Download I`m Just As Nervous As a Cat - Kentucky Pharmacists Association

“I’m Just As Nervous As a Cat”:
Treatment Updates for Anxiety
and Insomnia
MELINDA C JOYCE, PHARM.D., FAPHA, FACHE
KENTUCKY PHARMACISTS ASSOCIATION
JUNE, 2016
Disclosure
• Melinda C. Joyce “declare(s) no conflicts of interest, real or apparent,
and no financial interests in any company, product, or service
mentioned in this program, including grants, employment, gifts, stock
holdings, and honoraria.”
Objectives

Review use and guidelines for benzodiazepines and other anxiolytic
and hypnotic medications

Discuss some of the new medications that are available for the
treatment of insomnia

Evaluate the potential for abuse and addiction with anxiolytic and
hypnotic medications
Self-Assessment Questions
1.
Which of the following medications is not likely to cause anxiety?
a)
Pseudoephedrine (Sudafed)
b)
Prednisone
c)
Quetiapine (Seroquel)
d)
Methyphenidate (Ritalin)
Self-Assessment Questions
2.
Which of the following are considered to be first-line agents in the
treatment of generalized anxiety disorders?
a)
Sertraline (Zoloft)
b)
Alprazolam (Xanax)
c)
Amitriptyline
d)
Pregabalin (Lyrica)
Self-Assessment Questions
3.
Which of the following is a concern with sleep medications
a)
Serotonin syndrome
b)
Increase in suicidal ideation
c)
Liver toxicity
d)
Sleep-driving, eating, or talking
Anxiety Disorders
Anxiety is an umbrella term encompassing several psychiatric disorders
 Most common





Generalized Anxiety Disorder (GAD)
Social Anxiety
Panic Attack/Disorders
Phobias
In the past, obsessive-compulsive disorder (OCD) and post-traumatic disorder
(PTSD) were also considered anxiety disorders but in the most recent Diagnostic
Statistical Manual-5 (DSM-5) these disorders have been moved to other categories
 Globally, approximately 4.5% of the population (worldwide) suffer from an anxiety
disorder



Most prevalent psychiatric condition in the US other than substance abuse
Prognosis depends on the type of anxiety disorder
Pathophysiology of Anxiety Disorders


Not fully understood, but thought to be linked to dysregulation of
neurotransmitters

Gamma-aminobutyric acid

Serotonin

Dopamine

Norepinephrine
Patients with anxiety disorders often show heightened amygdala
responses to anxiety cues
Generalized Anxiety Disorder (GAD)

Common, chronic disorder that can be highly debilitating

Patients with GAD experience non-specific persistent fear and worry about situations
or objects in the absence of real danger



The persistent worry is excessive and unrealistic and often about everyday things

Agoraphobia (fear and avoidance of places or situations that increase panic and may make
the patient feel trapped, helpless, or embarrassed) may signal a more severe anxiety
Approximately 5% of people develop GAD over the course of their lifetime

Much more common in women than men

Develops early in life and can have long-term ramifications

Does seem to have a genetic predisposition
Very important to rule out drug-induced anxiety or other medical causes
Generalized Anxiety Disorder (GAD)

Any chronic disease can have a
component of anxiety




Irritable bowel disease
Heart disease
Menopause
Stroke
Increased Motor Tension
Pulmonary disorders, such as COPD
 Migraine headache
 There are high rates of co-morbidity
with other psychiatric disorders,
especially depression and substance
abuse

Autonomic Hyperactivity
Increased Vigilance
Easily fatigued
Shortness of breath
Feeling “keyed up” or hyper
Restlessness
Rapid heartbeat
Increased startling
Muscle tension
Dry mouth
Impaired concentration
Sleep disturbances
Dizziness
Irritability
Cold hands
Drugs Associated with GAD

Caffeine

Corticosteroids

Nicotine

Sympathomimetics

Alcohol

Antibiotics


Fluoroquinolones
Stimulants

Amphetamines

Methlyphenidate


Pseudoephedrine; Phenylephrine
Illicit substances

Cocaine; Bath salts;
Methamphetamine; MDMA
(Ecstasy); Marijuana
Social Anxiety Disorder (SAD)








Also known as social phobia
Intense fear and avoidance of negative public scrutiny, public embarrassment,
humiliation, or social interaction
Can be specific to a particular social situation, such as public speaking or can
manifest in most social situations
Symptoms often include blushing, sweating, and difficulty speaking
Typical age of onset is 13 years of age
30% of people with SAD report having symptoms for more than 10 years before
seeking help
Avoidance of the situation can be very problematic and in severe cases, lead to
complete isolation
Not the same as shyness
Panic Attack/ Disorder




