Transcript Power Point - New Mexico Pharmacists Association

Benzodiazepines Overuse
Steve Jenkusky, MD
January 29, 2017
Pharmacist Objectives
Participants will review the pharmacology of
benzodiazepines and be able to identify how various
benzodiazepines differ.
Participants will review how benzodiazepines are used
clinically, including risks and benefits.
Participants will learn the patterns of use of
benzodiazepines.
Participants will develop an understanding of the risks
around prescribing benzodiazepines and opioids,
including recent and relevant recommendations from the
CDC around pain management.
Technician Objectives
Participants will review the mechanism of action of
the benzodiazepine class and understand
difference between drugs in this class.
Participants will review how and when
benzodiazepines are used in specific disease states.
Participants will learn the patterns of use of
benzodiazepines.
Participants will develop an understanding of the
risks and benefits of benzodiazepines.
A Bit of History
Prior to discovery of benzodiazepines, included
alcohol, opium derivatives, paraldehyde, chloral
hydrate, bromides and especially, barbiturates. All had
limited effectiveness and high lethality.
In 1950, meprobamate (Miltown) was discovered with the hope that it might
be a safer alternative, but it was found not to be an anxiolytic, but caused
sedation, tolerance, abuse and still could be highly lethal. The first
benzodiazepine, chlordiazepoxide (Librium) was discovered in 1955, shortly
followed by the development of diazepam (Valium). Benzodiazepines were
found to not only be effective as anxiolytics, but were significantly safer than
barbiturates and meprobamate.
A Bit More History
Once hitting the market,
benzodiazepines became the
most widely prescribed drugs in
the world, and became known in
the press as “happy pills”, and as
“mother’s little helper” by the
Rolling Stones.
In the 1980’s it was recommended
that BZD’s be considered controlled
substances, and the “triplicate
prescription program” in New York
State was started.
Heavily marketed in the
1970’s, but then the risk of
dependence, abuse and
withdrawal syndromes
became evident.
After a period of controversy in the
US and Great Britain, the rational use
of BZD’s seemed to begin in the
1990’s, although controversy never
fully abated, and, now we find BZD’s
playing a role in the opioid epidemic
(see new black box warning).
Lopez-Munoz et al 2011
Benzodiazepines: Mechanism of Action
BZDs act at the level of the limbic, thalamic and
hypothalamic regions of the CNS, although there
are BZD receptors throughout the CNS.
• BZDs act by enhancing the actions of GABA, the brain’s primary inhibitory
neurotransmitter, at the GABA-BZD receptor complex.
• There are two BZD receptor subtypes on the GABA-A receptor that mediate
either sedation/sleep (type 1) or muscle relaxation, anticonvulsant activity, motor
coordination and memory (type 2).
• Essentially, BZDs have sedative, anti-anxiety, anticonvulsant and muscle relaxant
properties
Clinical Pharmacology 2017c
Currently Available Benzodiazepines
Anxiolytics
Hypnotics
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•
•
•
•
•
•
•
•
Alprazolam (Xanax)
Chlordiazepoxide (Librium)
Clonazepam (Klonopin)
Clorazepate (Tranxene)
Diazepam (Valium)
Lorazepam (Ativan)
Oxazepam (Serax)
Estazolam (ProSom)
Flurazepam (Dalmane)
Midazolam (Versed)*
Temazepam (Restoril)
Triazolam (Halcion)
Clinical Pharmacology 2017c
How to Tell One BZD From Another?
Why so many forms when all
BZDs do essentially the same
thing in the brain,
i.e., enhance GABA
transmission?
