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Benzodiazepines, Other Anxiolytic Medications, and Meditations: Selected Topics in Anxiety Management. 16 th Annual ETSU Nurse Practitioner/Physician Assistant Primary Care Conference March 27, 2011 , Johnson City, TN Jay M Griffith MD MHC Asst. Chief, Quillen VAMC

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benzodiazepines other anxiolytic medications and meditations selected topics in anxiety management

Benzodiazepines, Other Anxiolytic Medications, and Meditations: Selected Topics in Anxiety Management

16thAnnual ETSU Nurse Practitioner/Physician Assistant Primary Care Conference

March 27, 2011 , Johnson City, TN

Jay M Griffith MD

MHC Asst. Chief, QuillenVAMC

Clinical Associate Professor, ETSU

Dept of Psychiatry and Behavioral Sciences

Diplomate, ABPN Psychiatry and Pain Medicine

anxiety disorders biology limbic system prefrontal cortex
ANXIETY DISORDERS BIOLOGY- Limbic System – Prefrontal Cortex


Drives autonomic and emotional responses

HIPPOCAMPUS Evaluates threat contexts


Regulates limbic responses of amygdala and hippocampus




Diagram from Bisson 2007 BMJ Content created by Karleyton Evans, MD.

Adapted from Rauch, et al. CNS Spectrums. 1998;3(suppl 2):30-34.








anxiety disorders lifetime prevalence

- Social Phobia 13.3%

- Post Traumatic Stress Disorder (PTSD) 7.8%

- Generalized Anxiety Disorder (GAD) 5.1%

- Panic Disorder 3.5%

anxiety disorders epidemiology

- 25% Lifetime prevalence for all anxiety disorders

- High Comorbidity (depression, other anxiety disorders, substance use disorders)

- Generally occur in Females > Males

- 1/3 of Americans will experience a panic attack

anxiety disorders biology neurotransmitter systems

- Serotonin (SE) is most frequently implicated

- Norepinephrine (NE) and Dopamine (DA) have roles

- Calcium, glutamate, oxytocin, and other neurotransmitter/neuropeptide systems are relevant

(eg. Oxytocin Nasal decreases fear responses of social phobics to anxiety provoking social stimuli)

differential diagnosis of anxiety disorders dsm iv tr
Differential Diagnosis of Anxiety Disorders DSM-IV-TR

1. Anxiety, fear, avoidance, or increased arousal

2. R/O physiological/medication causes

3. R/O substance induced (caffeine) and obtain UDS

4. Unexpected Panic Attacks: Panic Disorder

5. Fear of humiliation: Social Phobia

6. 6 mos of excessive worry and anxiety: GAD

7. Traumatic event + reexperiencing: PTSD

panic disorder social phobia gad and ptsd
Panic Disorder, Social Phobia, GAD, and PTSD

Which of these anxiety disorders can have associated panic attacks?

Panic Disorder – basis of the diagnosis

Social Phobia – in public situations

GAD – during peaks of anxiety

PTSD – during heightened arousal

panic attack
Panic Attack

A Panic Attack is a discrete period in which there is the sudden onset of intense apprehension, fearfulness, or terror, often associated with feelings of impending doom. During these attacks, symptoms such as shortness of breath, palpitations, chest pain or discomfort, choking or smothering sensations, and fear of "going crazy" or losing control are present. DSMVI-TR

diagnostic criteria for adjustment disorder with anxiety or with mixed anxiety and depressed mood
Diagnostic criteria for Adjustment Disorder With Anxiety orWith Mixed Anxiety and Depressed Mood

The development of emotional or behavioral symptoms in response to an identifiable stressor(s) occurring within 3 months of the onset of the stressor(s).