With panic disorder, a person has brief attacks of intense terror and
apprehension, often accompanied by symptoms such as trembling, shaking,
confusion, dizziness, nausea, and difficulty breathing
Attacks can be triggered by stress or fear or the cause may not be known
In addition to the attacks, a diagnosis of pain disorder requires that the
attacks have chronic consequences

Worry over the attacks’ potential implications

Persistent fear of future attacks

Significant changes in behaviors related to the attacks

Hypervigilance of body functioning during the attacks
Often begins in young adulthood
Phobias
The largest category of anxiety disorders, which includes all cases in which
fear and anxiety is triggered by a specific stimulus or situation
 Between 5 and 12% of the population worldwide suffer from phobic
disorders
 Typically anticipate terrifying consequences from encountering the object
of their fear


Can be anything – animal; location (such as heights); particular situation
Patients usually realize that their fear is not proportional to the actual
potential danger but are still overwhelmed by it
 Patients typically work hard to avoid the object of their phobia, which can
significantly impact their quality of life
 Pharmacotherapy is generally not beneficial

Treatment Options
Anxiety Disorder
First-Line Agents
Second-Line Agents
Generalized Anxiety Disorder
• SSRIs
• SNRIs
•
•
•
•
Social Anxiety Disorder
• SSRIs
• SNRIs
• Clonazepam
• Gabapentin
• Pregabalin
Panic Disorders
• SSRIs
• SNRIs
• Benzodiazepines
• TCAs
• Phenelzine
Benzodiazepines
Buspirone
TCAs
Pregabalin
• Not all SSRIs or SNRIs are indicated as treatment options
• Phobias are not generally treated with medication
Alternatives
• Quetapine
Non-Pharmacologic Options



Should be part of a comprehensive approach for treating any of the anxiety disorders
Cognitive behavior therapy (CBT)

Focuses on identification, understanding, and changing thought and behavior patterns

Counseling can be very beneficial

Some studies show benefit with as little as 8 weeks of therapy
Exposure Therapy




Process for reducing fear and anxiety responses to specific triggers
Exercise
Yoga
Diet

Reduction of caffeine, processed sugars
Pharmacologic
Options
Selective Serotonin Reuptake Inhibitors
(SSRIs)

Widely prescribed medications for depression, some SSRIs also have
an indication for the treatment of anxiety disorders

Increases the amount of serotonin available in the brain at the
synapse

Decreases the amount of serotonin in the neuronal cells by inhibiting
the reuptake

It is theorized that by activating stress-adapting pathways, the SSRIs
reduce the somatic anxiety symptoms and the patient’s general
distress along with the additional amount of serotonin available at the
synapse
SSRIs
Although the mechanism of action is the same, there are differences
between the agents
 If a patient does not tolerate or respond to one SSRI, switch to another
SSRI before changing class or adding another agent
 It is important to taper off to avoid “withdrawal-like” symptoms



Use in pregnancy will depend on the agent, although most are classified
as either a Category C or D



Usually over a 2 week timeframe
Look at risk/benefit
The anti-anxiety effects may take 2 to 4 weeks for response
For acute therapy, 8 to 12 weeks, the response rates are between 60 and
68% with a 30% remission rate
SSRIs Side Effects

CNS stimulation:
 Anxiety,


GI effects: nausea, vomiting, diarrhea

Usually transient

Take medication with food

Taper dosage upward
Anorexia


nervousness, insomnia
May see some weight loss at first, but usually any weight loss is temporary
Lowered seizure threshold
SSRIs Side Effects

Sexual dysfunction – may be as high as 30-50% in both men and women
May be dose-related
 Often a reason for non-adherence
 Agents, such as sildenafil, do seem to be effective for sexual dysfunction caused
by antidepressants


Hyponatremia
May be seen in elderly patients
 Monitor at baseline


QT-Interval Prolongation
Has been noted with citalopram
 Consider ECG and measurement of QT-interval in patients with pre-existing
cardiac disease

Subtle Differences – Paroxetine (Paxil)





First antidepressant associated with an increase in suicidal tendency in
children and adolescents
Seems to cause more weight gain than other SSRIs
More sexual dysfunction – may be related to higher doses needed for
effect
“Withdrawal” can be seen – important to taper dosage and not abruptly
stop
Should not be used in pregnancy – category D

