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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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