These symptoms or behaviors are clinically significant as evidenced by either of the following:

  • marked distress that is in excess of what would be expected from exposure to the stressor
  • significant impairment in social or occupational (academic) functioning

Specify if:

Acute: if the disturbance lasts less than 6 months

Chronic: if the disturbance lasts for 6 months or longer

With Anxiety

With Mixed Anxiety and Depressed Mood DSIVM-TR

for all anxiety disorders in dsmiv tr there must be
For all anxiety disorders in DSMIV –TR, there must be:

Significant impairment in social or occupational (academic) functioning

anxiety disorder treatments
Anxiety Disorder Treatments

Panic Disorder – SSRI/SNRI – (use BZP early or late); Cognitive Behavior Therapy (CBT)

Social Phobia – SSRI/SNRI, (BZP), CBT; for performance anxiety (B-blocker, Toastmasters International)

GAD – SSRI/SNRI , buspirone, (BZP), pregabalin in Europe, CBT

PTSD – SSRI/SNRI(SNRIs not for hyperarousal), for nightmares and possibly hyperarousalconsider prazosin off label, no BZPs, Exposure-Based CBT

It may take 8-12 weeks to see a response




buspirone in gad
Buspirone in GAD
  • 5 HT1A partial agonist
  • NE metabolite
  • Begin 7.5mg bid then increase by 5mg q 2-3 days
  • BID or TID
  • Faster increases may produce jitteriness
  • 2-3 weeks before onset
  • A study demonstrated less efficacy for buspirone in those previously treated with a benzodiazepine
buspirone advantages
Buspirone Advantages

- No adverse cognitive effects

- No physiological dependence

- Not cross-tolerant with alcohol

- Few side-effects (jitteriness, headache)


Middle-aged male with a history of “panic attacks” 3-4 times a month and two phobias. + sexual side effects on SSRIs/SNRIs

Consumes 2-3 oz of liquor equivalents nightly and 3-4 oz on some occasions

Further history demonstrates he experiences GAD and when panic attacks occur during elevations of GAD intensity

1 month later 10mg tid of buspirone decreases anxiety by 70%

case continued
Case continued…

3 months later the patient calls to report increases of all anxiety symptoms

He is missing midday doses of medication

Change to BID and he’s had sustained benefit

prazosin in ptsd
Prazosin in PTSD

- α -1 adrenergic antagonist

- Most lipophilic drug in its class (crosses the blood brain barrier)

- Previous indications for hypertension (also used off label for benign prostatic hypertrophy) (triple play)

- Murray Raskind et al. reported a series of studies into its impact on the re-experiencing of PTSD symptoms, particularly nightmares


- Begin at 1mg hs and increase by 1mg/week to 10mg to 12 mg hs in males; 3mg hs in females

- Side Effects: First dose syncope and possible priapism; lowers LDL

- Efficacious in war-related and civilian PTSD

- May also be uptitrated in the AM at < than the HS dose

  • Addressing hyperarousal/hyperadrenergic c/o

First line PTSD treatment in the 2011 Harvard Algorithm (

anxiety stories year 1
Anxiety Stories: Year 1

“I’ve been feeling more stressed because ________ happened last week. Can give me something for this?”

“I need a nerve pill.”

“Yeah, my anxiety is better on the medication (citalopram) but I sure wish you’d give me something for my nerves.” (Longing for the halcyon days).

anxiety stories year 2
Anxiety Stories: Year 2
  • “If you aren’t giving me Valium then I don’t want any of your other medications” (walks out of the office)
  • “I want to make a complaint about one of your doctors who’s committing malpractice”
  • “Cancel my appointment with that doctor…he’s useless”

Benzodiazepines, Other Anxiolytic Medications, and Meditations: Selected Topics in Anxiety Management

benzodiazepine literature
Benzodiazepine Literature
  • Dispersed across 50 years
  • Many questions are still unanswered including:

appropriate indications for and durations of therapy and short and long-term adverse effects

  • There are vast differences of opinion both within the US and between the US and other countries regarding these issues

Benzodiazepines, Other Anxiolytic Medications, and Meditations: Selected Topics in Anxiety Management


benzodiazepine prescribing patterns
Benzodiazepine Prescribing Patterns

From 1969 to 1982 diazepam was the most prescribed medication in America with 2.3 billion tablets sold in 1978Lader 2011

world health organization programme on substance abuse rational use of benzodiazepines 1996
World Health Organization Programme on Substance Abuse: Rational Use of Benzodiazepines 1996

“In all studies concerning prescription patterns of benzodiazepines, it is noted that scarce information is given on diagnosis and/or indications for benzodiazepine prescriptions on patient charts, in contrast to prescriptions of various other (non-psychotropic) drugs (Buchsbaum et al. 1986).”

