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Anxiety
‘Just try not to worry’
MICHAEL WEBSTER, PHARMD, PHC, BCPP
Disclosures
Currently employed with Presbyterian Medical Group
No financial ties to any drug manufactures or unlisted corporations
We will be discussing off-label uses of a number of medications
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Learning objectives: Pharmacists
- Explain to patients the risks and benefits of various groups of anxiolytic medications
- Identify patients at high risk of adverse outcomes from anxiolytic medications
- Educate patients and prescribers on the risk of long term benzodiazepines
- Educate patients on use, side effects, and expectations of anxiolytic therapy
- Outline safe benzodiazepine taper plans for patients utilization
Learning objectives:
Pharmacy Technicians
- Identify medications frequently used for anxiety, both on label and off label uses
- Describe and differentiate common anxiety disorders
- Outline for patients realistic expectations of anxiolytic medications
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Fear and Anxiety
Fear- The emotional response to either real or perceived imminent threat
- Autonomic hyperarousal- Fight or Flight- Pounding and racing heart
- Tremor
- Sweating
- Escape behavior
Anxiety- Anticipation of future threat
- Muscle tension
- Hypervigilance
- Avoidant behavior
‘I have been through some
terrible things in my life, some of which actually
happened. We walk
around all our lives thinking
about things that will never
happen. We worry, dread, and fear what hasn’t
happened, and probably
never will.’
-Mark Twain
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Anxiety in the Brain
Involves many areas of the brain
- Amygdala- Subconscious threat evaluation
- Hippocampus- Memory storage and emotional learning
- Neocortex- Complex thought and worry
Anxiety vs Anxiety Disorder
An anxiety disorder must:
1. Not be attributable to a substance or medical condition
2. Persistent (6 months+)
3. Significant distress or impairment in functioning
4. Out of proportion to threat
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Substance induced anxiety
- Caffeine
- Albuterol
- Amphetamines
- Methamphetamines
- Adderall
- Methylphenidate
Anxiety due to a medical condition
Hyperthyroidism
Asthma
Pheochromocytoma
Irukandji syndrome
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Objective perspective
- Out of proportion to threat- Threat can be physical or mental- Risk of interpersonal rejection
- Significant distress or impairment- All anxiety induces distress
- Outside observer needed to gauge distress- Impairment from what?
Anxiety or Disorder
Jack invites his new friend Tom to go to Taos
to go skiing with him. Tom has never gone skiing before but is willing to go and learn.
Tom does great on the bunny hill on his first day and feels great. On the second day Jack takes Tom up the mountain on the
chair lift to try an easy trail.
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Anxiety or Disorder
At the top of the mountain Tom looks down
the mountain and is terrified. He feels his heart pound in his chest, his mouth goes dry,
he starts sweating, and he starts visibly trembling.
Jack and Tom ride the chairlift down the mountain. They rent snowshoes and go on a
beautiful hike. Tom never tries skiing again.
Is this anxiety, or an anxiety disorder?
Anxiety or Disorder
Elyn just got her first job as a barista.
On her first day she was extremely nervous that she might not do a good job, or make
a mistake. Her boss reassured her that this was normal on a first day and that it would go away after a few days.
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Anxiety or Disorder
A year later she is still working at the coffee
shop.
When she pulls up to work she reports
feeling a sense of dread.
She isn’t sleeping well at night, with her mind running through the mistakes she made at
work the day before
Anxiety or disorder?
Anxiety in many flavors
Most Common (2-7% of the population)
Generalized anxiety disorder
Social anxiety disorder (Social Phobia)
Panic Disorder
Agoraphobia
Less common
Separation anxiety disorder
Selective mutism
Specific PhobiasAnimal
Natural environment
Blood - Injection - InjurySituational
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Panic Attacks
Abrupt surge of intense fear and discomfort
with at least 4 of:
1. Palpitations, pounding heart,
accelerated heart rate2. Sweating3. Shaking or trembling
4. Sensation of shortness of breath5. Feelings of choking
6. Chest pain/discomfort7. Nausea or abdominal distress8. Feeling dizzy or faint
9. Paresthesias10. Derealization or depersonalization
11. Fear of losing control12. Fear of dying
Panic Disorder
Recurrent unexpected panic attacks
Followed by at least 1 month of:
Persistent fear or worry about future attacks
Significant maladaptive change in behavior
to avoid future attacks
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Agoraphobia
Marked fear or anxiety about two (or more)
of the following
1. Using public transportation
2. Being in open spaces (parking lots, marketplaces, bridges)
3. Being in enclosed places (shops,
theaters, cinemas4. Standing in line or being in a crowd
5. Being outside the home alone
Generalized Anxiety Disorder
1. Excessive anxiety and worry (apprehensive expectation), occurring more days than not for
at least 6 months, about a number of events or activities (such as work or school performance).