Pharmacokinetics
BZDs are differentiated by their
pharmacokinetic profiles, based on
lipophilicity and metabolism:
• Half-life (short, intermediate, slow)
• Onset-of-action (rapid, intermediate, slow)
• Metabolic pathways (with or without active
metabolites, with or without P450 involvement)
Clinical Pharmacology 2017
Pharmacokinetics
LONGER
ACTING
• Chlordiazepoxide
(Librium)
• Diazepam
(Valium)
• Clonazepam
(Klonopin)
MEDIUM
ACTING
• Lorazepam
(Ativan)
• Oxazepam
(Serax)
• Temazepam
(Restoril)
SHORT
ACTING
• Alprazolam
(Xanax)
• Triazolam
(Halcion)
• Midazolam
(Versed)
Pharmacokinetics
• Longer the half-life: more hang-over and
delayed/attenuated withdrawal (Clonazepam)
• Shorter half-life: greater withdrawal with interdose
rebound (Alprazolam)
• Hepatic impairment and elderly: shorter half-life,
3-hydroxy forms safer (Lorazepam, Oxazepam and
Temazepam)
• More lipophilic: rapid onset, produce euphoria,
wears off quickly (Alprazolam)
• Less lipophilic: slower onset, longer lasting, less
euphoric (Clonazepam)
• Diazepam is lipophilic but long half-life, so quick
onset, short acting in single dose, but will provide
steady state coverage with chronic, multiple dosing.
Clinical Pharmacology 2017
Benzodiazepines Are Used for:
Generalized anxiety disorder
(and generic anxiety)
Alcohol withdrawal
Muscle spasms, restless legs
Panic disorder
Seizures/epilepsy
Social phobia
Insomnia (“hypnotics”)
Catatonia
Sedation (procedures)
Akathisia
Manic agitation
Schatzberg AF, DeBattist, C 2015
Drug Interactions
Potentiates sedative effects of narcotics and alcohol, some P450
inhibitors could increase levels of BZDs metabolized by that system
(e.g., CYP3A4 inhibitors and alprazolam).
BZDs alone are generally safe in overdose, but
combined with other CNS depressants, will cause
death.
Clinical Pharmacology 2017
Side Effects
X
X
Tolerance to sedation occurs in 5-10 days, while
anxiolytic effects can continue indefinitely.
Physical dependence occurs more quickly if used well
above normal dose, but also can occur over months
with normal dosing.
Additional Side Effects:
• Memory impairment: anterograde amnesia with
shorter acting, higher doses, IV use (e.g.,
midazolam)
• Cognitive impairment with long-term usecontroversial: study showing 50% increase of
dementia!*
Baldwin et al 2013 | *Billot de Gage et al 2012 | **Markota 2016
• Sedation and psychomotor impairment: risk of
falls, motor vehicle accidents, fractures
• “Beers Criteria for Potentially Inappropriate
Medication Use in Older Adults” includes BZDs
due to risks of mental decline, delirium, falls,
fractures and car accidents in older adults**
Abuse and Withdrawal
If discontinued
suddenly:
• Psychological risk increased with
fast onset, short-acting or prn use
(e.g., alprazolam)
• Risk of abuse is relatively low
except in those prone to
substance use disorders and (I
believe) borderline personality
disorder
• Rebound anxiety and insomnia
can occur even with appropriate
use when discontinued
•
•
•
•
•
•
•
•
Hyperpyrexia
Seizures
Cognitive impairment
Hypertension
Muscle cramps
Anxiety, panic attacks
Insomnia
Perceptual disturbances
(hallucinations,
derealization)
• Death
Bisaga and Mariani 2015
A Very Simplified Approach
to the Assessment and Treatment of
Anxiety (and where BZDs fit in)
Anxiety
Acute onset
Chronic
Panic Attacks
Short-term BZDs
Buspirone or
SSRI/Effexor
SSRI
First Line Treatment of Anxiety Disorders
• Panic Disorder – SSRI/BZD,
exposure therapy
• Agoraphobia – exposure therapy
• Specific Phobia – exposure
therapy
• Social Phobia – exposure/CBT
therapy, SSRI/beta blockers
• Obsessive-Compulsive
Disorder – SSRI’s
• Posttraumatic Stress Disorder
(PTSD) – SSRIs/ CBT, exposure
therapy
• Acute Stress Disorder – supportive
therapy
• Generalized Anxiety Disorder
(GAD) – SSRIs/Effexor/Buspar,
psychotherapy
• Anxiety Disorder Due to Medical
Condition – optimal treatment of
medical condition
• Substance-induced Anxiety
Disorder – substance abuse
treatment
Schatzberg AF, DeBattist, C 2015
BZD Overuse and Consequences
Excessive and/or inappropriate prescribing?
Substance abuse?
Polysubstance abuse?
Polypharmacy?