“… it was found that initial benzodiazepine prescriptions were given in 35 and 38.5 per cent of cases respectively for other reasons than the recognized indications (van der Waals et al., 1993) (Zisselman et al., 1994).”

Writing controlled substances for non-FDA approved reasons


“One user in four uses the benzodiazepine for a year or longer.” Balter 1991

“Rates of use increase with age. Persons older than 65 years account for 27% of all benzodiazepine prescriptions and 38% of all benzodiazepine hypnotics.” IMS America 1991

APA Textbook of Psychopharmacology

Benzodiazepine studies were 2 months in duration

benzodiazepine effects
Benzodiazepine Effects
  • Hypnotic-sedative
  • Anxiolytic
  • Muscle relaxant
  • Anterograde amnesia
  • Antiseizure
benzodiazepine pharmacology
Benzodiazepine Pharmacology
  • Enhance GABA effects at the GABA-A receptor producing increased Cl- flux and inhibitory neurotransmission
  • Decrease SE and NE turnover (can generate depression)
  • Dependence involves dopaminergic systems
  • Endozapines are purported endogenous benzodiazepines
benzodiazepine pharmacodynamics
Benzodiazepine Pharmacodynamics ukAshton

benzodiazepine prescribing patterns1
Benzodiazepine Prescribing Patterns

Ranked 11th among all prescriptions in the USA, alprazolam is the #1 psychiatric drug

With 46.3 million in 2010, aprazolam prescriptions increased by 3 million/yr since 2006

IMS Health, National Prescription Audit, Dec 2010

tn top 10 most prescribed controlled substances 2010
TN Top 10 Most Prescribed Controlled Substances 2010

TN Top 10 Most Prescribed Controlled Substances 2010

1 Hydrocodone (Lortab, Vicodin) (TN is #2 in the US)

2 Alprazolam (Xanax) – steady for 3 years

3 Oxycodone (OxyContin, Roxicodone, generic)

4 Codeine

5 Clonazepam (Klonopin) – first year in the top ten

6 Zolpidem (Ambien)

7 Lorazepam (Ativan)

8 Diazepam (Valium)

9 Propoxyphene (Darvon, Darvocet)

10 Pregabalin (Lyrica) TN Drug Diversion Task Force

alprazolam the most difficult benzodiazepine to manage
Alprazolam: The Most Difficult Benzodiazepine to Manage?
  • Because of its short half-life, alprazolam is associated with behavioral reinforcement and interdose anxiety (“clock watching” )
  • These phenomena produce elevated anxiety and dose escalations

The Alprazolam to Clonazepam Switch Herman et al. 1987

problematic prescription
Problematic Prescription
    • Develop physiological tolerance while attempting to get control over anxiety
    • Later try taking as a prn
    • Withdrawal and anxiety which will be defined as anxiety or as “panic attacks”
    • Conditioned to rely upon Xanax (anecdote: crying spells with the mention of a minute dose reduction)
benzodiazepines revisited will we ever learn lader 12 2011 addiction
Benzodiazepines revisited—will we ever learn? Lader 12/2011 Addiction

With long term use there is:

Impaired performance on simple repetitive tasks for up to one year and for several years on tests of attention

Even after months or years the effects on episodic memory persist

Verbal memory is particularly affected

May take more than 6 months for the memory effects to completely resolve after stopping

benzodiazepines revisited will we ever learn lader 2011 addiction
Benzodiazepines revisited—will we ever learn? Lader 2011 Addiction


Increased risk of falls in the elderly

Increased risk of MVAs

Behavior problems- may cause paradoxical excitement in vulnerable groups including:

Borderline personality disorder

Impulse control diosrder

Ongoing alcohol disorders

benzodiazepine respiratory effects
Benzodiazepine Respiratory Effects

Sleep apnea: Inhibit respiratory response to CO2 and relax upper airway muscles

Can worsen sleep apnea or convert snoring into sleep apnea

Many authorities, including the FDA, consider benzodiazepines contraindicated in sleep apnea

benzodiazepines revisited will we ever learn lader 2011 addiction1
Benzodiazepines revisited—will we ever learn? Lader 2011 Addiction

“The niggling question of possible long term anatomical and biochemical changes in the brains of long-term users needs urgent attention to allay mounting concerns in view of the continuing extensive use of BZDs.”

maine benzodiazepine study group
Maine Benzodiazepine Study Group


“There is no evidence supporting the long term

use of BZDs for any mental health indication”

emergency department visits related to non medical use of agents dawn 2009
Emergency Department Visits Related to Non-Medical Use of Agents DAWN 2009

1,079,683 medications

Benzodiazepines 312,931

Alprazolam 112,552

Clonazepam 57,633

Diazepam 25,150

Lorazepam 36,582

mmwr july 8 2011 cdc
MMWR July 8, 2011 CDC
  • During 2003--2009, death rates increased for all substances except cocaine and heroin. The death rate for prescription drugs increased 84.2%, from 7.3 to 13.4 per 100,000 population. The greatest increase was observed in the death rate from oxycodone (264.6%), followed by alprazolam (233.8%) and methadone (79.2%). By 2009, the number of deaths involving prescription drugs was four times the number involving illicit drugs.
tennessee drug diversion task force
Tennessee Drug Diversion Task Force
  • Diverted Rx Drugs of Greatest Concern & Sources
  • “Hydrocodone(Lortab, Lorcet, Vicodin and generic equivalents), oxycodone(OxyContin, Roxicodone, and generic equivalents), and alprazolam (Xanax) are the top three most prescribed drugs and primarily are among the most commonly diverted and abused pharmaceuticals in the State of Tennessee. These three drugs prescribed and taken together form what is known to law enforcement as “the cocktail.”
tennessee prescription safety act of 2012
Tennessee Prescription Safety Act of 2012

TN Drug overdose deaths in Tennessee rose from 422 in 2001 to 1,059 in 2010

This bill, if approved, would require all prescribers and dispensers of schedule II, III, IV or V controlled substances to register in the PMP and check the database regularly

All new starts require a database review

Reviews could be conducted by licensed healthcare personnell and by one non-licensed person per practiceJ. Dreyzehner MD

TN Commissioner of Health

Prescription Substance Abuse Conference, ETSU, 2012

addiction and diversion purposes
Addiction and Diversion: Purposes
  • Addicted
  • Use with other illicit drugs to intensify the intoxicating effects, eg., benzodiazepine + methadone
  • Profit
  • To manage withdrawal symptoms associated with addictions to other drug classes
tennessee drug diversion task force value of prescription medications on the street
Tennessee Drug Diversion Task Force – Value of Prescription Medications on the Street

Diazepam (Valium)

5mg $3.00 - $5.00 10mg $4.00 - $5.00

Alprazolam (Xanax) 1mg $2.00 - $4.00 (#120 1mg= $480.00)2mg $4.00 - $8.00

warning signs of benzodiazepine misuse diversion
Warning Signs of Benzodiazepine Misuse/Diversion
  • Early refills, lost medications, patient initiated dose escalations
  • Increasing anxiety
  • Other addictions or misuses of substances, eg., previous alcohol addiction is a relative contraindication
benzodiazepine taper in tolerance
Benzodiazepine Taper in Tolerance
  • Cochrane review recommends 10 week taper Dennis et al 2006
  • APA Textbook of Psychopharmacology

Taper clonazepam and alprazolam no faster than 0.5mg every 2-3 weeks

May go even slower in complicated cases with a seizure history

the alprazolam to clonazepam switch herman et al 1997
The Alprazolam to Clonazepam Switch Herman et al. 1997
  • Provide clonazepam BID at a TDD at ½ of the of the alprazolam TDD (or at the same dose)
  • Inform patients it takes up to 7 days to make the cross-over
  • Throughout the 7 days the patient may take their previous prescription of alprazolam
  • Generally, during the 1-3 days they may need to continue the previous alprazolam prescription
  • Thereafter, they can take the alprazolam less frequently or take ½ of a pill
  • Should be off of the alprazolam at the end of 7 days

