Judicious Use of Benzodiazepines

Michael P. Sionzon, MD, DPBP

Department of Psychiatry and Behavioral Medicine,
Philippine General Hospital

Philippine College of Physicians

SMX Convention Center
May 5, 2013
 Disclosures
• Part-time consultant for Janssen
• Received honoraria for lectures from Janssen
and Medichem
SLEEPL
ESS
IN
SINGALON
 Case of RV
RV, 38 year old, married, female

1 year PTC

• Felt dizzy and lightheaded during a dental procedure

• Dentist took her BP and discovered that she had
hypertension
• Dental procedure was deferred and she was advised to
seek treatment for her HPN
• Beginning that night, she started to have difficulty
sleeping, occasionally waking up after only 2-3 hours of
sleep
Sought consult with a GP and anti-
hypertensive medications were given
• BP control was generally controlled but still with
occasional hypertensive spikes
• Insomnia became more frequent
• Initially prescribed with diphenhydramine, then
hydroxyzine but with no relief from insomnia

Consulted an internist

• BP meds were changed and prescribed with diazepam

BP was controlled and insomnia was
relieved by diazepam
• Would always request for a prescription of diazepam
during each consult
• A referral to a psychiatrist was suggested because of
concerns of dependence
• Prompted the patient to change doctors
• Subsequent doctors that she consulted gave the same
suggestions of a psychiatric referral
• One year and 3 doctors later, RV agreed to be referred
to a psychiatrist
 Objectives
• To discuss the rational use of benzodiazepines
as hypnotics and anxiolytics
• To present a suggested clinical approach to
the effective use of benzodiazepine for sleep
problems
 General Properties of Benzodiazepines

5 major actions

●
Hypnotic
●
Anxiolytic
●
Anticonvulsant
●
Muscle relaxant
●
Amnesic

Ashton H. Drugs 1994; 48(1): 25-40.

 General Properties of Benzodiazepines

5 major actions

●
Hypnotic
●
Anxiolytic
●
Anticonvulsant
●
Muscle relaxant
●
Amnesic

Ashton H. Drugs 1994; 48(1): 25-40.

Mechanism of Action

Benzodiazepines
enhance the
inhibitory effect
of GABA
 Neuromodulation

Antidepressants
Antipsychotics
Antihistamines

Pregabalin Monoamines can

Monoamine NT
(Dec. gluamate) modulate effects
(Dopamine, Benzodiazepine
of Glutamate
Serotonin, (Inc. GABA)
/GABA
Histamine, etc) =
Modulatory
Glutamate =
GABA =
Excitatory
Inhibitory

11
Stahl, Essential Psychopharmacology 2 nd ed.
 Pharmacokinetics of Benzodiazepines
Elimination Half- Asorption
Classification Drug Name Brand life [active Rate Effective
Name metabolite] (hours) Dose
Short-acting Midazolam Dormicum 2 hours Most rapid 7.5 mg
Alprazolam Xanor 6-12 hours Int 0.5 mg
Bromazepam Lexotan 10-20 hours Rapid 5-6 mg
Intermediate- Clobazepam Frisium 12-60 hours Slow 5-20 mg
acting
Clonazepam Rivotril 18-50 hours Int 0.5 mg
Estazolam Esilgan 10-24 hours Int 1-2 mg
Clorazepate Tranxene [36-100 hours] Rapid 15 mg
Diazepam Valium 20-100 Rapid 10 mg
[36-200] hours
Long-acting
Chlordiazepoxide Librium 5-30 Int 25 mg
[36-200] hours
Flurazepam Dalmane [40-250 hours] Rapid 15-30 mg

Rapid: < 1 hour

Int: 1-2 hours Greenblatt DJ et al. Br J Clin Pharmac 1981; 11(Suppl 1):11S-16S.
Slow: > 3 hours Labelle A et al. Can Fam Physician 1993; 39: 2205-8; 2211-3
 The Pros and Cons

Disadvantag
Advantage e
●
High efficacy
●
Rapid onset of
●
Dependence
●
Results from long-term use
action ●
Usually results from its use as
hypnotic and anxiolytic
●
Low toxicity

Ashton H. Drugs 1994; 48(1): 25-40.