Resulting in what seems to be a contribution
to ED utilization and death rates
Top US Psychiatric Prescriptions for 2013
1
Alprazolam: 48,465,000
7
Escitalopram: 24,920,000
2
Sertraline: 41,416,000
8
Duloxetine: 18,573,000
3
Citalopram: 39,445,000
9
Bupropion XL: 16,053,000
4
Fluoxetine: 28,258,000
10
Venlafaxine ER: 15,796,000
5
Lorazepam: 27,920,000
11
Diazepam: 14,335,000
6
Trazodone: 26,242,000
Grohol 2016
BZD Overuse and Consequences
Between 1996 and 2013, the
percentage of adults
receiving BZD prescriptions
increased from 4.1% to 5.6%.
Lorazepam equivalents went
from 1.1 kg/100,000 adults
to 3.6 kg/100,000 adults.
Annual increase of 2.5% in
prescriptions but a 9%/yr
increase in quantity.
Overall death rate
increased from
0.58/100,000 to
3.07/100,000.
Bachhuber et al, 2016
Emergency Department Visits
From 2005 to 2011, over 940,000 ED visits
involved BZDs, with visits increasing from
nearly 90,000 in 2005 to over 175,000 in
2011 (an increase of 94%).
BZDs
Alone
BZDs +
Opioids
BZDs +
Alcohol
BZDs +
Opioids +
Alcohol
2005
46,966
22,682
16,473
3,727
2011
89,310
50,561
27,452
8,229
SAMHSA, DAWN Report, 12/18/2014
ED Visits: Risk of Serious Outcomes
12-34 yo
35-44 yo
45-64 yo
65+
BZD alone
28%
30%
37%
39%
BZD + opioids
37%
43%
47%
59%
BZD + alcohol
35%
43%
51%
55%
BZD + opioids
+ alcohol
39%
47%
57%
70%
SAMHSA, DAWN Report, 12/18/2014
ED Visits: Risk of Serious Outcomes
SUMMARY:
Combining benzodiazepines
with opioids or alcohol
significantly increases the
risks of a serious outcome.
The number of patients
prescribed BZDs (as well as
opioids) have been
increasing.
Not all visits involving BZDs are
the result of prescribing practices.
Non-prescribed use or use of
amounts beyond what is
prescribed can be due to patient
efforts to control symptoms or for
“enjoyment,” including to
enhance the high from opioids.*
*Jones et al 2012
Benzodiazepine Use by Age
18-35:
2.6%
36-50:
5.4%
51-64:
7.4%
65-89:
8.7%
Female:Male ratio:
2:1
Lower % when managed by psychiatrists
Olfson M and King M 2015
Study of 300 Unintentional
Drug Deaths in NM, 2006-2008
INCREASE RISK OF DEATH
(adjusted odds ratio):
Male sex: 2.4
Buprenorphine Rx: 9.5
One or more sedatives: 3.0
Fentanyl: 3.5
Increased age: 1.3
Hydromorphone: 3.3
# of prescriptions:
1.1 for each added Rx
Methadone: 4.9
Oxycodone: 1.9
>40 MME: 12.2
Paulozzi LJ et al 2012
Study of 300 Unintentional
Drug Deaths in NM, 2006-2008
“
Having at least one prescription for a
sedative/hypnotic was a stronger risk factor than
having an opioid prescription. Overlapping opioid
or sedative/hypnotic prescriptions were strongly
associated with risk.
”
During the study period, 44% of New Mexicans over 10 years
of age filled a prescription for a controlled substance.
Paulozzi LJ et al 2012
Primary Benzodiazepine Abuse
A relatively small number of
individuals show problematic
use of BZDs
Perhaps 1% of the population
with non-medical use
In 2012, 478,000 with
sedative SUD (> heroin or
methamphetamine)
Risk factors for sedative SUD include:
• Participation in SUD self-help
groups
• Younger age
• Longer duration of BZD use
• Higher dosages
• Lower level of education
• Non-native cultural origin
• Outpatient treatment of SUD.
Bisaga and Mariani 2015
Primary Benzodiazepine Abuse
Having another BH disorder increases risk:
50% have another psychiatric disorder.
BZD abuse is a common secondary drug of abuse in
individual with opioid or alcohol SUDs.
40-50% of those in methadone or buprenorphine
treatment will test positive for BZDs.