2. The individual finds it difficult to control the worry.
3. The anxiety and worry are associated with three (or more) of the following six symptoms
1. Restlessness or feeling keyed up or on edge. 2. Being easily fatigued. 3. Difficulty concentrating or mind going blank. 4. Irritability.
5. Muscle tension. 6. Sleep disturbance (difficulty falling or staying asleep, or restless, unsatisfying sleep).
4. The anxiety, worry, or physical symptoms cause clinically significant distress or impairment
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Social Anxiety Disorder (social phobia)
1. Marked fear or anxiety about one or more social situations in which the individual is exposed
to possible scrutiny by others. Examples include social interactions (e.g., having a conversation, meeting unfamiliar people), being observed (e.g., eating or drinking), and
performing in front of others (e.g., giving a speech).
2. The individual fears that he or she will act in a way or show anxiety symptoms that will be negatively evaluated (i.e., will be humiliating or embarrassing; will lead to rejection or offend
others).
3. The social situations almost always provoke fear or anxiety. Note: In children, the fear or
anxiety may be expressed by crying, tantrums, freezing, clinging, shrinking, or failing to speak in social situations.
4. The social situations are avoided or endured with intense fear or anxiety.
Treatments
Psychological
- Cognitive Behavioral Therapy
- Exposure Therapy
- Mindfulness Based Therapy
Pharmacological
- Preventative vs Abortive
- Limited differentiation by specific disorder
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Professional Guidelines
- Anxiety Disorders Association of Canada
- British Association for Psychopharmacology
- National Institute for Health and Care Excellence (NICE)
- American Psychiatric Association - Panic disorder only
Benzodiazepines
- GABA-A positive allosteric
modulator
- GABA is a inhibitory
neurotransmitter
- When activated it sedates
the individual in a dose
responsive manner
- This is the same general
mechanism of many other
sedatives and depressants
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Differences
- There are dozens of subtypes of GABA-A receptor
- These subtypes are largely isolated to specific regions of the brain
- Depending on the selectivity benzodiazepines can have different clinical effects
- Alpha 1 subunit- sedation- Triazolam, Temazepam, Zolpidem*
- Alpha 3 subunit- muscle relaxation- Diazepam
- Alpha 6 subunit- amnesia- Midazolam
FDA Approved Indications
Panic
disorder
‘Anxiety’ Alcohol
Withdrawal
Seizures Muscle
spasm
Insomnia Anesthesia
Alprazolam X X
Chlordiazepoxide X X
Clonazepam X X
Diazepam X X X X
Lorazepam X X X
Midazolam X
Temazepam X
Triazolam X
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Differences- Half Life
Approximate Equivalent
Dose (mg)
Half Life (hrs)
Diazepam 10 20-100
Alprazolam 1 6-12
Clonazepam 0.5 18-50
Lorazepam 2 15
Safety Concerns
- Physical Dependence- Risk of addiction
- Regardless of abuse, physiological dependence is always seen
- Dementia- Seen in over a dozen long term observational studies
- Risk increased between 1.25 up to 3.5 times
- Overdose Risk- Does not independently suppress respiration
- Most severe when combined with opioids or other sedating medications
- 2016 FDA Black Box Warning
- Falls- Risk of falls and hip fractures up 50-100%
- Worsening of anxiety?