Individualize depending upon the patient’s medical status, compliance history, and the provider’s availability

benzodiazepine prescribing summary
  • Data support short term (up to 4-6 weeks) use for acute anxiety and when awaiting the onset of a the first-line agent (SSRI) in the treatment of a primary anxiety disorder
  • Select groups may require maintenance. This requires careful documentation with a risk-benefit analysis and consent, particularly in the elderly or medically infirm
benzodiazepine prescribing
Benzodiazepine Prescribing
  • Urine drug screens and random pill counts, or the absence of them, should be accounted for in the chart
  • Warning signs of diversion or other forms of misuse require documentation
  • They are contraindicated in any active substance use disorder and relatively contraindicated with any history of substance use disorders, especially in the case of alcohol addiction
clinician s guide to medications for ptsd www ptsd va gov
Clinician’s Guide to Medications for PTSD

There is concern that benzodiazepines cause

“difficulty integrating the traumatic experience, preventing optimal arousal in prolonged exposure therapy, …”

They may decrease the effectiveness of exposure therapies in other anxiety disorders.

SSRIs/SNRIs/buspirone/prazosin are not thought to cause such problems.

the anxiety continuum
The Anxiety Continuum
  • Overwhelming anxiety which blocks adaptation is pathological
  • However, optimal anxiety levels promote adaptation
  • When we venture into treating anxiety, we must be certain that our interventions are promoting adaptation and not hindering it
  • In this way of thinking, treating chronic anxiety with benzodiazepines is not unlike using opioids for chronic pain. Under these circumstances, we must base interventions on measurable changes in functioning and not on subjective reports
to justify any anxiety disorder intervention there must be
To justify any anxiety disorder intervention, there must be

Significant improvement in social or occupational (academic) functioning





The act of utilizing attention to guide changes in brain structure and function

meditation benefits
Meditation Benefits


Blood pressure





meditation benefits1
Meditation Benefits
  • Increases attention (the pathway to enhanced memory and intelligence)
  • Bolsters self-efficacy
  • Generates neuroplastic changes in the brain

Study Practice Meditators/Controls Brain regions greater in meditators

Lazar et al. Insight 20/15 Right anterior insula and right 2005 middle and superior frontal sulci

Pagnoni and Zen 13/13 Meditators showed no age-related

Cekic decline in the left putamen compared

2007 to actives

Hölzel et al. Insight 20/20 Left inferior temporal lobe, right 2008 insula, and right hippocampus

Vestergaard- Tibetan 10/10 Medulla oblongata, left superior and

Poulsen et al. inferior frontal gyri, anterior lobe

2009 the cerebellum and left fusiformgyrus

Luders et al. Multiple 22/22 Right orbito-frontal cortex, right

2009 thalamus, left inferior temporal lobe, right hippocampus

Grant et al. Zen 19/20 Right dorsal anterior, cingulate cortex, 2010 secondary somatosensory cortex

Holzel et al. Insight 16/17 left hippocampus, posterior cingulate, 2011 cortex, temporo-parietal junction, cerebellum

Gray Matter Increases Associated with Meditation

Adapted from Holzel et al. 2011

anxiety modulation neuroplasticity and meditation
Anxiety Modulation, Neuroplasticity, and Meditation



drives autonomic and emotional responses

HIPPOCAMPUS evaluates threat contexts (safe/unsafe)


Regulates limbic responses of amygdala and hippocampus


Diagram from Bisson 2007 BMJ Content created by Karleyton Evans, MD.

Adapted from Rauch, et al. CNS Spectrums. 1998;3(suppl 2):30-34.

concentration mindfulness meditation
Concentration/Mindfulness Meditation
  • Sit in a quiet area for 20 minutes or more
  • Direct your mind to an object of focus such as your breath, thinking “In” as you breathe in and “Out” as you breathe out
  • When your mind drifts away as it inevitably will, gently direct it back