Clin Pharmacol. 2006;61(6):761-766.
Haas HL, et al. Physiol Rev. 2008;88:1183-1241.
Strecker RE, Nalwalk J, Dauphin LJ, et al. Neuroscience. 2002;113(3):663-670.
Steininger TL, Alam MN, Gong H, et al. Brain Res. 1999;840(1-2):138-147.

Indirectly, histamine from the TMN
stimulates the noradrenergic arousal
pathway in the LC.1

Directly, histamine from the TMN binds to
excitatory histamine 1 (H1) receptors in the
cerebral cortex to promote arousal1

Preclinical data show:

In several animal models and humans,
histamine activity follows a circadian rhythm
with high levels during the active period and
low levels during the sleep period2

During wakefulness, TMN firing is maximal
and histamine levels are at their highest3

During sleep, brief histaminergic “pulses”
mark the transition from non-rapid eye
movement (NREM) to rapid eye movement
(REM) sleep4

Histamine levels rise sharply upon
awakening, promoting wakefulness4
Properties of H1 Antagonism Differ From Enhancing GABA
Effects dependent on degree of histamine (HA) activity

When there is no HA release, there are no effects

HA release is under circadian control1
There are parallel systems that can mediate arousal (orexin,
norepinephrine, dopamine, serotonin)

1.
2.
HA antagonism does not prevent the wake-promoting effects of the
other systems2
Stahl SM. CNS Spectr. 2008;13(12):1027-1038.
Steininger TL, Alam MN, Gong H, et al. Brain Res. 1999;840(1-2):138-147.
Silenor is a Histamine Antagonist with High Affinity for the H1
Receptor1,2
•
Silenor is a histamine
antagonist2

•
The exact mechanism by which
doxepin exerts its sleep
maintenance effect is unknown,
but is believed to be due to its
antagonism of the H1 receptor
Silenor has greater affinity for
the H1 receptor vs. other
receptors2

1.
2.
The clinical significance of
receptor binding is unknown
Silenor® Product Monograph, Paladin Labs Inc., December 2012
Stahl SM. Trends Psychopharmacol. 2008;13(12):855-865.
Pharmacokinetic (PK) Profile of Silenor
Mean Plasma Drug
Concentration (ng/mL)
0.40
3 mg
0.35
6 mg
0.30
0.25
0.20
0.15
0.10
0.05
0.00
0
•
•
•
•
Tmax
6
12
Time (hours)
18
24
The median time to peak concentrations is 3.5 hours after oral administration of a 6 mg dose to fasted
healthy subjects
Peak plasma concentrations increased in approximately a dose-proportional manner
The apparent terminal half-life (t½) of doxepin was 15.3 hours
The AUC was increased by 41% and Cmax by 15% when 6 mg Silenor was administered with a high fat meal
1.Silenor® Product Monograph, Paladin Labs Inc., December 2012
Silenor Helps Insomnia Patients Stay Asleep with Minimal
Treatment-emergent Side Effects
Incidence (%) of treatment-emergent adverse reactions in two longterm trials of adult and elderly patients
5-Week Adult Data1
3-Month Elderly Data2
PBO
3 mg
6 mg
PBO
3 mg
OVERALL
27%
35%
32%
52%
38%
Central Nervous System
14%
12%
12%
20%
11%
10%
5%
0%
14%
6%
Somnolence/Sedation
5%
9%
8%
5%
3%
Dizziness
1%
0%
0%
2%
2%
Memory Impairment
0%
0%
0%
1%
0%
Gastrointestinal
4%
4%
8%
12%
6%
Respiratory
3%
1%
1%
6%
5%
Psychiatric
1%
1%
3%
1%
2%
Dry Mouth
0%
0%
0%
2%
2%
Increased Appetite
0%
0%
0%
0%
0%
Headache
Other Events of Interest
*List of adverse events are not inclusive.
1. Adapted from Krystal A, et al. Sleep 2011. 2. Adapted from Krystal A et al. Sleep. 2010.
accompanied by residual
effects
at
Hour
9
at
any
point
Phase 3 Clinical Study of Adults With Chronic Insomnia
during the trial
Note: VAS data are inverted for consistency with DSST and SCT results; DSST=Digit-Symbol Substitution Test; SCT=symbol copying test; VAS=visual analog
scale.
Krystal A, et al. Sleep 2011; 34:1433-42.
Administration of Silenor: Impact of Food on Absorption
 Ingestion of a high-fat meal concurrently with administration of
6 mg Silenor
 Increased AUC by 41%
 Increased Cmax by 15%
 Delayed Tmax by approximately 3 hours compared with fasted
state
 For faster onset and to minimize potential for next-day effects,
Silenor should not be taken within 3 hours of a meal
 Silenor should be taken within 30 minutes of bedtime
Silenor ® (doxepin) Product Monograph. Montreal, Canada: Paladin Labs Inc., December 2012.
Silenor Does Not Affect Cardiac Repolarization
 Neither 6 mg Silenor nor 50 mg Silenor produced a
change in QTcI
 No differences in change in QTcI were observed between
men and women
 No clinically relevant effects on heart rate or AV
conduction were observed in the Silenor groups
 No clinical relevant morphologic ECG changes were
identified in any subject who received Silenor
ECG, electrocardiographic. AV, atrioventricular; CI, confidence interval.
Silenor ® (doxepin) Product Monograph. Montreal, Canada: Paladin Labs Inc., December 2012.
SLEEP DIARY
NATIONAL SLEEP FOUNDATION