Potential cardiac anomalies

Psychiatric issues in the infant – jitteriness; constant crying; insomnia – may be
related to withdrawal as paroxetine easily crosses the placental barrier
Selective Serotonin Norepinephrine
Reuptake Inhibitors (SNRIs)







Venlafaxine (Effexor; Effexor XR); Duloxetine (Cymbalta);
Desvenlafaxine (Pristiq)
Potentiate neurotransmitter activity in the CNS by inhibiting the
neural uptake of both serotonin and norepinephrine
May be useful for post-traumatic stress disorder (PTSD) along with
psychotherapy
Also useful as an adjunct for pain management
Often considered to be the next class of antidepressant to try when
SSRIs are not effective
Venlafaxine ER is commonly used for anxiety disorders
Pregnancy category C
SNRI Adverse Effects



GI –Nausea, vomiting, diarrhea

Usually transient

Starting with a low dose and slowly titrating upwards can be beneficial
Elevated blood pressure

Monitor at baseline and regularly during treatment

Starting with a low dose and slowly titrating upwards can be beneficial
Headache


Typically transient
Sexual dysfunction

May not be quite as common as with the SSRIs, but may occur
Tri-Cyclic Antidepressants
Amitriptyline (Elavil); Doxepin (Sinequan); Imipramine (Tofranil)
 Affect both norepinephrine and serotonin
 In addition to being used for depression and anxiety, often used for other issues, such
as low-dose for sleep; migraine prophylaxis; adjunct for pain
 Generally not a first-line agent for anxiety because of the cardiovascular and
anticholinergic effects


Imipramine is most often used for anxiety
Takes about 2 to 3 weeks to see clinical effect
 Must always be concerned about the potential for suicide – potentially fatal cardiac
arrhythmias
 No antidote
 Some recommend baseline EKG before initiation
 Total dosage can be given at bedtime to help alleviate side effects

Tri-Cyclic Antidepressants
Side Effects

Sedation

Low-dose doxepin (Silenor) is approved for insomnia, to improve sleep maintenance
and increase total sleep time by about 30 minutes
3 – 6mg at bedtime
 Expensive – both strengths are $9.99 each


Anticholinergic Effects


Constipation; Dry mouth; Blurred vision; Urinary retention
Hypotension

Sit or stand slowly
Weight gain
 Overdose – cardiac effects



Potentially life-threatening arrhythmias
Elderly much more susceptible to the side effects of the TCAs
Serotonin Syndrome (SS)
Potentially life-threatening condition that is clinically avoidable through medication vigilance
 Can be seen from most of the antidepressants
 Occurs when drugs acutely elevate serotonin levels in the CNS, promoting a rapid development
of symptoms
 Clinical triad of autonomic hyperactivity, neuromuscular changes, and altered mental status
 Mild



Moderate


Hyperreflexia, tremor, clonus, shivering, diaphoresis, tachycardia
Hypertension, mydriasis, hyperactive bowel sounds, mild agitation, tachycardia, febrile (core
temperature < 106)
Severe

Hyperthermia (core temperature > 106), severe hypertension, hypervigilance, hypertonicity,
delirium, coma
Serotonin Syndrome (SS)

Mechanism behind 
serotonergic activity with
proserotonergic agents
include:

Proserotonergic agents
include:

SSRIs

SNRIs

Tricyclic antidepressants

Buproprion

 release of serotonin

Inhibition of serotonin
metabolism

 presynaptic uptake

St John’s Wort

 serotonin formation

Opioids

Anti-emetics

Certain antibiotics
Treatment of SS
STOP proserotonergic agent
 Supportive care
 Control of hyperthermia and agitation

 Antipyretics
 Muscular
do not work
activity not from a hypothalamic response
Cyproheptadine (Periactin) may help block serotonin receptors
in the CNS
 Chlorpromazine (Thorazine) or olanzapine (Zyprexa) can be used
if a parenteral agent is required

Precautions – Suicidality
Significant Warning - Applies to all classes of antidepressants
 Black-boxed warning

 Antidepressants
increase the risk of suicidal thinking and behavior in
children, adolescents, and young adults (18-24 years of age) with
major depressive disorder and other psychiatric disorders
 Must closely monitor behaviors, especially in the first few months of
treatment and whenever there is an increase or decrease in dosage

Monitor weekly in the first few weeks, especially in patients
with co-morbid depression or those patients at high risk
Benzodiazepines
History of the Benzodiazepines

Chemist, Leo Sternbach first identified the compound
chlordiazepoxide

First marketed in the early 1960s by the Hoffman-LaRoche company

Chlordiazepoxide (Librium) – 1960

Diazepam (Valium) – 1963

At the time, there were few drugs available to treat anxiety,
depression, or insomnia