RATIONAL USE OF BENZODIAZEPINE
IN INSOMNIA
 Use in Insomnia
“Only when it is severe, Prescribing levels for
disabling or subjecting its use as a hypnotic
the individual to has remained constant
extreme distress” through the years

Ashton H. Drugs 1994; 48(1): 25-40.

 Types of Insomnia

Course Pattern Cause

●
Transient ●

●
Difficulty falling asleep
Frequent nocturnal
●

●
Physical (pain)
Physiological (jet lag)

Short- Psychological (stressful

●
● arousals
life event)
●
Early morning ●
Psychiatric (anxiety or
term ●
awakenings
General dissatisfaction ●
depression)
Pharmacologic
●
Chronic with quality of sleep (caffeine)

Ashton H. Drugs 1994; 48(1): 25-40.

 Efficacy of Benzodiazepines as Hypnotics

Improvement in Sleep Parameters

●
Hasten sleep onset
●
Decrease nocturnal awakening
●
Increase total sleep time
●
Impart a sense of deep, refreshing sleep

Different quality of sleep vs. natural sleep

●
Light sleep (stage 2) is prolonged
●
"Parang hindi natural ang tulog"
●
"Tulog pero gising pa rin ang diwa"

Ashton H. Drugs 1994; 48(1): 25-40.

 Disadvantages of Benzodiazepines as
Hypnotics Rebound Insomnia
Sleep is poorer than before
Tolerance treatment
treatment after
after withdrawal,
withdrawal, esp.
esp.
after
after regular
Sleep problems return regular long-term
long-term use
use
More likely with
with rapidly
to pre-treatment More
levelslikely agents
eliminated
eliminated agents
rapidly

after a few weeks

Need to increase dose
Depende
nce

Residual / Hangover effects

• Impairment of Respiratory Depression
• Decreased ventilatory
psychomotor
performance and response to
memory the next day hypercapnea
• More likely with slowly • Avoided in COPD
eliminated agents used
over the long-term
Ashton H. Drugs 1994; 48(1): 25-40.
Choice of Benzodiazepine Hypnotic

Rapid onset with medium duration of effect

●
Rapidly eliminated BDZ have higher risk of dependence
●
Long half-life BDZ carries risk of residual effects; may pose a danger in driving / machine operation

Special populations

●
Elderly: use shorter acting BDZ because decreased metabolism can lead to drug accumulation
●
Medically ill: may cause respiratory depression
●
Terminally ill: dependence becomes less of an issue
 Pharmacokinetics of Benzodiazepines
Elimination Half- Asorption
Classification Drug Name Brand life [active Rate Effective
Name metabolite] (hours) Dose
Short-acting Midazolam Dormicum 2 hours Most rapid 7.5 mg
Alprazolam Xanor 6-12 hours Int 0.5 mg
Bromazepam Lexotan 10-20 hours Rapid 5-6 mg
Intermediate- Clobazepam Frisium 12-60 hours Slow 5-20 mg
acting
Clonazepam Rivotril 18-50 hours Int 0.5 mg
Estazolam Esilgan 10-24 hours Int 1-2 mg
Clorazepate Tranxene [36-100 hours] Rapid 15 mg
Diazepam Valium 20-100 Rapid 10 mg
[36-200] hours
Long-acting
Chlordiazepoxide Librium 5-30 Int 25 mg
[36-200] hours
Flurazepam Dalmane [40-250 hours] Rapid 15-30 mg

Rapid: < 1 hour

Int: 1-2 hours Greenblatt DJ et al. Br J Clin Pharmac 1981; 11(Suppl 1):11S-16S.
Slow: > 3 hours Labelle A et al. Can Fam Physician 1993; 39: 2205-8; 2211-3
 Sleep Hygiene
• Sleep when sleepy
• Get up & try again
• Avoid caffeine & nicotine
• Avoid alcohol
• Bed is for sleeping (and sex) only
• No naps
• Sleep rituals
• Bath time
• No clock watching
• Exercise
• Eat right
• Right space
• Keep daytime routine the same
RATIONAL USE OF
BENZODIAZEPINES IN ANXIETY
Historical Development of Anxiolytic Drugs

Nash J and Nutt D. Psychiatry 2007; 6(4): 143-148.

