Transcript dupont_bz_kolodner_memorial_final

Benzodiazepines and Addiction: New
Thinking About Old Drugs
Robert L. DuPont, MD
President, Institute for Behavior and Health, Inc.
www.ibhinc.org
Kolodner Memorial Lecture: October 20, 2016
Learning Objectives
1.
2.
3.
4.
Separate physiological dependence from
addiction in benzodiazepine use
Distinguish typical patterns of benzodiazepine use
by anxious patients with and without substance use
disorders
Relate benzodiazepine use, with and without
prescriptions, to addiction treatment
Identify practical strategies for benzodiazepine
discontinuation
Introduction to Benzodiazepines
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Benzodiazepines (BZs) are the most frequently cited cointoxicants involved in opioid-related morbidity and
mortality
In 2010, the CDC reported 16,651 pharmaceutical
opioid-related overdose deaths based on death
certificate data – almost one of every three opioidrelated deaths in 2010 also involved BZs
In 2010, hospital emergency departments in the US
treated an estimated 345,691 patients for BZ
misuse/abuse
(Hwang, et al., 2016; Jones, Mack & Paulozzi, 2013; DEA 2013)
Estimated number of emergency department (ED) visits involving
benzodiazepines alone or in combination with opioids or alcohol, by
year (patients aged 12 and older): 2005 to 2011
(SAMHSA, 2014)
A Flat Trend Line
Past Month Illicit Use of Pain Relievers and Tranquilizers, by Year, by
Percentage of Persons Aged 12 or Older, 2002-2014
2.5
Percent
2
1.9
2.1
2
1.8
2.1
1.9
2.1
1.9
2
1.9
1.7
1.7
1.6
1.5
1
0.8
0.8
0.7
0.7
0.7
0.7
0.7
0.8
0.9
0.7
0.8
0.6
0.7
0.5
0
2000
2002
2004
2006
2008
2010
2012
2014
2016
Year
Pain Relievers
Tranquilizers
(CBSHQ 2015a)
3.5
Trends in 30-day Prevalence of Use of Tranquilizers,
Percentage of Respondents, by Year
3.3
8th Grade
3.1
3
2.9
2.4
Percent
2.5
2.9
2.8
2.7
2.3
2.3
2.6
2.2
1.9
12th Grade
2.5
2.4
2
1.5
2.6
10th Grade
2.7
2
2.3
2.1
1.9
1.7
1.4
1.2
1.2
1.3
1.3
1.1
1.2
1.2
2
1.6
2.1
1.6
2
1.7
1.2
1
1
0.8
0.9
0.8
0.8
0.5
0
2000
2002
2004
2006
2008
2010
2012
2014
2016
Monitoring the Future is an ongoing study of the behaviors, attitudes, and values of school students and
young adults. Each year, a total of approximately 50,000 students in 8th, 10th and 12th grades are surveyed
for, among other things, use of pharmaceutical drugs “without a doctor telling you to use them.” Several illicit
drugs showed declines in use in 2015. There were declines in students‘ use of MDMA (ecstasy, Molly), heroin,
synthetic marijuana (“K2,” “Spice”) and amphetamines. In 2015, there were no statistically significant increases
for any of the more than 50 classes and subclasses of drugs, including tranquilizers, that MTF tracks.
(Johnston, et al., 2015)
National Private Sector Data

A large study of 3+ million physician-ordered
laboratory tests conducted in 2015 showed that 54%
showed drug misuse
 Of
those, 45% showed evidence of use of one or more
drug in addition to prescribed drugs – a dramatic
increase from 35% in 2014
 A critical finding because combinations of drugs, e.g.,
opioids and sedatives, can result in severe consequences

Drug use that is unknown to prescribing physicians
can have serious impact on patients
(Quest Diagnostics, 2016)
Treatment Admissions, Aged 12 and Older, by
Primary Substance of Abuse, 2003-2013
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
TEDS is maintained by
SAMHSA’s Center for
Behavioral Health Statistics
and Quality
Includes records for substance
abuse treatment admissions
reported by state-run
treatment facilities
In 2013, TEDS collected data
on 1.74 million admissions of
which benzodiazepines
accounted for 0.9% of all
admissions by primary
substance of abuse
25,000
20,000
Number of Admissions