Available agents at the time were considered to be “habit forming”
and had multiple side effects
Benzodiazepines





Initially appeared to be less toxic and less likely to cause dependence than the
older drugs
A specific improvement was the lack of respiratory depression
Medical professionals immediately jumped on the benzo bandwagon
In the mid-to-late 1970s, benzodiazepines topped all “most frequently prescribed”
lists
Diazepam became a symbol of our fast-paced, heavily stressed society



Central theme of the book Valley of the Dolls
The rock hit by the Rolling Stones, Mother’s Little Helper, was about benzodiazepine use
Celebrity overdoses of benzodiazepines and other medications have continued and are
tabloid fodder

Marilyn Monroe; Anna Nicole Smith; Heath Ledger
Mechanism of Action





The exact mechanism of action is not completely understood
Took researchers about 15 years to determine that the
benzodiazepines impact gamma-aminobutyric acid (GABA), which is
chiefly an inhibitory neurotransmitter
When benzodiazepines bind to this neuroinhibitory receptor, neurons
are then less excitable
The skeletal muscle relaxation is produced by inhibiting spinal
polysynaptic afferent pathways
The anticonvulsant properties are due to enhanced presynaptic
inhibition
Classification of Benzodiazepines
Benzodiazepine
Peak Onset (Hrs)
Half-Life (Hrs)
Comparative Oral Dose
Chlordiazepoxide
2-4
5-30
10 mg
Diazepam
1
20-50
5 mg
Alprazolam
0.7-1.6
6-20
0.5 mg
Clonazepam
1-4
18-39
0.25 mg
Lorazepam
1-1.5
10-20
1 mg
Oxazepam
2-3
3-21
15 mg
0.5-1
1-4
--
Long-Acting
Intermediate-Acting
Short-Acting
Midazolam
Indications


Have anxiolytic, sedative, muscle relaxation, and anticonvulsant properties
Alcohol withdrawal (short-term)


Oxazepam is often preferred because of lack of metabolite
Generalized anxiety disorders (short-term)

No agent clearly superior
Insomnia – both sleep onset and sleep maintenance
 Panic attacks
 Pre-procedure sedation
 Muscle relaxer for spasms or dystonia
 Status epilepticus or refractory tonic-clonic seizures

Adverse Effects







Sedation
Lethargy
Respiratory depression
Impaired motor skills
Impaired judgment
Cognitive dysfunction
Delirium






Short-term memory impairment
Anterograde amnesia
Ataxia
Depressed mood
Exacerbation of COPD, sleep
apnea
Paradoxical disinhibition

May see an increase in anxiety,
irritability, or agitation in the
elderly or in children
Use in the Elderly

Especially susceptible to the sedative effects of the benzodiazepines



Partly due to reduced metabolism from aging
Beers Criteria List for potentially inappropriate medication use in the
elderly

Avoid benzodiazepines (any type) for treatment of insomnia, agitation, or
delirium

All benzodiazepines increase risk of cognitive impairment, delirium, falls,
fractures, and motor vehicle accidents in older adults
If benzodiazepines are used, the dose should always be half of the
usual adult dose
Tolerance

Tolerance to hypnotic effects develops rapidly, within a few days or
weeks of regular use

Some poor sleepers will report continued efficacy of the benzodiazepines
because they prevent rebound insomnia (a withdrawal symptom)

Tolerance to anxiolytic effects develops more slowly, over a few
months

Escalation of dosage and chronic use of benzodiazepines cause
additional adverse effects including depression and excessive sedation
Criteria for Dependence
1.
2.
3.
4.
5.
6.
7.
Tolerance as defined as either a need for markedly increased amounts of the
substance to achieve the clinical effect, or a markedly diminished effect with
continued use of the same amount of the substance
Withdrawal as defined by either the characteristic withdrawal syndrome for the
substance, or the same or similar substance is taken to avoid withdrawal
symptoms
The substance is taken in larger amounts or over a longer period than intended
There is a persistent desire or unsuccessful attempts to cut down or control
substance use
Time is spent in activities necessary to obtain the substance
Important activities are given up or reduced because of substance abuse
The substance use is continued despite knowledge of having a problem caused or
exacerbated by the substance
Criteria for Dependence
SAMHSA Data, The Dawn Report – December, 2014
Alprazolam

Although abuse of the opioids, especially hydrocodone and oxycodone are more
likely to be discussed, abuse of benzodiazepines is also prevalent