 Use in Anxiety
"Indicated for the short-
term relief of anxeity that Prescribing levels for
is severe, disabling or use as anxiolytics
causing unacceptable have decreased
distress"

Ashton H. Drugs 1994; 48(1): 25-40.

 Situations with Anxiety
Acute stress reactions in predictable situations

●
Air travel and dental appointments in phobic patients

Stress reactions after catastrophic events

●
Natural disasters and accidents
●
Bereavement

Anxiety disorders
●
Generalized Anxiety Disorder
●
Panic Disorder
●
Post-traumatic stress disorder
Ashton H. Drugs 1994; 48(1): 25-40.
 Efficacy of Benzodiazepines as Anxiolytics

Potent anxiolytics

●
Patients with anxiety disorders
●
Otherwise health patients undergoing stress

Should be combined with other treatments

●
Antidepressants
●
Psychotherapy

Ashton H. Drugs 1994; 48(1): 25-40.

Onset of Effect of Drugs for Anxiety

Combination
Antidepressant and BDZ

Nash J and Nutt D. Psychiatry 2007; 6(4): 143-148.

 Disadvantages of Benzodiazepines as
Anxiolytics
Dependence
Tolerance Contributing factors
Develops more Regular continuous
slowly than use at high doses
tolerance to Dependent
personality
hypnotic effect characteristics
Little evidence that Previous drug
they retain their dependence
efficacy after 4 35% of patients taking BDZ
for more than 4 weeks
months develop dependence

Affective reactions
• May aggravate depression Psychomotor impairment
• Increased suicidal tendency • Risk of traffic accident
• "Emotional anesthesia"
• Euphoria - may lead to
substance abuse
Ashton H. Drugs 1994; 48(1): 25-40.
 Choice of Benzodiazepine

Diazepam is benzodiazepine of choice

●
Rapid onset
●
Slow elimination protects plasma level concentration fluctuations
●
Minimizes withdrawal symptoms
●
Lesser risk for dependence

Ashton H. Drugs 1994; 48(1): 25-40.

 Bottomline

Mostly due to
Dependence
missed
Most
is usually
Benzodiazepi diagnosis of
reservations
associated
nes are anxiety and
revolvewith
effective and depression in
around
prolonged
safe patients with
dependence
use at higher
sleep
doses
problems

How do we prevent this?

 Correlation between Insomnia and Anxiety
and Depression

Reporting insomnia symptoms significantly increased the associations

with a range of conditions, especially mental conditions
OR for insomnia stratified by means
of different condition

Sivertsen B, et al., J Psychosom Res. 2009 Aug;67(2):109-116.

 Screening for Anxiety and Depression:
Hospital Anxiety and Depression Scale (HADS)

Anxiety
Depression

Grading:
0 – 7 = Non-case
8 – 10 = Borderline case
11+ = Case
Suggested Algorithm for Treatment of
Insomnia (1)
Benzodiazepine

Determine

Transient or Short-term Chronic

Suggested Algorithm for Treatment of
Insomnia (2)

HADS Benzodiazepine

No Anxiety or Depression With Anxiety or Depression

 Summary
• Benzodiazepines are effective and safe
hypnotics and anxiolytics
• Risk of dependence can be decreased by:
– Education (sleep hygiene)
– Using lowest possible dose for shortest possible
time; intermittent if possible
– Screening for anxiety and depression
– Combination therapy with antidepressants and
psychotherapy
THANK YOU FOR YOUR ATTENTION.