15,000
10,000
5,000
0
2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013
Tranquilizers
Benzodiazepines
Other tranquilizers
(CBHSQ 2015b)
How Did We Get Here?
Before the BZs




Alcohol
Opium
Then in 1903 the barbiturates
Wonderful at first – then addiction and overdose
deaths
Hoffman-La Roche



A tweak and we had Librium – the BZ Grandfather
– in 1955, marketed in 1960
A tamed cat that did not stagger
Valium came in 1963 (when I graduated from
medical school)
Four BZ Effects
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

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Reduced anxiety/fear
Reduced insomnia
Reduced muscle spasm
Reduced seizures
From Hoffman-LaRoche: Valium, Dalmane and
Klonopin
A new era of psychopharmacology – most widely
prescribed drugs in the world
Trouble in BZ Paradise



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Like barbiturates before them, the BZ “miracle” had
serious costs
Addiction – “booze in a pill”
Concerns over long-term effects – falls in the elderly,
automobile crashes, cognitive impairment
More recently, overdose deaths – not alone but in
combination
BZs in My Two Medical Lives

Addiction medicine starting in 1968
 BZs
a common threat – an unwelcome descendent of the
barbiturates

Anxiety disorders starting in 1978
 BZs
a uniquely useful medicine – with few problems
Patients Tell Physicians Which Group
They Are In – Without Words

Addicted Patients:
 High
BZ doses that escalate over time
 Use BZs with alcohol and other drugs – not alone but to
“boost” effects of other drugs

Non-Addicted Anxious Patients:
 Low
and stable doses
 Don’t drink much and don’t use other drugs

It ain’t rocket science – usually
Addiction vs. Physical Dependence
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Addiction
 Continued
use despite often serious behavioral
problems
 Lying, dishonesty

Physical dependence
 Tolerance
to drug effects and reversal of effects on
abrupt discontinuation
 No behavioral problems and no dishonesty
How to Treat?

Treatment of addiction:
 Substance
abuse treatment and long-term recovery
support – sobriety date – It’s Hard!

Treatment of physical dependence:
 Gradual
dose reduction and management of the return
of the symptoms that were being treated (e.g., anxiety,
insomnia, etc.) – It’s Easy!
Comorbid for Anxiety and Addiction


Treat these dual diagnosis patients like addicts, not
like non-addicted anxiety patients
There are exceptions and some of them actually
work out, but many don’t
Treatment of Anxiety / Panic and
Insomnia – with Addiction


Not BZ deficiency disorders
Non-pharmacologic treatment of anxiety is much
harder than giving a prescription for a pill
Principles of Anxiety Treatment
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It helps to be empathic – anxiety symptoms including
panic are not fatal, but they are worse because they
rob you of the enjoyment of your life
Anxiety disorder is a disease of quality people – the
overactive conscience, excessive empathy and the “what
if” trap
“Acceptance” is the all-purpose anxiety antidote
Fearing the symptoms escalates and prolongs them
Anxiety/panic is distressing but not dangerous
Treating anxiety without pills is a clinical challenge
Treatment


Current pattern of treatment of anxiety-absent
addiction – often is both an SSRI and a BZ
Empathize with anxious ADDICTS who not only have
to give up social drinking but also the use of BZs
What’s New Now
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The role of the BZs in the opioid epidemic
While the BZs do not suppress respiration on their
own (except with COPD) they “boost” the lethality
of drugs that do suppress respiration including
opioids and alcohol
Commonly found in blood of overdose deaths which
are rarely opioids alone
New Safety Measures
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Food and Drug Administration (FDA) announced
class-wide changes to drug labeling
Boxed warnings about the serious risks associated
with combined use of opioid medications and BZs
New medication guides for ~400 products
Patients receiving both should discuss risks with their
prescribing physicians
Warning for Opioid Analgesics
Warning for Prescription Opioid Cough
Products
Warning for Benzodiazepines
Study of Veterans Who Received Opioid
Analgesics
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27% of veterans who received opioid analgesics also
received BZs
About half of deaths from drug overdose occurred
when veterans were concurrently prescribed BZs and
opioids
Risk of overdose death increased with history of BZ
prescription
Increased risk of death with increase in BZ dose
 Temazepam was associated with a decreased risk of death
from overdose compared to clonazepam