Alprazolam (Xanax) is the most widely abused benzodiazepine, ranking third
behind hydrocodone and oxycodone

Alprazolam is quickly absorbed, which leads to euphoria

Alprazolam 2 mg consistently brings $3.00/tablet on the illicit market, making it
lucrative

Emergency room visits for alprazolam overdose doubled between 2005 and 2010


More toxic in an overdose setting than the other benzodiazepines

More difficult to taper off for discontinuation
Non-medical uses of alprazolam can quickly lead to physical dependence and if
combined with alcohol or opiates can enhance the effects of all of the agents
Withdrawal
The existence of a
benzodiazepine withdrawal
syndrome has been abundantly
demonstrated
 Withdrawal can be mild and
short-lived or severe and
protracted
 Severity is often associated with
prolonged or high-dose use, shortacting benzodiazepines, certain
personality types, and underlying
anxiety












Exacerbation of anxiety or insomnia
Sweating, night sweats
Perceptual distortions
Depersonalization
Hallucinations (both visual and
auditory)
Tingling, numbness, altered sensation
Formication
Sensory hypersensitivity
Muscle twitching
Confusion
Seizures
Management of Withdrawal
Has often been associated with a traumatic process for both the patient and the
provider
 Key strategies for successful discontinuation are gradual dosage tapering and
psychological support


Psychological support is necessary with panic disorder
Benzodiazepines should never be abruptly stopped
 With use over one year, taper only after the condition being treated is well
controlled
 Several different withdrawal strategies are often employed



Not one “best” strategy
If patients cannot tolerate a direct taper, can switch to clonazepam (Klonopin) at
an equivalent dose and then taper off the clonazepam using a direct taper
approach
Other Agents
for Anxiety
Disorders
Buspirone (BuSpar)

Structurally and pharmacologically unlike the benzodiazepines

Does not have anticonvulsant, muscle relaxation, motor impairment, or dependence properties

Serotonin partial agonist

Often considered to be a second-line option for anxiety because of:

Inconsistent reports of efficacy (especially long-term)

Very gradual onset of action- at least 2 weeks or longer with full clinical effect at 6 weeks

Lack of efficacy for any other potential concurrent depressive disorders

Usually requires multiple daily dosing (bid to tid)

Best use may be for patients with substance abuse issues as it has a very low potential for
dependence

Adverse Reactions

Dizziness; nausea; headache; dysphoria (at higher doses)

Most side effects are self-limiting and transient
Quetiapine (Seroquel XR)

First atypical antipsychotic agent approved for the acute and maintenance
treatment of bipolar depressive episodes


Also indicated for adjunctive therapy with major depressive disorder



Includes both manic and mixed episodes
Especially if anxiety or insomnia is prevalent
Although not a FDA-approved indication, quetiapine is used as a second-line
agent for anxiety
Do see differences between the immediate release and the extended
release forms
Once daily dosing
 Should be taken on an empty stomach for best absorption

Quetiapine

Sedation
Can be beneficial in patients with anxiety with insomnia
 Some controversy on whether this agent should be used for sleep in patients with no other
psychotic symptoms – not recommended



QT-interval prolongation
Metabolic syndrome – should have baseline labs and then monitor every 3 to 6 months






Extrapyramidal side effects


Weight gain (BMI)
Waist circumference
Fasting lipids
Glucose
Blood pressure
Akathisia
May see abuse - Baby heroin; Quall; Suzie-Q; Q-ball (when combined with cocaine or heroin)
Pregabalin (Lyrica)

Structural analog of GABA that is indicated for pain associated with diabetic peripheral
neuropathy or post-herpetic neuralgia


Also indicated as adjunctive therapy for refractory partial seizures
Does not have a FDA indication for anxiety, but is used as a second-line agent

Mechanism of action is thought to involve alpha-2 delta receptors that modulate nerve
transmissions in the brain and spinal cord.