AM &PM

My favourite…. Excellent review of daily habits, impact on day,
sleep hygiene….
WAKE UP I’M DONE
MERCI!
2012 Beers Criteria
Update
2012 Beers List Update
■
2012 Beers Criteria Identifies Inappropriate Meds for Elderly Patients1
■
Doxepin doses that are < 6mg (Silenor) are considered safe in the elderly
population
Organ System or Therapeutic
Category or Drug
Rationale
Recommendation
Quality of
Evidence
Strength of
Recommendation
Highly anticholinergic,
sedating, and cause
orthostatic hypotension;
safety profile of lowdose doxepin (< 6 mg/d)
is comparable with that
of placebo
AVOID
HIGH
STRONG
Central nervous system
Tertiary TCAs, alone or in
combination:
■ Amitriptyline
■ Chlordiazepoxide-amitriptyline
■ Clomipramine
■ Doxepin > 6 mg/d
■ Imipramine
■ Perphenazine-amitriptyline
■ Trimipramine
Use of doxepin < 6mg considered safe
http://www.americangeriatrics.org/files/documents/beers/2012BeersCriteria_JAGS.pdf
2012 Beers List Update (continued)
■
2012 Beers Criteria Identifies Inappropriate Meds for Elderly Patients1
■
List now includes active ingredients found in GABA-Agonist such as Ambien,
Lunesta and Sonata
Organ System or Therapeutic
Category or Drug
Rationale
Recommendation
GABA receptor agonist
that have similar adverse
events similar to those of
benzodiazepines in older
adults (e.g. delirium, falls,
fractures); minimal
improvement in sleep
latency and duration
AVOID
chronic use
(>90 days)
Quality of
Evidence
Strength of
Recommendation
MODERATE
STRONG
Nonbenzodiazepine hypnotics
 Eszopliclone (LUNESTA)
 Zolpidem
 Zaleplon
http://www.americangeriatrics.org/files/documents/beers/2012BeersCriteria_JAGS.pdf
Silenor is not Therapeutically Equivalent to
Generic Doxepin

Drugs are considered to be therapeutic equivalents only if they are pharmaceutical
equivalents and if they can be expected to have the same clinical effect and
safety profile when administered to patients under the conditions specified in the
labeling

aData
Doxepin’s pharmacokinetics are not linear and dose proportional. When going from 6mg
Silenor to 10mg doxepin there is 225% more drug in plasma at 8 hours, potentially leading
to an increase in side effects, specifically next-day residual effects and anticholinergic side
effects.
adapted from a randomized, open-label, 2-way crossover daytime study to assess the relative bioavailability of Silenor (doxepin) 6 mg tablets compared to
doxepin 50 mg capsules in healthy subjects (N=24). PK blood samples were collected pre-dose and up to 96 hours post-dose to evaluate AUC and Cmax. The
results demonstrated that Silenor® tablets do not produce the same pharmacokinetic profile as doxepin capsules, meaning that the maximum concentration
64
(Cmax) and total exposure (AUC) are not similar enough to conclude that the two forms of the drug are interchangeable, even when taking dose differences into
account. 10 mg doxepin was not included in this study. The actual relative bioavailability of 10 mg doxepin may vary from the estimated results presented in
these data. 10 mg doxepin is not an approved dose for the treatment of insomnia. Data on file. San Diego, CA: Somaxon Pharmaceuticals, Inc.