(Park, et al., 2015)
BZs in Methadone Treatment
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Study examined the relationship between intreatment illicit drug use and retention and dropout
of 604 MMT patients in Washington, DC
Those testing positive were three times more likely
to leave treatment than those who did not test
positive
Testing positive for one drug doubled the rate of
attrition; testing positive for multiple drugs
quadrupled the risk of attrition
(White, et al., 2015)
Some Puzzling Findings
Drug Test Result
Patients
Number
Percent
Dropping
Out
Odds Ratio
(95% CI)
p-value
Benzodiazepine – Not
Prescribed
38
16
42%
6.5
(3.2−13.5)
<.001
Benzodiazepine –
Prescribed
72
6
8%
0.8 (0.3−2.0)
0.83
(White, et al., 2015)
Prescribed vs. Non-Prescribed BZs
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Methadone patients who had their own
prescriptions for BZs did not dropout more than the
patients who did not use BZs
Those who had positive urines and did not have
their own prescriptions for those medicines had
much higher rates of dropout
 This
later group was younger and more male
(White, et al., 2015)
A Question
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
Why is it so common to have methadone and
buprenorphine patients who take BZs with and
without prescriptions and why do so few die of
overdose?
Two factors: tolerance and dose
Why?
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
When the two drugs are used in stable doses,
almost no matter how high apparently, overdoses
do not occur (tolerance)
But when they are used at higher doses, usually
much higher doses, than they had been used in the
prior week or two, death is all too common (dose)
Final Thoughts

Getting off BZs after chronic use
 Medically
easy – gradual dose reduction over several
weeks
 Clinically difficult – because of reversal of therapeutic
effects (e.g., insomnia and anxiety)
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With motivation – it can be done
Without motivation – not so much
CME Question 1

Which of the following is the most frequently cited
“co-intoxicant” in opioid overdose deaths?
A.
B.
C.
D.
Alcohol
Benzodiazepines
Cocaine
None of the above
CME Question 2

In about what percentage of all substance abuse
treatment admissions in 2013 was a
benzodiazepine the primary drug of abuse?
A.
B.
C.
D.
30%
20%
10%
1%
CME Question 3

Typical anxiety disorder patients without a history
of abuse of alcohol or drugs commonly show which
of these patterns of benzodiazepine use?
A.
B.
C.
D.
Gradual dose escalation to very high doses
Stable low doses over even very long periods of time
Drug-seeking behavior with multiple physicians
unknowingly prescribing benzodiazepines
Dishonesty about their use of alcohol and other drugs
CME Question 4

In a study of veterans prescribed opioid analgesics
what percent also received a benzodiazepine
prescription?
A.
B.
C.
D.
7%
17%
27%
57%
CME Question 5

In a methadone treatment program for opioid addicts,
what was the effect of benzodiazepine positive urine
drug tests on program retention compared to patients
not testing positive for benzodiazepines?
A.
B.
C.
D.
For those who did not have their own benzodiazepine
prescription there was no effect on retention
For those with their own benzodiazepine prescriptions
there was no effect on their retention
For both groups there was a marked reduction in retention
associated with benzodiazepine use
None of the above
Thank you!