Precautions




Renal insufficiency
CNS depressants, including alcohol
Important to taper dose (at least over 1 week) upon discontinuation to minimize seizure risk – no matter
reason for using the medication
Thrombocytopenia


CBC at baseline and periodically during treatment
More common adverse effects

Dizziness, drowsiness, dry mouth, peripheral edema, blurred vision, weight gain, difficulty
concentrating, euphoria (?)
Treatment Options for GAD
First-Line Agents

SSRI





Escitalopram* 10 mg once daily
Sertraline 50 mg once daily
Paroxetine* 20 mg once daily





SNRI
Venlafaxine ER* 37.5 – 75 mg once
daily
Duloxetine* 30 – 60 mg once daily

Alprazolam* 0.25 mg two to three times
a day
Buspirone* 7.5 mg twice daily
Pregabalin50 mg three times a day
TCAs


* - FDA approved indication
Second-Line Agents
Benzodiazepines
Imipramine 10-25mg once daily, titrated
to 50 to 100 mg total daily dose
Quetiapine XR 50 mg at bedtime,
titrated to 150 mg at bedtime
Pearls for GAD Treatment





Antidepressants are considered the first-line agents in the management of GAD
Although very efficacious, the anti-anxiety response of the antidepressants is usually
delayed by 2 to 4 weeks but should be the preferred agents for long-term maintenance
therapy
Important to monitor for suicidal ideation and side effects
Second –line agents: No benzodiazepine clearly superior in the treatment of GAD
Consider agent with medium or long half-life


Shorter acting agents pose higher risk of withdrawal, rebound, and dependence


Clonazepam; lorazepam; diazepam
Alprazolam
Benzodiazepines are ideally for short-term use only until the effects of the
antidepressant starts to work
Treatment Options for Social Anxiety
Disorder
First-line Agents


SSRI

Escitalopram* 5- 10 mg once daily

Citalopram 20 mg once daily

Sertraline 50 mg once daily

Paroxetine* 20 mg once daily

Paroxetine CR 12.5* mg po daily
SNRI

Venlafaxine ER* 75 mg once daily
* - FDA approved indication
Second-Line Agents
 Benzodiazepines

Clonazepam 1-4 mg po daily –
usually as an augmentation
Buspirone 10 mg twice daily
 Pregabalin 100 mg three times a
day
 Quetiapine XR 25 mg at bedtime
 Phenelzine 15 mg at bedtime

Pearls for Treatment of Social Anxiety
Disorder

Patients with generalized social anxiety disorder should be treated
aggressively




Any improvement in symptoms can be considered as success
Obstacles to effective treatment include

Avoidance of therapy secondary to fear and shame

Treatment directed toward somatic symptoms or concurrent conditions

Financial barriers
Patients often respond more slowly and less completely than patient with
other anxiety disorders
Pharmacotherapy plus cognitive behavioral therapy generally will have the
greater likelihood of maintaining response
Pearls for Treatment of Social Anxiety
Disorder

Antidepressants are the first-line choices

Benzodiazepines are commonly used in patients who cannot tolerate
or fail to respond to the antidepressants


If a benzodiazepine, such as clonazepam is used, a tapering regimen should
be employed after 6 months
If a patient is switched from another antidepressant to phenelzine, a
washout period should be followed to help decrease any potential
adverse drug-drug interactions
Treatment Options for Panic Disorders
First-line Agents


SSRI
Second-line Agents

Benzodiazepines

Escitalopram 10- 20 mg once daily

Alprazolam* 0.25 mg three times a day

Citalopram 20 mg once daily

Alprazolam XR 0.5 to 1 mg daily

Fluoxetine 10 mg once daily

Clonazepam* 1-4 mg po daily

Sertraline 25 mg once daily

Diazepam 2-5 mg three times a day

Paroxetine* 10 mg once daily

Lorazepam 0.5 -1 mg three times a
day
SNRI

Venlafaxine ER* 37.5 mg once daily
* - FDA approved indication

Imipramine 75 mg po daily

Phenelzine 15 mg at bedtime
Pearls for Treatment of Panic Disorder
Panic disorder is treated effectively with antidepressant therapy
 Although the SSRIs are considered to be first-line agents, benzodiazepines are the
most commonly used drugs for panic disorder
 The use of the benzodiazepines should be limited to short-term treatment
 In the acute phase, treatment with a benzodiazepine should be limited to one
month while the antidepressant is being slowly tapered upwards


The slow taper is necessary to not exacerbate the panic disorder from potential side
effects, such as nervousness, jitteriness, or insomnia
If patients are prescribed a benzodiazepine into the maintenance phase, patients
are more likely to suffer a relapse whenever attempts are made to discontinue the
benzodiazepine
 Must use alprazolam carefully due to abuse potential

Insomnia
Epidemiology of Sleep Disorders
Insomnia is a common disorder that can present in a variety of ways
 Sleep Latency – difficulty in falling asleep
 Sleep Maintenance – difficulty staying asleep
 Sleep Quality – Not feeling rested after a night’s sleep
 It is estimated that about 1/3 of Americans experience insomnia nightly
 First-line treatments for insomnia tend to focus on non-pharmacologic
interventions with drug therapy added to those approaches if necessary
 Insomnia may also present with other co-morbid conditions, such as pain,
depression or anxiety