BZDs may enhance an opioid high, are used when
withdrawing, can cause a high used alone, or may be
used to “self-medicate” a comorbid psychiatric
disorder, so the causes of misuse can be complicated.
Bisaga and Mariani 2015
FDA Requires Black Box Warning
for Benzodiazepines - 2016
“
Concomitant benzodiazepine use with opioids may
result in profound sedation, respiratory depression,
coma, and death: reserve concomitant use for patients
with inadequate alternative treatment options:
limit to minimum required dosage and duration; monitor patients for
signs and symptoms of respiratory depression and sedation.
”
CDC Guidelines for Opioid Use 2016
Give preference to
nonpharmacologic therapy and
nonopioid therapy for chronic pain.
Establish realistic goals for
treatment of pain and improvement
of functioning.
Opioid risks and benefits, provider
and patient responsibilities should
be discussed.
Initial treatment should be with
immediate-release opioids.
Lowest effective doses should be
used, extra care if prescribing > 50
MME/day, and avoiding using
>90MME/day.
For acute pain, use the lowest dose
and shortest duration of opioids.
CDC Guidelines for Opioid Use 2016
For chronic pain, opioid usage
should be regularly evaluated for
effectiveness.
Evaluate risk factors and use
strategies to reduce risk (e.g., offer
naloxone).
Prescription monitoring programs
should be regularly utilized.
Urine drug testing should be used.
Prescribing the combination of
opioid pain medication and
benzodiazepines should be avoided.
Substance abuse treatment
(including MATs) should be
offered for patients with
opioid use disorder.
Summary
BZDs are useful treatment for a variety of
illnesses, but may be over prescribed
BZDs generally are considered safe when not
combined with other sedatives, but there are
worrisome side effects especially with long-term
use and in the elderly
BZDs misuse mostly a risk for patients with SUDs
BZDs appear to significantly increase mortality
when combined with opiates
References
López-Muñoz F, Alamo C, García-García P. J Anxiety Disord. 2011 The discovery
of chlordiazepoxide and the clinical introduction of benzodiazepines: half a
century of anxiolytic drugs. May;25(4):554-62.
Clinical Pharmacology (https://www-clinicalkeycom.libproxy.unm.edu/pharmacology/resources/overviews?id=1216715)
Schatzberg, Alan F., DeBattista, Charles. 2015. Manual of clinical
psychopharmacology. Eighth edition. American Psychiatric Publishing.
Baldwin DS et al 2013. Benzodiazepine: Risks and benefits. A reconsideration. J
of Psychophamacology. 27(11)967-971.
Billioti de Gage S et al 2012. Benzodiazepine use and risk of dementia:
prospective population based study. BMJ 345:e6231
References
Markota M et al 2016. Benzodiazepine use in older adults: dangers, management,
and alternative therapies. Mayo Clin Proc 91(11):1632-1639
Bisaga A, Mariani JJ 2015. Chapter 17: Benzodiazepines and other sedatives and
hypnotics IN The APP Textbook of Substance Abuse Treatment. Galanter M, Kleber
HD, KT Brady, eds. American Psychiatric Publishing.. Citing the National
Prescription Audit.
Bachhuber MA et al 2016. Increasing benzodiazepine prescriptions and overdose
mortality in the United States, 1996-2013. AJPH 106:686-688.
SAMHSA, Center for Behavioral Health Statistics and Quality. (December 18, 2014)
The DAWN Report: benzodiazepines in combination with opioid pain relievers or
alcohol: greater risk of more serious ED visit outcomes. Rockville, MD.
References
Jones JD et al 2012. Polydrug abuse: a review of opioid and benzodiazepine
combination use. Drug and Alcohol Dependence 125(2012)8-18.
Olfson M, King M, Schoenbaum M. 2015. Benzodiazepine Use in the United States.
JAMA Psychiatry. 72(2):136-142.
Leonard J. Paulozzi et al. 2012. A History of Being Prescribed Controlled Substances
and Risk of Drug Overdose Death. Pain Medicine 13:87-95.
Centers for Disease Control and Prevention 2016. Guideline for prescribing opioids
for chronic pain. J Pain & Palliative Care Pharmacotherapy 30(2)138-140.