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Discontinuation
Withdrawal Symptoms
- Anxiety - Unmasking prior anxiety state
- Rebound Anxiety- Insomnia- Irritability
- Cravings- Tremor
- Nausea and vomiting- Fatigue- Hypersensitivity to light, sound, or touch
- Muscle twitching- Seizures
Risk factors
Long term use
High dose use
Frequency of administration
Short half life medications
Management of discontinuation
- Gradual reduction in dose is the rule
- Timeframe must take into account
frequency of use, dose, and duration of use
< 3 months- 1 week taper
3 months to 1 year - 1 month taper1+ Years- 3 month taper
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Evidence Based UsesDuration of Use Indication
Long term Refractory seizure disorders on the guidance of
neurology
Intermittent (< 2 doses a week) Social Phobia
Schizophrenia on the guidance of psychiatry
Insomnia
Short term (4 weeks maximum) Generalized anxiety disorder
Panic disorder
Alcohol Withdrawal
Adjunct treatment of mania on guidance of
psychiatry
Single dose Pre-procedure (ex: pre MRI)
Evidence based choice of drug
1. Longer half life agents almost always prefered
2. Alcohol withdrawal is best treated with Lorazepam due to lower need for hepatic
metabolism
-Alpha 1 subunit- sedation- Triazolam, Temazepam, Zolpidem*
-Alpha 3 subunit- muscle relaxation- Diazepam
-Alpha 6 subunit- amnesia- Midazolam
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Antidepressants
- Sertraline (Zoloft)
- Citalopram (Celexa)
- Escitalopram (Lexapro)
- Fluoxetine (Prozac)
- Paroxetine (Paxil)
- Venlafaxine (Effexor)
- Duloxetine (Cymbalta)
Choice of agent
Fluoxetine- very long half life, low risk of discontinuation symptoms and good if suspected poor
adherence. Generally more stimulating (give in AM)
Paroxetine- very short half life, highest risk for discontinuation symptoms, generally more sedating
(give at HS), significant anticholinergic properties and not recommended in elderly patients
Citalopram / Escitalopram- Exactly the same drug, escitalopram is active S-enantiomer, citalopram has added ‘contaminant’ of R-enantiomer which is main cause of citalopram
induced QTc prolongation.
Sertraline-
Venlafaxine- SNRI only at high doses (>150mg/day), increased risk of tachycardia
Duloxetine- balanced SNRI, useful for comorbid neuropathic pain states
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How do they work?
All have a common mechanism
of increasing serotonin
Anxiety is not a shortage of serotonin
Best theory is the drugs act to help your brain gradually rewire the ‘anxiety circuit’
Education points
- Role is to prevent anxiety and panic attacks, not to rapidly treat them - As such requires consistent daily use
- Starting at high doses or rapid dose increases can exacerbate anxiety- Start low (½ normal starting dose) and gradual escalate dose
- Delayed improvement- Improvement requires several weeks to occur, after reaching therapeutic dose
- Side effects- Sexual side effects
- Sedation OR Insomnia
- Nausea
- Foogy feeling
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Alternative antidepressants
Limited but generally positive evidence
Mirtazapine
Limited and mixed evidence
Bupropion
Vilazodone
Vortioxetine
Buspirone
- Scheduled use only- PRN use is essentially a placebo effect
- 5mg BID to 15mg TID
- Acts primaraly as a 5HT-1A agonist
- Downstream effects are largely similar to serotonergic antidepressants
- Given the difference in mechanism of action combination with SSRI’s is reasonable
- Extremely well tolerated, avoids sexual side effects
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Gabapentinoids
- Gabapentin and Pregabalin (Lyrica)
- Rapid onset of action
- Useful with PRN or regular dosing
- Lower abuse potential then benzodiazepines
- Pregabalin is extensively studied and approved for GAD in most of Europe
GABApentin or not?
Bind to Alpha 2- Delta sites on voltage
gated calcium channels
Decreases the release of excitatory
neurotransmitters (glutamate)
Excessive excitation in the amygdala
underlies anxiety
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Beta Blockers
Propranolol is the most well studied
Non-selective beta blockers work better
Concern with asthmatics
Mechanism is largely to blunt the sympathetic symptoms from anxiety
- Sweating
- Tremor
- Tachycardia and Palpitations
Limited clinical effects within the CNS, most evidence in performance anxiety (such as
presenting this presentation)
Hydroxyzine
Is not class wide effect for antihistamines
Anxiolytic effect has not been seen with diphenhydramine or other 1st gen antihistamines
Second generation antihistamines do not significantly cross into the brain
Studied dosing is 50-100mg QID
Clinical practice often uses lower doses to improve tolerability
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Hydroxyzine
Hydroxyzine is unique in having somewhat less anticholinergic properties then other 1st
gen in common use
Significantly longer half-life compared to diphenhydramine
Notable for weak activity as a 5HT-2A antagonist
Pamoate Vs Hydrochloride
Dosing is the same between the salt
form
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Antipsychotics
Last Line option
Reasonable for individuals with comorbid bipolar disorder or psychosis
Effective both on a ‘PRN’ or scheduled basis
Quetiapine, Olanzapine, and Risperidone are most studied
Antipsychotics
Even at very low does metabolic side effects are a significant concern
Lowest possible dose of always the rule
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Questions?
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