The underlying issue should be addressed
Non-Pharmacologic Approach


Keep a sleep journal for at least two weeks, tracking sleep times, caffeine
and alcohol intake, smoking, stressful situations
Improving sleep hygiene*







Avoiding over-the-counter sleep aids
No naps during the day
Avoid alcohol, nicotine, caffeine, especially shortly before going to bed
Avoid bright lights from the television, computers, video games, telephones
If not asleep within 15 to 20 minutes, get up and go to another room. Return to
bed only if drowsy
Relaxation or stress reduction techniques
Review medications for any that may impact sleep
* Not a complete list
Treatment Options for Insomnia

Non-Benzodiazepine Benzodiazepine Receptor Agonists (NBRAs)

Melatonin Receptor Agonist

Orexin Receptor Agonists

Benzodiazepines

Miscellaneous Agents

Antihistamines

Tri-Cyclic Antidepressants
“Z” Sleep Agents

Non-benzodiazepine Benzodiazepine Receptor Agonists (NBRAs)
Zolpidem (Ambien; Edluar; Ambien CR; Intermezzo; Zolpimist)
 Zalpelon (Sonata)
 Eszolpiclone (Lunesta)

Not benzodiazepines but appear to bind to benzodiazepine receptors
 All of the agents decrease sleep latency and are approved for use in
patients with sleep-onset latency
 Agents are used for different types of sleep disorders
 These agents are on the “Beers List” for drugs that should be avoided in
elderly patients due to an increased chance of falls, delirium, or
accidents


Third-party insurance plans often monitor the use of these agents
NBRA Adverse Effects

Can impair next day performance, including driving

Complex sleep-related behaviors, such as sleep-walking, sleep-eating,
and sleep-driving can occur without conscious awareness


High doses

Taking the drug at times other than at bedtime

Concurrent use with other sedating medications

Alcohol
If taken immediately after a meal, can see delayed onset of action
Zolpidem


Immediate-release Ambien is indicated for short-term sleep disorders, especially when a
benzodiazepine is contraindicated

Should not be used for more than 7 to 10 consecutive days

Sublingual form – Edluar

Oral spray - Zolpimist
Controlled-release Ambien CR – has an immediate release component so that the patient
can fall asleep and then a longer acting component to help keep the patient asleep


Not limited for short-term use only
Low-dose sublingual Intermezzo – should be used for middle of the night awakening when
there are at least four hours of sleep left

Sublingual tablets in very low doses (1.75 or 3.5 mg) that should only be allowed to dissolve under the
tongue and should not be swallowed whole

Should be taken on an empty stomach for the best effect
Zolpidem

Recent warnings about the use of zolpidem in women (January,
2013)
 Dose
should be decreased by half in women due to the fact that
zolpidem blood levels the next day can lead to significant
impairment
 The
 ED
use of alcohol can exacerbate this effect
visits related to zolpidem are up over 220%!
 FDA
is also considering a dose reduction in men as well
Zaleplon

Rapid-acting agent

Good for those patients with early morning awakening

Should be used when the patient can be asleep for about 4 to 6 hours

Indicated for short-term use (no more than 7 to 10 consecutive days)

Rebound insomnia is more likely at higher doses
Eszopiclone

Longest half-life






Duration of up to 8 hours in some patients
Indicated for chronic insomnia and can be taken for six months or longer
Has been shown to decrease sleep latency and to improve sleep maintenance
Unusual side effect of a bad metallic taste in mouth – tablets cannot be
broken or crushed
Should be used cautiously in patients with hepatic dysfunction or
impaired respiratory function
All patients should be started with 1 mg
Melatonin Agonist

Ramelteon (Rozerem)





Selective agonist of melatonin receptors
May be helpful for synchronization of circadian rhythms and sleep-wake cycle
Works quickly – should be taken just before retiring
Not recommended for patients with severe COPD or sleep apnea
Common adverse effects include:
Dizziness
 Nausea
 Fatigue
 Headache


No potential for abuse
Suvorexant (Belsomra)

New class of sedative/hypnotic classified as an orexin (hypocretin)
receptor antagonist

Orexin neuropeptide signaling system in a central promoter of wakefulness
 Narcolepsy/
 Insomnia


cataplexy caused by a deficiency in orexin (no wake drive)
may be caused by an abundance of orexin (signals wakefulness)
Blocking the binding of wake-promoting neuropeptides orexin A and orexin B
to the orexin-1 receptor and orexin-2 receptor suppresses the wake drive
Orexins may play a role in many other disorders
Suvorexant