Special thanks to John J. Coleman, PhD
References + Resources
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Center for Behavioral Health Statistics and Quality. (2015a). Behavioral health trends in the United States: Results from the
2014 National Survey on Drug Use and Health, (Table A1B); HHS Publication No. SMA 15-4927, NSDUH Series H-50. 2015.
Available: http://www.samhsa.gov/data/sites/default/files/NSDUH-FRR1-2014/NSDUH-FRR1-2014.pdf
Center for Behavioral Health Statistics and Quality. (2015b). Treatment Episode Data Set (TEDS): 2003-2013. National
Admissions to Substance Abuse Treatment Services. Rockville, MD: Substance Abuse and Mental Health Services
Administration, 2015. Available:
http://www.samhsa.gov/data/sites/default/files/2003_2013_TEDS_National/2003_2013_Treatment_Episode_Data_Set
_National.pdf
Centers for Disease Control and Prevention. (2016, January 1). Increases in drug and opioid overdose deaths – United
States, 2014. CDC Morbidity and Mortality Weekly Report, 64(50):1378-82. Available:
http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6450a3.htm?s_cid=mm6450a3_w
Drug Enforcement Administration, Office of Diversion Control. (2013, Jan). Fact Sheet: Benzodiazepines. Available:
http://www.deadiversion.usdoj.gov/drug_chem_info/benzo.pdf#search=benzodiazepine%20
DuPont, R.L., Greene, W.M., & DuPont, C.M. (in press). Sedatives/hypnotics and benzodiazepines. In A. Mack, R. Frances, K.
Brady (Eds.), Clinical Textbook of Addictive Disorders (4th ed.). New York, NY: Guilford.
DuPont, R. L., Greene, W. M. & Lydiard, R. B. (2007). Sedatives and hypnotics: Clinical use and abuse. In B. D. Rose (Ed.),
UpToDate. Waltham, MA: UpToDate.
DuPont, R. L. & Gold, M.S. (1995). Withdrawal and reward: Implications for detoxification and relapse prevention.
Psychiatric Annals, 25, 663-668.
Hwang, C.S., Kang, E.M., Kornegay, C.J., Staffa, J.A., Jones, C.M., & McAninch, J.K. (2016). Trends in the concomitant
prescribing of opioids and benzodiazepines, 2002-2014. American Journal of Preventive Medicine.
References + Resources
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Inter-University Consortium for Political and Social Research. (2014). National Survey on Drug Use and Health ComputerAssisted Interview Showcards and Pillcards (ICPSR 36361)
Johnston, L. D., Miech, R. A., O'Malley, P. M., Bachman, J. G., & Schulenberg, J. E. (2015, December 16). Monitoring the
Future High School Student Drug Survey. University of Michigan: Ann Arbor, MI. Available:
http://www.monitoringthefuture.org
Jones, C.M., Mack, K.A., Paulozzi, L.J. (2013). Pharmaceutical overdose deaths, United States, 2010. JAMA, 309(7): 657659.
Park, T. W., Saitz, R., Ganoczy, D., Ilgen, M. A., & Bohnert, A. S. B. (2015). Benzodiazepine prescribing patterns and
deaths from drug overdose among US veterans receiving opioid analgesics: a cohort study. BMJ, 10(Suppl 1): A48.
Quest Diagnostics. (2016). Quest Diagnostics Health TrendsTM Prescription Drug Monitoring Report 2016. Available:
http://questdiagnostics.com/dms/Documents/health-trends/2016_HealthTrendsReportQuestDiagnostics.pdf
Substance Abuse and Mental Health Services Administration. (2014, December 18). The DAWN Report: Benzodiazepines
in combination with opioid pain relievers or alcohol: greater risk of more serious ED visit outcomes. Rockville, MD: Author.
Available: http://www.samhsa.gov/data/sites/default/files/DAWN-SR192-BenzoCombos-2014/DAWN-SR192BenzoCombos-2014.pdf
White, W. L., Campbell, M. D., Spencer, R. D., Hoffman, H. A., Crissman, B. & DuPont, R. L. (2014). Patterns of abstinence
or continued drug use among methadone maintenance patients and their relation to treatment retention. Journal of
Psychoactive Drugs, 46(2), 114-122.