Indicated for the treatment of insomnia, characterized by difficulties with
sleep onset and/or maintenance
The recommended dose:

10 mg no more than once per night taken within 30 minutes of going to bed, with
at least 7 hours remaining before planned awakening

Maximum dose: 20 mg once nightly

Best if taken on an empty stomach to avoid delayed onset of action
Contraindicated in patients with narcolepsy


Although not contraindicated, should be used very cautiously in patients with
severe sleep apnea and advanced COPD
Has not been associated with rebound insomnia
Suvorexant

Warnings/ Precautions:

Daytime somnolence

Impaired driving and motor coordination

Depression or suicidal thinking

Compromised respiratory function
Suvorexant

Adverse Reactions



Drowsiness
Sleep paralysis
Hynagogic and hypnopomic hallucinations


Cataplexy-like symptoms


Vivid, highly disturbing hallucinations
Cataplexy – loss of muscle tone often after an emotional response (falling to floor after
laughing)
Potential drug-drug interactions



No issues identified with warfarin
Avoid in patients taking strong CYP3A inhibitors, such as ketoconazole
Would want to monitor digoxin levels
Benzodiazepines






Benzodiazepines decrease sleep latency and prolong the first two
stages of sleep
The differences in the various agents is primarily due to the duration
of action
The adverse effects for those benzodiazepines that are indicated as a
sedative/hypnotic are the same as those for anxiety
Should be reserved when other agents are not effective due to the
higher potential for dependence, tolerance, and rebound insomnia
Lowest dose possible should be used for the shortest period of time
Should not be used in the elderly
Classification of Benzodiazepines
Sedative/Hypnotic Agents
Benzodiazepine
Peak Onset (Minutes)
Half-Life (Hrs)
Comparative Oral Dose
60-120
> 100
15 mg
Estazolam
60-120
10-24
1 mg
Temazepam
60-120
4-18
15 mg
15-30
1.5 - 6
0.125 mg
Long-Acting
Flurazepam
Intermediate-Acting
Short-Acting
Triazolam
Sleep Med Warnings



All prescription sleep meds have warnings of strange sleep-related
behavior along with the potential for severe allergic reactions

Driving, eating, talking

Reactions are not common

May be worsened by alcohol or other CNS depressants

Patients must be told of these potential adverse effects
A MedGuide should be dispensed with the medications
Several quality initiatives regarding the use of sleep medications,
especially in the elderly
Pearls for the Treatment of Insomnia

First make sure that underlying causes of insomnia are addressed and
treatment for those disorders are optimized

Make sure that medications or substances that have the potential to be
CNS stimulants are not taken in the evening or at bedtime

Recommend non-pharmacologic approaches for all patients

Sleep medications should be used cautiously, if at all, in the elderly

Monitor for unusual adverse reactions

Benzodiazepines should be reserved as a last approach when other drug
treatments have not been effective
Key Points
Anxiety can have a variety of causes and if possible, the underlying cause should
be treated first
 The SSRIs are the first-line agents in the treatment of anxiety
 Benzodiazepines should be reserved for more refractory cases and used in the
lowest doses possible for the shortest period of time to help decrease potential
addiction


Alprazolam should be avoided if possible
Sleep disorders are common and knowing what type of sleep disorder a patient is
suffering from will help to direct the type of sleep medication to prescribe
 All agents must be used carefully with close monitoring
 All sleep medication have warnings about strange sleep-related behaviors
 Medications for both anxiety and insomnia should be used carefully in the elderly

Self-Assessment Questions
1.
Which of the following medications is not likely to cause anxiety?
a)
Pseudoephedrine (Sudafed)
b)
Prednisone
c)
Quetiapine (Seroquel)
d)
Methyphenidate (Ritalin)
Self-Assessment Questions
2.
Which of the following are considered to be first-line agents in the
treatment of generalized anxiety disorders?
a)
Sertraline (Zoloft)
b)
Alprazolam (Xanax)
c)
Amitriptyline
d)
Pregabalin (Lyrica)
Self-Assessment Questions
3.
Which of the following is a concern with sleep medications
a)
Serotonin syndrome
b)
Increase in suicidal ideation
c)
Liver toxicity
d)
Sleep-driving, eating, or talking
Melinda C. Joyce, Pharm.D., FAPhA, FACHE
[email protected]
270-745-1599